|Year : 2021 | Volume
| Issue : 4 | Page : 375-380
Rate and predictors of response to glucocorticoid therapy in patients of takayasu arteritis at a tertiary level hospital of Bangladesh: A longitudinal study
Farzana Shumy1, Ahmad Mursel Anam2, Minhaj Rahim Choudhury3, Md Abu Shahin3, Syed Atiqul Haq3, Md Zahid Amin4, Sumayia Minhaj5
1 Department of Rheumatology & Internal Medicine, Square Hospitals Ltd, Dhaka, Bangladesh
2 Department of Critical Care & Internal Medicine, Square Hospitals Ltd, Dhaka, Bangladesh
3 Department of Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
4 Department of Medicine, Central Police Hospital, Dhaka, Bangladesh
5 Department of Internal Medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
|Date of Submission||17-Feb-2021|
|Date of Acceptance||18-Jun-2021|
|Date of Web Publication||22-Dec-2021|
Dr. Farzana Shumy
Associate Consultant, Department of Rheumatology & Internal Medicine, Square Hospitals Ltd, Dhaka
Source of Support: None, Conflict of Interest: None
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 <15 months prior to the initiation of therapy and had no history of syncope, stroke, and complications such as aortic regurgitation and hypertension. Reappearance of a pulse was noted in three out of 11 patients. The presence of carotidynia (P = 0.03) was a significant predictor for the reappearance of pulse. After 6 months, one patient (9.1%) remained inactive with prednisolone alone and other subjects received methotrexate.
Conclusion: The response to prednisolone is variable in TA. The presence of carotidynia was a predictor for the reappearance of pulse. Monotherapy with prednisolone is not a good choice as an induction therapy.
Keywords: Glucocorticoid, predictors, remission, Takayasu arteritis
|How to cite this article:|
Shumy F, Anam AM, Choudhury MR, Shahin MA, Haq SA, Amin MZ, Minhaj S. Rate and predictors of response to glucocorticoid therapy in patients of takayasu arteritis at a tertiary level hospital of Bangladesh: A longitudinal study. Indian J Rheumatol 2021;16:375-80
|How to cite this URL:|
Shumy F, Anam AM, Choudhury MR, Shahin MA, Haq SA, Amin MZ, Minhaj S. Rate and predictors of response to glucocorticoid therapy in patients of takayasu arteritis at a tertiary level hospital of Bangladesh: A longitudinal study. Indian J Rheumatol [serial online] 2021 [cited 2022 Jan 21];16:375-80. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/4/375/333215
| Introduction|| |
Takayasu arteritis (TA), also known as pulseless disease, occlusive thromboaortopathy, or Martorell syndrome, is a rare idiopathic large vessel vasculitis (LVV). It is characterized by unknown etiopathogenesis and granulomatous vasculitis., The management of TA is sometimes difficult. About half of the patients become occupationally disabled and treatment contribute only to partially improve the quality of life. The European League Against Rheumatism (EULAR) has published the updated guidelines in 2018 to facilitate the management of TA based on the latest scientific evidence and expert opinion., New imaging methods are available for diagnosis and monitoring. To avoid rapid progression of the vascular lesion, early diagnosis and aggressive treatment with glucocorticoid and immunosuppressants are recommended. However, there is no evidence to corroborate whether an aggressive treatment improves the prognosis of TA. The aims of treatment are to control disease activity and preserve vascular competency with minimal side effects. Therefore, early therapy is crucial, and the benefits and risk of aggressive management should be weighed in patients with good prognosis., Newer biomarkers are currently being evaluated.
Females have lesser complications than males. Older age, presence of major complications, and progressive disease course are associated with unfavorable prognosis. Carotidynia, male gender, and raised C-reactive protein (CRP) are associated with relapse., The success of glucocorticoid therapy ranges from 20% to 100%. However, among the patients who achieved remission, over 50%–72% demonstrated relapse at the time of dose tapering., Glucocorticoids are the mainstay of treatment for TA and evidence on nonglucocorticoid immunosuppressant is scarce.,, Th variable efficacy of glucocorticoid treatment may be associated with the stage at which the treatment is introduced and the disease extent. On the other hand, there are studies encouraging the early use of immunosuppressive agents.,,, Patients with human leukocyte antigen (HLA) 24-B52-DR2 haplotype are prone to develop active disease, requiring an increased dose of corticosteroids, compared to those without. The optimally effective starting and maintenance doses of prednisolone and their agreement with the reduction protocol are not yet determined. The present study is intended to detect the rate of inactive disease to prednisolone monotherapy in patients with TA and to explore the characteristics of patients with TA who responded to treatment.
