Frequency of Disease Subsets and Spectrum of Organ Involvement and Interstitial Lung Disease Patterns in Patients of Systemic Sclerosis in Pakistani Population

By Umbreen Arshad¹, Muhammad Ahmed Saeed^1,2,3, Muhammad Rafaqat Hameed^1,2,3, Maryam Aamer¹, Shamas U Din¹, Hafiz Yasir Qamar¹

Affiliations

1. Department of Rheumatology, Central Park Teaching Hospital, Lahore, Pakistan
2. Department of Rheumatology, National Hospital and Postgraduate Medical Centre, Lahore, Pakistan
3. Department of Rheumatology, Arthritis Care Foundation, Lahore, Pakistan

doi: 10.29271/jcpsp.2025.05.646

ABSTRACT
Objective: To assess the frequency of disease subsets and the spectrum of organ involvement, particularly focusing on interstitial lung disease (ILD) patterns among patients with systemic sclerosis (SSc).
Study Design: Observational study.
Place and Duration of the Study: Institute of Rheumatic Diseases, Central Park Teaching Hospital, and its affiliated Arthritis Care Centre, Lahore, Pakistan, from July 2022 to December 2023.
Methodology: Data were extracted from electronic records and gathered using a questionnaire. Patients were classified into limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc) subsets based on clinical criteria. Gender, age, duration of disease, clinical features, and ILD patterns were compared between the groups.
Results: The mean age of the 68 (88.3%) female patients was 37.9 ± 11.2 years. Younger patients presented with diffuse scleroderma (36 ± 11.3 years) compared to those with limited scleroderma (40.2 ± 10.7 years). The most common clinical feature was Raynaud’s phenomenon (90.9%), followed by digital ulcers (41.6%). ILD was present in 68.8%, with non-specific interstitial pneumonia (NSIP) identified in 31.2%, usual interstitial pneumonia (UIP) in 19.5%, and fibrosing NSIP in 3.9%.
Conclusion: Systemic sclerosis predominantly affects younger females, with a higher diffuse cutaneous subtype. Raynaud’s phenomenon is the most common manifestation. ILD is a significant complication, with NSIP being the most common pattern observed.

Key Words: Systemic sclerosis, Rheumatic diseases, Limited cutaneous systematic sclerosis, Diffuse cutaneous systematic sclerosis.

INTRODUCTION

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterised by vasomotor irregularities, fibrosis, and related inflammatory symptoms. This condition impacts both the skin and internal organs, including the digestive tract, lungs, heart, kidneys, and blood vessels.¹ It is a severe illness with potentially life-threatening outcomes. The occurrence and frequency of SSc vary significantly worldwide, with an overall pooled prevalence of 30-120 cases per 100,000² and an incidence rate of 1.4 per 100,000 individuals per year.³
 

Despite its relatively low prevalence, systemic sclerosis has a substantial impact on patients and healthcare systems, carrying the highest mortality rate among all rheumatic diseases.⁴

Systemic sclerosis (SSc) is predominantly more common in females, with a reported female-to-male ratio ranging from 3:1 to 6:1, likely influenced by ethnic and regional factors.⁵  The disease is characterised by a diverse range of clinical manifestations,⁶ skin sclerosis being a key symptom. This is often assessed using the modified Rodnan skin score (mRSS), an easily identifiable measure of disease activity.⁷ Clinically, SSc is categorised based on the degree of skin involvement into two main subtypes: Limited cutaneous SSc (lcSSc), featuring skin thickening distal to elbows and knees, and diffuse cutaneous SSc (dcSSc), characterised by widespread changes in both distal and proximal skin areas.⁸

Cohorts have been established globally to observe the various manifestations of the disease and the different treatments patients receive.⁴ Therefore, this study was undertaken to ascertain the distribution of disease subtypes, the spectrum of organ involvement, and the ILD patterns in patients with systemic sclerosis at a tertiary care institution.

METHODOLOGY

This retrospective observational study was carried out at the Institute of Rheumatic Diseases, Central Park Teaching Hospital, and its affiliated Arthritis Care Centre, Lahore, Pakistan, from July 2022 to December 2023. Data from these centres were extracted from electronic records and gathered using a questionnaire. The study included individuals of both genders, aged between 15 and 60 years, who gave consent to the treatment and met the specified criteria for scleroderma. Individuals diagnosed with mixed connective tissue disease, overlapping syndromes, or localised systemic sclerosis (morphea) were excluded. Gender, age, duration of disease, clinical features, and ILD patterns were compared between the groups. ILD patterns were characterised on high-resolution computed tomography (HRCT) of lungs.

