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Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment
Abstract
Background:
We aimed to investigate the effects of immunosuppressive and biological agents on refractory Takayasu arteritis (TA) patients resistant to or dependent on glucocorticoids.
Methods:
Forty-four consecutive TA patients were enrolled, and the clinical characteristics and effectiveness of the immunosuppressive and biological agents in achieving and maintaining remission among glucocorticoid-resistant or glucocorticoid-dependent patients were investigated.
Results:
Fifteen patients showed favorable response to the initial glucocorticoid treatment, and 29 patients exhibited resistance to initial glucocorticoid treatment or relapsed with tapering glucocorticoid. Of the 29 patients, 5 responded to additional glucocorticoid treatment, and 22 of the remaining 24 glucocorticoid-resistant or glucocorticoid-dependent patients were prescribed immunosuppressive agents. Methotrexate was the most commonly used in these patients as the first-line treatment. In total, 10 patients maintained remission using immunosuppressive agents, with the effectiveness of each agent about 20%. The only significant difference between patients who were and were not able to achieve and maintain remission with immunosuppressive agents was the presence of the HLA-B52 allele (p<0.0001). Biological agents were administered to 6 patients refractory to immunosuppressive agents. All patients were administered tumor necrosis factor (TNF) inhibitors as the first-line treatment, and 3 patients maintained remission. Anti-interleukin-6 receptor antibody was administered to 2 patients who were resistant to the TNF inhibitors, and 1 patient achieved and maintained remission.
Conclusion:
In our cohort, 64% of the glucocorticoid-resistant or glucocorticoid-dependent patients maintained remission through a combined treatment with glucocorticoid, immunosuppressive agents, and/or biological agents. The combined use of immunosuppressive and biological agents appears to be a promising treatment option for achieving and maintaining remission in refractory TA patients.
... Nowadays, biologic agents play a central role in the management of TAK, since most of the patients have a refractory/relapsing disease not adequately controlled by glucocorticoid monotherapy [19]. However, as a consequence of the rarity of this disease and the lack of controlled studies, there is still much uncertainty regarding how bDMARD therapy should be properly managed. ...
... This is not the first report about the use of intensified doses of infliximab in refractory TAK. In their work including 15 patients, Quartuccio et al. described two patients who received respectively infliximab 7.5 and 8 mg/kg every 6 weeks [15], and further examples can be found in other cohorts [11,12,19,20]. In addition, in a recent prospective study with infliximab-biosimilar (CT-P13), Park et al. reported a need to increase drug dosage in all the 12 patients included, even if they used a starting dose lower than ours (5 mg/kg every 8 weeks) [21]. ...
... Another element of interest we found in our study is that patients who needed dose escalation were apparently younger both at TAK diagnosis and infliximab start. The influence of age on the outcome of TAK patients has already been explored by other groups, but it was not found to correlate with the risk of relapse or a worse prognosis [3,26] or with the risk of conventional steroid-sparing agents failure [19]. However, a specific evaluation including only refractory TAK patients requiring biologic drugs has never been performed. ...
Objectives
To evaluate effectiveness and safety of infliximab dose escalation in Takayasu arteritis (TAK) patients. To identify factors associated with refractoriness to standard-dose infliximab.
Methods
Medical records of infliximab-treated TAK patients from a large single-centre observational cohort were reviewed. Infliximab therapy duration, concomitant therapies, and reasons for dose escalation and therapy suspension were evaluated. Occurrence of adverse events was recorded. A comparison between patients who maintained infliximab standard-dose and those who needed dose-escalation was performed. Factors associated with refractoriness to standard dose were analysed.
Results
Forty-one patients were included. Starting infliximab dose was 5 mg/kg 6-weekly and 28 patients (68%) needed dose escalation. Persistence/recurrence of clinical symptoms was the most frequent reason for escalation. Median therapy duration was 39 (IQR, 26–61) months in the standard-dose group and 68 (38–87) months in the intensified-dose group. In the intensified-dose-group, infliximab was suspended in eight patients (29%) after a median of 38 (31–71) months, due to loss of response (n = 7) or patient’s request (n = 1). Patients in the intensified-dose group had a higher number of relapses (3.4 vs 0.8 events/patient) and received a higher cumulative steroid dose (1.7 [1.6–2.3] vs 1.3 [1–1.6] g/month of prednisone). Three patients from the intensified-dose group had serious infections; one patient from the standard-dose group developed paradoxical psoriasis. At univariate analysis, age at diagnosis and age at infliximab start were associated with infliximab escalation.
Conclusion
In TAK, dose escalation is safe and allows to optimise infliximab durability in refractory patients. Younger patients seem to be more refractory to standard dosages.
... Methotrexate Five observational studies assessed methotrexate in TAK [33,60,64,67,93]. Among the two studies reporting outcomes with methotrexate alone [33,64], pooled proportion of patients attaining at least partial clinical response was 50% (95% CI 33-67%, 34 patients, I 2 not assessable, Fig. 2). ...
... Methotrexate Five observational studies assessed methotrexate in TAK [33,60,64,67,93]. Among the two studies reporting outcomes with methotrexate alone [33,64], pooled proportion of patients attaining at least partial clinical response was 50% (95% CI 33-67%, 34 patients, I 2 not assessable, Fig. 2). One study assessed angiographic stabilization (88%, 95%CI 62-98%, 16 patients, Fig. 3) [33] and proportions of relapses (44%, 95%CI 20-70%, 16 patients, Fig. 4c) [33]. ...
... Azathioprine Two observational studies assessed azathioprine in TAK [35,64]. The pooled proportion of patients attaining at least a partial clinical response was 84% (95% CI 64-98%, 22 patients, I 2 not assessable, Fig. 2). ...
The pharmacotherapy of Takayasu arteritis (TAK) with disease-modifying anti-rheumatic drugs (DMARDs) is an evolving area. A systematic review of Scopus, Web of Science, Pubmed Central, clinical trial databases and recent international rheumatology conferences for interventional and observational studies reporting the effectiveness of DMARDs in TAK identified four randomized controlled trials (RCTs, with another longer-term follow-up of one RCT) and 63 observational studies. The identified trials had some concern or high risk of bias. Most observational studies were downgraded on the Newcastle-Ottawa scale due to lack of appropriate comparator groups. Studies used heterogenous outcomes of clinical responses, angiographic stabilization, normalization of inflammatory markers, reduction in vascular uptake on positron emission tomography, reduction in prednisolone doses and relapses. Tocilizumab showed benefit in a RCT compared to placebo in a secondary per-protocol analysis but not the primary intention-to-treat analysis. Abatacept failed to demonstrate benefit compared to placebo for preventing relapses in another RCT. Pooled data from uncontrolled observational studies demonstrated beneficial clinical responses and angiographic stabilization in nearly 80% patients treated with tumour necrosis factor alpha inhibitors, tocilizumab or leflunomide. Certainty of evidence for outcomes from RCTs ranged from moderate to very low and was low to very low for all observational studies. There is a paucity of high-quality evidence to guide the pharmacotherapy of TAK. Future observational studies should attempt to include appropriate comparator arms. Multicentric, adequately powered RCTs assessing both clinical and angiographic responses are necessary in TAK.
... Основу стандартной схемы лечения АТ составляют ГК [3,11,12], однако более чем у половины пациентов не удается достичь стойкой ремиссии на фоне монотерапии ГК, в связи с чем дополнительно назначают цитостатики (МТ, азатиоприн, ЦФ) [3,11]. При рефрактерном течении АТ, как и при других системных васкулитах, используют альтернативную терапию различными иммуносупрессантами [3,12]. ...
... Основу стандартной схемы лечения АТ составляют ГК [3,11,12], однако более чем у половины пациентов не удается достичь стойкой ремиссии на фоне монотерапии ГК, в связи с чем дополнительно назначают цитостатики (МТ, азатиоприн, ЦФ) [3,11]. При рефрактерном течении АТ, как и при других системных васкулитах, используют альтернативную терапию различными иммуносупрессантами [3,12]. Имеется опыт применения пуринового нуклеозида флударабина при рефрактерном гранулематозе с полиангиитом [13], которому также свойственна гранулематозная воспалительная реакция. ...
... Безрецидивная выживаемость через 6 месяцев лечения ТЦЗ была выше, чем в группе плацебо (50,6 и 22,9% соответственно), но различия не достигли статистической значимости (р=0,059). Согласно данным предварительных исследований, преимущественно включавших рефрактерное заболевание, в результате лечения ТЦЗ ремиссия или улучшение наблюдаются у 85% больных АТ [11,12,15,18,20,22,23]. При сравнении результатов применения ТЦЗ и ингибиторов ФНО-α при рефрактерном АТ, частота достижения полной или частичной ремиссии через 3 месяца составила соответственно 90 и 81%, через 12 месяцев -77 и 100% [14]. ...
Thanks to progress in understanding of Takayasu’s arteritis pathogenesis, the role of biological therapies is expanding, especially in refractory diseases. Robust data are still lacking to draw conclusions concerning the use of interleukin (IL)-6 inhibitors in Takayasu’s arteritis. The article presents own experience of the use of tocilizumab (TCZ) for Takayasu’s arteritis after insufficient response to previous treatment with glucocorticoids, methotrexate, cyclophosphamide, fludarabine and intolerance of cyclophosphamide, glucocorticoids. As result of TCZ treatment (600 mg IV every 4 weeks for 24 months), a stable Takayasu’s arteritis remission was achieved and confirmed by fluorodeoxyglucose-positron emission tomography.The inhibition of IL-6 can be considered as a promising innovative strategy for the treatment of Takayasu’s arteritis, primarily with insufficient response, intolerance or contraindications to standard therapy.
... Основу лечения до настоящего времени составляют глюкокортикоиды (ГК) в начальной дозе 0,5-1 мг/кг в сутки в течение месяца для индукции ремиссии с последующим снижением дозы до поддерживающей [6]. Однако менее чем у половины пациентов удается достичь стойкой ремиссии на фоне монотерапии преднизолоном и снижения его дозы до 10 мг и ниже, что требует дополнительного применения цитостатических препаратов, таких как метотрексат (МТ), азатиоприн, препараты микофеноловой кислоты (микофенолата мофетил -ММФ), циклофосфамид (ЦФА), а при их неэффективности -генно-инженерных биологических препаратов (ГИБП) [6][7][8][9]. ...
... При этом в фазу высокой активности заболевания концентрация его возрастает [11,12]. За поcледние 10-15 лет в мире накопился некоторый опыт применения ингибиторов ФНОα, таких как инфликсимаб (ИНФ), этанерцепт (ЭТЦ) и адалимумаб (АДА), при артериите Такаясу [8,[13][14][15]. ...
... В ряде исследований, несмотря на небольшие размеры выборок, показана их достаточная эффективность и безопасность при рефрактерном к стандартной иммуносупрессивной терапии заболевании. Частота наступления ремиссии при этом достигает 90%, однако рецидивы не редки [8,[13][14][15][21][22][23][24]. Ранее нами были опубликованы данные собственного опыта лечения ингибиторами ФНОα при резистентном к стандартным противоревматическим препаратам артериите Такаясу, в результате которого в 89% случаев удалось достичь ремиссии заболевания [15]. ...
Certolizumab pegol (CZP) is the only pegylated biological agent (BA) that does not contain an Fc fragment, which minimizes its transplacental transfer. Takayasu arteritis mostly occurs in reproductive-aged women.
Objective : to evaluate the efficacy and safety of CZP used to treat standard immunosuppressive therapy-resistant Takayasu arteritis.
Subjects and methods . The retrospective study enrolled 6 female patients aged 18 to 35 years with Takayasu arteritis who received CZP. The median disease duration before BA usage was 66 months (24 to 204 months). The median duration of immunosuppressive therapy prior to CZP treatment was 92 months (14 to 132 months). All the female patients had taken glucocorticoids and methotrexate before and during CZP therapy. Only four patients had received two to five immunosuppressive drugs at different times prior to BA administration. Three patients had previously used other BAs. The disease activity was determined by the National Institute of Health (NIH) criteria. The Indian Takayasu Clinical Activity Score (ITAS2010) was used. The disease activity was recorded in all the patients prior to CZP therapy.
Results and discussion . The median duration of CZP treatment was 17 months (6 to 24 months). The median erythrocyte sedimentation rate after CZP usage decreased from 22.5 to 10.5 mm/h; the median C-reactive protein level dropped from 7.8 to 0.39 mg/dl (p<0.05), the median daily dose of prednisolone was reduced from 20 to 8.75 mg (p<0.05). All the patients achieved complete remission an average of 4 months after starting CZP therapy. Three patients were still in remission after 12–24 months. One relapse of the disease was recorded following 24 months. ITAS2010 reduced from 1–4 to 0 in five patients and to 2 in one patient with recurrence. There was a good tolerance in five female patients. The adverse events were herpes labialis in two cases, community-acquired pneumonia in one case, and postoperative abscess in one case too.
