European Journal of Cardiovascular Medicine

The family of autoimmune illnesses most frequently included in the category of connective tissue diseases is systemic sclerosis. The yearly occurrence is getting close to 20 per million people and might be underreported. Although no prevalence studies have been conducted, 500 cases per million people would be a fair estimate. Global scleroderma trends show that patients in North America, South America, and Europe have higher rates of SSc than individuals in East Asia. However, the indigenous peoples of Canada had the highest prevalence (47 per 100,000) (Pope n.d.) (J 2012) [1,2]. With an estimated frequency of 12 per lakh in the general population, epidemiologic data from India are limited (AN n.d.). [3]

From demographic point of view, the disease spares children and its incidence is steadily increasing among adults with age. It is most common and most severe in black women, but there is no significant racial prejudice overall. (Gary S. Firestein n.d.) [4]

The clinical and pathologic manifestations of SSc are caused by abnormalities of the innate/adaptive immune system that lead to the production of autoantibodies and cell-mediated autoimmunity, microvascular endothelial cells/small vessel fibroproliferative vasculopathy, and fibroblast dysfunction that leads to excessive accumulation of collagen and other matrix components in the skin and internal organs (D. P. al 2015). [5] The widespread pathologic process in systemic sclerosis leads to vascular insufficiency and fibrosis, which diminishes the reserve function of many organ systems. There are 2 clinical subsets according to the extent of skin involvement: diffuse cutaneous SSc (dcSSc) (skin damage proximal to elbows and/or knees or that affects thorax and/or abdomen at any given time during the disease) and limited cutaneous SSc (lcSSc) (skin damage distal to elbows and knees without involvement of either thorax or abdomen) (Alexia Esquinca-González n.d.) [6]

It is unclear exactly how much genetic predisposition contributes to SSc and what causes it. In addition to directly causing tissue damage and inflammation, drugs may also indirectly cause disease pathogenesis by altering gene expression through epigenetic processes. Although familial clustering of a disease is thought to be a sign of hereditary illness vulnerability, it can also be explained by common genetic background, shared environmental exposures, or the interplay between genes and environment (Boileau C n.d.)(Wang Y 2019) [7,8]

Study type and design: It is an Observational, cross sectional, non-interventional, hospital based study.

Study setting: The present study was conducted among the patients attending IPD and OPD of the Department of Medicine and the Critical Care Unit of North Bengal Medical College and Hospital, Darjeeling.

Study period: 1^st April 2021 to 31^st March 2022.

Place of study: Department of Medicine, North Bengal Medical College, Darjeeling

Study population: All patients meeting the ACR/EULAR 2013 diagnostic criteria of Systemic sclerosis attending the Medicine Department of North Bengal Medical College, Darjeeling, fulfilling the Inclusion criteria and exclusion criteria for this study, will be included.

Sample size: All consecutive patients of Systemic sclerosis admitted to the Medicine Department meeting the Inclusion and Exclusion criteria during the study period will be included in the study. An estimated number of 1 such patient every week from the hospital records of the past three years will lead to a sample size of 52 patients during the study period of one year.

Case, control required or not: Observational cross-sectional study, no control population required.

Inclusion criteria:

1.  Age between 18 – 60 years
2. Patients fulfilling ACR/EULAR  2013 diagnostic criteria of Systemic sclerosis

Exclusion criteria: Patients with the any one or more of the following will be excluded from the present study:

1. Patients with pre-existing cardiovascular disease not attributable due to Systemic Sclerosis.
2. Disorders like hypertension, diabetes, dyslipidemia and thyroid illnesses which are likely to alter the CARDIO-VASCULAR risk factor profile.
3. History of regular chronic alcoholism and smoking which is likely to alter cardio-vascular profile

Statistical Analysis:

