Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Residual serum fibrinogen as a universal biomarker for all serotypes of Myasthenia gravis.

Myasthenia Gravis (MG) is an autoimmune disease associated with severe neuromuscular weakness. Diagnostic confirmation of MG is typically delayed and secured in about 85% and 50% of patients with generalized and ocular MG, respectively with serum antibodies. We have identified a sensitive and specific diagnostic biomarker for various MG serotypes with quantitative proteomics. Serum proteomes of 18 individuals (MG patients, healthy controls (HC), Rheumatoid Arthritis (RA) were quantified in a pilot study and occurrence of high residual fibrinogen was validated by immunoblotting and further investigated by targeted mass spectrometry on the sera of 79 individuals (31 MG of various serotypes, 30 HC, 18 RA). Initial proteomic analysis identified high residual fibrinogen in MG patient sera which was then validated by antibody-based testing. Subsequently, a blinded study of independent samples showed 100% differentiation of MG patients from controls. A final serological quantification of 14 surrogate peptides derived from α-, ß-, and γ-subunits of fibrinogen in 79 individuals revealed fibrinogen to be highly specific and 100% sensitive for MG (p < 0.00001), with a remarkable average higher abundance of > 1000-fold over control groups. Our unanticipated discovery of high levels of residual serum fibrinogen in all MG patients can secure rapid bedside diagnosis of MG.

Incidental findings on FDG-PET/CT in large vessel vasculitis.

This study aims to determine the number and type of incidental findings detected on positron emission tomography (PET)/CT in a cohort of patients with large vessel vasculitis (LVV). Reports from PET/CT studies along with the medical charts of a cohort of patients with LVV from a Rheumatology clinic in Edmonton, Alberta, Canada, were retrospectively reviewed. Incidental findings from PET/CT, along with follow-up studies and their diagnosis were documented. The data was analyzed with descriptive statistics. The disease activity of 40 patients, with an average age of 65.8 years, was investigated using PET/CT. A statistically significant increase in incidental findings with age was observed. A total of 61 incidental findings were found in 26 (65%) patients. Of these findings, 25 were in the abdomen and pelvis. The most common incidental finding was lymphadenopathy. Follow-up investigations of incidental findings lead to 5 clinically significant findings including metastatic adenocarcinoma, Mycobacterium avium infection, papillary thyroid carcinoma, pheochromocytoma, and stroke. PET/CT is a reliable tool for determining disease activity in LVV patients and the implications of incidental findings need to be discussed with patients by the ordering care provider. This study demonstrates that incidental findings on PET/CT scan are common and increase with age in patients with LVV. A significant number of patients required further investigation for incidental findings. Key Points • Incidental findings on PET/CT scan are common in our patient population with LVV. • Frequency of incidental findings in our patient population with LVV increased with age. • Findings from this study can be used by ordering providers to have an informed conversation with their patient about the frequency of incidental findings on PET/CT scans.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study.

Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls. Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected. Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20-79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes. Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS. Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01).

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Skin disorders and interstitial lung disease: Part II-The spectrum of cutaneous diseases with lung disease association.

Part 2 of this 2-part CME introduces dermatologists to noninfectious inflammatory skin diseases associated with pulmonary involvement. In many cases, dermatologists may be the first physicians recognizing respiratory complications associated with these diagnoses. Because pulmonary involvement is often the leading cause of morbidity and mortality, dermatologists should be comfortable screening and monitoring for lung disease in high-risk patients, recognizing cutaneous stigmata of lung disease in these patients and referring to pulmonary specialists, when appropriate, for prompt treatment initiation. Some treatments used for skin disease may not be appropriate in the context of lung disease and hence, choosing a holistic approach is important. Interstitial lung disease and pulmonary hypertension are the most common pulmonary complications and a significant cause of mortality in autoimmune connective tissue diseases, especially systemic sclerosis, dermatomyositis, and mixed connective tissue disease. Pulmonary complications, notably interstitial lung disease, are also common and life-threatening in sarcoidosis and vasculitis, while they are variable in neutrophilic and autoimmune blistering diseases.

Skin disorders and interstitial lung disease: Part I-Screening, diagnosis, and therapeutic principles.

