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Abstract
Background: Autoimmune connective tissue diseases (AICTD) present with a myriad of clinical manifestations, including cutaneous. These disorders occur because of immune dysregulation that produces autoantibodies targeting connective tissue and internal organs. Screening these autoantibodies not only aids in the diagnosis but also in predicting specific organ involvement and the risk of complications related to the disease. Aims: This study was conducted (a) to study various cutaneous and systemic manifestations of AICTD, (b) to study the antinuclear antibody (ANA) profile and (c) to determine the association between systemic manifestations and antinuclear antibodies. Methodology: Thirty cases of autoimmune connective tissue disease were recruited for the study. A physical examination, clinical profile and ANA profile were done. Results: Nonscarring alopecia (83.3%) was the commonest cutaneous manifestation noted, followed by photosensitivity (73.3%). The most common system affected was musculoskeletal (67%), followed by renal (40%). Anti-dsDNA antibodies were significantly associated with musculoskeletal involvement (85%) with a P value of 0.038 and anti-Sm antibodies with neurological involvement (87%), followed by renal involvement (75%) with a P value of 0.018 and 0.001, respectively. Anti-SCL 70 antibodies were significantly associated with lung involvement (75%), with a P value of 0.009 and the presence of anti-SS-A antibodies with cardiovascular involvement (40%) with a P value of 0.014. Conclusion: Antinuclear antibodies are diagnostic as well as prognostic biomarkers for AICTD and contribute to precision medicine. These antibodies serve as markers to pursue involvement of organs, which in turn helps the treating physician to choose appropriate preventive measures.
Keywords: Antinuclear antibody, autoimmune connective tissue diseases, cutaneous manifestations, systemic manifestations
Introduction 
Autoimmune connective tissue diseases (AICTD) are polygenic clinical illnesses with multifactorial origins, consequent to complex interactions between hereditary and environmental variables.[1] These disorders are characterised by immune dysregulation that produces autoantibodies. These autoantibodies can aid in the diagnosis, management and prediction of disease prognosis. Their interpretation, however, is dependent on the type and titer of the autoantibody and the AICTD in question. Immune response and inflammation in AICTD can cause connective tissue damage along with internal organs damage. Specific autoantibodies have a high degree of disease specificity along with organ specificity, making them useful diagnostic as well as prognostic tools.
Materials and Methods All patients diagnosed with connective tissue disorders attending the dermatology outpatient department of a tertiary care hospital were recruited into the study after obtaining informed consent and institutional ethical clearance. A detailed history and clinical examination were done to note the various clinical manifestations; a complete blood picture, biochemical profile, complete urine examination, electrocardiography (ECG) and antinuclear antibody (ANA) profile were done. A skin biopsy was done whenever necessary. Other investigations like pulmonary function test, high-resolution computed tomography, endoscopy and magnetic resonance imaging were done in consultation with and as advised by the physician.
Inclusion criteria
All cases of autoimmune connective tissue disorders of all ages and both sexes were included in the study.
Exclusion criteria
Patients clinically diagnosed with connective tissue disorders who were unwilling to participate in the study were excluded.
Statistical analysis
Statistical data analysis was performed using SPSS version 20.0. The Chi-square test is used to find the significance of the studied variables.
Significant values
*Suggestive significance of P value: <0.05 was considered statistically significant.
Observations and Results In our study, the majority of the patients belonged to 21–40 years age group (46.6%), in which the youngest patient was 14 years old and the oldest patient was 60 years old.
Out of 30 cases, 29 (96.7%) were females and 1 (3.3%) were males.
Out of 30 cases of connective tissue diseases, systemic lupus erythematosus (SLE) (66.6%) [Table 1] was the most common condition, followed by systemic sclerosis (Ssc) (20%), overlap syndrome (6.60%) and mixed connective tissue disease (MCTD) (6.60%).
Of the various cutaneous manifestations in autoimmune connective tissue disorders noted in our study, non-scarring alopecia (83.3%) was the commonest presentation, followed by photosensitivity (73.3%), as presented in [Table 2].
The various systemic manifestations of autoimmune connective tissue disorders as presented in our study are given in [Table 3]. The musculoskeletal system (67%) is the most common, followed by the renal system (40%).
In this study, all 30 patients recruited had a positive ANA. The various ANAs seen were anti-ds DNA (46%), anti-Sm (26.6%), anti-scl 70 (26.6%), anti-SSA (16.6%) and others such as anti-U1RNP (6%), anti-ribosomal P (6%) and anti-Mi2 (3%) as mentioned in [Table 4].
