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Indian J Dermatol
Indian J Dermatol
IJD
Indian J Dermatol
Indian Journal of Dermatology
0019-5154
1998-3611
Wolters Kluwer - Medknow India

IJD-69-365a
10.4103/ijd.ijd_251_24
E–IJD®: Original Article
Pigmentary Changes in Systemic Sclerosis are Associated with More Severe Cutaneous Sclerosis and Severity of Other Systems: A Cross-sectional Study from India
Mittal Setu 1
Khaitan Binod K. 2
Ramam M. 2
Khanna Neena 2
Mahajan Rahul 2
Bhalla Ashu Seith 3
Singh Manoj K. 4
Sreenivas V. 5
1 From the Department of Dermatology, Mayo Clinic, Rochester, MN, USA
2 Department of Dermatology and Venereology, AIIMS, New Delhi, India
3 Department of Radiodiagnosis, AIIMS, New Delhi, India
4 Department of Pathology, AIIMS, New Delhi, India
5 Department of Biostatistics, AIIMS, New Delhi, India
Address for correspondence: Prof. Binod K. Khaitan, Department of Dermatology and Venereology, AIIMS, New Delhi - 110 029, India. E-mail: binodkhaitan@hotmail.com
Jul-Aug 2024
19 8 2024
69 4 365365
3 2024
4 2024
Copyright: © 2024 Indian Journal of Dermatology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Background:

Pigmentary changes of the skin in systemic sclerosis in the form of diffuse hyperpigmentation and salt-and-pepper pigmentation are well documented in the literature; however, its association with disease severity and extent of underlying internal organ involvement has not been well studied.

Aims:

To assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement.

Methods:

This was a cross-sectional descriptive study conducted in a tertiary care teaching hospital from December 2014 to November 2016. Consecutive patients of systemic sclerosis attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association criteria were recruited. Skin sclerosis was quantified using modified Rodnan skin score (MRSS), whereas pigmentary changes were calculated in terms of percentage of body surface area involved by rule-of-nine method. Investigations were carried out depending on organ involvement and as per respective specialty consultations with focus on pulmonary, cardiac, and gastrointestinal systems.

Results:

Of the 50 patients recruited, all had cutaneous involvement in the form of binding down of skin, followed by pigmentary changes. MRSS was significantly higher in patients with any pigmentary alteration (P = 0.03) compared to those without any pigmentary changes. There was a rising trend in between the MRSS severity and the proportion of patients with hyperpigmentation, and it was statistically significant (P = 0.04). Among systemic involvement, lung was involved in the form of interstitial lung disease in 94% patients (n = 47). However, skin pigmentation of any type was associated with lower high-resolution computed tomography scores (P = 0.02).

Conclusion:

This study shows that in systemic sclerosis patients presenting with pigmentary skin manifestations, cutaneous sclerosis is significantly higher.

KEY WORDS:

Cutaneous sclerosis
pigmentation
systemic sclerosis
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pmcIntroduction

Systemic sclerosis (SSc) is a multisystem disease characterized by the hallmark of progressive fibrosis of the skin, with the potential to involve internal organs, resulting in considerable morbidity and mortality.[12] Binding down of skin is the most common presenting complaint in patients with SSc, followed by pigmentary changes.[34] Pigmentary changes in the absence of sclerosis can also help identify these patients.

Patients with diffuse cutaneous SSc and short duration of Raynaud’s phenomena before development of skin changes are a marker for early visceral organ damage. There is paucity of data regarding the morphology of pigmentary changes associated with SSc and its association with severity of skin sclerosis and organ involvement. Hence, this study was carried out in order to assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement.