The data analysis utilised the statistical software SPSS version 27. Descriptive statistics (mean, standard deviation) were used to summarise quantitative variables, while numbers and percentages were employed for qualitative variables. Categorical variables were compared between groups using the Chi-Square or Fisher’s exact test, and a non-parametric Mann-Whitney U test (visualised by histograms) was conducted for continuous variables. Stratification based on gender and types of scleroderma was performed, with statistical significance set at a p-value below 0.05.

Table I: Demographic and clinical characteristics of the scleroderma cohort.
 

Variables		Mean ±SD	Frequency (n)	Percentage (%)
Age (years)		37.9 ± 11.2
Age group (years)	15-30	-	24	31.2
	31-45	-	33	42.9
	46-60	--	20	26
Gender	Male	-	9	11.7
	Female	-	68	88.3
Age at onset of disease (years)		30.69 ± 11.09	-
Duration of disease (years)		7.21 ± 5.57	-
Disease subtype	lcSSc	-	35	45.5
	dcSSc	-	42	54.5
Manifestations	-	-	-	-
Raynaud’s phenomenon	Present	-	70	90.9
Digital pits	Present	-	28	36.4
Digital ulcers	Present	-	32	41.6
Gangrene	Present	-	10	13
Skin	Calcinosis	-	3	3.9
	Sclerodactyly	-	71	92.2
	Salt and pepper rash	-	2	2.6
	Telangiectasia	-	1	1.3
Musculoskeletal	Arthralgia	-	37	48.1
	Arthritis	-	33	42.9
	Flexion contractures	-	7	9.1
Gastrointestinal	GERD	-	12	15.6
	Dyspepsia	-	6	7.8
	Dysphagia	-	7	9.1
Cardiac	Cardiomyopathy	-	5	6.5
	PAH	-	18	23.4
	MI	-	2	2.6
ILD		-	53	68.8
ILD patterns on HRCT	NSIP	-	24	31.2
	UIP	-	15	19.5
	Fibrosing NSIP	-	3	3.9
	Indeterminate	-	3	3.9
	N/A	-	7	9.1
Pattern of cDMARD	-	-	-	-
Initial treatment	MTX		18	23.4
	AZA	-	11	14.3
	CYC	-	4	5.2
	MMF	-	41	53.2
	Tocilizumab	-	1	1.3
Addition of a new medicine	Cyclophosphamide	-	1	1.3
	RTX	-	7	9.1
	RTX + Mycophenol	-	3	3.9
	Mycophenol	-	7	9.1
	Azathioprine	-	1	1.3
Mean dose of prednisolone	5mg	-	38	49.4
	7mg	-	6	7.8
	10mg	-	10	13
	Off steroids	-	21	27.3
Outcome as per physician global assessment	Improved	-	7	9.1
	Stable	-	44	57.1
	Active	-	20	26
	Worsening	-	2	2.6
	Death		1	1.3

Table II: Stratification of clinical presentations and organ involvement between males and females with scleroderma.

