|Year : 2021 | Volume
| Issue : 4 | Page : 402-407
Derivation of Sa-MoDEI score from DEI. Tak for prognostication in Buerger's Disease - Preliminary data of a prospective observational cohort
Gregory Pathrose1, Albert A Kota1, Prabhu Premkumar1, Prasanna Samuel2, Shivraj Padiyar3, Deepak Selvaraj1, Prasanta Padhan3, Debashish Danda3
1 Department of Vascular Surgery, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||10-May-2021|
|Date of Acceptance||16-Aug-2021|
|Date of Web Publication||22-Dec-2021|
Dr. Debashish Danda
Department of Clinical Immunology and Rheumatology, Christian Medical College and Hospital, Ida Scudder Road, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Buerger's disease or thromboangitis obliterans (TAO) is a segmental occlusive inflammatory condition of vessels. Assessment of disease activity in TAO is challenging. There is no dedicated prognostication score available till date for Buerger's disease. Hence, our aim was to prognosticate outcomes in patients with diagnosed Buerger's disease using Sa-MoDEI score, a novel disease extent index (DEI) derived and modified from DEI. Tak score used in Takayasu's arteritis.
Patients and Methods: In this prospective observational study, patients with TAO presenting to the Department of Vascular Surgery from June 2007 to April 2009 were studied. Shinoya's criteria were used to diagnose patients with Buerger's disease. Patients were scored on the basis of vascular, laboratory, and other clinical presentations as detailed in the Sa-MoDEI pro forma. They were followed up for 12 months after baseline scoring. Amputation was considered a bad outcome. The receiver operating characteristic curve was used to delineate a specific cut-off Sa-MODEI score to define bad outcomes. Factors associated with bad outcomes were analyzed using Cox proportional hazards model.
Results: There were 84 patients with Buerger's disease. All were male with a significant history of tobacco use (smoking cigarettes or “beedis” [leaf cigarettes used in south Asian nations especially in countryside], chewing tobacco, and inhaling snuff). The mean age was 39 years (standard deviation [S. D] ± 6.8). Duration of smoking was 15.35 years (S.D ± 6.2); 65 patients were in good outcome and 19 patients in bad outcome group. The optimal Sa-MoDEI score cut-off for the bad outcome was 8 which corresponded with Youden's Index. Independent factors associated with bad outcome on multivariate analysis were age of onset below 39 years (Hazard Ratio [HR] = 6.00, 95% confidence interval [CI] (1.35–26.67), P = 0.019) and Sa-MoDEI score above 8 (HR = 9.77, 95% CI (2.60–36.71), P = 0.001).
Conclusions: Sa-MoDEI score can be used as a tool to predict limb salvage in Buerger's disease.
Keywords: Buerger's disease, modified disease extent index score (Sa-MoDEI), prognostication, Takayasu's arteritis, thromboangitis obliterans
|How to cite this article:|
Pathrose G, Kota AA, Premkumar P, Samuel P, Padiyar S, Selvaraj D, Padhan P, Danda D. Derivation of Sa-MoDEI score from DEI. Tak for prognostication in Buerger's Disease - Preliminary data of a prospective observational cohort. Indian J Rheumatol 2021;16:402-7
|How to cite this URL:|
Pathrose G, Kota AA, Premkumar P, Samuel P, Padiyar S, Selvaraj D, Padhan P, Danda D. Derivation of Sa-MoDEI score from DEI. Tak for prognostication in Buerger's Disease - Preliminary data of a prospective observational cohort. Indian J Rheumatol [serial online] 2021 [cited 2022 Jan 24];16:402-7. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/4/402/333217
| Introduction|| |
Peripheral arterial disease is one of the two major categories of peripheral vascular diseases. These may be further classified as obstructive or vasospastic. Obstructive diseases include arteriosclerosis obliterans and Thromboangiitis obliterans (Buerger's disease), while the prototype of the vasospastic condition is Raynaud's disease. Thromboangiitis obliterans (Buerger's disease) is an occlusive disease which mainly affects the small- and medium-sized arteries, veins, and perineural vessels. Seen usually in young adult smokers, it is characterized by a nonatherosclerotic segmental inflammation in the absence of proximal embolic source, trauma, diabetes, hyperlipidemia, or autoimmune disease. As its diagnosis is primarily on the basis of its clinical characteristics, Shinoya suggested that the term Buerger's disease was more appropriate than Thromboangiitis obliterans.