| Methods|| |
The longitudinal study was conducted at the outpatient and inpatient departments of Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, from June 2016 to March 2018. All consecutive patients who fulfilled at least three of the American College of Rheumatology classification criteria for TA were included. Patients with active TA were selected according to the Indian Takayasu activity score (ITAS)-CRP and ITAS-2010. The exclusion criteria considered were patients on glucocorticoid or immunosuppressive drugs at the time of evaluation, who were reluctant to take part in the study, age > 50 years, and patients who had malignancy, end-stage renal failure, and hepatic failure. An informed written consent form was received from all the selected subjects and they were follow-up regularly in the vasculitis clinic.
All the selected patients received prednisolone (1 mg/kg). The patients were also prescribed anti-ulcerant (omeprazole 20 mg daily), calcium (1000 mg daily), Vitamin D (800 IU daily), and acetylsalicylic acid (75 mg daily). The patients were followed after 1 month of prednisolone. If ITAS-CRP was < 5, the disease was considered inactive. If the ITAS-CRP score remained ≥ 5, the disease was considered active. Immunosuppressive agents (methotrexate) were added to those patients who remained active after 1 month of prednisolone treatment and to those who became active during tapering of prednisolone. The patients were followed and disease activity was monitored according to ITAS-CRP scores. In inactive patients, the dose of prednisolone was reduced to 10% of the previous dose per week up to 10 mg and subsequently to 1 mg/month. The dose of methotrexate was started 10 mg weekly and increased up to 25 mg, according to the patient's clinical response, along with 5 mg folic acid weekly.
The patient's clinical profile and data collected were age, sex, characteristics of the disease at onset (sign, and symptoms), and disease duration. The outcome measure evaluated was Indian Indian Takayasu Activity Score - C-Reactive Protein (ITAS-CRP). Complications at presentation determined by physical examination and relevant investigations evaluated were aortic regurgitation, ischemic heart disease, eye complications, aortic aneurysm, renal disorders, hypertension, and brain ischemia., Laboratory tests conducted were erythrocyte sedimentation rate (ESR), CRP, liver and kidney functions tests, and other tests in necessary cases. All outcome measures were assessed at presentation, after 1 month of prednisolone therapy, then 3 monthly for 6 months, including the ITAS-CRP scores. The study was approved by the Ethics Committee of Bangabandhu Sheikh Mujib Medical University, Shahbagh, Dhaka, Bangladesh IRB approval number is BSMMU/2017/8881, date 28-08-2017. The study was performed by following the Declaration of Helsinki principles and informed consent was obtained from all the participants before enrolment.
Statistical analysis was done by SPSS (version 22) IBM® SPSS® Statistics version 22 (IBM Corp. NY, USA, 2013). Numerical variables were presented as median (interquartile range) and standard deviation. Categorical data were presented as total number and percentage of cases. Percentage of remission was expressed as proportion. Comparison of median of different variables, namely age duration of disease, hemoglobin, white blood cell (WBC), platelet, ESR, CRP, creatinine and ITAS-CRP, and ITAS2010 before and 1 month after steroid treatment was performed using ANOVA between no remission and remission groups. Comparisons between groups like those with pulse reappearance and those who did not were performed by Mann–Whitney U-test for continuous nonnormal distribution variables and Fisher's exact test for categorical variables. Paired t-test was done to compare ITAS-CRP before and after 1 month of prednisolone administration. Comparisons between active and inactive groups were carried out using independent t-test and Fisher's exact test for continuous and categorical variables, respectively. The accepted significance level was 5% (P < 0.05).
| Results|| |
A total of 12 consecutive TA patients were selected for treatment. Eleven patients were followed up for 6 months, as one patient died after 15 days. The corresponding median age noted for no remission and remission groups was 22.5 (22.0–23.75) and 27 (25.0–30.0) years. The median duration of disease noted in the respective groups was 15 (7.5–40.5) and 6 (3.0–6.0) [Table 1]. Comparison of median between remission and no remission groups showed that variables, namely age, duration of disease, WBC, platelet, ESR, CRP, serum creatinine, and ITAS-CRP before and after treatment were not statistically significant [Table 1]. However, ITAS2010 1 month after steroid treatment was found to be statistically significant between the groups (P 0.0001). Claudication and pulselessness were the two common symptoms observed. The clinical characteristics of 12 patients at baseline are summarized in [Table 2].