Variables	Overall			Females			Males
	lcSSc n (%)	dcSSc n (%)	p-value*	lcSSc	dcSSc	p-value*	lcSSc	dcSSc	p-value*
Age (years) (median (IQR))	42 (13)	33 (18)	0.09**	42 (13)	33 (17)	0.21	36 (26)	31 (23)	0.34
Onset disease age (years) (median (IQR))	34 (15)	27.5 (18)	0.13**	35 (14)	27 (19)	0.77	22 (23)	28 (19)	0.34
Disease duration (years) (median (IQR))	5 (4)	5.5 (6)	0.78**	5 (4)	6 (7)	0.87	3.5 (17)	4 (4)	0.32
Raynaud’s phenomenon	33 (94.3)	37 (88.1)	0.45	29 (93.5)	33 (89.2)	0.53	4 (100)	4 (80)	0.34
Digital pits	11 (31.4)	17 (40.5)	0.48	9 (29)	15 (40.5)	0.32	2 (50)	2 (40)	0.76
Digital ulcers	11 (31.4)	21 (50)	0.11	9 (29)	18 (48.6)	0.1	2 (50)	3 (60)	0.76
Gangrene	4 (11.4)	6 (14.3)	0.75	4 (12.9)	6 (16.2)	0.701	0	0
Skin
Sclerodactyly	31 (88.6)	40 (95.2)		27 (87.1)	35 (94.6)		4 (100)	5 (100)
Muscoloskeletal	-	-	-	-	-	-	-	-	-
Arthralgia	18 (51.4)	19 (45.2)	0.86	16 (51.6)	17 (45.9)	0.89	2 (50)	2 (40)	0.76
Arthritis	14 (40)	19 (45.2)		12 (38.7)	16 (43.2)		2 (50)	3 (60)
Flexion contractures	3 (8.6)	4 (9.5)		3 (9.7)	4 (10.8)		0	0
Gastrointestinal
GERD	6 (17.1)	6 (14.3)	0.72	5 (16.1)	6 (16.2)	0.66	1 (25)	0	0.16
Dyspepsia	3 (8.6)	3 (7.1)		3 (9.7)	2 (5.4)		0	1 (20)
Dysphagia	4 (11.4)	3 (7.1)		4 (12.9)	3 (8.1)
Cardiac
Cardiomyopathy	3 (8.6)	2 (4.8)		3 (9.7)	2 (5.4)		0	0	0.71
PAH	11 (31.4)	7 (16.7)		10 (32.3)	6 (16.2)		1 (25)	1 (20)
ILD	22 (62.9)	31 (73.8)	0.3	21 (67.7)	28 (75.7)	0.47	1 (25)	3 (60)	0.29
*Chi-square or Fisher’s exact test; **Mann Whitney U-test; IQR: Interquartile range.

RESULTS

Of the 77 patients, 9 (11.7%) were male and 68 (88.3%) were female, with a female-to-male ratio of 7.6:1. The mean age of the patients at presentation was 37.9 ± 11.2 years. Those with diffuse scleroderma were much younger (36 ± 11.3) years than those with limited scleroderma (40.2 ± 10.7) years. The general demographic and clinical characteristics of the patients are represented  in  Table I.

Table II compares the limited and the diffuse subtypes. In the limited subtype, 4 (11.4%) were males and 31 (88.6%) were females, whereas in the diffuse subtype, 5 (11.9%) were males and 37 (88.1%) were females. Concerning the initial presenting symptom in all patients, Raynaud’s phenomenon was the most prevalent, with 33 (94.3%) in the lcSSc and 37 (88.1%) in the dcSSc subset. Additionally, no significant variance was noted between the two subsets. Further, when stratified, no significant gender differences in clinical manifestations and organ involvement in SSc patients were found.

DISCUSSION

SSc, though rare, carries a higher mortality rate and profoundly affects the quality of life⁸ compared to other musculoskeletal disorders. Within the spectrum of SSc subtypes, dcSSc stands out as a major concern characterised by rapid progression and early involvement of vital organs such as the lungs, heart, and kidneys, posing life-threatening risks.

In the current study, a higher frequency of systemic sclerosis was noted among women compared to men. The study included 9 (11.7%) male and 68 (88.3%) female patients, resulting in a female-to-male ratio of 7.6:1. This observation aligns with the findings of Alam et al., who also reported a female predominance with a female-to- male ratio of 7.4:1.⁹ Conversely, studies by Coi et al. in Italy,¹⁰ and El Basel and Khalil among Egyptian patients¹¹ reported lower female-to- male ratios of 6.5:1, and 4.3:1, respectively, differing from the results of this research. Other investigations on systemic sclerosis patients have also shown a female preponderance, but with even higher female-to-male ratios compared to this study, such as those conducted by Elbraky et al.,¹² Asif et al.,¹ and Horimoto et al.,¹³ which reported female-to-male ratios of 14:1, 16:3, and 28.6:1, respectively.

