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scleroderma or systemic sclerosis ( ssc ) is a complex autoimmune disease affecting 1/100,000 individuals among the caucasian population .
higher rates have been reported in usa , australia , and eastern europe and lower rates have been reported in northern europe and japan . even though current clinical and diagnostic utilities have led to a better understanding of the disease
scleroderma is a heterogeneous disease with a wide range of clinical manifestations ranging from mild skin fibrosis with minimal internal organ disease to severe skin and organ involvement .
the three main pathological events that are involved in scleroderma pathogenesis are mainly endothelial damage , fibrosis , and autoimmune dysregulation .
etiopathogenesis of scleroderma is characterized by fibroproliferative alterations , cellular and humoral immune abnormalities resulting in a severe and often progressive fibrotic process .
scleroderma can also be subdivided according to different criteria , such as involvement of organs and the presence of specific antibodies which are hallmarks of the disease .
these autoantibodies are disease - specific and usually mutually exclusive and correlate with the extent of skin involvement and associated disease manifestations .
the most common are dna topoisomerase ( anti - scl70 ) , anti - centromere antibodies ( cenp a and/or b protein ) .
these autoantibodies are marker antibodies for relatively distinct clinical phenotypes of ssc where anti - scl70 antibodies are a marker for dcssc and ssc patients with clinically significant pulmonary fibrosis with a poor prognosis whereas anti - centromere antibodies typically are associated with lcssc , uncommon pulmonary fibrosis , and late onset of pulmonary hypertension but generally are associated with an overall good prognosis [ 3 , 4 ] .
geoepidemiologically it has been noted that clinical features and presence of these disease - specific autoantibodies vary across the globe and ethnicities . the low incidence of ssc and the clinical variability result in difficulties in understanding the disease pathogenesis .
there is an unmet need for validated biomarkers for scleroderma disease diagnosis , classification , and future therapeutic approach for management of scleroderma patients .
this study was designed to look at differences in the clinical features among subset of scleroderma patients with an emphasis on autoantibodies in scleroderma patients from mumbai , western india .
this prospective study was conducted in 110 scleroderma patients from rheumatology department of king edward memorial hospital , mumbai , india , and national institute of immunohaematology , mumbai , india , over the period of 3 years ( 20102012 ) .
this study was carried out after obtaining the requisite ethics committee approval and a written consent from patients .
scleroderma patients were classified according to american college of rheumatology / european league against rheumatism ( acr / eular ) criteria [ 6 , 7 ] .
ssc patients were classified into two clinical subgroups based on the extent of skin involvement , limited cutaneous ssc ( lcssc ) , and diffuse cutaneous ssc ( dcssc ) that are associated with different clinical complications and prognoses .
diffused cutaneous ( dcssc ) patients had delayed raynaud 's phenomenon , severe constitutional symptoms , arthralgias , carpal tunnel , puffy hands and legs , palpated tendon friction rubs , skin thickening progressing from fingers to trunk rapidly , potentially severe pulmonary fibrosis , and cardiac and renal involvement .
lcssc patients had raynaud 's phenomenon alone for years , rate constitutional symptoms , minimal arthralgias , puffy fingers , telangiectasias and late calcinosis , skin thickening limited to hands and face , and mild pulmonary fibrosis .
severe organ system involvement noted like musculoskeletal involved joints / tendons of fingertip to palm distance 4.0 +  cm and severe proximal muscle weakness on physical examination .
severe renal manifestations involved  renal crisis  with serum creatinine 3.0 +  mg / dl at any time .
pulmonary arterial hypertension was diagnosed by right - sided heart catheterization according to standard definitions .
pulmonary fibrosis was seen on chest radiography and raynaud 's phenomenon was self - reported or reported in patients with at least a 2-phase colour change in finger(s ) and often toes consisting of pallor , cyanosis , and/or reactive hyperemia in response to cold exposure .
pregnant and postmenopausal women , smokers , patients with diabetes , and patients with significant hyperlipemia were excluded .
standard investigations like cbc , esr , routine biochemical tests ( renal and liver function tests and electrolytes ) , chest x ray , and ecg were carried for all patients .
