A systemic connective tissue disease called systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs, autoantibody synthesis and small artery vasculopathy. [1-3]. It is of unknown cause which shows extreme heterogeneous clinical presentation with variable and unpredictable course [4]. The prevalence of SSc estimates 254 case per million [3] with a higher female-to-male ratio 3 to 5:1 [5]. The average age of onset was 38.8 years. The average age for limited SSc was 40 years and 37.1 years for diffuse SSc. [6]. Classified: [7] into localized scleroderma and generalized scleroderma. The limited systemic sclerosis is distinguished by skin thickening localized to locations distal to the elbows and knees and is often linked with less severe internal organ involvement [10]. The diagnosis is made if the patient shows three or more CREST syndrome symptoms (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) [11]. The diffuse systemic sclerosis variant causes skin thickening proximal to the elbows and knees as well as distal areas and is associated with additional organ damage. [10]. Diagnosis of SSc depend on the Rheumatology/European League against Rheumatism Classification Criteria for the Classification of Systemic Sclerosis [7]. There is no single laboratory test that confirms the diagnosis. 90% of patient have positive antinuclear antibody therefore a negative test by indirect immunofluorescence makes the diagnosis of scleroderma very unlikely. In SSc, numerous kidney involvement patterns have been documented. [12], the major manifestation is scleroderma renal crisis (SRC). This condition is characterized by accelerated phase hypertension including headache, visual changes, or seizures and acute kidney injury [13,11]. However, some people are asymptomatic, have undiagnosed hypertension and have an abrupt rise in creatinine; as a result, patients at high risk are those with early, active diffuse skin involvement. [11]. Rapidly progressing diffuse skin involvement, corticosteroid use and positive anti-RNA polymerase III antibodies were found to more than twofold the risk of developing SRC. [14] and positive speckled antinuclear antibody [15]. Normotensive SRC has a higher mortality and poorer renal outcome compared to hypertensive SRC; this is explained by a delay in diagnosis and a greater likelihood of myocardial involvement [16]. The laboratory findings in scleroderma renal crisis These comprise consumptive thrombocytopenia, micro-angiopathic hemolysis (schistocytes) (50%) and high renal function tests (urea and creatinine) [7]. On dipstick urinalysis, there is typically both microscopic hematuria and proteinuria. Proteinuria is mild or moderate (about 2 g per day) and microscopical examination shows granular casts [13].

About 50 patients in total with SSc were selected and included in the study during their visit to the Rheumatology Units in Baghdad Teaching Hospital. According to the 2013 American College of Rheumatology/European League Against Rheumatism criteria for the categorization of systemic sclerosis, they were determined to have SSc. [7]. They were compare with an additional group of 59 comparably aged and sexed healthy controls.

Exclusion Criteria

If patients have overlap syndrome, they were excluded, diabetes mellitus, renal stone and other causes of renal impairment. Ages and smoking status of all patients and controls were asked about, employment status, educational status and past medical history. The data collected from scleroderma patients include disease duration, disease subtype, other symptoms and signs and drug history. We also measured blood pressure, Body Mass Index (BMI) according the equation BMI = weight (Kg)/height (m²) and estimated glomerular filtration rate using Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) for patients less than 70yr old and the Modification of Diet in Renal Disease (MDRD) for patient 70yr and more.

Examination of Statistics

The data were coded and analyzed by using the SPSS version 23. Number, percentage were used to represent the categorical data and mean ± standard deviation was used to represent the numerical data. Chi-square test (Fischer exact test when not applicable) and independent student t-test were used to confirm significance. Statistical significant considered whenever the p-value was less than 0.05.

The mean age of patients and control group was 43±12SD, 42±13 SD respectively, the males represented 14% of patients group and 16.9% of control group while females was 86% of patients group and 83.1% of control group, the majority of patients (85.7%) and control group (83.1%) was non-employed, the highest percentage of patients group (68%) and of control group (64.9%) was with primary education ,the majority of patients (91.8%) and of control group (94.9%) was nonsmoker and the highest percentage of patients group (36%) was with overweight while of control group (57.6%) was obese .No significant difference was reported with all parameters except with BMI categories (p = 0.001) as seen in Table 1.

