Spectrum of cutaneous manifestations of connective tissue diseases in North-East India

INTRODUCTION

Connective tissue diseases (CTDs) are chronic inflammatory disorders characterized by the production of autoantibodies targeting collagen and elastin present in various connective tissues. These multisystem disorders exhibit a female preponderance and encompass conditions such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis-dermatomyositis (DM), Sjogren’s syndrome (SS), mixed connective tissue disease (MCTD), rheumatoid arthritis (RA), and overlap syndrome (OS). With a prevalence of 3–5% in the general population,^[1] CTDs result from an interplay of genetic and environmental factors, manifesting in a wide range of clinical presentations, from limited cutaneous disorders to life-threatening major organ involvement. Cutaneous features such as malar rash, discoid rash, photosensitivity, oral ulcers, and non-scarring alopecia are crucial diagnostic criteria for SLE and often appear months or years before other symptoms, underscoring the significance of mucocutaneous manifestations in CTDs. While data exist regarding different CTDs and their systemic manifestations, information specifically on their dermatological aspects remains limited. This study aims to observe, document, and analyze the predominant skin lesions in patients from North-East India.

MATERIALS AND METHODS

This was a hospital-based, cross-sectional, observational study conducted at a tertiary care center from May 2021 to June 2022, after receiving approval from the Institutional Ethics Committee (NEIGR/IEC/M14/T6/2021). All patients diagnosed with any form of connective tissue disease (lupus erythematosus [LE], SSc, DM, MCTD, OS, RA, SS) and presenting to the Dermatology or General Medicine outpatient department, with or without comorbidities, were included in the study. Patients with other concurrent dermatological conditions or drug-induced skin lesions were excluded. Written informed consent was obtained at the initial patient contact, followed by a comprehensive history taking and physical examination. Clinical photographs were taken as necessary. Data were recorded on a case record form; tabulated in an MS Excel spreadsheet; and analyzed using frequency, percentages, and mean ± standard deviation (±SD).

RESULTS

The study involved 147 patients with CTDs, aged between 10 and 69 years (mean age: 36.26 years). The prevalence of CTDs among dermatology outpatients was 1.35%. The majority were females (124, 84%), with a male-to-female ratio of 1:5. The mean disease duration was 3.06 ± 1.97 years.

LE was the most common CTD (98, 67%), followed by RA (18, 12%) and MCTD (13, 9%). SSc and OS each constituted six patients, 4%, while DM and SS accounted for four patients, 3%, and two patients, 1%, respectively.

Raised skin lesions (91, 62%), photosensitivity (82, 56%), joint pain (81, 55%), and Raynaud’s phenomenon (66, 45%) were the most frequent presenting features. Nail changes, predominantly periungual erythema, were observed in 30 patients, 20%. Systemic involvement was seen in 48 patients, 33%, with the respiratory system (15, 10%) and renal system (13, 9%) being most commonly affected. The comprehensive clinical profiles of various CTDs are detailed in Table 1.

ANA positivity was found in 85.7% (126) of patients. RA factor was positive in 17% (25). Specific autoantibodies detected were anti-dsDNA (42, 29%), anti-Ribosomal P (23,16%), anti-Sm (14, 10%), anti-U1RNP (13, 8%), anti-RO52 (9, 6%), anti-SS-a (7, 5%), anti-Scleroderma (SCL)70 (7, 5%), anti-Ku (6, 4%), anti-Jo1 (5, 4%), anti-SS-b (4, 3%), anti-AMA M2 (4, 3%), anti-PM-Scl (4, 3%), anti-centromere (1, 1%), and anti-nucleosome (1, 1%).