Clinical efficacy of prednisolone
Eleven patients who received prednisolone (1 mg/kg body weight) were followed up, as one patient succumbed to death due to unknown cause. According to the ITAS-CRP score, five patients (45.45%) out of 11 became inactive after 1 month and four among them (80%) became active again during prednisolone tapering (15–20 mg). One patient (9.1%) remained inactive with prednisolone monotherapy after 6 months, whereas the other 10 patients demonstrated a significant increase in ITAS-CRP score (P < 0.031) during tapering of prednisolone. Methotrexate was administered to 10 patients, i.e. six patients who remained active after 1 month of prednisolone and four patients who became active again during tapering of prednisolone. Among these 10 patients, two subjects had active disease during tapering of prednisolone [Table 3].
|Table 3: Results of prednisolone treatment in patients with Takayasu arteritis|
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Symptoms and signs during therapy
ITAS-CRP score reduced significantly in all patients (18.27 vs. 3.82; P = 0.000, [Figure 1]). Reappearance of upper limb pulses was noted in three out of 11 patients after 1 month of prednisolone. In other patients, the pulse did not reappear even after adding methotrexate. Five out of 11 patients achieved inactive disease status after 1 month of prednisolone. The study compared the patients who demonstrated the pulse reappearance with that of subjects who did not [Table 4]. Carotidynia was the prominent symptom (P = 0.03) noted in subjects who demonstrated the reappearance of pulse. The other factors between the two groups were not significant.
|Table 4: Difference between two groups (pulse did not reappear, pulse reappeared)|
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Factors predicting response to prednisolone monotherapy
To identify the factors predicting the prednisolone monotherapy response, Fisher's exact test was used to evaluate qualitative variables like symptoms and independent t-test for quantitative variables such as disease duration, baseline CRP, and ITAS-CRP. P values were not significant for any of these variables [Table 4] and [Figure 2]. None of the patients who responded to prednisolone had ischemic features such as syncope, transient ischemic attack, stroke, or complications like aortic regurgitation and hypertension.
| Discussion|| |
The current prospective study has reported the rate of response to prednisolone monotherapy in Bangladeshi patients with active TA as 46%. Although corticosteroids are the mainstay of treatment for TA, different studies have reported variable efficacy rates (ranging from 20% to 100%). Moreover, recent studies have found the initial response to prednisolone monotherapy as < 20%., This is in concurrence with the current finding, which showed that 9.1% of the patients remained inactive with prednisolone monotherapy after 6 months.
According to the response to initial glucocorticoid treatment, TA has been classified into the following two groups:
- Monophasic, when a patient achieved remission after initial glucocorticoid treatment and did not exhibit a flare until the end of the observation period
- Initial treatment-resistant/relapsing, when a patient could not achieve remission with initial glucocorticoid treatment or exhibited a flare during tapering of glucocorticoid, until the end of the observation period.,, Less than half of the patients became inactive after 1 month of prednisolone therapy.
The HLA type in TA is related to the pathogenesis and response to treatment. For example, the HLA-B52-allele-positive patients may require treatment at high doses. The treatment effect is also related to the stage and extent of the disease. The mean duration of the disease and baseline ITAS-CRP score were lower in the current remission group. The range of ITAS scores seen in active disease assists in quantitative grading of disease severity. Among the five patients, who became inactive after 1 month, four (80%) became active during tapering of prednisolone. In the present study, ten out of 11 (90%) patients eventually needed immunosuppressive medication. These results are compatible with other studies that reported the relapse in 55%–90% of the patients following corticosteroid tapering.,, Studies on TA patients noted that 46%–84% required additional immunosuppressive treatment to achieve remission and taper corticosteroids., In addition, 23% of TA patients did not achieve remission, even after receiving immunosuppressive agents.
As 80% of patients eventually need immunosuppressive medication, it is important to address whether all should be started with initial prednisolone treatment combined with immunosuppressive medications. The EULAR and many other authors have recommended that immunosuppressive agents should be considered for induction of remission in LVV as adjunctive therapy because TA remains active in subclinical level, despite glucocorticoid therapy.