Conclusion . CZP in Takayasu arteritis was shown to be an effective drug for remission induction and maintenance. The presented results of the first experience in treating this disease with CZP are indicative of its promising further investigation as a steroid-sparing drug in patients with refractory vasculitis. One of the important advantages of CZP is its supposed high safety throughout pregnancy.
... Этиология AТ неизвестна, обсуждается влияние генетических факторов, при этом АТ рассматривают как типичную болезнь HLA I класса, в отличие от другой формы СВ крупных сосудов -гигантоклеточного артериита (ГКА), который связывают с HLA II класса [2][3][4]. Продемонстрирована связь АТ с HLA-Bw52, HLA-B39 [3,5] и отмечено, что пациенты с аллелью HLA-B52 хуже отвечают на стандартное лечение иммунодепрессантами и нуждаются в назначении ГИБП [6]. ...
... Также проанализированы результаты применения ТЦЗ у 115 больных АТ по данным предварительных исследований, опубликованных в 30 доступных источниках литературы в виде небольших серий или отдельных наблюдений [6,22,. ...
... Эффек тивность и безопасность тоцилизумаба у больных артериитом Такаясу по данным предварительных исследований В 30 литературных источниках [6,22, были обнаружены сообщения в общей сложности о 115 больных АТ, получавших лечение ТЦЗ, как правило, для индукции ремиссии. Большинство публикаций содержали единичные наблюдения, в четырех исследованиях представлены небольшие серии из 10-16 пациентов [32,40,43,50]. ...
The need for further improvement of treatments for Takayasu’s arteritis (TA), the progress in understanding the mechanisms of the disease, and the introduction of biological agents (BA) in rheumatology practice have created preconditions for developing a new TA pharmacotherapy using BA associated with interleukin 6 (IL-6) inhibition.
The authors describe their two own cases of tocilizumab (TCZ) use for complicated TA. They analyze the results of TCZ treatment by the data of preliminary trials in 115 patients with TA, which have been published in 30 literature sources, as well as the results of Phase III double-blind, randomized placebo-controlled trials (RPCTs) of the safety and efficacy of TCZ in 18 patients with refractory TA. In one case with a long history of complicated TA, the control of TA activity and the reduction in the dose of glucocorticoids due to TCZ use contributed to the favorable course of pregnancy and labor. In the other case with the onset of TA and focal pulmonary tuberculosis (TB) treated with anti-TB drugs during TCZ monotherapy for 6 months could control TA and achieve TB cure.
Preliminary trials showed that TCZ treatment-induced remission or improvement was observed in 85% of patients with TA, including that with a refractory course. RPCTs indicated that the relapse-free survival after 6-month maintenance treatment with TCZ was higher than that in the placebo group (51 and 23%, respectively); but the differences failed to reach statistical significance (p = 0.0596). Due to the fact that a recurrence of TA can occur in patients treated with TCZ, it is appropriate to combine this drug with cytostatic drugs, methotrexate in particular.
The use of IL-6 inhibitors should be considered as a potentially effective and relatively safe innovative (off-label) treatment for refractory TA in patients with intolerance or contraindications to standard therapy, which requires further larger randomized clinical trials. Since now there is no universal imaging method that could provide comprehensive information on the status of vessels in TA; the standardization of future clinical trials of BAs requires the improvement of methods for evaluating the efficiency of treatment for TA; moreover, monitoring of disease activity should include a comprehensive assessment of clinical data, current laboratory biomarkers, and instrumental imaging techniques, primarily non-invasive ones.
... The difficulty for accurate TA diagnosis is compounded by the lack of specific diagnostic serologic tests; traditional biomarkers such as CRP and ESR levels are indicative of clinical inflammation but not all cases of active TA disease present with changes in ESR and CRP levels. 5,6 Therefore, high index of suspicion is warranted in patients presenting with angina without any other identifiable risk factors or young adults diagnosed with hypertension and arterial bruits. We have reported an uncommon case of a middle-aged female patient presenting with severe AR associated with aortic aneurysm as a secondary complication of TA. ...
... Although the patient was diagnosed with TA at a relatively later stage, the condition; however, was amenable to immunosuppressive therapy and symptoms improved adequately to allow for the postponement of the surgical intervention. Despite improvement following surgery, valve detachment after anastomotic aneurysm may still occur due to the fragility of aortic wall or annular tissue because of TA. 4 Previous studies 5,7 found that immunosuppressive agents achieved remission in patients with TA anywhere from 46% to 84% success rate. Similarly, early medical intervention for TA management prior to surgery even with complication of severe forms of AR has been further demonstrated with implementation of effective treatment using newer biological agents. ...
... It is now generally accepted to only consider surgical intervention after the medical therapy is instigated in order to reduce inflammation to manageable levels. 5 McGraw et al 9 also suggested a delay in the surgical intervention was deemed necessary as it complicated the need to manipulate the inflamed tissue leading to worsening of the outcome such as valve detachment or dilatation of the residual aorta. Previously, Matsuura et al 8 reviewed the late outcome of surgical treatment for aortic valve regurgitation due to TA and its relation with inflammation over 24 years in 90 patients and found an overall survival rate of 76.1% after 15 years follow up. ...
Objectives
To assess the prevalence and associations of mesenteric panniculitis (MP) using multi-detector CT (MDCT).
Methods
This retrospective study included 4758 consecutive patients who underwent abdomino-pelvic MDCT between January 2012 and December 2014 at Jordan University Hospital, Amman, Jordan. Radiological database was searched for MP diagnosis and patients with suspected MP were re-evaluated by an experienced radiologist to confirm the diagnosis. Data on all patients with confirmed MP diagnosis were subsequently collected and analyzed.
Results
Computed tomography features of MP were identified in 90 patients (41 males, 49 females), a prevalence of 1.9%. Mesenteric panniculitis was identified in both asymptomatic and symptomatic patients. Malignancy was found in 28 MP patients (31%) and 44 of the MP patients (49%) had prior history of abdomino-pelvic surgery. Mesenteric panniculitis was significantly more frequently associated with prior abdomino-pelvic surgery (p=0.0001) and the likelihood of associated malignancy in patients with MP was 2.1-fold higher than in patients without MP (p=0.0013).
Conclusion
Mesenteric panniculitis can be reliably diagnosed by MDCT due to its typical CT appearance. Its identification is important because of its significant association with malignancy and because it represents one of the differential diagnoses in patients with nonspecific symptoms referred for abdomino-pelvic CT.
... The difficulty for accurate TA diagnosis is compounded by the lack of specific diagnostic serologic tests; traditional biomarkers such as CRP and ESR levels are indicative of clinical inflammation but not all cases of active TA disease present with changes in ESR and CRP levels. 5,6 Therefore, high index of suspicion is warranted in patients presenting with angina without any other identifiable risk factors or young adults diagnosed with hypertension and arterial bruits. We have reported an uncommon case of a middle-aged female patient presenting with severe AR associated with aortic aneurysm as a secondary complication of TA. ...
... Although the patient was diagnosed with TA at a relatively later stage, the condition; however, was amenable to immunosuppressive therapy and symptoms improved adequately to allow for the postponement of the surgical intervention. Despite improvement following surgery, valve detachment after anastomotic aneurysm may still occur due to the fragility of aortic wall or annular tissue because of TA. 4 Previous studies 5,7 found that immunosuppressive agents achieved remission in patients with TA anywhere from 46% to 84% success rate. Similarly, early medical intervention for TA management prior to surgery even with complication of severe forms of AR has been further demonstrated with implementation of effective treatment using newer biological agents. ...
... It is now generally accepted to only consider surgical intervention after the medical therapy is instigated in order to reduce inflammation to manageable levels. 5 McGraw et al 9 also suggested a delay in the surgical intervention was deemed necessary as it complicated the need to manipulate the inflamed tissue leading to worsening of the outcome such as valve detachment or dilatation of the residual aorta. Previously, Matsuura et al 8 reviewed the late outcome of surgical treatment for aortic valve regurgitation due to TA and its relation with inflammation over 24 years in 90 patients and found an overall survival rate of 76.1% after 15 years follow up. ...
We present an uncommon case of a 48-year-old female patient with symptomatic presentation of a severe aortic regurgitation with aneurysm of the ascending aorta and progressive dyspnea. Detailed investigation of laboratory tests and imaging identified Takayasu’s arteritis (TA) as the underlying etiology. Computed tomography scan revealed complete occlusion of the right carotid artery as well as stenosis at the origins of left subclavian and vertebral arteries. In addition, cardiac magnetic resonance angiogram showed aneurysm at the proximal segment of right subclavian artery. Intervention with corticosteroids effectively diminished the need for immediate surgical intervention. Treating physicians should always consider differential diagnosis of TA in the presence of atypical clinical findings in all patients with cardiac problems especially when there is valve involvement. © 2017, Saudi Arabian Armed Forces Hospital. All rights reserved.
... Glucocorticoid monotherapy in TAK generally leads to a good short-term clinical response, but most patients relapse upon GC tapering or discontinuation. 10,11,25 Unfortunately, long-term GC treatment causes toxicity in the majority of cases. 26 There are no randomized controlled trials assessing the efficacy and safety of different nontarget immunosuppressants either against placebo or in head-to-head comparisons in patients with TAK. ...
... However, very-low quality evidence from retrospective observational studies, mostly including relapsing or refractory patients, suggests that nontargeted immunosuppressants in combination with GCs may decrease the risk of disease relapse and the GC exposure when compared with GC monotherapy. 25,[27][28][29][30][31][32][33][34][35][36] Until more evidence is available, we conditionally recommend adding a nontargeted immunosuppressant such as methotrexate, 27,29,30 leflunomide, 28-33 mycophenolate mofetil, 28,35,36 or azathioprine 34 to the GC taper in patients with newly diagnosed disease presenting with nonsevere clinical manifestations in an attempt to maintain disease remission and spare the use of GCs. The choice of nontargeted immunosuppressant should be individualized, and the decision may be influenced by the physician's experience, comorbidities, safety profile, and patient's preferences including childbearing plans. ...
Objective
To develop the first evidence-based Pan American League of Associations for Rheumatology (PANLAR) guidelines for the treatment of Takayasu arteritis (TAK).
Methods
A panel of vasculitis experts developed a series of clinically meaningful questions addressing the treatment of TAK patients in the PICO (population/intervention/comparator/outcome) format. A systematic literature review was performed by a team of methodologists. The evidence quality was assessed according to the GRADE (Grading of Recommendations/Assessment/Development/Evaluation) methodology. The panel of vasculitis experts voted each PICO question and made recommendations, which required ≥70% agreement among the voting members.
Results
Eleven recommendations were developed. Oral glucocorticoids are conditionally recommended for newly diagnosed and relapsing TAK patients. The addition of nontargeted synthetic immunosuppressants (e.g., methotrexate, leflunomide, azathioprine, or mycophenolate mofetil) is recommended for patients with newly diagnosed or relapsing disease that is not organ- or life-threatening. For organ- or life-threatening disease, we conditionally recommend tumor necrosis factor inhibitors (e.g., infliximab or adalimumab) or tocilizumab with consideration for short courses of cyclophosphamide as an alternative in case of restricted access to biologics. For patients relapsing despite nontargeted synthetic immunosuppressants, we conditionally recommend to switch from one nontargeted synthetic immunosuppressant to another or to add tumor necrosis factor inhibitors or tocilizumab. We conditionally recommend low-dose aspirin for patients with involvement of cranial or coronary arteries to prevent ischemic complications. We strongly recommend performing surgical vascular interventions during periods of remission whenever possible.
Conclusion
The first PANLAR treatment guidelines for TAK provide evidence-based guidance for the treatment of TAK patients in Latin American countries.
... These results are compatible with other studies that reported the relapse in 55%-90% of the patients following corticosteroid tapering. [14,24,25] Studies on TA patients noted that 46%-84% required additional immunosuppressive treatment to achieve remission and taper corticosteroids. [21,26] In addition, 23% of TA patients did not achieve remission, even after receiving immunosuppressive agents. ...
... Studies have noted that around 20% of patients showed monophasic self-limiting illness and 12% presented as inactive burnt-out disease and did not show any sign of relapse, without immunosuppressive medications. [22,24,28,29] Hence, it is paramount to investigate whether immunosuppressive medication should be initiated in uncomplicated and monocomplicated cases or should consider initial monotherapy in patients with Stage 1 disease. On the other hand, inflammation is a risk factor for atherosclerosis and early treatment in patients with progressive complicated disease may lead to a better prognosis. ...
Objectives: This study aimed to assess the rate of inactive disease in Bangladeshi patients with Takayasu arteritis (TA) treated with prednisolone and to identify the characteristics in patients that may guide in choosing induction therapy.
Methods: The longitudinal study enrolled active TA patients who received 1 mg/kg/day of prednisolone. Disease activity was assessed by Indian Takayasu Activity Score - C-Reactive Protein (ITAS-CRP) and ITAS2010 at baseline and after 1, 3, and 6 months. The patients who did not achieve inactive disease or again became active during tapering of prednisolone received methotrexate.