Anti-dsDNA antibodies were noted to be significantly associated with musculoskeletal involvement, as shown with a P value of 0.038 [Table 5]. Anti-Sm antibodies were significantly associated with renal and neurological involvement, with a P value of 0.018 and 0.001 [Table 5]. The presence of anti-SCL 70 antibodies was significantly associated with lung involvement, as shown with a P value of 0.009 [Table 5]. The presence of anti-SS-A antibodies was significantly associated with cardiovascular involvement, as shown with a P value of 0.014 [Table 5].
Table 5: Association between systemic manifestations and various antinuclear antibodiesAmong 30 patients with connective tissue disorders, 22 (73.3%) had anaemia (<11 gm/dl), 20 (66.6%) had leukopenia (<4000/mm3) and 7 (23.3%) had thrombocytopenia (<100000/mm3). Twenty-three (76.6%) had raised (ESR) Erythrocyte Sedimentation Rate.
Ten (33.3%) patients among 30 cases of autoimmune connective tissue disorders were significantly associated with proteinuria (>0.5 g/24 hours) and eight (26.6%) had elevated creatinine levels
Patients with anti-Sm antibodies (26.6%) were significantly associated with proteinuria (>0.5 g/24 hours) and elevated creatinine levels.
Discussion SLE, scleroderma, dermatomyositis, MCTD, Sjogren's syndrome, rheumatoid arthritis and overlap syndrome/undifferentiated connective tissue disorders are AICTD, which causes multisystem illnesses along with musculoskeletal symptoms. They present with specific symptoms, ambiguous symptoms or overlapping manifestations, making diagnosis difficult. ANAs are autoantibodies that have the ability to bind to and destroy specific structures within the cell nucleus[2] that are of critical importance for the healthy functioning of tissues or organs. Extractable nuclear antigens/soluble cellular antigens are a diverse category of ribonuclear and non-histone proteins that have a variety of roles in nuclear metabolism.[3]
The objective behind this study was to explore associations between a specific system involvement, the resultant clinical manifestation and ANA profile in CTDs, if any, in AICTDS.
Diffuse non-scarring alopecia was the commonest cutaneous manifestation seen in 25 patients (83.3%), followed by photosensitivity in 22 patients (73.3%), malar rash in 18 patients (60%), oral ulcers in 12 patients (40%) and Raynaud's phenomenon in 10 patients (33.3%).
Of the 30 patients with connective tissue diseases, the majority were found to suffer from SLE in 66.6% (20) of the cases, followed by Ssc in 20% (6) patients. MCTD was seen in 2 patients (6.6%) and overlap syndrome in 2 patients (6.6%).
An international survey of LE by Vitali et al.[4] found malar rash (40%), alopecia (24%) and oral ulcers (19%) to be the most frequent dermatologic signs. Furthermore, approximately 20% of patients had cutaneous manifestations as the initial symptom of Lupus Erythematosus (LE).[5] This emphasises the importance of cutaneous findings as diagnostic clues.
Among the various systems affected in our study, the musculoskeletal system is the most common, followed by the renal system. 67% of patients displayed (20 cases) musculoskeletal system involvement, represented by symptoms like proximal muscle weakness, arthralgia and arthritis. Around 40% of patients (12 cases) had renal system involvement with proteinuria, pedal oedema and facial puffiness.
Cervera R et al.[6] reported joint involvement as the most common feature observed in patients with SLE and has been noted in up to 95% of their patients.
Denton and Black[7] reported that patients who presented with widespread sclerosis involving regions proximal to the neck and proximal limbs were associated with diffuse Ssc. The most common systemic complication was due to the involvement of the gastrointestinal tract, which can lead to altered motility, bacterial overgrowth and malabsorption.
Among 20 clinically diagnosed cases of SLE, histopathology shows vacuolar degeneration of the basilar epithelial layer, oedema of the dermis, focal extravasation of erythrocytes and dermal fibrinoid deposits.
Among six clinically diagnosed Ssc cases, histopathology revealed hyalinized collagen, excessive deposition of collagen, atrophic eccrine and pilosebaceous glands, a sparse lymphocytic infiltrate in the dermis and loss of subcutaneous fat.
Among two cases of overlap syndrome histopathologically correlated as Ssc
Among two cases of MCTD, one case was histopathologically correlated as SLE and 1 case as Ssc.