Disease extent index in Takayasu's Arteritis (D. E. I. Tak) score was evolved to assess disease extent in Takayasu's arteritis (TA), which is a large vessel vasculitis predominantly seen in Asian countries, Brazil and Mexico. This tool contains 59 items in 11 organ-based systems. This system was devised after validating it on 143 patients diagnosed to have Takayasu's arteritis by American College of Rheumatology 1990 criteria. This is in a usable size and format and is now being applied to collect data on the pattern of aorto-arteritis (TA) in collaborating clinics across India and elsewhere in the world. Preliminary work has been done using DEI. Tak score to assess the outcomes in Buerger's disease.
Thromboangitis obliterans (TAO) is a slowly progressive disease with a history of obscure advent and it is often difficult to quantitate severity and progression.
A retrospective study done by Padhan et al. revealed that both Birmingham vasculitis assessment score (BVAS) and D. E. I Tak score can be used to prognosticate outcomes in patients with Buerger's disease. In that study, the mean BVAS scores were 10.29 ± 1.26 and 10.88 ± 2.57 and mean DEI. TAK score were 5.29 ± 1.75 and 7.93 ± 2 in the good and bad outcome subsets (P = 0.038, P = 0.014), respectively.
However, as mentioned above, it was designed to assess the extent of disease in Takayasu's arteritis and many items in it are not applicable to Buerger's disease.
Nevertheless, Takayasu's arteritis and Buerger's disease do share common characteristics like the elevation of inflammatory markers and systemic features like fever, malaise, arthralgia, myalgia, and weight loss in addition to pulse loss and gangrene. Involvement of genitourinary blood vessels leading to impotence and recurrent abortions also can occur in both conditions.
On the other hand, large vessels like the aorta and its major branches at origin and related territories like the central nervous system, heart, renal, pulmonary, and GI vasculature are not usually affected in Buerger's disease. Similarly, items in DEI. TAK-like mucous membranes, pulse loss affecting carotids, subclavian and femoral vessels are not commonly affected in Buerger's disease.
In view of the similarities and dissimilarities between Takayasu's arteritis and Buerger's disease with respect to restricted pattern and type of vessel involvement, a novel scoring system tailor-made for Buerger's disease was derived from DEI. Tak score at our center by selecting only the commonly attributable items.
This score was, however, never tried out earlier, although its mother scores namely DEI. Tak and BVAS were found to be useful prognostication tools in TAO.
The aim of the study, therefore, was to prognosticate outcomes in patients with diagnosed Buerger's disease using this novel score named as sa-MoDEI. The objectives were to study associations of bad outcomes in Buerger's disease with all relevant clinical variables including this newly derived composite index.
| Patients and Methods|| |
This prospective observational study was done in the department of vascular surgery from June 2007 to April 2009. All patients diagnosed to have Buerger's disease were included in the study. Shinoya's criteria was used to diagnose patients with Buerger's disease. The inclusion and exclusion criteria are given in [Supplementary Table 1].
The sa-MoDEI score was designed keeping in mind the clinical features of Buerger's disease by consensus of 2 rheumatologists and 2 vascular surgeons. This modified DEI measures 30 items in 8 organ-based systems which are involved in Buerger's disease. Only items commonly known to be present in Buerger's disease were chosen from DEI. Tak score for the derivation of the Sa-MoDEI score as its constituents. Each item is given a score of 1 and the total score is calculated as the sum of all the positive items. Items of this scoring system, therefore, by default originate from BVAS, the mother tool of D. E. I. Tak score; and we named it as “modified DEI” prefixed with Sa in memory of late Dr. Sunil Agarwal who designed it (Sa-MoDEI score).
The Sa-MoDEI score was used to assess the study population on the first visit to the hospital in a prospective manner, after obtaining informed consent [Supplementary Table 2]. Patients were followed up for 12 months and the clinical outcomes were assessed on each visit with the direct interview. Those who could not be reached on follow-up were accessed by telephonic interview.