Table 1: Sociodemographic Characteristics of Patients with Scleroderma and Controls

The findings of current study showed that the majority of patients was with stage 1 CKD were (82%). The number and percentage of patients with stage 2 and stage 3-a CKD was significantly higher in SSc patients compared to control group (p = 0.01) as displaced in Table 2.

Table 2: Stages of Chronic Kidney Disease in Patients with Scleroderma and Control Group

The results showed that the frequency of patients who had CKD of stage 2 and stage 3-a were significantly higher among hypertensive scleroderma patients in comparison to normotensive patients as shown in Table 3.

Table 3: Blood Pressure in Scleroderma Patients According to Chronic Kidney Disease Stage

The results of current study indicated that there was a significant association (p = 0.02) between the duration of the scleroderma in term of early and late disease and chronic kidney disease as there were a higher frequency of patients of late disease with grade 2 and 3 of impairment as displaced in Table 4.

Table 4: Association between Disease Duration and Chronic Kidney Disease in Scleroderma Patients

The results showed that out of 9 patients with renal impairment 9 had Raynaud’s phenomena, 8 had pitting scar, 7 had telengectasia, dyspnea, ILD and dyspepseia,6 had arthralgia, 5 had digital tip ulcer while other symptoms were presented to lower extent. No significant differences were reported with all symptoms p≥0.05 as showed in Table 5.

Table 5: Association between Renal Impairment and Symptoms of Scleroderma

The results showed that the frequency of patients with CKD stage 2 and 3 among patients on steroid treatment was significantly higher in comparison to those who not received steroid as seen in Table 6,7.

Table 6: Association of Chronic Kidney Disease and Steroid Use in Scleroderma Patients

Table 7: The Prevalence of Hypertension in Systemic Sclerosis among Different Studies

This study showed that the males represented 14% of patients group and 16.9% of control group while females was 86% of patients group and 83.1% of control group which is comparable with the results of Carreira et al. [22]. The mean age of patients and control group was 43±12, 42±13 respectively and this finding is comparable with a previous study done by Morgan et al. [23]. 82% of patients had scleroderma of limited type and 18% of diffuse type and mean duration of the disease was 7.4±1.4 years. The percentage of Raynaud’s phenomena was 94% which is in agreement with that found in other study [23]. The Raynauds phenomenon may be explained by the vasospasms are accompanied by progressive structural damage, including proliferation of the arterial intima, adventitial fibrosis and collagen deposition [24].

The digital ulceration represented 56% of patients which is higher than that of Morgan et al. study that showed 31% of patients experienced digital tip ulcerations [23]. This may be due to difference in sample size. Digital tissue ischemia may occur in patients with secondary RP, leading to recurrent digital ulcerations, rapid deep tissue necrosis and amputation [11].

The current study reported that telangiectasia was found in 75.5%, this finding is comparable with Hurabielle et al. study that showed 86% of patients with SSc have telangiectasias [25]. It is believed to be caused by dilated capillaries [11]. Dysphagia was reported in 52% of patients which is higher than that found in Mohammed et al. study which was 29% of patients [26]. This may be due to the difference in the sample size. Esophageal symptoms resulting from reduced lower esophageal sphincter pressure and dysmotility of the lower two thirds of the esophagus include reflux, heartburn and dysphagia to solid foods [27]. Lung disease (ILD), confirmed by high resolution CT scan represents 66%of the patients which is comparable to a previous study done by Pagalavan et al. that reported that 74% of patients had ILD [6]. The connective tissue and small vessels are mostly affected which leads to the characteristic fibrosis and vascular obliteration of the skin and internal organs, particularly of the heart, lungs [28].