For statistical analysis, data were initially entered into a Microsoft Excel spreadsheet and then analyzed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 5). Numerical variables were summarized using means and standard deviations, while categorical variables were described with counts and percentages. Two-sample t-tests, which compare the means of independent or unpaired samples, were used to assess differences between groups. Paired t-tests, which account for the correlation between paired observations, offer greater power than unpaired tests. Chi-square tests (χ² tests) were employed to evaluate hypotheses where the sampling distribution of the test statistic follows a chi-squared distribution under the null hypothesis; Pearson's chi-squared test is often referred to simply as the chi-squared test. For comparisons of unpaired proportions, either the chi-square test or Fisher’s exact test was used, depending on the context. To perform t-tests, the relevant formulae for test statistics, which either exactly follow or closely approximate a t-distribution under the null hypothesis, were applied, with specific degrees of freedom indicated for each test. P-values were determined from Student's t-distribution tables. A p-value ≤ 0.05 was considered statistically significant, leading to the rejection of the null hypothesis in favour of the alternative hypothesis.

Table 1: Distribution of study population according to duration of illness, Patients taking medication, Skin involvement (n=50)

Table 2: Clinical symptoms of the study population, Clinical Signs (n=50)

Figure 10: ECG Abnormalities in Study population

Figure 11: Distribution of study population according to PAH

Majority (78%) of the study population had duration of illness of 1-5 years followed by 12% and 10% having 6-10 years and more than 10 years respectively, 78% of the study subjects took medicines regularly after diagnosis where as 22% did not. Majority (88%) of the study population had diffuse skin involvement. A large group of patients had complained of Raynaud’ phenomenon (76%) and GERD (27%). 10% and 8% patients complained of shortness of breath and cough respectively. No patients complained of chest pain. Occurrence of different clinical signs like digital gangrene (18%), nail changes (32%), bipedal edema (10%), clubbing (10%), Loud P2 (14%), cyanosis and raised JVP in 2% each in the study population. 80% study population had normal ECG. 10% population had RBBB. LBBB and       Bi-fascicular block was seen in 4% each.  18% of study population had PAH in echocardiography.

According to the study population's demographic analysis, 38% of the patients had onset ages between 31 and 40 years, whereas 32% and 26% of the patients had onset ages between 20 and 30 and 41 and 50 years, respectively. Just 4% of patients were older than 50 at the time of start. This implies that disease onset varies with age, with the majority occurring between the ages of 20 and 50.

94% of the participants in this study were female, according to gender analysis. This is consistent with previous research that has characterized SSc as mostly a condition affecting women.

Investigating into the clinical history of the patients’ family we found that 8% to have a positive family history. In our study group duration of illness we found that 78% of the patients to have disease onset ≤5 years back and only 10% has duration of illness more than 10 years. 78% of our patients were already on medication pertaining to SSc or its immediate complication.

88% of the patients in my study exhibited diffuse skin involvement, according to the clinical profile. Out of the study sample, only 45 individuals had limited skin involvement. According to Amaka Odonwodo et al. [9], 30–40% of patients have diffuse SSc. The vast majority of diffuse skin involvement is indicative of selection bias, which occurs when patients with more severe conditions arrive at this tertiary care facility. Of the participants in the study, 48% had moderate anemia and 36% did not. Our population's ECG was normal in 80% of cases. Among the others, RBBB (10%) and LBBB (4%) were the most common findings. Jelena Nešković et al [10]. The duration of illness appeared to have a positive correlation with the presence of detectable PAH. Those with disease duration ≥11 years had 44.4% PAH compared to 33.3% and only 4.8% in the 6-10 years and 1-5 years duration of illness respectively. 18% of our patients had PAH in echocardiography. Neal F. Chaisson et al [11]

Pearson coefficient of correlation for incidence of PAH with duration of illness is 80.12 and P value is less than 0.02 suggesting strong correlation of developing PAH as duration of illness increases. Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients by MARCO A ALABA et al [12].