This study evaluated the following parameters: Demographic parameters namely age, sex, smoking in years, duration of symptoms before inclusion in the study, clinical and relevant laboratory parameters like acute phase reactants e.g., Erythrocyte sedimentation rate (ESR), and C reactive protein (CRP), apart from the sa-MoDEI scoring. Patients were categorized into two groups depending upon the outcomes. Patients with good outcomes were those who improved with conservative management or any treatment that prevented amputation or salvaged the affected limb (e.g., drugs, chemical sympathectomy, or other limb salvaging modalities like bypass procedures). Patients requiring amputation were grouped under bad outcomes. Data were analyzed for any association of relevant demographic, clinical, laboratory data, or the score of composite index sa-MODEI with the outcome.
Descriptive statistical methods were used to summarize all study variables. Continuous variables were described using means and standard deviations (SDs), and categorical variables using frequencies and percentages. Normality was determined using means, SDs, histogram and using Kolmogorov–Smirnov tests. Independent t-test was used to compare means between study groups. Receiver operating characteristic curve analysis was used and the area under the curve was calculated to evaluate the sa-MoDEI scores. Here the sensitivity and (1-specificity) were calculated for each potential cut-off in the range of Sa-MoDEI score, and empirical plot was created. The value of Sa-MoDEI score closest to the top left corner that minimizes misclassification was used to choose an “optimal cut-off-point.”
Further, Youden index (sensitivity + specificity-1) that maximizes correct classification was also calculated for confirmation. Kaplan-Meier curve was generated to examine the time to limb loss, and factors associated with it were analyzed using Log-rank tests in the univariate analysis, and Cox proportional hazard model in the multivariate analyses. STATA 11.0 (Stata Corp, College Station, Tx, USA) was used for the analysis process.
The study was conducted in accordance with declarations of Helsinki 1964 and its subsequent amendments for biomedical studies on human subjects; the study was approved by the Institutional review board (IRB) and the ethics committee of Christian Medical College Hospital, Vellore (IRB number: 6700/Nov 2008).
| Results|| |
A total of 84 patients, all males with diagnosed Buerger's disease were enrolled in the study. Of which, 65 had good outcomes and 19 had bad outcomes [Table 1]. The mean age was calculated to be 39 (±6.7) years. The mean duration of symptoms before presentation to us and that of smoking were 9.45 (±2.4) months and 15.35 (±6.2) years, respectively. The mean pulse loss was 4 (±2). ESR was raised in 40 (47%) patients, while CRP was elevated in 50 (59.5%) patients at baseline.
Receiver operating characteristic analysis
The ideal cut off point for the sa-MoDEI score to predict worse outcome was 8 with the area under the curve of 0.94 (95% confidence interval [CI] [0.89–0.99]; [Figure 1]), which corresponded to the maximum Youden's index (Youden index = 0.73). Using this cut-off, sa-MoDEI scores were classified as “8 or below” and “above 8.” By this cut-off, 14 out of the 19 patients with bad outcome had a score “above 8,” with a sensitivity of 73%; and of the 65 patients with good outcome, 60 had a score of “8 or below” with a specificity of 92%.
|Figure 1: Area under the receiver operating characteristic curve and Youden index. Receiver operating characteristic curve (score vs. outcome)|
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Univariate and multivariate analysis
In the univariate analyses, age of onset below 39 years, presence of fever, rest pain, pulse loss of more than 4 vessels, and elevated inflammatory markers namely ESR and CRP, and sa-MoDEI score “above 8” were associated with bad outcome [Table 1]. Duration of smoking was not found to be a statistically significant predictor of bad outcomes in our study. On multivariate analysis [Table 2], the only independent predictors of worse outcomes were the sa-MoDEI score above 8 (Hazard Ratio [HR] 9.78; P-< 0.001) and age of disease onset below 39 years (HR 6; P = 0.019), when adjusted for other relevant parameters.