Methods

This was a cross-sectional descriptive study conducted in the departments of Dermatology and Venereology, Pathology, Radio-diagnosis, and Biostatistics in a tertiary care teaching hospital over a period of 2 years after obtaining institutional ethical committee clearance (IESC/T-470/23.12.2014). Sixty-six consecutive patients of SSc attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association (ARA) criteria, irrespective of their age or gender, were recruited into the study after obtaining informed consent. Exclusion criteria included patients with localized scleroderma (morphea) and overlap syndrome. Detailed clinical history and a thorough cutaneous examination were done with particular attention to pigmentary changes, which was calculated in terms of percentage of body surface area involved by rule-of-nine method. Skin sclerosis was quantified using modified Rodnan skin score (MRSS) by two independent clinicians, and a consensus figure was taken if there was variation between the two observers. Detailed respiratory and cardiovascular system examinations were also done in addition to other systemic examinations.

For evaluating pulmonary involvement, 6-minute walk test, chest radiograph, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) were performed. For cardiac involvement, electrocardiography (ECG) and 2-D echocardiography (ECHO) were done. In addition, barium swallow was done to detect any gastrointestinal (GI) involvement, and X-ray of hands and relevant joints was taken to look for absorption of terminal phalanges and arthritis. Other investigations were carried out depending on the organ involvement and as per the advice of respective specialty consultation as per the hospital practice.

Involvement of major organ system was defined as follows:

Lung involvement was considered present if the forced vital capacity (FVC) was less than or equal to 75% predicted or definite interstitial changes were noted on the chest radiograph.

Renal involvement was defined by a serum creatinine level that was higher than the upper limit of normal or the occurrence of scleroderma renal crisis (SRC). SRC was said to be present if the serum creatinine level was more than or equal to 2.0 mg/dl and/or malignant hypertension occurs with a blood pressure greater than or equal to 160/110 mm Hg on at least two occasions at least 12 hours apart, accompanied by either persistent abnormalities in the urine [proteinuria, hematuria (unrelated to menses) or casts] or evidence of microangiopathic hemolytic anemia.

Joint involvement was considered present if there was one or more tender joint.

Cardiac involvement was defined by a history of, or presence of, congestive heart failure, cardiac arrhythmia requiring medication, pericarditis, moderate to large pericardial effusion, or cardiomegaly, or by a cardiothoracic ratio of more than 0.5 on the chest radiograph.

Involvement of the lungs was assessed both qualitatively and quantitatively. Based on the HRCT findings, a qualitative assessment was done by the presence or absence of ground glass opacity, fibrosis, bronchiectasis, consolidation, nodules, cysts, honeycombing, air trapping, hyperinflation, or any other abnormality, whereas a semiquantitative assessment was done by dividing the lungs into three zones, namely, upper, middle, and lower, on either side, and the following scoring system was used for involvement in each zone with a maximum score of 24.

<25% of parenchyma involved – score 1

25–50% of parenchyma involved – score 2

50–75% of parenchyma involved – score 3

>75% of parenchyma involved – score 4

All relevant data were entered in a predesigned proforma.

Statistical analysis

The following parameters were analysed statistically:

The linear trend of proportion (%) of cases with severe MRSS among patients with no pigmentation, either hyperpigmentation or salt-and-pepper pigmentation, and both hyperpigmentation and salt-and-pepper pigmentation was assessed using a trend Chi-square test.

The association between organ involvement (yes/no) with morphology of pigmentary changes was assessed by using Chi-square/Fisher’s exact test.

Severity of cutaneous sclerosis and lung involvement with morphology of pigmentary changes and other organ involvement:

The average MRSS and HRCT scores between cases with and without hyperpigmentation, salt-and-pepper pigmentation, any pigmentation, and other organ involvement were compared using Student’s t-test/Wilcoxon’s rank sum test.

The association between the severity of MRSS and pigmentation categories was assessed by a trend Chi-square test separately for each pigmentary category.

The self-reported duration of disease was compared among different pigmentation categories using Wilcoxon’s rank sum test.

All analyses were carried out using Stata version 14.1. A P value of < 0.05 was considered to be statistically significant.