anti - nuclear antibodies ( ana ) ( biorad , usa ) , anti - endothelial cell antibodies ( aeca ) ( euroimmune , germany ) , and anti - keratinocyte antibodies ( aka ) ( euroimmune , germany ) were tested by indirect immunofluorescence test ( iif ) .
anti - scl70 antibodies ( anti - i ) , anti - centromere antibodies , and anti - cyclic citrullinated peptide ( ccp ) antibodies were tested by elisa using commercially available kits ( euroimmune , germany ) .
continuous variables were expressed as mean  sd . pairs of groups were compared using student 's test for normally distributed continuous distribution .
a total of 110 patients with scleroderma having mean age of 34.7  10.7 years at evaluation and a mean disease duration of 43.7  35.4 years were included in the study ( table 1 ) .
there were 100 females ( 91% ) and 10 males ( 9% ) included in this study .
the female to male ratio was 10  :  1 . at evaluation women were slightly older than males with mean  sd of 35.6  10.5 as compared to males ( 30.7  5.7 ) .
the disease duration ranged between 6 and 120 months with a mean  sd of 43.7  35.4 .
it was observed that 45 patients ( 40.9% ) had dcssc lesions and 32 patients ( 29.1% ) had lcssc lesions .
the remaining 33 patients ( 30% ) had other autoimmune overlaps wherein patients had features of scleroderma combined with features of a second connective tissue disease at the time evaluation .
clinical presentation revealed that 108 patients ( 98.2% ) had cutaneous manifestations , 85 patients ( 77.3% ) had pulmonary manifestations , 12 patients ( 10.9% ) had renal involvement , 43 patients ( 39.1% ) had musculoskeletal involvement , 8 patients ( 7.3% ) had gastrointestinal involvement , and 15 patients ( 13.5% ) had cardiovascular involvement .
as shown in table 2 , the overall frequency of ana in ssc patients studied was 85.5% .
it was observed that 60 patients ( 63.9% ) had speckled pattern , 17 patients ( 18.1% ) had nucleolar pattern , 7 patients ( 7.4% ) had centromere pattern , 2 patients ( 2.1% ) had rim / peripheral pattern , and the remaining 2 patients ( 2.1% ) had speckled and nucleolar pattern .
the frequency of anti - scl70 antibodies , anti - centromere antibodies , aeca , and aka was 62.7% , 22.7% , 30% , and 40.9% , respectively . for anti - scl70 antibodies among dcssc compared with lcssc
there was a statistically significant difference ( p < 0.0115 , or = 3.5030 , and 95% ci = 1.32569.2570 ) . when anti - centromere antibodies were compared in both the groups
, there was a statistically significant difference noted ( p < 0.0044 , or = 0.1626 , and 95% ci = 0.04650.5684 ) . when dcssc and lcssc patients were compared statistically , there was no statistically significant difference for ana , aeca , and aka ( p > 0.05 ) . when dcssc and lcssc patients together were compared with overlap patients ,
geoepidemiology studies suggest that systemic sclerosis ( ssc ) is more common , occurs only at a younger age , and is more severe in african americans than caucasians .
the major differences noted were mainly in their clinical and serological phenotypes . these differences can be further related to different environmental exposure as well as immunogenetic makeup of these patients .
the studies on clinical and serological profile of ssc patients have important implications for both clinical interventions and future pathogenic studies .
de souza mller et al . had documented 65.62% , 26.04% , and 8.33% frequency for dcssc , lcssc , and overlap among their total ssc patients from brazil .
indian data on ssc patients revealed that , among north and south indian ssc patients , the clinical presentation varies [ 10 , 11 ] .
though there are a few published records from western india there is no information available from the eastern part of the country giving details of clinical profile of indian ssc patients .
demographic and serological similarities / differences in indian scleroderma patients in various regions across the country are as shown in table 4 [ 1015 ] .
ssc - related autoantibodies among scleroderma patients were compared in different ethnicities like caucasian americans , african americans , and latin americans by krzyszczak et al . .
the reported frequency of anti - scl70 and anti - centromere antibodies was 15% , 17% , respectively , in caucasian american , 35% , 0% in african american , and 20% , 40% among latin american ssc patients .
had reported an incidence of 94.2% ana positivity among german ssc patients and among brazilian ssc patients , 92.4% ana positivity had been reported [ 4 , 16 ] .
johnson et al . had reported a much lower incidence ( 17% ) for anti - scl70 autoantibodies among canadian ssc patients , as compared to 62.7% in the present study whereas the incidence for anti - centromere antibodies was 29% which was similar to the present study ( 22.7% ) .