Kaplan-Meier survival curve generated also depicted amputation-free survival rates in patients with Buerger's disease at 3, 6, and 9 months as 93%, 83%, and 79% respectively in this cohort [Figure 2].
|Figure 2: Kaplan-Meier curve. Shows amputation-free survival in patients with Buerger's disease in the Kaplan-Meier graph. The amputation free survival rates at 3, 6, and 9 months were 93%, 83%, and 79%, respectively|
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| Discussion|| |
Our study using sa-MoDEI as a prognostication score generated the first prospective observational data in our cohort of TAO. We found that patients with a score above 8 is significantly likely to require an amputation (HR 9.78), while patients with scores of <8 could be largely managed conservatively with drugs, chemical sympathectomy, or other rare limb salvaging modalities like bypass procedures.
Patients who presented at an earlier age (<39) were also found to have a bad outcome. This may imply that patients of Buerger's disease with a longer duration of untreated disease ended up with amputations. All other parameters studied were either insignificant in multivariate analysis or their occurrence in both arms was in insufficient numbers for meaningful comparison.
In a retrospective study done by the same group (Padhan et al.), claudication pain and absence of upper limb pulses were found in higher proportion of patients with bad outcomes. There was a significant difference in scores between the groups with good and bad outcomes using BVAS and D. E. I. Tak score (P = 0.038 and P = 0.014, respectively) in that study.
Of the 84 patients in our present cohort, only 6 were available for follow-up visits, while others were contacted over the phone. Twenty-three patients could not be followed up due to lack of contactable phone numbers. Since majority of our patients had good outcomes during follow-up interviews, it may also reflect minimized or reduced symptoms related to disease severity in most cases in the long run; and such good outcomes are usually attributed to the cessation of smoking.
Studies across the world had looked at the risk factor profile of outcome in Buerger's disease. In a study done by Cooper et al., and associates, who followed 111 patients with Buerger's disease for a mean of 15.6 ± 10.1 years found that risk of amputation was 11% at the end of 5 years, 21% at 10 years and 23% at 20 years. Tobacco abstinence was associated with good prognosis and it was inferred that the risk of amputation continues in ongoing smokers up to a median of 14.8 years (±3.4) years, but the risk of amputation was eliminated by 8 years after tobacco cessation.
There was excessive late mortality in patients with Buerger's disease in US population which were attributed to associated involvement of cardiac vasculature. According to Le Joncour et al., nonwhite ethnicity, limb infection, and continuation of smoking were associated with adverse vascular outcomes. The effect of smoking and its cessation on bad outcomes like amputation has been variably reported in the literature. [Table 3] summarizes outcome of various treatment options in Buerger's disease from literature.,,,, While Sugimoto et al. reported beneficial effects of therapeutic angiogenesis, they could not establish beneficial effects of cessation of smoking in their cohort with 30 years' data. Similarly, Desai et al. also failed to find any correlation between limb salvage and smoking cessation, similar to our present study that revealed no independent association between duration of smoking and bad outcome. On the other hand, 3 other older Japanese studies and a Turkish study had attributed smoking as a definite association of adverse vascular outcome in Buerger's disease,,, Fazeli found an association of increased severity of disease among low socioeconomic strata according to their study done in Iran.
Therefore, there is widely contradictory clinical data in the literature related to the outcome of Buerger's disease including its association with smoking; it may be largely due to the paucity of any objective follow-up tool to assess this disease uninfluenced by any co-existing confounder. In light of this, our preliminary data using this novel instrument sa-MoDEI may be useful and warrants further comprehensive validation studies.
Our results should be interpreted with caution due to few limitations. The present study is limited by a single center data with a shorter duration of follow-up and relatively smaller size of the cohort; these limitations prohibited us from comprehensive validation of results using discovery and validation cohorts. Further, we also did not assess the test-retest reliability of the sa-MoDEI score. However, our results are unlikely to be influenced by measurement errors as substantial differences in the distribution of scores were observed between patients with bad and good outcomes. Hence, despite the limitations, our findings do suggest that the sa-MoDEI score can be used to classify patients into two well-discriminated groups from the prognostic point of view. Future studies should focus on the validation of this score in a large cohort of patients to integrate it as a clinical prognostic tool.
| Conclusions|| |
Independent predictors of bad outcomes like amputation in Buerger's disease include the age of onset below 39 years and a sa-MoDEI score higher than 8. Sa-MoDEI score can be used to prognosticate outcomes in patients with Buerger's disease.
Financial support and sponsorship
Internal fluid grant, Christian Medical College, Vellore.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]