Results

Fifty-six patients with SSc fulfilled the inclusion criteria; however, six did not complete the evaluation and hence were excluded. The median age in females and males was 33.5 years (range: 16–58) and 32 years (range: 24–66), respectively, with an F: M ratio of 7.33:1. The mean age at onset of symptoms for females and males was 27.21 ± 11.21 years and 34.5 ± 18.09 years, respectively. The disease duration ranged from 9 months to 25 years, with a median of 57 months in females and 42 months (range 12–72) in males. Out of the 50 patients, 6 patients (12%) were treatment-naive, whereas 2 patients (4%) had received only symptomatic treatment like calcium channel blockers, mozapride, and proton pump inhibitors. Of the remaining 42 patients (84%), 20 patients had received immunosuppressive agents in the past and were currently off treatment, whereas the remaining 22 patients were currently receiving immunosuppressive agents like oral corticosteroids in the form of daily dosing as well as dexamethasone pulse therapy and various adjuvants, namely, methotrexate, cyclophosphamide as part of dexamethasone-cyclophosphamide pulse therapy or otherwise, and azathioprine apart from other symptomatic treatment.

Table 1 summarises the clinical characteristics, both cutaneous and extracutaneous features, of the study cohort. All patients recruited in the study had cutaneous involvement in the form of binding down of skin with MRSS ranging from 4 to 46. Based on MRSS, patients were arbitrarily classified into three categories, namely, mild sclerosis (MRSS ≤ 20), moderate (MRSS 21–34), and severe skin sclerosis (MRSS ≥ 35). Of these, sclerodactyly was seen in 45 patients (90%), difficulty in flexion/extension of fingers in 31 patients (62%), and difficulty in mouth opening in 35 patients (70%). Pigmentary changes were the second commonest cutaneous manifestation seen in 46 patients (92%; Figures 1–3) and most prominent on extensor aspects of extremities and over bony prominences. Hyperpigmentation was the commonest form of pigmentary change in 42 patients (84%) (diffuse generalised with 100% BSA involvement in 31 patients and BSA involvement ranging from 4%–53% in 11 patients). This was followed by salt-and-pepper pigmentation in 22 patients (44%), of which 18 patients were overlapping with hyperpigmentation. The common sites were forehead, dorsum of nose, retro auricular area, chest, and extensor aspects of forearm and legs involving 1%–38% BSA. In some patients, it was also seen in the suprapubic area and lower abdomen. Scar depigmentation was seen in 3 patients (6%). Generalized itching was found to be a common symptom and was complained by 22 patients (44%). The itching was mild in intensity in 10 patients (20%), moderate in 9 patients (18%), and severe in 3 patients (6%).