Pulmonary artery hypertension was present in 10% of patients while in the study of Mendoza et al. none of the patients had clinical features of pulmonary arterial hypertension [29]. This may be due to difference in the sample size. Elevated pulmonary pressures are a result of either systolic or diastolic dysfunction as confirmed by low cardiac output. With pulmonary hypertension–ILD, the elevated pulmonary pressures are considered to be a result of chronic hypoxia secondary to underlying lung disease [7]. Arthralgia was noted in 75.5% of patients which is comparable with Mohammed et al. results which were (84%) of patients [26]. The course of the joint manifestations is either intermittent or chronic remittent. As the cutaneous involvement progresses, there is severe tethering and contracture of the underlying joints with impairment of movement and function [10]. The majority of patient and were with stage 1 CKD (82%). The percentage of patients with stage 2 was 14% and stage 3-a was 4% which was significantly higher in comparison to control group (1.7% were in stage 2). This finding was lower than that found in Gigante et al. study which was 46% in stage 2 and 17% in stage 3 [30] and in Kingdon et al. study which was 33% in stage 2 and 16% in stage 3 [31]. This may be due to the difference in the sample size. Progressive vascular damage leads to neointima formation, luminal narrowing and obliteration of small- and medium- sized arteries in multiple vascular beds [10]. The frequency of patients who had CKD of stage 2 and stage 3-a were significantly higher among hypertensive scleroderma patients in comparison to normotensive patients with 8 of 11 hypertensive scleroderma patients (72.7%) had renal impairment at different stages. This was higher than the result of Gupta et al. study that showed 5 of the 11 hypertensive scleroderma patients (45.5%) had renal impairment [32]. This may be related to the different genetic and environmental factors. SRC is characterized by juxtaglomerular hyperplasia; progressive reduction in renal blood flow, aggravated by vasospasm, leads to severe hyperreninemic hypertension that culminates in malignant hypertension [18]. 

The results showed that there was no significant association between the gender of the scleroderma patients and CKD although the findings showed that 7/43 of scleroderma female patients and 2/7 male patients had renal impairment at various stages. This is within the range of a previous study of Shanavas et al. which showed that 7/38 patients had renal impairment consisting of one male and six female patients [19]. This finding can be explained by that the disease is more common among women (3 to 7: 1 female-to-male ratio) [2].

The results of current study indicated that there was a significant association between duration of the scleroderma in term of early and late disease and estimated glomerular filtration rate status as that all the patients (100%) with renal impairment were with late disease, where as another study done by Shanavas et al. found that out of the total seven patients with renal impairment, six of them (86%) developed renal impairment at early disease [19]. This is due probably to difference in disease characteristics including disease duration. In early disease, histologic sections show accumulation of myxoid material in the intima of interlobular arteries, while afferent arterioles demonstrate fibrinoid necrosis. Later on vessels undergo intimal proliferation, while glomeruli develop ischemic changes with collapse and wall thickening [10]. 

The results showed that out of 9 patients with renal impairment, 5 had digital tip ulcer, which is unlike the result of Khimdas et al. study that showed that digital ulcers were not associated with renal crisis [33]. Fingertip digital ulcers are believed to be ischaemic due to macrovascular disease proximal to the digital artery [34].

The results showed that 44.4% of patients with renal impairment had dysphagia which is comparable to the result of Shanavas et al. study which was 31.5% [19]. Esophageal symptoms resulting from reduced lower esophageal sphincter pressure and dysmotility of the lower two thirds of the esophagus include reflux, heartburn and dysphagia to solid foods [27].

The findings of this study showed that there was a significant association between use of steroid and renal impairment as the results showed that the frequency of patients with stage2 and 3 among patients on steroid treatment was 33.3% which is less than what is found in Gupta et al. study which showed that 69% of steroid using scleroderma patients had renal impairment [32]. The SSc patients who receive corticosteroids are at greatest risk of SRC; however, there is no evidence of a causal effect (35).