The use of immunosuppressive decreases the severity of vascular involvement and high relapse rate, and it also improves the outcome of TA. It has also been observed that patients fail to maintain remission, without immunosuppressives.,,, However, the clinical course of TA is highly variable. 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.,,, 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. However, it is unclear whether early immunosuppressive treatment should be followed in all cases., A review by Misra et al. has also noted that patients with TA also possess elevated cardiovascular risk and need appropriate management. The researchers have also reported that methotrexate, azathioprine, and mycophenolate mofetil might delay angiographic progression. The current study has noted that patients who did not show remission following corticosteroid monotherapy had a long history of symptoms, more ischemic symptoms, and presence of complications. However, this finding was not statistically significant and regression analysis was not possible due to the smaller sample size.
The present study compared the characteristics between two groups (subjects with pulse reappearance and those who did not). Out of 11 patients, three patients regained the pulse following prednisolone, but the pulse did not reappear in other subjects, even after adding immunosuppressive agents. Carotidynia has been identified as a significant predictor of reappearance of pulse (P = 0.03). Vascular narrowing could be due to active inflammation and it is difficult to determine whether the pulse loss in LVV is due to irreversible vessel damage or reversible disease activity. The presence of carotidynia probably indicates an active inflammatory process, which might be present in a very early stage of TA. If the damage is due to fibrosis of the vessel wall caused by a dysregulated inflammatory process, the damage will not be reversible, even with immunosuppressive medication.,,, The disease duration and ITAS-CRP scores were lower in patients in whom the pulse reappeared, but the CRP was higher, possibly an indication of active inflammation. By consensus, seven ITAS2010 items (five cardiovascular systems items together with stroke and hypertension) were considered for scoring. High baseline ITAS scores (2 or more) reflect the extensive loss of pulse and cardiovascular consequences, which might be irreversible with immunosuppressive medication.
Literature review shows that very limited prospective studies have been conducted in TA and most of the data are available from retrospective analyses. The prospective nature with a 6-month follow-up duration is one of the major strengths of the study. The patients were evaluated by single researcher, and each visit specifically addressed elements of the disease status (e.g. active, inactive). The activity and outcome of the disease were determined by ITAS scores, incorporating almost all the disease features of TA. The study subjects were administered with the same prednisolone dose, they had no prior exposure to the drug, and there was no difference in the duration of treatment. The study has certain limitations. The sample size was much smaller and follow-up angiographic study was not possible and HLA analysis was not done. Well-designed multicenter prospective cohort studies are warranted to conduct a robust analysis of predictors of clinical response to prednisolone. Such evidence helps to establish criteria regarding the choice of initial therapy and to determine the monophasic group. It will eventually help in clinical practice to identify the groups of patients; in whom we can avoid the harmful effects of immunosuppressive medications.
| Conclusion|| |
The response to prednisolone monotherapy is variable in TA. Proper identification of baseline factors in TA might help a physician to decide the optimal induction regimen, i.e. prednisolone alone or combined with immunosuppressive agents. In most of the patients, prednisolone monotherapy would not be appropriate. Further prospective multicenter studies are needed to clarify this question.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Keser G, Direskeneli H, Aksu K. Management of Takayasu arteritis: A systematic review. Rheumatology (Oxford) 2014;53:793-801.
Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: A review. J Clin Pathol 2002;55:481-6.
Maffei S, Di Renzo M, Bova G, Auteri A, Pasqui AL. Takayasu's arteritis: A review of the literature. Intern Emerg Med 2006;1:105-12.
Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al.
EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68:318-23.
Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E, et al.
2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79:19-30.
Dejaco C, Ramiro S, Duftner C, Besson FL, Bley TA, Blockmans D, et al.
EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis 2018;77:636-43.
Ishikawa K, Maetani S. Long-term outcome for 120 Japanese patients with Takayasu's disease. Clinical and statistical analyses of related prognostic factors. Circulation 1994;90:1855-60.
Comarmond C, Biard L, Lambert M, Mekinian A, Ferfar Y, Kahn JE, et al.
Long-term outcomes and prognostic factors of complications in Takayasu arteritis: A multicenter study of 318 patients. Circulation 2017;136:1114-22.