Table 1 Baseline cutaneous and extracutaneous features of the study cohort

	Number (n=50)	Percentage	
Cutaneous features			
 Binding down	50	100%	
  • Modified Rodnan Skin Score (MRSS) (Range, out of 51)	4-46		
   • Mild skin sclerosis (MRSS ≤20)	27	54%	
   • Moderate skin sclerosis (MRSS 21-34)	18	36%	
   • Severe skin sclerosis (MRSS ≥35)	5	10%	
Sclerodactyly	45	90%	
Difficulty in flexion/extension of fingers	31	62%	
Difficulty in mouth opening	35	70%	
Pigmentary changes	46	92%	
 • Hyperpigmentation	42	84%	
 • Salt-and-pepper pigmentation	22	44%	
 • Both hyperpigmentation and salt-and-pepper pigmentation	18	36%	
 • Scar depigmentation	3	6%	
Raynaud’s phenomenon	43	86%	
Digital pitted scarring	42	84%	
Fingertip ulcerations	41	82%	
Pain in fingers	34	68%	
Gangrene	5	10%	
Lung involvement			
 Dyspnea			
  Grade 0	22	44%	
  Grade 1	12	24%	
  Grade 2	13	26%	
  Grade 3	3	6%	
 Chest X-ray			
  Abnormal	26	52%	
  Normal	24	48%	
 Pulmonary function tests			
  FVC ≤75%	42	84%	
  FVC >75%	8	16%	
HRCT chest			
 Interstitial lung disease	47	94%	
  Non-specific interstitial pneumonia (NSIP)	40		
   NSIP only	30		
   NSIP fibrotic	6		
   NSIP + post infective sequelae	4		
  Usual interstitial pneumonia	7	14%	
 Qualitative findings			
  Ground glass opacity	46	92%	
  Fibrosis	38	76%	
  Cysts	26	54%	
  Bronchiectasis	20	40%	
  Honeycomb pattern	11	22%	
  Air trapping	6	12%	
  Nodules	5	10%	
  Consolidation	3	6%	
 Main pulmonary artery diameter			
  <2.8 cm	42	84%	
  >2.8 cm	8	16%	
 Pulmonary arterial hypertension on echocardiography	9	18%	
  Mild (25–40 mm Hg)	8		
  Moderate (41–55 mm Hg)	Nil		
  Severe (>55 mm Hg)	1		
Gastrointestinal involvement			
 GI symptoms	27	54%	
 Dysphagia	19	38%	
 Reflux symptoms	16	32%	
 Abdominal pain	2	4%	
 Diarrhoea	1	2%	
 Constipation	1	2%	
 Hematemesis	Nil		
 Melena	Nil		
 Barium swallow			
  Normal	13	26%	
  Abnormal	37	74%	
   Motility disorder	34		
   Esophageal dilatation	22		
   Gastroesophageal reflux	8		
 Cardiac involvement			
  Cardiac symptoms			
   Palpitation	1	2%	
   Chest pain	Nil		
   Syncope	Nil		
 Echocardiogram			
  Normal	48	96%	
  Abnormal (p pulmonale)	2	4%	
 ECHO			
  Normal	38	76	
  PAH	9	18	
  Grade 1 LVDD	1	2	
  Mild RV dilatation with mild TR	1	2	
  Mild AS with AR	1	2	
Laboratory investigations			
 Routine baseline investigations			
  Anemia	12	24%	
  Transaminitis and anti-HCV antibody positivity	1	2%	
 ANA			
  Positive	48	96%	
   Homogenous	27		
   Nucleolar	10		
   Speckled	4		
   Mixed	2		
   Not known	5		
 Negative	2	4%	
Itching	22	44%	
 Mild	10		
 Moderate	9		
 Severe	3		

Figure 1 (a and b): Salt-and-pepper pigmentation

Figure 2 Diffuse (a) and patchy (b) hyperpigmentation

Figure 3 Reticulate hyperpigmentation

Association of clinical features with severity scores

The mean MRSS in patients with any pigmentation alteration was 21.71 ± 10.02, which was significantly higher than those without 11.5 ± 4.79 (P = 0.03). The mean MRSS of the patients with hyperpigmentation was higher than those without hyperpigmentation (22.04 ± 10.09 vs. 14.87 ± 8.04; P = 0.06). In the patients with salt-and-pepper pigmentation, the mean MRSS was slightly higher than those without (22.59 ± 10.45 vs. 19.57 ± 9.76; P = 0.37). On the contrary, the mean HRCT score of the patients without any pigmentation was higher than those with pigmentation (17 ± 4.76 vs. 10.80 ± 5.15; P = 0.02). Table 2 depicts the strength of association of various clinical features with the disease severity scores. Of the 27 patients with mild MRSS, 20 patients (74.07%) had hyperpigmentation, while out of 18 patients with moderate MRSS, 17 patients (94.44%) had hyperpigmentation and among those with severe MRSS (5 patients), all patients (100%) had hyperpigmentation. This increasing trend in proportion of patients with hyperpigmentation with increasing MRSS was statistically significant (P = 0.04). On comparing salt-and-pepper pigmentation with MRSS grading, out of 5 patients with severe MRSS, 4 patients (80%) had salt-and-pepper pigmentation, but it was comparable in mild and moderate MRSS groups (P = 0.25).