Results: Among 12 active TA patients, one patient succumbed to death after 15 days. ITAS2010 1 month after steroid showed a significant difference between remission and nonremission patients (P 0.0001). However, five out of 11 (45.45%) patients became inactive. These five patients had onset of symptoms
... Zusätzliche Erfahrungen mit der TCZ-Behandlung bei TAK liegen aus prospektiven und retrospektiven, nicht kontrollierten Fallserien mit überwiegend zuvor therapierefraktärem Verlauf vor. In diesen Auswertungen wurde unter Einsatz von TCZ eine Reduktion der Krankheitsaktivität und/oder des GC-Bedarfs berichtet [1,86,173,175,187,201,259,279]. ...
... Diverse Autoren berichten den erfolgreichen Einsatz der TNF-Inhibitoren Adalimumab, Etanercept und Infliximab zur Behandlung der TAK in offenen, nicht kontrollierten Studien und Fallserien, wobei die meisten Fallberichte zum Einsatz von Infliximab vorliegen [51,94,114,173,174,181,197,199,201,214,233,240]. Kleine Fallserien berichten auch über den erfolgreichen Einsatz von Golimumab und Certolizumab [198,256] [20,179]. ...
... Five studies fulfilled the inclusion criteria of the systematic review, namely one randomised clinical trial, 20 two non-randomised clinical trials 11,21 and two historical cohorts. 22,23 Study characteristics and results are summarised in Table 2. ...
... The two non-randomised clinical trials by Serra and Hoffman fulfilled 1 out of 22 21 Our systematic search identified one randomised clinical trial (n = 242), 20 two non-randomised clinical trials (n = 20), 11,21 and two historical cohorts (n = 80). 22,23 The methodological quality and the quality of publication of all three clinical trials were considered low. ...
Introduction:
Takayasu arteritis (TA) is a rare systemic vasculitis that affects large vessels often resistant to treatment and associated with high morbidity and mortality. Treatment is defied by the relapsing nature of the disease and frequent adverse effects of corticosteroids and immunosuppressors, rendering failure of treatment in a significant portion of patients. Considering the low quantity and quality of published studies focusing on treatment of TA, synthesis and critical assessment of the available evidence is fundamental to establish recommendations for clinical practice.
Objective:
To evaluate the effectiveness and safety of clinical interventions for TA.
Methods:
Systematic review conducted in accordance to recommendations stated in the Cochrane Handbook, with inclusion of all comparative studies focusing on any type of clinical intervention for TA.
Results:
Five comparative studies were included (one randomised clinical trial, two non-randomised clinical trials, and two historical cohorts) totalling 342 patients, aiming at the assessment of effectiveness of corticosteroids, immunosuppressors, biologics and other types of pharmacological treatment for distinct clinical presentations of TA. The quality of studies, assessed by the use of instruments developed specifically for each study design, was considered low. Data scarcity and clinical heterogeneity prevented quantitative synthesis (meta-analysis).
Conclusion:
Despite an extensive literature search, few comparative studies with small sample sizes were retrieved. The quality of these studies was considered low, preventing recommendations on effectiveness and safety of the studied interventions for clinical practice. Until new comparative studies with more robust sample sizes are conducted, treatment of TA should be guided individually taking into account the severity of disease and the availability of treatment options.
... 36) This further emphasizes the logic behind early initiation of GC-sparing therapy. 37) A Turkish study group issued a definition of refractory TAK as shown in Supplemental Table III. 14) Conventional immunosuppressive agents: In TAK, there is no large RCT on the efficacy of different immunosuppressive (IS) agents. ...
Takayasu arteritis (TA or TAK) is a chronic large vessel vasculitis with predilection to affect the aorta and its branches. The new 2022 ACR/EULAR classification criteria for Takayasu arteritis incorporated imaging characteristics as an absolute requirement. ESR and CRP fails in accuracy as disease activity markers. Pentraxin 3 appears to be a relatively superior biomarker, which correlates with ITAS 2010 as per several studies. PET-CT is also increasingly being studied for assessing disease activity with variable results. The management of TAK involves use of steroids with upfront steroid sparing immunosuppressive agents. MMF is one such conventional DMARD/immunosuppressant with good efficacy and better safety profile, as reported in various cohort studies. Tocilizumab is proved to be a rapid remission inducing agent in refractory Takayasu arteritis in observational studies. TNF inhibitors in many uncontrolled studies showed good responses, and there is a need for good RCTs for confirmation. JAK inhibitors have also been used with success in a few reports.
... For these reasons, clinicians will often use other non-glucocorticoid drugs for the treatment of Takayasu arteritis. 5,6 Azathioprine is one of the non-glucocorticoid drugs that has been used for the treatment of Takayasu arteritis. 7 As a result of its ability to suppress the proliferation of B and T cells after administration by inhibiting their synthesis of new purines, azathioprine has found application as an immunomodulator, immunosuppressor, and steroidsparing agent. ...
Key Clinical Message
Azathioprine, used for vasculitis and connective tissue diseases, carries long‐term cancer risks. This case report raises awareness among healthcare providers about such risks and emphasizes the need for taking necessary precautions to avoid them while treating such diseases.
Abstract
We present an Azathioprine‐induced lymphoma case in a 51‐year‐old male patient with Takayasu arteritis who presented with painless cervical swelling, itching, weight loss, and decreased appetite. This case report aims to increase awareness of the potential long‐term cancer risks associated with azathioprine use in the treatment of chronic diseases.
... However, these drugs were associated with progression of imaging changes (in 4 out of 15 patients) [46]. Another prospective study observed that 3 out of 6 patients treated with anti-TNFα achieved and maintained remission [47]. A retrospective multicenter study of TAK patients treated with anti-TNF or tocilizumab found no significant differences in safety and efficacy, despite one tuberculosis reactivation in an infliximab-treated patient [28]. ...
Objective:
Vasculitis are a very heterogenous group of systemic autoimmune diseases, affecting large vessels (LVV), small vessels or presenting as a multisystemic variable vessel vasculitis. We aimed to define evidence and practice-based recommendations for the use of biologics in large and small vessels vasculitis, and Behçet's disease (BD).
Methods:
Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice on autoimmune diseases management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2022. Preliminary recommendations were drafted by working groups for each disease and voted in two rounds, in June and September 2021. Recommendations with at least 75% agreement were approved.
Results:
A total of 32 final recommendations (10 for LVV treatment, 7 for small vessels vasculitis and 15 for BD) were approved by the experts and several biologic drugs were considered with different supporting evidence. Among LVV treatment options, tocilizumab presents the higher level of supporting evidence. Rituximab is recommended for treatment of severe/refractory cryoglobulinemic vasculitis. Infliximab and adalimumab are most recommended in treatment of severe/refractory BD manifestations. Other biologic drugs can be considered is specific presentations.
Conclusion:
These evidence and practice-based recommendations are a contribute to treatment decision and may, ultimately, improve the outcome of patients living with these conditions.
... However, some patients do not respond to these drugs. Biologic agents, including tumor necrosis factor (TNF) inhibitors (TNFi) and tocilizumab, which targets interleukin-6 (IL-6), have also been reported to be effective in several prospective and retrospective studies (9)(10)(11)(12)(13)(14)(15)(16), and both agents are recommended by EULAR for the treatment of TAK patients who are refractory to treatment (17). However, many patients with TAK may still not respond adequately to any of the above-listed drugs, and new treatments are needed for patients with TAK. ...
Objective
Tumor necrosis factor (TNF) alpha and interleukin‐17 (IL‐17) are thought to be involved in the pathogenesis of Takayasu arteritis (TAK), and TNF inhibitors (TNFi) are recommended for the treatment of TAK. The present study was undertaken to investigate the efficacy of secukinumab, an IL‐17A monoclonal antibody, compared to treatment with TNFi.
Methods
This was a prospective, single‐center, open‐label cohort study. Patients with active TAK who did not respond to treatment with glucocorticoids combined with 2 immunosuppressive agents were treated with either secukinumab or TNFi as an add‐on therapy without an increased dosage of glucocorticoids. A complete response was defined as complete resolution of signs and symptoms of active disease, normal values of inflammatory markers, no progression on imaging of involved arteries, and dose of glucocorticoid <15 mg/day. A partial response was similarly defined as a complete response except with an erythrocyte sedimentation rate <40 mm/hour and C‐reactive protein level of <20 mg/liter.
Results
Nineteen patients in the secukinumab group and 34 patients in the TNFi group were enrolled. The demographic data and inflammatory markers of the 2 groups were comparable at baseline. Complete response and partial response for patients treated with secukinumab and TNFi were 31.6% and 58.8% (P = 0.057), respectively, at 3 months and 52.6% and 64.7%, respectively, at 6 months (P = 0.389).
Conclusion
Our findings suggest that secukinumab and TNFi are effective for patients with TAK who do not respond to oral glucocorticoids and conventional immunosuppressive agents, with similar response rates at 3 and 6 months. image
... TA patients with arterial thrombotic lesions were also noted. TA patients who received cyclophosphamide and/or biological agents at any time were considered as treatment-resistant cases or severe diseases [11,12]. A history of antiaggregant and/or anticoagulant use was also recorded. ...
Background:
The significance of antiphospholipid antibodies (aPL) is controversial in Takayasu arteritis (TA). This study was conducted to explore the frequency of aPL and their association with disease-related complications in TA.
Methods:
: This cross-sectional study was conducted to investigate the presence of anti-cardiolipin (aCL), anti-beta 2 glycoprotein- 1(aβ2G1) antibodies, and lupus anticoagulant (LA) in TA patients. TA patients admitted to the Department of Rheumatology of Hacettepe University Faculty of Medicine between December 2015 and September 2016 who fulfilled the American College of Rheumatology (ACR) classification criteria for TA were consecutively enrolled in the study. Patients were grouped according to aPL positivity and compared in terms of disease manifestations, type of vascular involvement at diagnosis, and vascular complications/interventions attributable to TA.
Results:
Fifty-three TA (49 female) patients were enrolled in the study. We detected 9 (16.9%) patients with IgM and/or IgG aβ2G1 and/or LA positivity. There were no patients with positive aCL. All aβ2G1 titers were low. There were no differences in terms of symptoms, signs, type of vascular involvement, the number of patients with disease-related complications or vascular interventions/surgery between aPL (+) and aPL(-) groups (p > 0.05 for all). The number of patients with thrombotic lesions was similar between the groups (p > 0.05). There were no patients with a history of venous thrombosis or on anticoagulant treatment in the aPL(+) group. Only 1 patient with IgM aβ2G1 (+) had a history of pregnancy loss.
Discussion:
Our results indicate that aPL positivity is not rare in TA. On the other hand, all aPL titers were low and no differences were found in the frequency of disease-related complications between aPL(+) and aPL(-) patient groups. Only TA patients with atypical manifestations with high suspicion of aPL-related complications should be considered to be investigated for aPL.
... However, there is little clinical information regarding the therapeutic strategy, prognosis, or relapse rate under immunosuppressive therapy in TAK with pulmonary infarction. In several previous case reports, glucocorticoid treatment was effective for TAK complicated with pulmonary artery lesion, and we have previously reported the course of TAK during the first year of glucocorticoid treatment with azathioprine [5]. ...
Takayasu arteritis (TAK) is a vasculitis that causes inflammation in the arterial walls of large blood vessels. The complication rate of pulmonary artery lesion in TAK has been reported to be relatively high. Severe pulmonary artery stenosis can cause pulmonary infarction in rare cases. A 48-year-old woman had experienced cough and fever persistently for 3 months and visited a city hospital. Contrast-enhanced computed tomography (CT) and positron emission tomography (PET)-CT scans revealed TAK complicated with left pulmonary artery lesion. Contrast-enhanced CT couldn’t detect wall thickening in the left smaller bifurcated pulmonary artery branch, but PET-CT did reveal this inflammation. Several weeks after we initiated treatment with high-dose prednisolone, the patient’s symptoms and inflammatory findings disappeared. PET-CT may be useful for evaluating the inflammation of the pulmonary artery in TAK, and high-dose steroid monotherapy as induction therapy may be effective for TAK complicated with pulmonary artery lesions causing pulmonary infarction.
... [43] Patients with relapsing disease on glucocorticoids alone were noted to sometimes exhibit a response to adjuvant therapy with TNF inhibitors. [44] Thus, although steroids are often the first-line agent for both TkA and GCA, the specific adjuvant therapies used differ, with TNF inhibitors preferred for TkA and IL-6 inhibitors (e.g., tocilizumab) for GCA. ...