In this study, all 30 patients recruited had a positive ANA, with titres ranging from 1:80 (33.3), 1:100 (60%) and 1:160 (6.6%). The various anti-nuclear antibodies seen were anti-dsDNA (46%) showing a homogenous pattern, anti-Sm (26.6%) showing both peripheral and homogenous pattern, anti-scl 70 (26.6%) showing both speckled and nucleolar pattern, anti-SSA (16.6%) showing rim pattern and speckled pattern and others such as Anti-U1RNP, Anti-Mi2 and Anti-ribosomal P in small proportions.
Among 20 cases of SLE, 13 patients (65%) had anti-dsDNA antibodies, six (30%) were found to have anti-Sm ab, three (15%) had anti-SSA and two (10%) had anti-ribosomal P antibodies. All six cases of Ssc had anti-scl 70 (100%) or anti-topoisomerase 1 antibodies in addition to one patient with anti-dsDNA, two with anti-SSA and one with anti-Mi2. In two cases of mixed connective tissue disorder, anti-U1RNP antibodies were demonstrated. Autoantibodies to double-stranded DNA are an essential marker in the diagnosis and monitoring of disease activity in SLE. The anti-Sm ab antigen is highly specific for SLE but was found only in ∼25% of SLE patients. The U1RNP antigen was noted in patients with SLE plus Ssc, that is, with MCTD.
Yaniv G et al.[8] described as many as 180 or more self-antigens as targets in SLE, of which only a few are common, including anti-Sm/RNP, anti-Ro/SS-A, anti-La/SS-B and anti-dsDNA. Steen VD[9] stated that Ssc is characterised by the presence of two classical autoantibodies: anti-topoisomerase I (ATA, Scl-70) and anti-centromere. In recent years, the presence of antibodies against a wider range of antigens has been demonstrated, namely RNA polymerase III, fibrillarin, etc.
Venables PJ[10] stated that since the anti-U1-RNP antibody is the serologic hallmark of MCTD, anti-U1-RNP and its antigen may play a role in the pathogenesis of MCTD. In our study, both cases demonstrated positivity for anti-U1-RNP antibodies. Thus, the results of almost all the studies cited above are consistent with those of our present study. The autoantibody profiles in various AICTDs in our study are in consistency with the findings in the noted studies.
In our study, the presence of anti-dsDNA antibodies was significantly associated with musculoskeletal involvement. Doria A and Gatto[11] stated that IgG anti-dsDNA autoantibodies play an important role in the pathogenesis of SLE, particularly in the induction of nephritis, and in lupus nephritis patients IgG anti-dsDNA antibodies, and immune complexes are detectable in the glomeruli of patients. A study by K Narayanan et al.[12] found anti-dsDNA to be predominantly associated with musculoskeletal and mucocutaneous symptoms (90%).
In our study, the presence of anti-Sm antibodies was significantly associated with renal and neurological involvement. Migliorini P et al.[13] reported that anti-Sm antibodies are associated with the severity and activity of renal involvement, which is in accordance with our study.
In our study of anti-SCL, 70 antibodies were significantly found to be associated with lung involvement. All six cases of Ssc in this study were found to have anti-scl 70 (100%) or anti-topoisomerase 1 antibodies. Sharon D et al.[14] stated that anti-topoisomerase I (anti-Scl-70) antibodies and anti-U3RNP antibodies are associated with pulmonary fibrosis and a poor prognosis.
In our study, the presence of anti-SS-A antibodies was significantly associated with cardiovascular involvement. A study by Lazzerini PE et al.[15] observed that anti-Ro antibody-positive adult patients with connective tissue disease may have disturbances in cardiac repolarization. Anti-Ro antibody-positive patients had significantly longer mean corrected QT intervals than anti-Ro antibody-negative patients.
But in the study, patients had chest pain and palpitations on exertion that were not associated with ECG abnormalities.
Conclusion ANAs are a characteristic feature of autoimmune connective tissue disorders and are useful as diagnostic as well as prognostic biomarkers. Measurement of relevant autoantibodies contributes to precision medicine because they could be utilised as a diagnostic marker to pursue involvement of organs, as in our study, anti-Sm antibody is associated with renal involvement and anti-dsDNA with the musculoskeletal system. Thus, ANAs are useful in disease subsetting, which offers the opportunity to predict future outcomes early in the disease course as their strong association exists with organ involvement.
Acknowledgment
We declare that the study was assessed and approved by the Institutional Ethics Committee/Institutional Review Board. We express our gratitude to the Indian Association of Dermatologists, Venereologists and Leprologists for supporting this project through the IADVL Postgraduate thesis grant.
Financial support and sponsorship
IADVL Postgraduate thesis grant.
Conflicts of interest
There are no conflicts of interest.
References 
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