The current study showed that the percentage of hypertension status is higher than that found in previous Iraqi studies one done by Mohammed et al. [26] &other by Abdulla et al. [36], as shown in table 9. The prevalence of primary hypertension is increasing in the last years worldwide. This may be due to changes in the life style, processed food and certain risk factors such as aging, obesity, smoking and gender differences [37].

• The prevalence of renal impairment among SSc patients was higher (18%) compared to controls (1.7%)

• The incidence of hypertension in SSc is obviously increasing

• Steroid use is a predictor of renal impairment in SSc patients

1. Gorial, F.I. “A novel study of predictive utility of serum melatonin in diagnosis of systemic sclerosis: A case-control study.” The IPMJ, vol. 16, no. 3, 2017, pp. 224–228.

2. Wigley, F.M. and F. Boin. “clinical features and treatment of scleroderma.” Kelley & Firestein’s Textbook of Rheumatology, edited by G.S. Firestein et al., 10th ed., Elsevier, 2017, pp. 1424–1460.

3. Barnes, J. and M.D. Mayes. “Epidemiology of systemic sclerosis: Incidence, prevalence, survival, risk factors, malignancy and environmental triggers.” Current Opinion in Rheumatology, vol. 24, 2012, pp. 165–170.

4. Horimotoa, A.M. et al. “Incidence and prevalence of systemic sclerosis in campo grande, state of mato grosso do Sul, Brazil.” Revista Brasileira de Reumatologia, vol. 57, no. 2, 2017, pp. 107–114.

5. Varga, J. “Systemic sclerosis epidemiology, pathology and pathogenesis.” Primer on the Rheumatic Diseases, edited by J.H. Klippel et al., 13th ed., Springer, 2008, pp. 351–358.

6. Pagalavan, L. and S.G. Ong. “Demography, clinical and laboratory features of systemic sclerosis in a malaysian rheumatology centre.” Medical Journal of Malaysia, vol. 62, no. 2, 2007, pp. 117–121.

7. Fischer, A. “Systemic sclerosis.” Rheumatology Secrets, edited by S.G. West, 3rd ed., Elsevier Mosby, 2015, pp. 141–153.

8. Denton, C.P. “Advances in pathogenesis and treatment of systemic sclerosis.” Clinical Medicine, vol. 16, no. 1, 2016, pp. 55–60.

9. Pattanaik, D. et al. “Pathogenesis of systemic sclerosis.” Frontiers in Immunology, vol. 6, 2015, p. 272.

10. Rooper, L.M. and F.B. Askin. “Pathology of systemic sclerosis.” Scleroderma: From Pathogenesis to Comprehensive Management, edited by J. Varga et al., 2nd ed., Springer Science+Business Media, 2017, pp. 141–159.

11. Hummers, L.K. and F.M. Wigley. “Scleroderma.” Current Diagnosis & Treatment: Rheumatology, edited by J.B. Imboden et al., 3rd ed., McGraw-Hill Education, 2013, pp. 214–223.

12. Galluccio, F. et al. “Points to consider in renal involvement in systemic sclerosis.” Rheumatology, vol. 56, 2017, pp. 49–52.

13. Stern, E.P. et al. “Management of renal involvement in scleroderma.” Current Treatment Options in Rheumatology, vol. 1, 2015, pp. 106–118.

14. Toescu, S.M. et al. “Steroid-induced scleroderma renal crisis in an at-risk patient.” British Medical Journal, 2014, pp. 1–3.

15. Odei, E.A. “Scleroderma renal crisis in a normotensive patient.” Kidney International Reports, vol. 1, 2016, pp. 311–315.

16. Tok, P.L. et al. “Normotensive scleroderma renal crisis.” Annals Academy of Medicine, vol. 47, no. 6, 2018, pp. 223–225.

17. Shanmugam, V.K. and V.D. Steen. “Renal disease in scleroderma: An update on evaluation, risk stratification, pathogenesis and management.” Current Opinion in Rheumatology, vol. 24, no. 6, 2012, pp. 669–676.