Amongst males (23, 16% of patients), LE (78%) was the predominant CTD, followed by RA (13%) and DM (5%). Common complaints included raised skin lesions (65%), joint pain (43%), hair loss (39%), and Raynaud’s phenomenon (35%). Cutaneous manifestations were scarring alopecia (25%), localized DLE plaque (around 20%), and vasculitic purpura (20%). Renal and hematological involvement was notable, with over half exhibiting antinuclear antibodies (ANA) positivity. Chronic cutaneous LE (CCLE) was diagnosed in a significant majority, with an incidence rate

The pediatric age group (8, 5.44%) showed female preponderance (100%). Mean age was 14 ± 2.56 years. Here, LE (7, 87.5%) was predominant, and one MCTD case exhibited both LE and DM features. Disease duration ranged from 0.5 to 3 years (mean 2.31 ± 1.033 years). Among LE patients, acute cutaneous LE (ACLE) was most common (75%), followed by CCLE (25%) and SCLE (12.5%). Three patients presented with combined ACLE, CCLE, and SCLE features. Prevalent symptoms were photosensitivity, oral lesions (7, 87.5%), fever, Raynaud’s phenomenon (6, 75%), raised skin lesions, joint pain, and hair loss (5, 63%). Mucocutaneous manifestations included mucosal ulcers (6, 75%), malar rash (5, 63%), erythematous plaques (5, 63%), and non-scarring alopecia (4, 50%). Other manifestations ranged from psoriasiform plaques to periorbital erythema. One patient had pyoderma gangrenosum. Systemic involvement, primarily renal and hematological, was noted in 3 patients (37.5%). Various cutaneous manifestations of different connective tissue diseases are depicted in Figures 1-4.

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Figure 1:

Cutaneous manifestations of Lupus erythematosus (LE) (A) Malar rash of ACLE. (B) Discoid lupus erythematosus lesions of CCLE. (C) Vasculitic lesions seen over palms – Nonspecific lesion of LE. (D) Decreased hair density due to non-scarring alopecia – Nonspecific lesion LE. approximately 4 times higher than subacute cutaneous (SELE).

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Figure 2:

Cutaneous manifestations of Systemic Sclerosis (SSc). (A) Calcinosis cutis seen over elbow with surrounding skin showing ‘salt and pepper’ pigmentation in SSc. (B) Stiff and mask-like facial appearance with microstomia, thinning of lips, beak-shaped nose, telangiectasias over cheeks and Barnett neck sign seen in SSc.(C) Sclerodactyly in Diffuse cutaneous SSc. (D) Bulbous fingers with ragged cuticle and digital ulcerations seen in Limited cutaneous SSc.

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Figure 3:

Cutaneous manifestations of Dermatomyositis (DM). (A) Heliotrope rash and facial rash of DM. (B) Periungual erythema with ragged cuticle and splinter haemorrhages seen in DM. (C) Gottron’s papule and Gottron’s sign seen over the dorsum of hands in DM. (D) Shawl sign - Confluent macular violaceous erythema over neck seen in DM.

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Figure 4:

Cutaneous manifestations of mixed connective tissue disease (MCTD). (A) Urticarial vasculitis lesions over the trunk seen in MCTD. (B) Pyoderma gangrenosum lesion over leg – Nonspecific lesion of MCTD. (C) Multiple Erythema nodosum lesions seen over lower limb. (D) Bluish discolouration of fingers in Raynaud’s phenomenon.

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DISCUSSION

Cutaneous manifestations are common features of CTDs and can serve as important diagnostic clues and indicators of disease activity, guiding treatment decisions. This study highlights the variations in the prevalence and characteristics of skin manifestations across different age groups, regions, and genders. The prevalence of CTDs in our study (1.35%) was lower than the reported range of 3–5%,^[1] potentially due to the COVID-19 pandemic, which may have led to fewer patient visits. Gender disparities were noted, with females exhibiting a higher frequency of manifestations. These findings were consistent with previous Indian studies,^[1-3] reflecting the hormonal influence in CTD pathogenesis, especially in women. The mean age of patients was 36.26 years, with a significant proportion (29.90%) in the age group of 31–40 years, reflecting the typical onset period for many autoimmune diseases, with high prevalence observed after puberty in most patients. The mean disease duration of 3.06 years highlights the chronic nature of these conditions and the potential for delayed diagnosis, which can complicate management and worsen prognoses. While CTDs are more prevalent in adult females, cutaneous manifestations in children and males remain understudied. Males with CTDs may exhibit distinct patterns of skin involvement. In children, cutaneous features may be the initial presenting signs of an underlying connective tissue disease, making their recognition vital for prompt intervention and prevention of long-term complications. Table 2 provides an in-depth comparison of this study with various other studies conducted in India.^[1-3]