Numerous inflammatory, neoplastic, and genetic skin disorders are associated with interstitial lung disease (ILD), the fibrosing inflammation of lung parenchyma that has significant morbidity and mortality. Therefore, the dermatologist plays a major role in the early detection and appropriate referral of patients at risk for ILD. Part 1 of this 2-part CME outlines the pathophysiology of ILD and focuses on clinical screening and therapeutic principles applicable to dermatological patients who are at risk for ILD. Patients with clinical symptoms of ILD should be screened with pulmonary function tests and high-resolution chest computed tomography. Screening for pulmonary hypertension should be considered in high-risk patients. Early identification and elimination of pulmonary risk factors, including smoking and gastroesophageal reflux disease, are essential in improving respiratory outcomes. First-line treatment interventions for ILD in a dermatological setting include mycophenolate mofetil, but the choice of therapeutic agents depends on the nature of the primary disease, the severity of ILD, and comorbidities and should be the result of a multidisciplinary assessment. Better awareness of ILD among medical dermatologists and close interdisciplinary collaborations are likely to prevent treatment delays improving long-term outcomes.

A case series of dermatomyositis following SARS-CoV-2 vaccination.

Background/Objective: The most significant adverse events following SARS-CoV-2 vaccination are myocarditis and pericarditis. Myositis and dermatomyositis have been reported following SARS-CoV-2 infection, but vaccine-induced dermatomyositis (DM) has not been reported. Our case series aimed to characterize new onset dermatomyositis or disease-related flares following SARS-CoV-2 vaccination. Materials and methods: A total of 53 patients from our institution with a new or pre-existing diagnosis of DM were recruited and consented. Phone interviews were conducted to obtain vaccination status and symptoms following vaccination. Electronic medical records were reviewed to extract age, sex, autoantibody profiles, comorbidities, immunomodulatory therapies, creatine kinase (CK) values, and SARS-CoV-2 vaccination dates from the provincial vaccination registry. For patients who reported disease flares, records were reviewed for the onset and nature of symptoms, extent of organ involvement and changes in immunomodulation. Results: On average, patients received 2.62 vaccine doses (range 1-3 doses). A total of 3 of 51 patients (5.88%) experienced dermatomyositis symptoms following vaccination. Two patients were newly diagnosed with dermatomyositis, one requiring hospitalization. Reported symptom onset following vaccination ranged from 1 to 30 days. Of note, all of these patients had normal CK values, even though there was muscle biopsy-confirmed myositis in one patient. Eight patients in the cohort (15.1%) had asymptomatic CK elevation (<1.5 X ULN). Conclusion: New onset dermatomyositis or flare up of pre-existing dermatomyositis may be a rare complication in SARS-CoV-2 vaccination although no studies can support a true correlation. Several pathophysiologic mechanisms are proposed.

Generalized Tetanus in a Canadian Farmer Following Orthopedic Surgery.

Tetanus is extremely rare in developed countries. We report the first documented case of tetanus in the province of Alberta since 2016: a farmer that developed trismus, shoulder stiffness, and fevers eight days following orthopedic surgery. Tetanus immunoglobulin elicited rapid recovery. We highlight risk factors, pathogenesis, epidemiology, and diagnostic challenges.

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.

OBJECTIVE: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. METHODS: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. RESULTS: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. CONCLUSION: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

Metabolomic profile overlap in prototypical autoimmune humoral disease: a comparison of myasthenia gravis and rheumatoid arthritis.

INTRODUCTION: Myasthenia gravis (MG) and rheumatoid arthritis (RA) are examples of antibody-mediated chronic, progressive autoimmune diseases. Phenotypically dissimilar, MG and RA share common immunological features. However, the immunometabolomic features common to humoral autoimmune diseases remain largely unexplored. OBJECTIVES: The aim of this study was to reveal and illustrate the metabolomic profile overlap found between these two diseases and describe the immunometabolomic significance. METHODS: Metabolic analyses using acid- and dansyl-labelled was performed on serum from adult patients with seropositive MG (n = 46), RA (n = 23) and healthy controls (n = 49) presenting to the University of Alberta Hospital specialty clinics. Chemical isotope labelling liquid chromatography mass spectrometry (CIL LC-MS) methods were utilized to assess the serum metabolome in patients; 12C/13C-dansyl chloride (DnsCl) was used to label amine/phenol metabolites and 12C/13C-p-dimethylaminophenacyl bromide (DmPA) was used for carboxylic acids. Metabolites matching our criteria for significance were selected if they were present in both groups. Multivariate statistical analysis [including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA)] and biochemical pathway analysis was then conducted to gain understanding of the principal pathways involved in antibody-mediated pathogenesis. RESULTS: We found 20 metabolites dysregulated in both MG and RA when compared to healthy controls. Most prominently, observed changes were related to pathways associated with phenylalanine metabolism, tyrosine metabolism, ubiquinone and other terpenoid-quinone biosynthesis, and pyruvate metabolism. CONCLUSION: From these results it is evident that many metabolites are common to humoral disease and exhibit significant immunometabolomic properties. This observation may lead to an enhanced understanding of the metabolic underpinnings common to antibody-mediated autoimmune disease. Further, contextualizing these findings within a larger clinical and systems biology context could provide new insights into the pathogenesis and management of these diseases.

Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy.

PURPOSE: To describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy. CASE: A 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy. RESULTS: There was no significant improvement in the patient's symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected. CONCLUSION: Combined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy.

Optimal length and usefulness of temporal artery biopsies in the diagnosis of giant cell arteritis: a 10-year retrospective review of medical records.

BACKGROUND: In giant cell arteritis, temporal artery biopsies often show vasculitis with giant cell formation, but optimal biopsy length for diagnosis is debated. We reviewed temporal artery biopsies from a 10-year period in the province of Alberta, Canada, to identify an ideal biopsy length in the diagnostic process for giant cell arteritis. METHODS: We retrospectively reviewed electronic medical records of patients who had undergone a temporal artery biopsy procedure in Alberta between Jan 1, 2008, and Jan 1, 2018, as reported in the Data Integration and Management Repository of Alberta Health Services. We extracted data on baseline demographic characteristics (sex and age), inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), temporal artery biopsy characteristics (side of biopsy and postfixation length), and final pathological diagnoses. All positive biopsies were reviewed by a single pathologist to ensure uniformity of pathological interpretation, with subsequent discordant results removed from analysis. Predictors of positive pathological diagnosis of giant cell arteritis were modeled by logistic regression, and the Akaike information criterion was used to compare logistic regression models with varying biopsy length cutoffs (0·5, 1·0, 1·5, 2·0, and 2·5 cm) to determine a change point for diagnostic sensitivity in postfixation length. FINDINGS: We extracted data on 1203 temporal artery biopsies; after removal of 13 discordant biopsies, 1190 biopsies from 1163 patients were reviewed. The mean age of patients was 72·0 years (SD 10·3) and 799 (68·7%) patients were women. 222 (18·7%) temporal artery biopsies were positive for giant cell arteritis. In univariable analysis, increases in age (71·3 years [SD 10·6] in negative biopsies vs 75·3 years [8·3] in positive biopsies; odds ratio [OR] 1·04 [95% CI 1·02-1·06]; p<0·0001)), ESR (36 mm/h [IQR 18-62] in negative biopsies vs 57 [31-79] in positive biopsies; 1·01 [1·01-1·02]; p<0·0001), CRP (12·1 mg/L [IQR 3·3-35·1] in negative biopsies vs 41·8 [14·6-82·4] in positive biopsies; 1·01 [1·01-1·01]; p<0·0001), and biopsy length (1·2 cm [IQR 0·9-1·7] in negative biopsies vs 1·6 [1·1-2·0] in positive biopsies; 1·28 [1·09-1·51]; p=0·0025) were associated with a positive pathological diagnosis. In multivariable analysis adjusted for age, ESR, and CRP, age (adjusted OR 1·04 [95% CI 1·02-1·05]; p=0·0001), CRP (1·01 [1·00-1·01]; p=0·0006), and biopsy length (1·22 [1·00-1·49]; p=0·047) remained statistically significant predictors. The Akaike information criterion determined a change point of 1·5 cm for diagnostic sensitivity. INTERPRETATION: Accounting for postfixation shrinkage, our findings suggest a 1·5-2·0 cm prefixation length as the optimal biopsy length to diagnose patients with giant cell arteritis, with greater lengths unlikely to provide significant additional diagnostic yield to justify risks associated with surgery. FUNDING: None.

Coexistent rheumatoid arthritis and gout: a case series and review of the literature.

Since 1964 to present, there have been more than 33 cases of concomitant rheumatoid arthritis (RA) and gout reported in the literature. The objective of this study is to present a case series of patients with coexistent rheumatoid arthritis and gout and to provide a review of the literature. A retrospective review of a rheumatology patient database at the University of Alberta was performed (2004-2017). Patient charts were reviewed and the 1987 ARA Revised Classification Criteria for RA and 1977 ARA Classification Criteria for gout were applied to each patient. For gout, positive monosodium urate crystals on synovial fluid analysis, synovial/node biopsy, or positive dual-energy CT-gout protocol were used to satisfy the diagnosis of gout if available. Thirteen patients were identified with both RA and gout (nine men and four women). The mean age was 68.6, while the mean age at the onset of first disease was 55.3 and onset of second disease was 64.4. Eight patients were initially diagnosed with RA and subsequently developed gout, while five patients were first diagnosed with gout and subsequently developed RA. Standard radiographs showed findings characteristic of RA and gout in affected joints. In joints affected by both diseases, the gout findings predominated and the RA changes were milder. Rheumatoid arthritis and gout do coexist in the same patient, contrary to popular belief. Understanding that both conditions can occur concomitantly is necessary for clinical awareness, especially in patients with polyarticular disease that is difficult to treat.