There are multiple vasculitides which are distinguished based on multiple criteria, including size of affected vessels, distribution of vessels affected, histopathologic differences, genetic factors, and age at presentation. Takayasu's arteritis (TkA) and giant cell arteritis (GCA) are the two main medium to large vessel vasculitides. These vasculitides are associated with different racial predilections, vascular distributions, age groups, diagnostic criteria, and treatments. Nevertheless, the many shared histopathologic features, genetic factors, and overlap in presentation of these two diseases suggest that they may actually be variable presentations of the same disease process, i.e., large vessel vasculitis. This article will review the genetics, histopathology, disease mechanisms, and diagnostic criteria for both TkA and GCA. Overall, despite major advances our understanding of these two diseases, it is still debated whether these two large vessel vasculitides represent two distinct diseases processes or simply variations of the same disease.
... [43] Patients with relapsing disease on glucocorticoids alone were noted to sometimes exhibit a response to adjuvant therapy with TNF inhibitors. [44] Thus, although steroids are often the first-line agent for both TkA and GCA, the specific adjuvant therapies used differ, with TNF inhibitors preferred for TkA and IL-6 inhibitors (e.g., tocilizumab) for GCA. ...
There are multiple vasculitides which are distinguished based on multiple criteria, including size of affected vessels, distribution of vessels affected, histopathologic differences, genetic factors, and age at presentation. Takayasu's arteritis (TkA) and giant cell arteritis (GCA) are the two main medium to large vessel vasculitides. These vasculitides are associated with different racial predilections, vascular distributions, age groups, diagnostic criteria, and treatments. Nevertheless, the many shared histopathologic features, genetic factors, and overlap in presentation of these two diseases suggest that they may actually be variable presentations of the same disease process, i.e., large vessel vasculitis. This article will review the genetics, histopathology, disease mechanisms, and diagnostic criteria for both TkA and GCA. Overall, despite major advances our understanding of these two diseases, it is still debated whether these two large vessel vasculitides represent two distinct diseases processes or simply variations of the same disease.
... Indeed, a recent imaging study indicated that vascular damage was more prominent in TAK more than in giant cell arteritis (GCA) [4]. To reduce the cumulative dose of GCs while suppressing TAK flare-ups and progression of vascular damage, the importance of adjunct therapy is being increasingly recognised [5]. Accordingly, methotrexate, anti-interleukin-6 receptor (anti-IL-6R) antibody, and tumour necrosis factor inhibitors are now recommended for TAK [6]. ...
Objectives
To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK).
Methods
A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients.
Results
Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0–5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography–computed tomography, and two on treatment intensification.
Conclusions
We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.
... CTX and MTX were the most common DMARDs (in 27.8% and 24.1%, respectively) to be combined with GCs. However, Ohigashi has reported that more than 50% of TAK patients treated with GC monotherapy suffered from disease flare during GC dosage tapering [27]. Considering the high rate of relapse after GC therapy, immunosuppressive agents and/or biological agents are supplemented to provide more benefits. ...
To evaluate the efficacy and safety of tocilizumab (TCZ) in the treatment of refractory Takayasu arteritis (TAK). Eleven refractory TAK patients treated with TCZ at the First Affiliated Hospital of Anhui Medical University between 2017 July and 2020 December were respectively analyzed. We also respectively analyzed the studies on TCZ efficacy in patients with TAK, from PubMed/MEDLINE, Elsevier Science Direct between January 2010 and April 2021. The median age of 11 patients was 34(19–46) years. After 3 months of TCZ, a significant drop was found in median NIH (3[2–5] at baseline vs 1[0–2] after 6 months; p < 0.05), ITAS-2010 score (8.5[6–11] vs 6[1–10]; p < 0.05). One (9%) patient experienced relapse during TCZ treatment. After withdrawal of TCZ, one patient (9%) underwent relapse and nine patients (81%) were spared of GC use. In literature review, a total of 211 patients (mean age 35 years) were analyzed, including 80 (38%) Chinese and 169 females (80%). Among the 211 patients, (154 patients) 73% achieved remission after the last infusion of TCZ; TAK relapsed in 6% of patients during TCZ treatment and 5% of the TCZ patients after the withdrawal of TCZ. A total of 95 types of adverse events were observed in the literature. Infection was the most common adverse effect, occurring in 50% of patients. TCZ could serve as an efficacious and safe agent for refractory TAK.
... This study showed that patients who were HLA-B52-positive and had LVV with GCA features exhibited lower rates of biologics usage and relapse compared to patients who were HLA-B52-positive with TAK, who were more also likely to be refractory to treatment or experience relapse compared to the HLA-B52-negative ones. This was consistent with previous reports [30], whereas patients who were HLA-B52-positive with GCA showed no obvious differences in clinical course compared to the HLA-B52-negative ones. These results suggest that there is a difference in therapeutic response between patients who were HLA-B52-positive with TAK and patients who were HLA-B52-positive and had LVV with GCA features. ...
Background
This study aimed to identify new characteristics of elderly onset large-vessel vasculitis (EOLVV) by focusing on human leucocyte antigen (HLA) genotype, polymyalgia rheumatica (PMR), and affected vascular lesions observed on positron emission tomography/computed tomography (PET/CT) imaging.
Methods
We retrospectively studied 65 consecutive Japanese patients with large-vessel vasculitis (LVV) who had extracranial vasculitis lesions and underwent PET/CT imaging. PET/CT images were assessed using the semi-quantitative PET visual score of each affected vessel, and the PET vascular activity score (PETVAS) and number of affected vessels were calculated. Subjects were subsequently grouped based on age at onset, superficial temporal artery (STA) involvement, and presence of PMR and compared each group according to HLA genotype. Unsupervised hierarchical cluster analysis was used to identify the patients with similar characteristics in terms of affected vascular lesions detected through PET/CT imaging. The clinical characteristics and PET/CT findings of the population newly identified in this study were examined.
Results
Twenty-seven patients with EOLVV did not meet the American College of Rheumatology 1990 criteria for giant cell arteritis (GCA) and Takayasu arteritis and were considered as unclassified EOLVV (UEOLVV). The unsupervised hierarchical cluster analysis revealed that UEOLVV with PMR and large-vessel GCA (LV-GCA) formed a cluster of LVV with GCA features (i.e., PMR and/or STA involvement) when restricted to patients who were HLA-B52-positive. Patients who were HLA-B52-positive with LVV and GCA features had similar clinical characteristics and patterns of affected vessels and presented with diffuse LVV lesions. HLA-B52-positive patients who had LVV with GCA features also presented with higher PETVAS, more affected vessels, and lower rates of biologics usage and relapse compared to HLA-B52-positive patients with TAK.
Conclusions
Patients who had UEOLVV with PMR had similar characteristics to patients with LV-GCA. Patients who were HLA-B52-positive and had LVV with GCA features presented with diffuse vascular lesions and may comprise a core population of Japanese patients with EOLVV. The findings of HLA-B52 positivity and diffusely affected vessels in patients with EOLVV can be considered as suspicious findings of LV-GCA.
... Current clinical practice guidelines recommend GC as the mainstay of remission. However, an observational study 37 showed that more than 70% of TAK patients fail GC monotherapy. Moreover, with a high relapse rate of 50% in TAK patients on GC dose tapering, DMARDs (most cyclophosphamide) and/or biological agents are also added to the treatment regimen 10 . ...
Objective:
We aimed to systematically review biological agents' efficacy and safety in patients with Takayasu arteritis (TAK).
Materials and methods:
A systematic literature search of 7 electronic databases, including MEDLINE (via PubMed), EMBASE, Elsevier ScienceDirect, EBSCO, Springer Link, Web of Science, and Cochrane Library on the efficacy of biological agents on patients with TAK was conducted. Only studies published in English and with a sample size >5 patients with TAK were included. Two reviewers independently selected studies, extracted data and assessed its methodological quality. Random effects meta-analyses of various effect measures were performed.
Results:
According to the title and abstract, 961 studies were identified and screened. Subsequently, 31 studies from 29 observational studies and 2 randomized-controlled trials (RCTs), which included a total of 517 patients with TAK that met the inclusion and exclusion criteria, were selected. Observational studies showed a high risk of bias. Pooled remission rates of biological agents were 66% (95% CI: 58%-73%; I2=59%), and the remission rates of anti-tumor necrosis factor (TNF) agents and tocilizumab (TCZ) were similar: 65% (95% CI: 56%-73%; I2=49%) and 70% (95% CI: 55%-86%; I2=69%), respectively. Pooled relapse rates were 23% (95% CI: 15%-31%; I2=66%). The relapse rate was 28% (95% CI: 16%-40%; I2=68%) for anti-TNF agents and 17% (95% CI: 7%-26%; I2=49%) for TCZ. The remission rate of TCZ was slightly higher (p>0.05), but the relapse rate was statistically significantly lower than that of anti-TNF agents (p=0.017). Furthermore, biological agents significantly decreased the doses of glucocorticoid (GC) and levels of acute phase inflammation markers (ESR, CRP) while the proportion of patients with new angiographic lesions or progression of previously noted lesions were 11% (95% CI: 4%-18%; I2=59%). RCTs with a small sample size showed abatacept was ineffective, and TCZ was underpowered to detect a difference in time to relapse compared to placebo. The most common adverse event of biological agents was infection (6%, 95%CI: 2%-10%). No deaths were reported.
Conclusions:
Although the beneficial effects of biological agents are encouraging in enhancing disease remission, reducing the levels of acute phase inflammation markers and decreasing the treatment doses of GC in patients with TAK, there is still a risk of relapse. More refined studies with larger cohorts are necessary before drawing a definitive opinion.
... Addition of many immunosuppressive agents such as methotrexate, tacrolimus, azathioprine, cyclosporine, and cyclophosphamide has been applied in steroid-resistant cases and sometimes results in favorable outcomes [ 7 , 8 ]. However, remission induction can only be achieved in around 20-30% with single use of these agents administered together with steroids [7] . Also, the effectiveness and side effects for each drug are highly variable and the evidence for utility of these agents for management of TAK is scarce, preventing wide-spread use. ...
Background
Although high-dose glucocorticoids are effective in suppressing active inflammation of Takayasu arteritis (TAK), many patients experience relapse during tapering of glucocorticoids. Recently, the interleukin-6 receptor antibody, tocilizumab (TCZ), was reported to be effective for steroid-resistant TAK. However, there are no objective ways of diagnosing TAK recurrence because TCZ suppresses inflammatory biomarkers.
Objectives
To investigate the efficacy of TCZ at 1-year follow-up and of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography for detection of recurrence of inflammation during TCZ treatment.
Methods and Results
We treated 19 patients with refractory TAK with TCZ. TCZ was discontinued in 2 cases because of side effects. Abatement of arteritis symptoms along with reduction of glucocorticoid dosage was achieved in 12 patients, resulting in a remission induction rate of 70.6%. The dosage of glucocorticoid was reduced from 16.1 ± 10.2 mg to 3.8 ± 1.7 mg at 1 year (p<0.001) in these patients. In the remaining 5 patients, glucocorticoid tapering led to exacerbation of symptoms and glucocorticoid dose had to be increased. FDG-PET scan results closely matched clinical course in all 5 patients with recurrence even during TCZ treatment, while the scan was negative for the remaining 12 patients.
Conclusions
TCZ injection provides robust steroid-sparing effect and improvement of inflammation without significant adverse effects. Recurrence of inflammation can be detected by FDG-PET even during TCZ treatment.
... 7 Methotrexate (MTX) is an immunosuppressant that is most commonly used in these patients, and it has been reported to be a promising treatment option to achieve and maintain remission in refractory TA patients. 8 Other drugs, such as leflunomide, have also been reported to cause quick induction and sustained remission of TA, especially in refractory cases, and therefore, these drugs should be considered to be an alternative treatment for TA. 9 Additional biotherapeutic agents, such as tumor necrosis factor (TNF) inhibitors, have recently been approved for TA treatment. However, neither provide much more benefit than corticosteroids. ...
Liver injury in Takayasu arteritis (TA) is a rare phenomenon. Most symptoms are nonspecific, and the exact pathogenesis remains to be elucidated. Early diagnosis and new treatment methods are important for an improved prognosis. A summary of the clinical information and mechanistic analyses may contribute to making an early diagnosis and development of new treatment methods. A PubMed search was conducted using the specific key words “Takayasu arteritis” and “liver” or “hepatitis” or “hepatic”. Symptoms and treatment of TA with an accompanying liver injury were reviewed retrospectively. Many factors are presumed to be involved in the mechanism of TA with liver injury, including the immune response, genes, infections, and gut microbiota. There are several lines of evidence indicating that immune dysfunction is the main pathogenic factor that triggers granuloma formation in TA patients. However, the role of genetics and infections has not been fully confirmed. Recently, the gut microbiota has emerged as an essential component in the process. We reviewed in detail the current concepts that support the complex pathogenesis of TA accompanied by liver injury, and we presented recent theories from the literature. Finally, we discussed future research directions of liver injury in TA.