LE was the most common CTD (67%), followed by RA (12%) and MCTD (9%). Our study found a lower prevalence of SSc compared to other studies,^[1-3] indicating either underreporting or a genuine lower incidence in this region, likely influenced by genetic, environmental, and socio-cultural factors. Cutaneous manifestations were present in all LE patients, with ACLE being the predominant subtype, contrasting with other studies,^[2-5] reporting CCLE as the most common subtype. Malar rash (41%) and mucosal ulcers (28%) were the most frequent specific lesions, consistent with previous reports.^[3,6] The higher incidence of photosensitive malar rash in sunny regions aligns with the role of ultraviolet light exposure in exacerbating LE lesions. Systemic involvement was observed in 33% of the patients, with respiratory (10%) and renal (9%) systems being the most commonly affected. This underscores the multisystem nature of CTDs and the critical need for a multidisciplinary approach to management. The high prevalence of positive ANA (85.71%) and other specific autoantibodies, such as anti-dsDNA (29%) and anti-Ribosomal P (16%), in this cohort supports the utility of these markers in diagnosing and monitoring CTDs.

In SSc patients, limited cutaneous SSc was the predominant subtype, similar to other Indian studies.^[3,7] Raynaud’s phenomenon (100%), sclerosis (100%), and salt-and-pepper pigmentation (67%) were the most common manifestations, aligning with the other studies.^[2,3,8] Systemic involvement, primarily respiratory and gastrointestinal, was observed in 67% of patients, consistent with studies by Begum et al.^[3] and Dyavannanavar and Malkud.^[9] but different from Subba et al.^[2] There are only a few reports on the frequency of autoantibodies in Indian SSc patients. Pradhan et al.^[10] reported 85.5% ANA positivity in SSc patients. The frequency of anti-Scl70, anti-centromere, anti-endothelial cell antibodies, and anti-keratinocyte antibodies was 62.7%, 22.7%, 30%, and 40.9%, respectively.^[10]

All DM patients presented with proximal muscle weakness. Gottron’s papules, periorbital erythema, shawl sign, and Holster sign were the most frequent specific lesions, corroborating existing literature.^[11,12]

ANA positivity was observed in 100% of patients, with anti-Jo1, AMA-2, and anti-Ku positivity in 50% of cases, consistent with previous reports.^[12] In the MCTD and OS group, LE and DM were the most common associations, similar to previous studies.^[2,13,14] Joint pain (77%) and Raynaud’s phenomenon (54%) were the predominant manifestations, with respiratory system involvement being the most common systemic involvement, aligning with previous reports.^[15]

RA patients exhibited rheumatoid nodules (28%) and vasculitic lesions (28%), with RA factor positivity in all patients, consistent with previous Indian studies.^[2,16] The prevalence of rheumatoid nodules was lower than reported in Western countries,^[17] but vasculitic lesions were more common than in some studies.^[18] Extra-articular cutaneous manifestations are said to usually present late and have no correlation with disease activity or severity.

The two Sjogren’s syndrome patients presented with xerosis (100%), vasculitic lesions (50%), and angular cheilitis (50%), which are commonly reported cutaneous manifestations of Sjogren’s.^[19,20] ANA, anti-SS-A, and anti-SS-B positivity were observed, aligning with existing literature.^[20]

CONCLUSION

CTDs present with a plethora of signs and symptoms that require a coordinated, multidisciplinary approach to care. Due to the preponderance of cutaneous manifestations, particularly in the early course of the disease, dermatologists have a distinct role to play. Early referral and diagnosis are crucial for a favorable outcome. Regional differences in cutaneous features observed, likely influenced by genetic, environmental, and socio-cultural factors, suggest the need for region-specific community-based studies and guidelines. Recognizing these can facilitate targeted screening and tailored management of the disease. In addition, the lack of data on CTDs, especially in rural and underserved regions, highlights a wider problem of healthcare access, underscoring the need for better diagnostic and treatment options.