Wen D, Du X, Ma CS. Takayasu arteritis: Diagnosis, treatment and prognosis. Int Rev Immunol 2012;31:462-73.
Ohigashi H, Haraguchi G, Konishi M, Tezuka D, Kamiishi T, Ishihara T, et al.
Improved prognosis of Takayasu arteritis over the past decade – comprehensive analysis of 106 patients. Circ J 2012;76:1004-11.
Muratore F, Pipitone N, Salvarani C. Standard and biological treatment in large vessel vasculitis: Guidelines and current approaches. Expert Rev Clin Immunol 2017;13:345-60.
Ahmed S, Shenoy P, Danda D, Misra R. Sustained remission in Large Vessel vasculitis: Do they ever burn out? Indian J Rheumatol 2019;14:304-11. [Full text]
Bicakcigil M, Aksu K, Kamali S, Ozbalkan Z, Ates A, Karadag O, et al.
Takayasu's arteritis in Turkey-clinical and angiographic features of 248 patients. Clin Exp Rheumatol 2009;27:S59-64.
Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum 2007;56:1000-9.
Origuchi T, Fukui S, Umeda M, Nishino A, Nakashima Y, Koga T, et al.
The severity of Takayasu arteritis is associated with the HLA-B52 allele in Japanese patients. Tohoku J Exp Med 2016;239:67-72.
Águeda AF, Monti S, Luqmani RA, Buttgereit F, Cid M, Dasgupta B, et al.
Management of Takayasu arteritis: a systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis. RMD Open. 2019;5:e001020.
Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al
. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33:1129-34.
Misra R, Danda D, Rajappa SM, Ghosh A, Gupta R, Mahendranath KM, et al.
Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology (Oxford) 2013;52:1795-801.
Hoffman GS, Merkel PA, Brasington RD, Lenschow DJ, Liang P. Anti tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 2004;50:2296-304.
Watanabe Y, Miyata T, Tanemoto K. Current clinical features of new patients with Takayasu arteritis observed from cross country research in Japan: Age and sex specificity. Circulation 2015;132:1701-9.
Chatterjee S, Flamm SD, Tan CD, Rodriguez ER. Clinical diagnosis and management of large vessel vasculitis: Takayasu arteritis. Curr Cardiol Rep 2014;16:499.
Kim ES, Beckman J. Takayasu arteritis: Challenges in diagnosis and management. Heart 2018;104:558-65.
Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al
. Takayasu arteritis. Ann Intern Med 1994;120:919-29.
Ohigashi H, Tamura N, Ebana Y, Harigai M, Maejima Y, Ashikaga T, et al
. Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. J Cardiol 2017;69:774-8.
Tombetti E, Di Chio MC, Sartorelli S, Bozzolo E, Sabbadini MG, Manfredi AA, et al
. Anti cytokine treatment for Takayasu arteritis: State of the art. Intractable Rare Dis Res 2014;3:29-33.
Muratore F, Pipitone N, Salvarani C. Standard and biological treatment in large vessel vasculitis: guidelines and current approaches. Expert Rev Clin Immunol. 2017;13:345-60.
Pacheco RL, Latorraca COC, de Souza AWS, Pachito DV, Riera R. Clinical interventions for Takayasu arteritis: A systematic review. Int J Clin Pract 2017;71:e12993.
Tombetti E, Mason JC. Takayasu arteritis: Advanced understanding is leading to new horizons. Rheumatology (Oxford) 2019;58:206-19.
Vaideeswar P, Deshpande JR. Pathology of Takayasu arteritis: A brief review. Ann Pediatr Cardiol 2013;6:52-8.
Seyahi E, Ugurlu S, Cumali R, Balci H, Seyahi N, Yurdakul S, et al.
Atherosclerosis in Takayasu arteritis. Ann Rheum Dis 2006;65:1202-7.
Misra DP, Wakhlu A, Agarwal V, Danda D. Recent advances in the management of Takayasu arteritis. Int J Rheum Dis 2019;22 Suppl 1:60-8.
Nakagomi D, Jayne D. Outcome assessment in Takayasu arteritis. Rheumatology (Oxford) 2016;55:1159-71.
Cassone G, Colaci M, Giuggioli D, Manfredi A, Sebastiani M, Ferri C. Carotidynia possibly due to localized vasculitis in a patient with latent Mycobacterium tuberculosis infection. Case Rep Vasc Med 2013;2013:585789.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]