Non-compliance to regular medication was found to be a predisposing factor for developing PAH. 54.5% patients among those who did not take regular medication or lost to follow up developed PAH whereas only 7.7% among the compliant patients developed PAH. The coefficient of correlation is 64.02 with P value less than 0.02 suggesting a modest and positive correlation. 37.5% of the patients with PAH had age of onset 20-30 years, 10.5% patients with age of onset 31-40 years and 7.7% patients had 41-50 years.  This shows early disease onset favours development of PAH. Also P-value is 0.003 showing strong statistical correlation between them.

Ten percent of the study group showed RV dysfunction, and 23.08% of all patients with RV dysfunction had onset ages between 41 and 50. The age of onset for 6.25% and 5.26% of the patients, respectively, was 21–30 years and 31–40 years. This indicates that the majority of patients with RV dysfunction had onset ages between 41 and 50, whereas none of the patients with onset ages over 50 had RV dysfunction. P- value is 0.016 suggesting statistical correlation. 4% patients with RV dysfunction had duration of illness 1-5 and 6-10 years each and 2% of patients had duration >11 years. So the distribution is almost equally divided. P value 0.06 suggestive of no statistical correlation. In our study population 12% patients developed pericardial effusion out of which 8% were mild and 4% moderate. 10% patients had left ventricular dysfunction. Majority (8%) of them had diastolic dysfunction. 

The investigation leads us to the conclusion that people with systemic sclerosis typically develop between the ages of 20 and 50. When evaluating the profile of cardiovascular illness, we discovered tricuspid regurgitation, pericardial effusion, PAH, right and left ventricular dysfunction, and atherosclerotic plaques that resulted in stenosis of both CCA. Diffuse skin involvement, Reynaud’s phenomenon and GERD were the most common clinical presentation. Conduction system abnormality in the form of Bundle branch block was found to be the most common ECG abnormalities found in the study. Also we have noticed that Left ventricular diastolic dysfunction is much more common than systolic dysfunction. Right Ventricular dysfunction does not affected by Duration of illness, but increased age of onset of disease has a positive correlation with right ventricular dysfunction.

1. Leonardo Martina Calderon, and Janet E. B. Pope. "Scleroderma Epidemiology Update." Current Opinion in Rheumatology.
2. Mayes, M. D., and J. Barnes. "Systemic Sclerosis: Incidence, Prevalence, Survival, Risk Factors, Malignancy, and Environmental Triggers." PubMed, 2012.
3. Chandrasekaran, Radhakrishna B., and A. N. "Rheumatoid Arthritis and Connective Tissue Disorders: India and South-East Asia." PubMed.
4. Budd, Ralph C., Sherine E. Gabriel, Gary A. Koretzky, Iain B. McInnes, James R. O'Dell, and Gary S. Firestein. Firestein & Kelley’s Textbook of Rheumatology, 11th ed., Elsevier.
5. Pattanaik, Debendra, et al. "Pathogenesis of Systemic Sclerosis." Pathogenesis of Systemic Sclerosis, June 2015.
6. Benavides-Suárez, Sergio A., Andrea Sierra-Sepúlveda, and Alexia Esquinca-González. "Systemic Sclerosis Pathogenesis and Emerging Therapies, Beyond the Fibroblast." Biomedical Research International.
7. Allanore, Yves, P. Dieudé, and C. Boileau. "Immunogenetics of Systemic Sclerosis."
8. Shu, Y., et al. "Epigenetic Mechanisms: An Emerging Role in Pathogenesis and Its Therapeutic Potential in Systemic Sclerosis." The International Journal of Biochemistry & Cell Biology, June 2019.
9. Odonwodo, Amaka, Talel Badri, and Anis Hariz. "Systemic Sclerosis Overview." National Library of Medicine, August 2022.
10. Nešković, Jelena. "Electrocardiographic Findings in Systemic Sclerosis." Serbian Journal of Experimental and Clinical Research, December 2018.
11. Hassoun, Paul M., M.D., Neal F. Chaisson, M.D. "Systemic Sclerosis-Associated Pulmonary Arterial Hypertension." Chest, October 2013, pp. 1346-1356.
12. Velasco, César, M.D., et al. "Early- Versus Late-Onset Systemic Sclerosis." Medicine, March 2014.