... It has been reported that the dose of 10-15 mg/week for MTX was effective and safe for TAK in previous studies. 31,32 In the meanwhile, to avoid the adverse events, especially abnormal liver functions and myelosuppression, the doses of MTX we used were low. However, whether the lower dose of MTX could have significantly affected the efficacy of the drug itself still needs to be confirmed in further randomized controlled trials. ...
Aims
The study investigates the effectiveness and safety of methotrexate (MTX) versus leflunomide (LEF) in 12-month treatment of Takayasu arteritis (TAK).
Methods
This was a cohort study. Patients diagnosed with TAK between 1 January 2013 and 1 January 2019 were enrolled from First Hospital of China Medical University and Zhongshan Hospital of Fudan University. Patients had active disease and were treated with glucocorticoid combined with LEF or MTX. Treatment response, imaging assessment and side-effects were evaluated during 12-month follow-up.
Results
In total, 68 patients were enrolled (40 cases treated with LEF and 28 treated with MTX). At baseline, age, sex, disease duration and disease activity index showed no significant differences between groups. Prevalence of complete remission (CR) at 6 months was significantly higher in the LEF group than that in the MTX group (LEF versus MTX: 72.50% versus 53.57%, p = 0.04), though the CR prevalence at 9 months and 12 months showed no significant differences between groups. At 9 months, the prevalence of treatment resistance was much lower in the LEF group compared with MTX group (5.41% versus 11.54%, p = 0.03). Furthermore, prevalence of disease relapse in the LEF group was lower than that in MTX group at 12 months (7.24% versus 16.67%, p = 0.03). Patients with high baseline C-reactive protein levels (⩾15 mg/L) carried a higher risk of treatment resistance (OR = 1.36, 95% CI 1.07–13.41, p = 0.06) and disease relapse (HR = 2.51, 95% CI 1.36–12.98, p = 0.04).
Conclusion
LEF might provide a quicker treatment response with lower prevalence of disease relapse compared with that elicited in MTX during 12 months follow-up for TAK.
... In patients not responding adequately to therapy with csDMARDS + GC (refractory or relapse), EULAR recommends the use of TNF-α inhibitors (TNFi) or TCZ [10]. A descriptive prospective cohort study investigating the effects of escalating therapy with csDMARDs and then with bDMARDs (TNFi or TCZ) in TA patients that did not respond to GC showed that 64% of patients treated with bDMARDs achieved sustained remission [74]. ...
Purpose of Review
Guidelines for the management of large vessel vasculitides have been recently updated by several scientific societies. We have evaluated the current recommendations for treatment of giant cell arteritis (GCA) and Takayasu arteritis (TA) and addressed potential future therapeutic strategies.
Recent Findings
While glucocorticoids (GCs) remain the gold standard for induction of remission, many patients relapse and acquire high cumulative GC exposure. Thus, GC-sparing therapies such as methotrexate are recommended for selected patients with GCA and all patients with TA. Recent high-quality evidence shows that tocilizumab is an effective GC-sparing agent in GCA. Non-biologic and biologic immunomodulators also appear to have GC-sparing properties in TA.
Summary
Tocilizumab is now considered to be part of the standard treatment for GCA, particularly with relapsing disease, but questions on its use such as length of treatment and monitoring of disease activity remain open. High-quality evidence to guide treatment of TA is still lacking.
... Approval for off-label tocilizumab had to be sought as its use for TA in Europe remains currently unlicensed. Observational evidence supports the use of biologic therapy, including IL-6 receptor antagonists and TNF inhibitor in TA. 3,4,[12][13][14] A recently published randomized controlled trial, however (TAKT trial), did not show any statistical difference between time of relapse in TA patients who are treated with GC alone and those who are treated with IL-6 inhibition in combination with GC. However, all patients in this trial had refractory disease and therefore may have longer disease duration and previous treatment failures. ...
... 86 A descriptive prospective cohort study assessing the effects of escalating therapy with conventional synthetic DMARDs and then with biologic DMARDs (TNFi or TCZ) in refractory TA not responding to GC demonstrated that 64% of patients achieved and maintained remission with bDMARD treatment. 87 There was one retrospective case series (n=7) of refractory TA treated with rituximab as first-line bDMARD, but despite treatment four out of seven patients still had persistent disease at follow-up. 88 The other important medical issues relate to the management of hypertension and the prevention and treatment of thrombosis. ...
Takayasu’s arteritis (TA) is a rare, idiopathic, chronic inflammatory disease with cell-mediated inflammation, involving mainly the aorta and its major branches. It leads to stenosis, occlusion or aneurysmal degeneration of large arteries. The clinical presentation is characterized by an acute phase with constitutional symptoms, followed, months or years later, by a chronic phase in which symptoms relate to fibrosis or occlusion of vessels. Conventional angiography, the gold standard method for initial diagnosis, appears to have been replaced with new imaging modalities such as magnetic resonance angiography (MRA) and 18Ffluorodeoxyglucose positron emission tomography (FDGPET) in recent years. These are also used for the assessment of disease activity. New tools for disease assessment such as Indian Takayasu’s Arteritis Score 2010 (ITAS2010) and color Doppler ultrasound (CDUS) aim to better characterize and quantify disease activity. Leflunomide, tumor necrosis factor (TNF)-± antagonists, and tocilizumab are new options for patients resistant to conventional therapies. Prognosis is possibly getting better, with lower mortality in recent years due to recent advancement in investigations and management. J Bangladesh Coll Phys Surg 2020; 38(1): 35-45
... Although glucocorticoids are very effective for treatment of both GCA and TAK, relapse is common following reduction of the dose 4,5 . In such cases, methotrexate, an immunosuppressive drug, is used for sparing of glucocorticoids while preventing relapse [6][7][8] . Newer biologics, such as neutralizing antibodies for TNF-α, IL-6, and/or IL-12/IL-23p40, have also been developed for GCA and TAK 9 . ...
IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn−/− mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1–, TNF– and IL-17A–dependent aortitis. We found that expression of II25 mRNA was increased in the aortae of Il1rn−/− mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis in Il1rn−/− mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found that Il25−/−Il1rn−/− mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression of Il17a and Tnfa—but not Il4 or Il13—in local lesions compared with Il1rn−/− mice. Tissue–, but not immune cell–, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor–expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae of Il1rn−/− mice, contributing to exacerbation of development of IL-1–, TNF– and IL-17A–dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.
... 68 A descriptive prospective cohort study assessing the effects of escalating therapy with csDMARDs and then with bDMARDs (TNFi or TCZ) in refractory TAK not responding to GC demonstrated that 64% of patients achieved and maintained remission with bDMARD treatment. 69 There was one retrospective case series (n=7) of refractory TAK treated with rituximab as first-line bDMARD, but despite treatment four out of seven patients still had persistent disease at follow-up. 70 There have not been any important safety concerns from the use of bDMARDs in RCTs even though anecdotal reports from observational studies have reported TB reactivation with TNFi treatment. ...
Objective
To collect available evidence on management of large vessel vasculitis to inform the 2018 update of the EULAR management recommendations.
Methods
Two independent systematic literature reviews were performed, one on diagnosis and monitoring and the other on drugs and surgical treatments. Using a predefined PICO (population, intervention, comparator and outcome) strategy, Medline, Embase and Cochrane databases were accessed. Eligible papers were reviewed and results condensed into a summary of findings table. This paper reports the main results for Takayasu arteritis (TAK).
Results
A total of 287 articles were selected. Relevant heterogeneity precluded meta-analysis. Males appear to have more complications than females. The presence of major complications, older age, a progressive disease course and a weaker inflammatory response are associated with a more unfavourable prognosis. Evidence for details on the best disease monitoring scheme was not found. High-quality evidence to guide the treatment of TAK was not found. Glucocorticoids are widely accepted as first-line treatment. Conventional immunosuppressive drugs and tumour necrosis factor inhibitors were beneficial in case series and uncontrolled studies. Tocilizumab failed the primary endpoint (time to relapse) in a randomised controlled clinical trial; however, results still favoured tocilizumab over placebo. Vascular procedures may be required, and outcome is better when performed during inactive disease.
Conclusions
Evidence to guide monitoring and treatment of patients with TAK is predominantly derived from observational studies with low level of evidence. Therefore, higher-quality studies are needed in the future.
... [95][96][97][98][99][100] Efficacy of tumour necrosis factor (TNF)-inhibitors in TAK has been reported in one prospective and several retrospective open-label uncontrolled studies/case series. [101][102][103][104][105][106][107][108][109][110][111] Overall, the reported reductions in disease activity in all these case series need to be interpreted with caution, because disease activity in TAK may decrease as a result of continued GC therapy over time. In contrast to the positive trends observed in GCA, the RCT of abatacept did not show any signs of efficacy in TAK. ...
Background
Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations.
Methods
Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations.
Results
Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40–60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons.
Conclusions
We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice.
... 9 TA patients who were treated with cyclophosphamide (CYC) and/or biologic agents were considered as having severe or treatment-resistant disease. 10,11 All patients underwent complete transthoracic echocardiography (TTE) examination. Standard imaging was performed in the left lateral decubitus position using a commercially available cardiac ultrasound system (Acuson Sequoia C256, Siemens, CA, USA). ...
Aim:
To determine the frequency and define the causes of pulmonary hypertension (PH) in patients with Takayasu arteritis (TA).
Method:
Sixty-four TA patients were evaluated by transthoracic echocardiography (TTE). Having an estimated systolic pulmonary arterial pressure (sPAP) ≥40 mm Hg by echocardiography or if performed, mean PAP ≥25 mm Hg in right heart catheterization was defined as PH. Clinical, imaging and laboratory results of the TA patients were obtained from hospital files.
Result:
In total, seven (10.9%) patients had PH. Four patients had PH due to left-sided heart disease (group 2 PH), three patients due to pulmonary arterial involvement (PAI; group 4 PH) and one patient due to atrial septal defect (group 1 PH). In one patient, combination of PAI, aortic insufficiency and pulmonary venous return anomaly was present and he was considered to have both group 2 and group 4 PH. PAI was more frequent (42.9% vs 15.7%) in patients with PH but the difference was not statistically significant. The percentage of patients treated with cyclophosphamide and/or biologics was higher in the group with PH as compared to the group without PH (P = 0.015). One patient with group 4 PH had been on pulmonary arterial hypertension (PAH)-specific agents for 8 years.
Conclusion:
Pulmonary hypertension is not infrequent in TA patients and all the potential causes of PH should be carefully evaluated. Patients with severe or treatment-resistant disease are prone to have PH. PAH-specific agents may be effective in patients with group 4 PH.
Giant cell arteritis (GCA) and Takayasu arteritis (TAK), as the main representatives of large vessel vasculitis, are rheumatological autoimmune disorders associated with inflammatory vessel wall changes in the arterial system that can lead to many types of organ damage.
In this review the current scientific evidence on the diagnostics and treatment of large vessel vasculitis is evaluated and discussed.
In addition to the medical history and clinical presentation, imaging techniques nowadays represent the core of large vessel vasculitis diagnostics and have largely replaced the histological confirmation of GCA. After the diagnosis, acute treatment with glucocorticoids should be initiated as rapidly as possible but in the long term this should be tapered out or replaced by a steroid-sparing basic treatment. In contrast to GCA with already available options and other biologic disease-modifying antirheumatic drugs (DMARDs) about to be approved, there are still no approved biologic DMARD treatment options available for the less common TAK.
In contrast to the substantial progress in imaging diagnostics of large vessel vasculitis and with respect to the treatment of GCA, the much rarer TAK still requires intensive research efforts, especially to improve the treatment situation.
Background
The efficacy of tocilizumab (TCZ) in the treatment of Takayasu arteritis (TA) was demonstrated in randomized controlled trials. The objective of this study was to analyze the effectiveness of combining TCZ with glucocorticoids (GC) as induction therapy in patients with TA.
Method
This was a retrospective observational study including 32 patients with newly-diagnosed TA. Clinical effectiveness of TCZ in maintaining relapse-free remission and GC-tapering were compared between patients who were treated with TCZ plus GC and those who were treated with GC with or without immunosuppressants.
Results
The study comprised 32 patients (27 women/5 men) with a median age of 25.5 years (range, 13–72). In the TCZ group (n = 14), patients received TCZ in combination with GC as an induction therapy. In the non-TCZ group (n = 18), patients were treated with single-agent GC or GC plus immunosuppressant. In the matched analysis, relapse-free survival rate was significantly higher in the TCZ group as compared to the non-TCZ group during GC taper.
Conclusion
TCZ, in combination with GC, would be an effective alternative induction regimen for patients with TA.
Objective:
To compare the treatment efficacy and safety of tofacitinib (TOF) versus methotrexate (MTX) in Takayasu arteritis (TAK).
Methods:
Fifty-three patients with active disease from an ongoing prospective TAK cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and TOF, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analysed during 12 months.