Table 2 Association of clinical features with severity scores

Characteristics	Number	MRSS (mean±SD)	P	HRCT score (mean±SD)	P	
Hyperpigmentation						
 Yes	42	22.04±10.09	0.06	11.26±4.81	0.91	
 No	8	14.87±8.04		11.5±8.05		
Salt-and-pepper pigmentation						
 Yes	22	22.59±10.45	0.37	10.45±6.02	0.32	
 No	28	19.57±9.76		11.96±4.77		
Any pigmentation						
 Yes	46	21.71±10.02	0.03	10.80±5.15	0.02	
 No	4	11.5±4.79		17±4.76		
Dyspnea						
 Yes	28	20.32±10.11	0.65	11.75±5.45	0.50	
 No	22	21.63±10.22		10.72±5.29		
GI symptoms						
 Yes	27	22.85±10.92	0.12	11.44±5.01	0.83	
 No	23	18.6±8.65		11.13±5.84		
Abnormal PFT (FVC ≤75%)						
 Yes	42	20.61±10.02	0.65	12.57±4.67	< 0.001	
 No	8	22.37±10.94		4.62±3.5		
Abnormal barium swallow						
 Yes	37	20.78±10.29	0.89	12.16±5.54	0.05	
 No	13	21.23±9.83		8.84±3.99		

Discussion

The pigmentary changes that have been described in the systemic sclerosis include diffuse generalised hyperpigmentation, salt-and-pepper pigmentation, localised hypopigmentation or hyperpigmentation in areas of sclerosis, streaky hyperpigmentation on a background of depigmentation, and reticulated hyperpigmentation.[56] Although the exact cause for hyperpigmentation or hypopigmentation is still not known, some studies have shown the role of keratinocyte-derived endothelin-1 and stem cell factor in the pathogenesis of hyperpigmentation.[78] Salt-and-pepper pigmentation has been correlated with vasculopathy, which is core to the pathogenesis of the disease with perifollicular retention of pigmentation due to rich capillary network surrounding the hair follicle.[910]

In our study, skin involvement was seen in all 50 patients with binding down being a universal feature. Sclerodactyly was seen in 90% of patients, which was more or less similar to the study from eastern India (82.6%)[11] and a US-based study including 3 ethnic groups (80–89%).[12] The frequency of Raynaud’s phenomenon in our patient was 86% and was similar to various studies from different parts of the world. The frequency of fingertip ulcerations has been variable in different studies ranging from 47.4% to 82%. In our study, fingertip ulceration was present in 82% of patients.

Pigmentary changes were seen in 92% of patients and were found to be the second most common presenting cutaneous feature in our patients. A similar frequency was noted in the previous study from our centre (91%),[4] a study from Iraq (83%),[13] and the African American ethnic group of USA (82%).[12] In our study, hyperpigmentation of varying degrees was seen in 84% of cases, whereas salt-and-pepper pigmentation was present in 44% of cases. At places, the pin-point depigmented macules coalesce to form large, depigmented macules, especially around the joints mimicking depigmented macules of vitiligo. Though salt-and-pepper pigmentation is usually seen later than hyperpigmentation, in 8% of cases, salt-and-pepper pigmentation was one of the presenting complaints of the patients. During the study period, we noticed that pigmentary changes, both hyperpigmentation and salt-and-pepper pigmentation, improved in some after initiation of immunosuppressive therapy. Since it was a cross-sectional study, the percentage of patients with pigmentary changes in this study might not depict the actual picture as a large number of patients were already on immunosuppressive therapy at the time of evaluation and the actual frequency of pigmentary changes might be more than this.