18. Cavoli, G.L. et al. “Scleroderma renal crisis.” Journal of Rheumatic Diseases and Treatment, vol. 3, no. 1, 2017, pp. 1–3.

19. Shanavas, N. and A.K. Das. “Profile of systemic sclerosis and associated renal involvement.” Archives of Medicine and Health Sciences, vol. 3, no. 2, 2015, pp. 209–214.

20. Uriarte, M.H. et al. “Scleroderma renal crisis debute with thrombotic microangiopathy: A successful case treated with eculizumab.” Hindawi, 2018, pp. 1–4.

21. Chabtini, L. et al. “Scleroderma renal crisis.” Systemic Sclerosis – An Update on the Aberrant Immune System and Clinical Features, edited by T. Radstake, InTech, 2011, pp. 177–196.

22. Carreira, P.E. et al. “Gender differences in early systemic sclerosis patients: A report from the EULAR scleroderma trials and research group (EUSTAR) database.” Clinical and Experimental Rheumatology, vol. 36, no. 113, 2018, pp. 68–75.

23. Morgan, N.D. et al. “Clinical and serological features of systemic sclerosis in a multicenter African American cohort: analysis of the genome research in African American scleroderma patients’ clinical database.” Medicine, vol. 96, no. 51, 2017, pp. 1–10.

24. Allanore, Y. et al. “Systemic sclerosis.” Nature Reviews Disease Primers, vol. 1, 2015, pp. 1–21.

25. Hurabielle, C. et al. “Skin telangiectasia and the identification of a subset of systemic sclerosis patients with severe vascular disease.” Arthritis Care & Research, vol. 68, no. 7, 2016, pp. 1021–1027.

26. Jassim, N.A. et al. “Renal involvement in 25 patients with systemic sclerosis.” The IPMJ, vol. 1, 2009, pp. 1–6.

27. Jimenez, S.A. and C.T. Derk. “Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis.” Annals of Internal Medicine, vol. 140, 2004, pp. 37–50.

28. Jaeger, V.K. et al. “Incidences and risk factors of organ manifestations in the early course of systemic sclerosis: A longitudinal EUSTAR study.” PLOS ONE, 2016, pp. 1–15.

29. Mendoza, F.A. et al. “Endothelial cells expressing endothelial and mesenchymal cell gene products in lung tissue from patients with systemic sclerosis–associated interstitial lung disease.” Arthritis & Rheumatology, vol. 68, no. 1, 2016, pp. 210–217.

30. Gigante, A. et al. “Evaluation of chronic kidney disease epidemiology collaboration equation to estimate glomerular filtration rate in scleroderma patients.” Rheumatology, vol. 51, 2012, pp. 1426–1431.

31. Kingdon, E.J. et al. “Calculated glomerular filtration rate is a useful screening tool to identify scleroderma patients with renal impairment.” Rheumatology, vol. 42, 2003, pp. 26–33.

32. Gupta, R. et al. “Prevalence of renal involvement in indian patients with systemic sclerosis.” Indian Journal of Medical Sciences, vol. 61, 2007, pp. 91–96.

33. Khimdas, S. et al. “Associations with digital ulcers in a large cohort of systemic sclerosis: Results from the canadian scleroderma research group registry.” Arthritis Care & Research, vol. 63, no. 1, 2011, pp. 142–149.

34. Hughes, M. and A.L. Herrick. “Digital ulcers in systemic sclerosis.” Rheumatology, vol. 56, 2017, pp. 14–25.

35. Denton, C.P. et al. “Renal complications and scleroderma renal crisis.” Rheumatology, vol. 48, 2009, pp. 32–35.

36. Abdulla, T.A. and R. Al-Adhagdh. Study of Systemic Sclerosis in Iraqi Patients. 1992. Diploma thesis, Diploma in Rheumatology and Medical Rehabilitation.

37. Salem, H. et al. “Worldwide prevalence of hypertension: A pooled meta-analysis of 1670 studies in 71 countries with 29.5 million participants.” Journal of the American College of Cardiology, vol. 71, no. 11, 2018.