Results:
The CR rate was higher in the TOF group than in the MTX group (6 months: 85.19% vs 61.54%, p=0.07; 12 months: 88.46% vs 56.52%, p=0.02). During 12 months' treatment, patients in the TOF group achieved a relatively lower relapse rate (11.54% vs 34.78%, p=0.052) and a longer median relapse-free duration (11.65±0.98 vs 10.48±2.31 months, p=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the TOF group than that in the MTX group (p<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (p>0.05). Prevalence of side effects was low in both groups (3.70% vs 15.38%, p=0.19).
Conclusion:
TOF was superior to MTX for CR induction, a tendency to prevent relapse and tapering of the GCs dose in TAK treatment. A good safety profile for TOF was also documented in patients with TAK.
We evaluated clinical response, normalization of inflammatory markers, angiographic stabilization (primary outcomes), relapses and adverse events (secondary outcomes) in Takayasu arteritis (TAK) patients following corticosteroid monotherapy. MEDLINE, EMBASE, Web of Science, Scopus, Pubmed Central, Cochrane library, clinical trial databases and major international Rheumatology conferences were searched for studies reporting outcomes in TAK following corticosteroid monotherapy (without language/date restrictions). Risk ratios were calculated for controlled studies. Proportions were pooled for uncontrolled studies. Heterogeneity was assessed using I2 statistic. Quality assessment of individual studies utilized the Newcastle–Ottawa scale. GRADE methodology ascertained certainty of individual outcomes across studies. Twenty-eight observational studies (1098 TAK) were identified. Twenty-three uncontrolled studies (580 TAK) were synthesized in meta-analysis. Clinical response was observed in 60% (95% CI 45–74%, 19 studies), normalization of inflammatory markers in 84% (95% CI 54–100%, 4 studies) and angiographic stabilization in 28% (95% CI 6–57%, 4 studies). Relapses occurred in 66% (95% CI 18–99%, 4 studies). Adverse events were reported in 51% (95% CI 2–99%, 4 studies). All pooled estimates had considerable heterogeneity, unexplained by subgroup analyses (time period, geographic location or number of patients). Two studies reported lesser restenosis following vascular surgery and fewer relapses when corticosteroids were combined with immunosuppressants compared with corticosteroid monotherapy. All outcomes had very low certainty. While corticosteroid monotherapy induces clinical response in most TAK patients, angiographic stabilization is observed in fewer than one-third. Most patients relapse following corticosteroid withdrawal. Preliminary evidence supports up-front addition of immunosuppressants to retard angiographic progression and reduce relapses (PROSPERO identifier CRD42021242910).
Objective: We present a rare case of Takayasu arteritis complicated by eosinophilic granulomatosis with polyangiitis (EGPA), followed by common carotid artery occlusion. Case Presentation: A 49-year-old woman with a history of EGPA rapidly developed left hemiplegia. MRI revealed acute infarction in the right middle cerebral artery territory. The right common carotid artery was not visualized on magnetic resonance angiography. She was transferred to our hospital for a detailed examination. Her erythrocyte sedimentation rate and C-reactive protein level were slightly increased. PET-CT showed high uptake in the aortic arch, right innominate artery, and common carotid artery, which supported the diagnosis of Takayasu arteritis. Rest ¹²³I-IMP-SPECT demonstrated low uptake in the right middle cerebral artery territory; therefore, subclavian-carotid bypass for revascularization of the right carotid artery was performed. She eventually recovered well from the surgery and was discharged home. Conclusion: Revascularization for common carotid artery occlusion of Takayasu arteritis with EGPA was safe and effective in improving the neurological status, and it should be performed while the disease is inactive.
Giant cell arteritis (GCA) and Takayasu Arteritis (TAK) are two systemic granulomatous vasculitides affecting medium- and large-sized arteries. Similarities in GCA and TAK regarding the clinical presentation, the systemic inflammatory response and the distribution of the arterial lesions, have triggered a debate over the last decade about whether GCA and TAK represent two different diseases, or are age-associated different clinical phenotypes of the same disease. On the other hand, there are differences regarding epidemiology, several clinical features (eg, polymyalgia rheumatica in GCA) and treatment. The aim of this review is to present the latest data regarding this question and to shed some light on the differences and similarities between GCA and TAK regarding epidemiology, genetics, pathogenesis, histopathology, clinical presentation, imaging and treatment. The existing data in literature support the opinion that GCA and TAK are different clinical entities.
Despite advances in the diagnosis and treatment, the mortality rate of Takayasu arteritis (TAK) is still elevated even today. The diagnosis is often made after a long time delay and the course of the disease is characterized by progressive structural vascular lesions. Recently, new recommendations for the management of large vessel vasculitis were published by the European League Against Rheumatism (EULAR). For induction of remission oral glucocorticoids (GC) are administered in an initial daily dose of 40–60 mg. As experience has shown that the cumulative GC demand in TAK is high, GC-sparing treatment with moderately potent immunosuppressants, such as methotrexate, azathioprine and mycophenolate mofetil is recommended from the time of initial diagnosis. In cases of a relapsing course, tocilizumab or tumor necrosis factor (TNF)-alpha inhibitors can be used as an additive off-label treatment. If vascular stenoses persist despite supposedly sufficient inflammation control and if these stenoses are symptomatic, vascular surgery or interventional treatment procedures can be indicated. Such revascularization or even surgical procedures for the treatment of aneurysms should be performed during phases of sufficient drug control of the vasculitis. In quite a few patients progressive vascular lesions continue to develop despite clinical and laboratory analytical remission. Due to the poor correlation of clinical symptoms and acute phase markers with the progression of vascular lesions, the distinction between active and inactive diseases is often a challenge in the clinical practice. Imaging studies can then support therapeutic decisions but are not yet formally and comprehensively validated in the long-term course of TAK.
Objective:
We retrospectively investigated drug retention rate (DRR) and reasons for discontinuation of seven biologic disease-modifying anti-rheumatic drugs (bDMARDs) in Takayasu's arteritis (TA) in a real-world setting.
Methods:
TA patients followed-up in our center fulfilling the 1990 ACR criteria and treated with ≥1 bDMARD were selected. Data about disease duration, number of bDMARDs, reasons for bDMARDs discontinuation, and concomitant conventional synthetic (cs)DMARDs were collected. Survival curves were examined by the Kaplan-Meier method and compared using a stratified log-rank test. 24-month DRR was calculated. Hazard ratio (HR) for concomitant csDMARDs and for previous bDMARDs was evaluated. A comparative sub-analysis between anti-TNFα drugs and tocilizumab was performed.
Results:
We identified 50 patients and 86 bDMARD-courses. No significant differences were observed in age and disease duration between the seven groups. Infliximab was the most frequent first-line bDMARD (78.6%). At bDMARDs initiation, all patients were prescribed prednisone (mean dose, 13.5 ± 10.3 mg/day) and 85.2% concomitant csDMARD therapy. 43% of treatment courses were stopped by 24 months. Golimumab had the highest DRR (71.4%), followed by infliximab (69%), adalimumab (56.3%), abatacept (50%), tocilizumab (41.1%), anakinra (0%) and rituximab (0%), p = 0.016. Concomitant csDMARDs therapy showed positive effects on DRR (HR=2.87, 95% CI=1.19-6.92, p = 0.019). Anti-TNFα drugs had significantly higher DRR compared to tocilizumab (67.2% vs 41.1%, p = 0.028). Even in these subgroups, csDMARDs showed positive effects on DRR (HR=3.79, 95% CI=1.49-9.6, p = 0.005).
Conclusions:
Anti-TNFα agents had the highest DRR overall and a higher DRR in a head-to-head comparison with tocilizumab. Concomitant csDMARDs had a significant positive effect on bDMARDs DRR.
A 23-year old female patient with ulcerative colitis (UC) who had been successfully treated with infliximab (IFX) plus 5-aminosalicylated acid (5-ASA) developed Takayasu arteritis (TAK). She refused to take glucocorticoids to treat TAK. IFX was discontinued and 8 mg/kg of tocilizumab (TCZ) was added to 5-ASA. Her symptoms such as fever, chest pain disappeared within a week along with serum CRP. TCZ was administered every 2 weeks for 2 months and monthly thereafter. After 1-year treatment of TCZ mono-therapy, arterial wall thickening also improved. In addition, UC has been in remission without any gastrointestinal symptoms. TCZ mono-therapy is effective for TAK and might not compromise UC.
Background:
Takayasu's Arteritis (TAK) affects mostly young women and causes significant morbidity. Most patients are refractory to glucocorticoids (GC) or relapse when GC doses are reduced. The objective of this study is to summarize the literature pertaining to the effectiveness of non-GC drugs for the treatment of TAK.
Methods:
MEDLINE and Embase were searched for English-language studies of TAK patients with a sample size >5. Studies were included if the effectiveness of non-GC drugs for the treatment of TAK was reported. Random effects meta-analyses of various effect measures were performed.
Results:
Of the 915 studies identified by the search, 14 of small molecule immunosuppressants (IS) and 25 of biologic therapies were included. Studies had a high risk of bias. Pooled remission rates were similar for both categories of non-GC drugs: 58% (95% CI: 40-74%) and 64% (95% CI: 56-72%), respectively. The relapse rate was 54% (95% CI: 39-68%) for IS therapies and 31% (95% CI: 22-41%) for biologics. Both significantly decreased GC doses and acute phase reactants. Observational studies suggested that anti-TNF agents were more effective than IS at maintaining remission. Randomized-controlled trials (RCTs) of biologics were of small sample size: abatacept was not effective and the trial of tocilizumab was underpowered to detect a difference in time to relapse versus placebo. Serious adverse events were uncommon.
Conclusions:
Non-GC agents were moderately effective in inducing remission in TAK, but relapse rates were high. Larger, better designed studies are required to determine the optimal treatment regimen for TAK.
Objective:
To evaluate the treatment effects of the IL-6R antibody tocilizumab and cyclophosphamide (CTX) in patients with Takayasu arteritis (TA) and explore the mechanism by analyzing their effects on various cytokines.
Methods and materials:
This study included 9 TA patients treated with tocilizumab, 15 TA patients treated with CTX and 24 healthy controls. Treatment effects were evaluated based on: (1) Kerr score and Indian Takayasu Clinical Activity Score (ITAS2010), (2) improvement of previous lesions and occurrence of new vascular lesions on magnetic resonance angiography (MRA), (3) changes in various cytokine levels, (4) glucocorticoid sparing, and (5) adverse effects. ELISA was used to analyze the cytokine levels.
Results:
Before treatment, all the patients had active disease accompanied with elevated C-reactive protein (CRP), serum amyloid A (SAA), interleukin (IL)-6 and pentraxin-3 (PTX3). Moreover, an imbalance in the MMP-TIMP system was also observed in these patients. Among them, IL-6 and MMP-9 levels were significantly associated with vascular enhancement scores and stenosis scores, respectively. At 6months after treatment, improved clinical manifestations and glucocorticoids sparing were observed in both groups without any severe side effects. Although no significant improvement occurred in the vascular stenosis, thickness and enhancement scores in both groups, a more degree of decrease of ESR, CRP level, significantly decreased MMP-9 level and increased MMP-2 level were found in the tocilizumab group than in the CTX group.
Conclusions:
The IL-6R antibody may be more effective in mitigating vascular inflammation and remodeling than CTX via inhibition of IL-6 and MMP-9.
Treatment of large-vessel vasculitis (LVV) remains challenging. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose or after GC withdrawal. In addition, GCs are fraught with numerous adverse events. The aim of this study was to assess the efficacy and safety of the anti-IL-6 receptor (IL-6R) antibody tocilizumab (TCZ) in patients with LVV.
Four patients with active LVV (two with GCA and two with Takayasu arteritis) received monthly TCZ infusions (8 mg/kg bodyweight) for 6 consecutive months. Two patients were treatment naïve, while two had relapsing disease. Disease activity and drug tolerability were assessed clinically and by laboratory tests at study entry and subsequently every month for 6 months of TCZ treatment, while an [(18)F]fluorodeoxyglucose PET (PET/CT) scan was performed before and after treatment. In addition, a semi-quantitative clinical evaluation was performed at baseline and at 3 and 6 months using the Indian Takayasu activity score and the Kerr indices. After TCZ, MTX was used as maintenance therapy.
All patients treated with TCZ therapy had a satisfactory clinical and laboratory response, while PET/CT findings significantly improved in all cases. No serious adverse events were noted. Only one patient had a transient increase in liver enzymes.
In this small group of patients with LVV, treatment with TCZ was effective and well tolerated. Further, larger studies are required to confirm our findings.
Takayasu's arteritis (TA) is a chronic, inflammatory vasculitis affecting the aorta and its major branches. Although it is more prevalent in Far-East Asia, the distribution of the disease is worldwide with different vascular involvement patterns and clinical manifestations. The objective of this study was to evaluate the demographic, clinical, angiographic and prognostic features of TA patients in Turkey.