Itching was also a frequent complaint in our patients, seen in 44% of cases, while studies from France and Canada reported a prevalence of 62.3%[14] and 43%,[15] respectively. In the study from Canada,[15] it was found that itching was independently associated with both severity of skin involvement and GI involvement. This suggests that it might be an important indicator for progression of disease and visceral involvement. In our study, itching was noticed more in patients with salt-and-pepper pigmentation (P = 0.057), which might be suggestive of a feature of progressive disease. It could also be partly attributed to the generalised dryness or xerosis of the skin which is seen in SSc. Some of the patients attributed itching as the cause of salt-and-pepper pigmentation. The exact cause of salt-and-pepper pigmentation still remains unknown. It may be hypothesised that itching may cause damage to the melanocytes akin to melanocytorrhagy and may lead to depigmentation. But larger studies with immunohistochemical evaluation are required to understand these changes.

HRCT is able to detect almost 90% of the cases of ILD, whereas the detection rate of lung involvement is 40–75% with PFT.[16] Non-specific interstitial pneumonia (NSIP) was the commonest pattern seen on HRCT in our study, which is well described in the literature. Thus, our study re-emphasizes that HRCT acts as a sensitive tool for detecting lung involvement in SSc and can facilitate early detection even in asymptomatic patients. In our study, the detection rate with PFT was also reasonably good and was able to detect asymptomatic cases.

On correlating the clinical features with the mean MRSS score, we found that patients with presence of any form of pigmentary changes had a higher mean MRSS score as compared to those without pigmentary changes, which was found to be statistically significant. We also found that patients with hyperpigmentation had a higher mean MRSS as compared to patients without hyperpigmentation. This rising trend may indicate that patients with more types of pigmentary changes may have severe MRSS. Further studies with a larger sample size are required for a definite conclusion. We observed that the pigmentary changes, especially the salt-and-pepper pigmentation, are also an early feature of rapid progression and severe organ involvement in SSc. This simple clinical finding can act as an indicator for early prediction of severe involvement and the screening, investigations, and initiation of treatment can be optimized accordingly, especially in the settings where diagnostic tools for organ involvement are limited. Data regarding this are also lacking in the published English literature.

Interestingly, the mean HRCT scoring of the patients without any pigmentary changes was more than in patients with pigmentary changes and was statistically significant. This seems counterintuitive but could be attributed to the fact that the lung changes usually do not reverse with treatment, but the pigmentary changes do. No significant correlation of mean MRSS was found with salt-and-pepper pigmentation and GI involvement. Patients with GI involvement had a higher mean HRCT score as compared to patients without GI involvement. This may indicate that patients having involvement of one organ may have tendency of multiple organ involvement. No significant conclusion could be drawn on correlating pigmentary changes with duration of disease as a majority of the patients were already on treatment in the form of disease-modifying agents which could alter the morphology of pigmentary changes, and it may improve almost completely also. Further, patients whose disease course was static after aggressive treatment in the past also possibly had enough time for resolution of pigmentary changes. Unless the study is done on only treatment-naive patients, this aspect cannot be commented upon.

Limitations

The major limitation of our study was the study being conducted in a tertiary care centre; the majority of the patients visiting our centre had received or were receiving some form of immunosuppressive therapy altering the course of disease. It may have contributed to lack of association among the various factors and pigmentary changes. This being a cross-sectional study, only the current disease status was taken into consideration and rapidity of progression of the disease in the past could not be analysed. So, a longitudinal study would be better to understand the progression of disease and to see the sequence of appearance of pigmentary changes.

Conclusion

Concluding, we found that patients with presence of any form of pigmentary changes had a higher mean MRSS score as compared to those without pigmentary changes. However, a longitudinal study with a larger sample size is required to better understand the progression and severity of disease and to see the sequence of appearance of pigmentary changes and correlate it further.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

I would like to acknowledge Dr Geetali Kharghoria for her contribution.
==== Refs
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