In this study, the average age of disease onset was found to be 30.69 ± 11.09 years, with specific ages of 32.6 ± 10.5 years for lcSSc and 29.1 ± 11.5 years for dcSSC subtypes. In contrast, Hughes and Harrick. indicated an onset age range of 55-69 years,¹⁴ while Li et al. reported an average onset age of 48 years.¹⁵

Regarding the distribution of disease subtypes, the present study demonstrated a higher prevalence of the diffuse scleroderma subtype. Out of 77 patients, 42 (54.5%) were diagnosed with dcSSc, while 35 (45.5%) had lcSSc. These findings align with Khaliq et al.¹⁶ and Asif et al.¹ who reported a higher incidence of 55% and 58% dcSSc compared to 55% and 38% lcSSc, respectively. However, Li et al. found that 65.6% of patients had limited scleroderma in their investigation.¹⁵ Additionally, El Basel and Khalil reported that 61 (81.3%) patients had limited scleroderma, while 14 (18.7%) patients had diffuse scleroderma, resulting in a diffuse-limited ratio of 1:4.3.¹¹

Raynaud's phenomenon, the predominant feature of this condition, was identified in 90.9% of patients in this study. Li et al. reported an incidence of 88.5%,¹⁵ while Khaliq et al. observed a 100% prevalence in their research.¹⁶ Secondary complications such as digital pitting and digital ulcers, arising from prolonged Raynaud's phenomenon, were noted in 36.4% and 41.6% of individuals, respectively. These rates were lower compared to the findings by Khaliq et al., who reported frequencies of 89% and 82%, respectively. Among gastrointestinal symptoms, GERD (15.6%) was the most prevalent, followed by dysphagia (9.1%) and dyspepsia (7.8%). These results showed a notably lower occurrence compared to earlier research by Khaliq et al. where dysphagia ranged from 21.8 to 87%, and GERD was reported at 38%.¹⁶

In the present study, ILD was detected in 68.8% of individuals, with a higher prevalence in dcSSc (73.8%) compared to lcSSc (62.9%). This trend is consistent with prior research indicating a greater incidence of ILD in the diffuse subtype of scleroderma. Interestingly, Khaliq et al. noted a substantial occurrence of ILD in lcSSc patients as well, possibly due to the delayed onset of ILD in this subset of patients. The tertiary care setting of their patient cohort suggests that these individuals had been living with the disease for an extended period, leading to the development of various disease complications.¹⁶

The study's findings indicated that non-specific interstitial pneumonia (NSIP) was the most common form of ILD, accounting for 31.2% of cases, with usual interstitial pneumonia (UIP) representing 19.5% and fibrosing non-specific interstitial pneumonia (Fibrosing NSIP) 3.9% only. In contrast, Jafri et al. reported idiopathic pulmonary fibrosis (IPF) as the predominant ILD at 38.8%, followed by non-specific interstitial pneumonitis (NSIP) at 15.1%.¹⁷ Similarly, Zubairi et al. identified idiopathic pulmonary fibrosis (IPF) in 40.4% of patients and non-specific interstitial pneumonia in 19.7% of patients.¹⁸

This study has certain limitations. Firstly, being conducted at a single tertiary care hospital with a small sample size could affect the generalisability and reliability of the results to different populations and settings. Secondly, potential ethnic or geographic influences on disease subsets and organ involvement patterns in systemic sclerosis were not adequately addressed in the study. Therefore, future research should incorporate multi-centre studies and take into account these factors for a more thorough comprehension.

CONCLUSION

Systemic sclerosis in the present population exhibits a higher prevalence among females, with a slightly elevated proportion of individuals having the diffuse type of the disease. Raynaud’s phenomenon emerged as a prominent initial manifestation across subsets, emphasising its importance in early disease recognition. Importantly, the findings of this study suggest that gender does not significantly influence the clinical manifestations or organ involvement in SSc.

DISCLOSURE:
This paper was presented in the 26^th Asia-Pacific League of Associations for Rheumatology Congress (APLAR), held in Suntec, Singapore from 21 to 25 August 2024.

ETHICAL APPROVAL:
The Institutional Ethical and Review Board of Central Park Medical College and Teaching Hospital gave approval for this study.

PATIENTS’ CONSENT:
The participants provided informed and written consent for the study, ensuring confidentiality and adherence to ethical guidelines outlined in the Declaration of Helsinki.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
UA: Design of the work, data collection, analysis, and drafting of the work.
MAS, MRH, MA, SUD, HYQ: Design of the work and data analysis.
All authors approved the final version of the manuscript to be published and agreed to be accountable for all aspects of the work.

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