Clinical and angiographic findings of 248 TA patients (228 female, 27 male) followed at 15 Rheumatology Centers were prospectively evaluated according to a predefined protocol.
The mean age was 40.1 years (30.2 years at the clinical onset). Clinical manifestations included constitutional symptoms in 66%, absent or diminished pulses in 88%, bruits in 77%, extremity pain in 69%, claudication in 48%, hypertension in 43% and cerebrovascular accidents (CVA) in 18% of the patients. Renal artery stenosis, aortic regurgitation and pulmonary hypertension were present in 26%, 33% and 12%, respectively. According to the new angiographic classification, type V (50.8%) and Type I (32%) were the most frequent types of involvement. Corticosteroids were the main treatment in 93% of the patients alone (9%) or in combination with immunosuppressive agents (84%). Most frequently preferred immunosuppressive agents were methotrexate (63%), azathioprine (22%) and cyclophosphamide (13%). Remission was observed at least once in 94% of the patients and sustained remission in 71% during follow-up.
The demographical, clinical and angiographic findings of TA patients in our series were similar to those reported from Japan, Brazil and Colombia. Combination therapies with immunosuppressive agents were the preferred choice of treatment in Turkey.
In this retrospective longitudinal cohort study we included 52 patients with Takayasu arteritis (TA) who were on regular follow-up at the Vasculitis Unit of Universidade Federal de São Paulo between 2003 and 2009. The mean age at study was 38 years and the mean age at diagnosis was 29 years. Patients were followed for a mean 74.3 months. A relapse-remitting course was observed in 41 patients (78.8%) whereas 9 (17.3%) had a monophasic course and only 2 (3.8%) patients were chronic-active. Disease remission was achieved in 50 patients (96.2%). Angiographic type V was observed in 42.3% of TA patients at diagnosis and in 61.5% during follow-up. The most affected arteries were the abdominal aorta (63.5%) and left subclavian (60.6%). Prednisone was used by 94% of TA patients and immunosuppressive agents were prescribed for 51 (98%) patients. Methotrexate was used by 82.7%, followed by cyclophosphamide (26.9%), azathioprine (25.0%), anti-TNFα agents (5.8%) and leflunomide (5.8%). Although, forty patients (76.9%) used prednisone and methotrexate as initial treatment, 75% of them developed new vascular lesions along follow-up. Eighteen TA patients (34.6%) needed to change immunosuppressive therapy due to failure or toxicity, among them 83.3% presented new lesions. Surgical treatment was performed in 34.6% of patients and restenosis was observed in 13.5% in a median time of 11 months after surgery. In conclusion besides prednisone and methotrexate is largely used in TA, the majority of patients still develop new arterial lesions along time.
Background: We aimed to describe the recent clinical characteristics of Takayasu arteritis (TA). Methods and Results: We enrolled 106 consecutive TA patients and compared the clinical characteristics of patients with TA onset before 1999 and after 2000, patients with onset at age less than 39 years and more than 40 years, patients with monophasic and relapsing-remitting clinical course, and patients with and without human lymphocyte antigen (HLA)-B52 allele. Among the patients with TA onset after 2000, the time from onset to diagnosis had decreased; the frequency of occlusion in aortic arch branches and the complication of moderate or severe aortic regurgitation (AR) had decreased, and the maximum dose of prednisolone and the use of immunosuppressive agents had increased. In patients with onset at age more than 40 years, the complications of coronary artery lesions and hypertension had increased, and the incidence of moderate or severe AR had decreased. In the relapsing-remitting group, the maximum dose of prednisolone and the use of immunosuppressive agents had increased, and the mean dose reduction rate of prednisolone was significantly high. There was no significant difference between patients with and without HLA-B52 allele. Conclusions: The prognosis of TA patients has improved over the past decade, which may be related to early diagnosis because of the development of noninvasive diagnostic imaging tools and improved medical treatments. (Circ J 2012; 76: 1004-1011)
Takayasu arteritis (TA) is a rare nonspecific inflammatory disease of unknown cause, predominantly affecting the aorta and its main branches, coronary arteries, and pulmonary arteries of young females. It induces a variety of nonspecific inflammatory symptoms and ischemic symptoms due to stenotic lesions. Further progression of TA causes destruction of the arterial wall media, leading to aortic regurgitation and aneurysms or rupture of the involved arteries. Although serological tests specific for TA are not available, new better biomarkers are emerging such as pentraxin3 and matrix metalloproteinases. Recent advances in imaging modalities including magnetic resonance angiography, computed tomography (CT), sonography, and fluorodeoxy glucose positron emission tomography/CT (FDG-PET/CT) allow earlier and accurate diagnosis of TA. Duration between onset of the disease and diagnosis has become much shorter during the last decade. Medical treatment for TA is also changing. In addition to the traditional glucocorticoids and immunosuppressants, many new biological agents are being applied to patients with TA refractory to conventional treatment with favorable results. As for treatment for vascular complications, efficacy of endovascular treatment is still a matter of controversy because of the high rate of restenosis at an early stage after the procedure. Based on these advances, the prognosis and quality of life of TA patients have improved to a great deal. However, there are many issues that remain to be solved in the management of TA.
Background:
Patients with Takayasu arteritis (TA) often show recurrence under steroid treatment without an elevation of C-reactive protein (CRP). There is a report that matrix metalloproteinase (MMP)-2, MMP-3, MMP-9 and pentraxin3 (PTX3) could be sensitive biomarkers, but the characteristics of these biomarkers have not been established.
Methods and results:
We enrolled 45 consecutive patients; 28 were grouped in an active phase as evidenced by clinical recurrence within 2 years of blood sampling. Circulating levels of high-sensitivity (hs)CRP, MMPs, and PTX3 were determined. Patients in an active phase showed higher levels of hsCRP, MMP-9, and PTX3. Area under the receiving operating characteristics curves of hsCRP and PTX3 were significantly higher than that of MMP-9. Among the 28 patients with active TA, 71% was positive for hsCRP and 82% for PTX3. Patients without recurrence showed significantly higher plasma levels of MMP-9. There was a positive correlation between the plasma MMP-3 level and the prednisolone dose. However, PTX3 and MMP-9 levels did not have such a correlation.
Conclusions:
PTX3 and MMP-9, which are not affected by prednisolone, could be sensitive biomarkers for assessing TA activity. Evaluation of MMP-9 may suggest prior existence of TA.
Objective. To identify the role of methotrexate (MTX) in the treatment of persistent or recurrent Takayasu arteritis that is refractory to treatment with glucocorticoids (GC) alone.
Methods. An open-label pilot study of weekly low-dose MTX + GC treatment was performed. Outcome was evaluated according to clinical characteristics, laboratory abnormalities, findings on routinely performed angiographic studies, and ability to withdraw GC and MTX therapy. Eighteen patients entered the study; 2 dropped out, and 16 were followed up for a mean period of 2.8 years (range 1.3–4.8 years).
Results. Weekly administration of MTX (mean stable dose of 17.1 mg) and GC resulted in remissions in 13 of 16 patients (81%). However, 7 patients (44%) had relapses as GC was tapered to or near discontinuation. Retreatment again led to remission, and 3 of 7 patients in this group have successfully stopped GC therapy. Of those patients who achieved remission, 8 (50%) have sustained remissions of 4–34 months (mean 18 months), and 4 of this group have not required GC or MTX therapy for 7–18 months (mean 11.3 months). Three patients experienced disease progression in spite of treatment.
Conclusion. About half of all Takayasu arteritis patients have chronic active disease for which GC therapy alone does not provide sustained remissions that allow withdrawal of treatment. Weekly low-dose MTX is an effective means of inducing remission and minimizing GC therapy and toxicity in most of these patients. Further long-term studies will be required to assess the durability of remission and the need for maintenance MTX therapy in this subset of Takayasu arteritis patients.
The guidelines for medical treatment of Takayasu arteritis established in 1987 by the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan are presented. The first part of the guidelines concerns treatment with adreno-corticosteroids and the second part concerns other medical treatment. A review of the literature referring to steroid therapy and other medical treatment of Takayasu arteritis is also included.
Objective:
The interleukin-6 pathway is up-regulated in giant cell arteritis (GCA), Takayasu arteritis (TA), and polymyalgia rheumatica (PMR). We retrospectively assessed the outcomes of 10 patients with relapsing/refractory GCA, TA, or PMR treated with tocilizumab (TCZ).
Methods:
Patients with GCA (n = 7), TA (n = 2), and PMR (n = 1) received TCZ. Seven subjects had failed at least 1 second-line agent. The outcomes evaluated were symptoms of disease activity, inflammatory markers, ability to taper glucocorticoids, and cross-sectional imaging when indicated clinically.
Results:
The mean followup time of this cohort since diagnosis was 27 months (range 16-60 months). The patients were treated with TCZ for a mean period of 7.8 months (range 4-12 months). Before TCZ therapy, the patients experienced an average of 2.4 flares/year. All patients entered and maintained clinical remission during TCZ therapy. The mean daily prednisone dosages before and after TCZ initiation were 20.8 mg/day (range 7-34.3 mg/day) and 4.1 mg/day (range 0-10.7 mg/day), respectively (P = 0.0001). The mean erythrocyte sedimentation rate declined from 41.5 mm/hour (range 11-68 mm/hour) to 7 mm/hour (range 2.2-11.3 mm/hour; P = 0.0001). The adverse effects of TCZ included mild neutropenia (n = 4) and transaminitis (n = 4). One patient flared 2 months after TCZ discontinuation. An autopsy on 1 patient who died from a postoperative myocardial infarction following elective surgery revealed persistent vasculitis of large and medium-sized arteries.
Conclusion:
TCZ therapy led to clinical and serologic improvement in patients with refractory/relapsing GCA, TA, or PMR. The demonstration of persistent large-vessel vasculitis at autopsy of 1 patient who had shown a substantial response requires close scrutiny in larger studies.
We conducted a single-center retrospective study to compare the characteristics of Takayasu arteritis (TA) among white, North African, and black patients in a French tertiary care center (Hospital Pitié-Salpêtrière, Paris). Eighty-two patients were studied (82.9% female) during a median follow-up of 5.1 years (range, 1 mo to 30 yr). Among these 82 patients, 39 (47.6%) were white, 20 (24.4%) were North African, and 20 (24.4%) were black patients. Median age at diagnosis was 39.3 years (range, 14-70 yr) in white patients vs. 28.4 years (range, 12-54 yr) in North African (p = 0.02), and 28.0 years (range, 13-60 yr) in black patients (p = 0.08). Patients aged >40 years at TA onset were more frequently white than non-white (40.0% vs. 18.6%, p = 0.03). North African patients had more frequent occurrence of ischemic stroke (p = 0.03) and poorer survival (p = 0.01) than white patients. Type V of the Hata classification was the most frequent type among white (38.5%), North African (65.0%), and black patients (40.0%). Corticosteroids were used in 96.1% of patients. Fifty-three percent of white and North African patients, and 44% of black patients required a second line of immunosuppressive treatment (p = 0.60). Vascular surgical procedures were respectively performed in 46.1%, 50.0%, and 55.0% of white, North African, and black patients, p = 0.81. The 5-year and 10-year survival rates were 100% and 95.0%, respectively, in white patients; 67.4% at both 5 years and 10 years in North African patients; and 100% at both 5 years and 10 years in black patients. This study is one of the first direct comparisons of TA profiles among patients of distinct ethnic backgrounds. Our data support the idea that late-onset TA or an overlap between TA and large-vessel giant cell arteritis may be observed in white patients. North African patients have a higher occurrence of ischemic stroke and poorer survival than white patients.
To assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies.
Retrospective single-centre study of 25 patients with refractory TAK.
Patients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2-84)) and 9 with ETA (median 28 months (range 4-82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer.
In this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.
We reviewed retrospectively 126 (5 male, 121 female) patients suffering from Takayasu arteritis who had been treated in our clinics from 1971 to 1990. The patients' ages ranged from 19 to 80 yrs old (1990) with a mean age of 48.7 +/- 11.8 years. HLA typing analysis in 98 patients revealed that 45 patients (47%) were confirmed as carrying the Bw52 antigen, a high result that is statistically significant as compared with that in healthy Japanese. Arteriograms (performed in 75 patients) revealed that 28 patients (37%) were affected in the aorta and its main branches by this disease (type IV by Nasu's classification) and 23 patients (31%) were affected only in the main branches (type I). The C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) improved significantly from 2.55 +/- 0.28(+) and 57.0 +/- 5.69 mm/hr to 0.53 +/- 0.12(+) and 31.2 +/- 3.45 mm/hr, respectively after treatment including steroid and antiplatelet therapy (P < 0.01). Patients with Bw52 exhibited more severe inflammatory conditions than those without Bw52. Lung scintillations performed in 81 patients showed pulmonary arterial lesions in 50 patients (62%). Echocardiograms revealed aortic regurgitation (AR) in 44 patients (35%), with a significant difference noted between the Bw52 positive group and the Bw52 negative group [29/40 (73%) versus 11/47 (23%), respectively, P < 0.001]. Patients with Bw52 were prescribed higher doses of steroids (P < 0.05) for longer periods (P < 0.01) than those without Bw52.(ABSTRACT TRUNCATED AT 250 WORDS)
The guidelines for medical treatment of Takayasu arteritis established in 1987 by the Systemic Vascular Disorders Research Committee, Ministry of Health and Welfare of Japan are presented. The first part of the guidelines concerns treatment with adrenocorticosteroids and the second part concerns other medical treatment. A review of the literature referring to steroid therapy and other medical treatment of Takayasu arteritis is also included.