Microscopic Polyangiitis with Spinal Cord Involvement: A Case Report and Review of the Literature.

BACKGROUND: Microscopic polyangiitis (MPA) is an ANCA-associated vasculitis (AAV; ANCA denotes antineutrophil cytoplasmic antibody) that causes necrotizing inflammation of small blood vessels. Renal and pulmonary manifestations are common whereas central nervous system (CNS) involvement, and in particular spinal disease, is rare. METHODS: We reviewed a case of MPA presenting with spinal intradural hemorrhage and intracerebral hemorrhage. We also summarized all reported cases of AAV with spinal cord involvement in the literature (database search included MEDLINE, Embase, Scopus, and Proquest with no date or language restriction). RESULTS: We reviewed 20 cases of AAV with spinal cord involvement (12 granulomatosis with polyangiitis [GPA], 4 eosinophilic granulomatosis with polyangiitis, 2 MPA, and 2 cases diagnosed as AAV only) and reported demographic information, clinical features, methods of diagnosis, treatment, and patient outcome. Although CNS involvement has been associated with a poor prognosis, 14 of 18 cases that reported outcome data achieved remission during follow-up. Death occurred in 3 patients diagnosed with GPA and in 1 patient with MPA. Our patient with MPA deteriorated rapidly despite use of prednisone and died. CONCLUSIONS: AAV can present with brain and spinal cord involvement, even in the absence of systemic disease. CNS disease may be responsive to immunosuppressive therapy (e.g., steroids and cyclophosphamide) in several of the cases reviewed.

IgA Cutaneous Purpura Post-Renal Transplantation in a Patient With Long-Standing IgA Nephropathy: Case Report and Literature Review.

BACKGROUND: IgA vasculitis is a small-vessel vasculitis caused by deposition of IgA antibodies in tissues. IgA nephropathy and IgAV have long been considered related conditions. OBJECTIVE: To assess the prevalence and implications of new-onset Henoch-Schönlein purpura (HSP) after renal transplant in patients with underlying IgA nephropathy. METHODS: The PubMed database was searched for keywords such as IgAV, IgA vasculitis, Henoch-Schönlein purpura, HSP, IgA nephropathy, and renal transplant. RESULTS: Two cases of new-onset IgA vasculitis post-renal transplant after stopping the prednisone or receiving seasonal influenza vaccine have been reported. We report the case of new-onset IgA cutaneous vasculitis in a renal transplant patient with IgA nephropathy after reduction in his prednisone dosage. CONCLUSION: The new development of cutaneous IgA vasculitis is unusual in renal transplant patients with IgA nephropathy. Despite these patients' being immunosuppressed, the presence of IgA vasculitis could signal the recurrence of IgA nephropathy.

Syphilitic myositis: a case-based review.

To present the clinical and pathological findings in patients presenting with myositis caused by syphilis. The literature is reviewed, and pathophysiologic factors discussed. A 49-year-old Caucasian heterosexual male with a known history of stable human immunodeficiency virus (HIV) and hepatitis C (HCV) co-infection, developed progressive muscle weakness over 10 weeks. He discontinued his medications; however, he had on-going muscle symptoms. A muscle biopsy was performed, consistent with mild myositis. While on prednisone therapy, he developed panuveitis and vertigo. CSF studies were positive for syphilis (Treponema pallidum). He was started on appropriate antibiotic therapy with complete clinical resolution. This patient presented with myositis and panuveitis as a manifestation of acute onset of syphilis. Syphilis is an uncommon cause of myositis. In patients with HIV and/or HCV, the disease itself and side effects of the medications must be considered. As patients with HIV may have co-infections, syphilis must be considered, especially when unresponsive to traditional management.

Takayasu's arteritis progression on anti-TNF biologics: a case series.

Takayasu's arteritis (TA) is a rare granulomatous vasculitic disease that affects the aorta and its major branches. Recent studies have suggested that anti-TNFα biological therapies are highly effective in treating TA refractory to conventional immunosuppressive therapy. We describe two patients with TA: one with progressive TA despite management with two different anti-TNFα agents, infliximab and adalimumab, and another who developed TA while treated with infliximab for the management of pre-existing Crohn's disease. From our observations, we believe that a multicentered randomized study should be designed to assess the extent of resistance to these agents when different therapeutic doses are employed for managing TA.