To evaluate prospectively the clinical features, angiographic findings, and response to treatment of patients with Takayasu arteritis.
60 patients with Takayasu arteritis were studied at the National Institute of Allergy and Infectious Diseases between 1970 and 1990 and were followed for 6 months to 20 years (median follow-up, 5.3 years).
Data on clinical features, angiographic and laboratory findings, disease course, and response to therapy were all recorded and stored in a computer-based retrieval system.
The Warren Magnuson Clinical Center of the National Institutes of Health.
In our series of patients, Takayasu arteritis was more common in Asian persons compared with persons from other racial groups. Females (97%) were most frequently affected. The median age at disease onset was 25 years. Juveniles had a delay in diagnosis that was about four times that of adults. The clinical presentation ranged from asymptomatic to catastrophic with stroke. The most common clinical finding was a bruit. Hypertension was most often associated with renal artery stenosis. Only 33% of all patients had systemic symptoms on presentation. Sixty-eight percent of patients had extensive vascular disease; stenotic lesions were 3.6-fold more common than were aneurysms (98% compared with 27%). The erythrocyte sedimentation rate was not a consistently reliable surrogate marker of disease activity. Surgical bypass biopsy specimens from clinically inactive patients showed histologically active disease in 44% of patients. Although clinically significant palliation usually occurred after angioplasty or bypass of severely stenotic vessels, restenosis was common. Medical therapy was required for 80% of patients, whereas 20% had monophasic self-limiting disease. Immunosuppressive treatment with glucocorticoids alone or in combination with a cytotoxic agent failed to induce remission in one fourth of patients; about half of those who achieved remission later relapsed.
In North America, Takayasu arteritis is a rare disease. It is heterogeneous in presentation, progression, and response to therapy. Current laboratory markers of disease activity are insufficiently reliable to guide management. Most patients require repeated and, at times, prolonged courses of therapy. Although mortality was low, substantial morbidity occurred in most patients.
In this retrospective review 102 Indian and 80 Japanese patients with Takayasu arteritis were compared in regard to their clinical manifestations and angiographic findings. Regardless of nationality, most patients were initially affected in their teens or twenties. Japanese patients were female in a larger ratio compared with the ratio in India. Clinically, the two groups exhibited several different features. More Japanese patients were found to be pulseless (P < 0.01) whereas many Indian patients were hypertensive (P < 0.01). Inflammatory conditions in Japanese patients were more severe (P < 0.01) and tended to be more prolonged than those in the Indians. More Japanese patients suffered from aortic regurgitation (P < 0.01), but Indians suffered from hypertension (P < 0.01). Angiographic findings revealed that the aortic arch and its branches were mainly involved in Japanese patients (type I, IIa) whereas the abdominal aorta and its branches were mainly involved in Indian patients (type IV). However, the diffusely involved type (type V) was the one most commonly found in both countries. From the analyses of vascular lesions in both Indian and Japanese patients, 510 and 396, respectively, different progressions of vasculitis are speculated. In Japanese patients, vasculitis generally occurs in the ascending aorta, the aortic arch, and/or its branches and extends into the thoracic and abdominal aorta, subsequently forming various complicated lesions with prolonged inflammatory activity. On the other hand, in Indian patients, vasculitis generally occurs in the abdominal aorta involving renal arteries, subsequently extending into the thoracic aorta within one or two decades, simple vascular lesions being formed. Data analysis suggests that this morbid condition progresses differently in India and Japan, in spite of some common etiologic factor(s).
Takayasu arteritis (TA) is a chronic vasculitis that primarily affects large elastic arteries. Monitoring of disease activity is crucial because the disease tends to progress despite treatment with glucocorticoid and/or immunosuppressive agents. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have generally been used as disease activity markers, but these are nonspecific inflammatory markers and lack the sensitivity and specificity to accurately monitor the disease status. Given the histological findings characterized by destruction of elastic fibers, we hypothesized that matrix metalloproteinases (MMPs) could be useful as markers of disease activity in TA.
A consecutive series of 25 patients with TA were enrolled in this study. According to the National Institutes of Health criteria of disease activity, 11 were in an active phase and the remaining 14 were in remission. Circulating levels of MMP-2, MMP-3, and MMP-9 were determined by ELISA in all patients with TA and controls. MMP-2 levels were higher in patients with TA than in controls, but no correlation was found between serum MMP-2 and disease activity score. In contrast, MMP-3 and MMP-9 levels in patients with active disease were higher than in patients in remission and controls, and a positive correlation was demonstrated between circulating levels of MMP-3 or MMP-9 and disease activity score. The high levels of MMP-3 and MMP-9 improved when patients underwent remission.
The present results indicate that MMP-2 can be helpful in diagnosing TA and that MMP-3 and MMP-9 can be used as activity markers for TA.
Granulomatous inflammation is a typical feature of Takayasu arteritis (TA), and tumor necrosis factor (TNF) is important in the formation of granulomas. In this study, we assessed therapy with anti-TNF agents in patients with TA that was not controlled by glucocorticoid therapy or other immunosuppressants.
We conducted an open-label trial of anti-TNF therapy at 3 academic medical centers over a period of 4.25 years. Fifteen patients with active, relapsing TA (median 6 years) were selected. Seven received etanercept (later changed to infliximab in 3 patients), and 8 received infliximab. Relapses had occurred in all patients while they were receiving glucocorticoids and, in 13 patients, additional immunosuppressive drugs. No other agents were added to the treatment regimen concurrently with anti-TNF. If patients were receiving cytotoxic agents, the dosage was not increased. Clinical symptoms were recorded, and physical examinations, laboratory studies, and serial magnetic resonance imaging were performed.
The median daily dose of prednisone required to maintain remission prior to anti-TNF therapy was 20 mg. Ten of the 15 patients achieved complete remission that was sustained for 1-3.3 years without glucocorticoid therapy. Four patients achieved partial remission, with a >50% reduction in the glucocorticoid requirement. At a median of 12 months of followup, the median dose of prednisone was 0. Therapy failed in 1 patient. In 9 of the 14 responders, an increase in the anti-TNF dosage was required to sustain remission. Two relapses occurred during periods when anti-TNF therapy (etanercept) was interrupted, but remission was reestablished upon reinstitution of therapy.
In this pilot study of relapsing TA, addition of anti-TNF therapy resulted in improvement in 14 of 15 patients and sustained remission in 10 of 15 patients, who were able to discontinue glucocorticoid therapy. Anti-TNF may be a useful adjunct to glucocorticoids in the treatment of TA. Our results justify a randomized, controlled clinical trial of anti-TNF therapy for TA.
Takayasu arteritis remains a therapeutic challenge. In spite of current treatments, progression of vascular lesions is observed frequently. The purpose of this article is to describe advances in therapeutic strategies for Takayasu arteritis.
Immunosuppressive agents including methotrexate, mycophenolate mofetil, and azathioprine added to corticosteroids can bring Takayasu arteritis into remission in many patients. Unfortunately, relapse is common when prednisone is tapered to dosages of 15 mg/day or less. A better understanding of pathogenesis has lead to trials with anti-tumor necrosis factor-alpha agents in patients with refractory disease. Preliminary results are encouraging. For patients who require revascularization intervention, both surgical and endovascular procedures can be performed that are safe, with low morbidity and mortality. The best long-term outcomes are achieved with conventional bypass grafts. Percutaneous transluminal angioplasty provides good results for short lesions. In contrast to the results in treating atherosclerosis, the use of conventional stents may not yield long-term vessel patency in Takayasu arteritis. Persistent inflammation and endothelial dysfunction may put patients with Takayasu arteritis at risk for premature atherosclerosis.
In the future, greater therapeutic success may be achieved by addressing both the inflammatory and the myointimal proliferative components of Takayasu arteritis. New drugs that target intimal hyperplasia, as well as drug-eluting stents, deserve to be studied for possible utility as adjuncts to present treatments.
To investigate the clinical characteristics and outcomes of Takayasu's arteritis (TA) using standardized criteria for diagnosis, disease activity, and angiographic classification, and to identify the predictive factors for remission, angiographic progression, and mortality in patients with TA.
One hundred and eight patients who fulfilled the 1990 American College of Rheumatology (ACR) classification criteria for TA were studied. Their clinical features, laboratory findings, angiographic findings, and clinical outcomes were evaluated retrospectively. The disease activities were assessed using the National Institutes of Health (NIH) criteria for active disease, and the angiographic types were classified using the International TA Conference in Tokyo 1994 angiographic classification.
Angiographic classification showed that type I was the most common, followed by types V and IV. Ninety-one patients had active disease at diagnosis, and remission was achieved in 81.3% of them. Among those who experienced remission and those who had stable disease at diagnosis, 28.6% experienced a relapse. A low erythrocyte sedimentation rate (ESR) at diagnosis and treatment with glucocorticoid were found to be independent predictors for remission, and the stable disease activity at diagnosis was an independent predictor for the quiescence of vascular lesions on follow-up angiography. Survival rates were 92.9% at the fifth year and 87.2% at the tenth year, and the presence of two or more complications was a risk factor for mortality.
These findings could provide useful information on the clinical features, angiographic findings, and outcomes in TA, particularly on the assessment of patients at risk of a poor outcome.
To describe the clinical, laboratory, and radiographic manifestations of Takayasu arteritis (TA) in a cohort from the US, evaluate the response to interventions, remission and relapse rates, and disease progression, and compare these observations with those from other cohorts in the US, Japan, India, Italy, and Mexico.
Seventy-five patients were retrospectively studied using a uniform database that included clinical, laboratory, and imaging data. Vascular imaging studies were performed at least yearly to monitor disease progression.
Common manifestations at disease onset included loss or asymmetry of pulses (57%), limb blood pressure discrepancy (53%), and bruits (53%). Eleven percent of patients were asymptomatic prior to disease diagnosis. Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries.Ninety-three percent of longitudinally followed patients attained disease remission of any duration, but only 28% sustained remission of at least 6 months' duration after prednisone was tapered to <10 mg daily. Both angioplasty and vascular surgery were initially successful, but recurrent stenosis occurred in 78% of angioplasty and 36% of bypass/reconstruction procedures. More than two-thirds of patients had difficulty performing routine daily activities and approximately one-fourth of all patients were unable to work. Our cohort was similar to the National Institutes of Health, Italian, Japanese, and Mexican cohorts in terms of the predominance of female subjects and disease manifestations, but differed from the Indian cohort in that the latter group had a higher frequency of male subjects, abdominal aorta and renal artery involvement, and hypertension.
Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction. Attempts to restore vascular patency are often initially successful, but restenosis occurs frequently. Chronic morbidity and disability occur in most patients with TA in the US.
Mycophenolate mofetil (MMF) has recently been reported as a useful alternative immunosuppressive drug in autoimmune diseases including in Takayasu arteritis (TA). The aim of this study was to verify the efficacy and tolerability of MMF administration in controlling TA disease activity and allowing glucocorticosteroid reduction. Ten consecutive active TA patients followed at the Vasculitis Clinic were enrolled from January 2003 to 2006 and received oral MMF (2 g/day) for an average of 23.3 months. Disease activity assessed using the National Institutes of Health criteria, clinical features, and inflammatory laboratory findings were evaluated. Five patients had received at least one immunosuppressive drug before administration of MMF (four methotrexate, two azathioprine, and one chlorambucil) but had not achieved clinical and laboratory remission. The other five patients received MMF as their first immunosuppressive drug because of an important disease flare during steroid dose reduction. Clinical activity disappeared in all patients with MMF therapy, except in one patient who abandoned the study because of an important headache, attributed to the drug. Moreover, the MMF therapy allowed significant tapering of the prednisone dose in the rest of the nine patients (24.5 +/- 17.1 vs 5.8 +/- 7.8 mg/day; p = 0.0019). Reinforcing this finding, a significant reduction in inflammatory laboratory parameters, erythrocyte sedimentation rate (24.7 +/- 15.5 vs 12.8 +/- 10.8 mm/h; p = 0.036) and C-reactive protein (24.0 +/- 14.9 vs 11.2 +/- 10.7 mg/l; p = 0.0167), was observed. In summary, MMF therapy reduced clinical and laboratory parameters of TA disease activity, suggesting that this drug is a promising immunosuppressive drug, particularly in refractory cases and as a steroid-sparing agent.