19% , 21% anti - scl70 antibodies and anti - centromere antibodies from pittsburg , usa , 17% , 16% from toronto , 35% , 27% from madrid , and 22% , 28% from berlin ssc cohort had been documented . among brazilian ssc patients anti - scl70 frequency reported was 17.8% which was mainly associated with dcssc ( p < 0.015 ) whereas anti - centromere antibodies ( 33.3% ) were commonly associated with lcssc subtypes .
had reported a total incidence of 30.1% for anti - scl70 antibodies where dcssc subtype was strongly associated with anti - scl70 autoantibodies ( p < 0.0001 ) .
frequency of anti - centromere antibodies reported by the same group was 35.9% and a positive correlation was found in lcssc patients with anti - centromere antibodies ( p
< 0.0001 ) . de souza mller et al . also had reported a positive correlation of anti - centromere antibodies with lcssc form ( p < 0.01 ) which are similar to the present study .
previous studies had shown that anti - centromere antibodies were strongly associated with renal dysfunction in lcssc patients and cenp - b was a major target antigen reported for aeca in lcssc patients indicating the association between anti - centromere antibodies and aeca autoantibodies leading to aeca mediated endothelial dysfunction due to an underlying autoimmune mechanism [ 1821 ] .
further endothelial dysfunction may be associated with high incidence of cerebrocardiovascular diseases which needs to be studied in ssc patients .
this study throws light on a need for some biomarker antibodies and discovery of new target antigens among scleroderma patients and their immunodiagnostic potential .
these disease - specific antibodies along with disease phenotype variation across the country will help in understanding the geoepidemiological picture of scleroderma in different geographical regions in india .
this could possibly represent new diagnostic and/or prognostic markers of scleroderma in the near future .
background . systemic sclerosis ( ssc , scleroderma ) is a disorder characterized by fibrosis of skin and visceral organs . 
 pathogenesis of scleroderma is complex and is incompletely understood as yet . 
 autoantibodies in ssc represent a serologic hallmark which have clinical relevance , with diagnostic and prognostic potential . objectives . to study distribution of clinical manifestations and to identify frequency of autoantibodies among subtypes of scleroderma patients from western india 
 . methodology . 
 one hundred and ten scleroderma patients were clinically classified according to the american college of rheumatology / european league against rheumatism ( acr / eular ) criteria . 
 all these patients were in active stage of disease . 
 clinical manifestations were recorded at the time of presentation . 
 autoantibodies were tested in them by indirect immunofluorescence test and elisa . 
 immunoglobulin levels were estimated by nephelometer . 
 these parameters were further correlated with clinical presentation of the disease . 
 results . 
 scleroderma patients had m  :  f ratio of 1  :  10 where mean age at evaluation was 34.7  10.7 years and a mean disease duration was 43.7  35 months . 
 clinical subtypes showed that 45 patients ( 40.9% ) had diffused cutaneous ( dcssc ) lesions , 32 patients ( 29.1% ) had limited cutaneous ( lcssc ) lesions , and 33 patients ( 30% ) had other autoimmune overlaps . 
 the overall frequency of ana in ssc patients studied was 85.5% . 
 the frequency of anti - scl70 , anti - centromere , anti - endothelial cell antibodies ( aeca ) , and anti - keratinocyte antibodies ( aka ) was 62.7% , 22.7% , 30% , and 40.9% , respectively . 
 anti - scl70 antibodies were significantly high ( 75.6% versus 46.9% ) among dcssc patients ( p < 
 0.0115 ) whereas anti - centromere antibodies were significantly high ( 9% versus 38% ) among lcssc patients when these two subtypes were compared ( p < 0.0044 ) . conclusion . 
 this study supports that there are geoepidemiological variations among scleroderma patients for their clinical presentation , autoantibody profile , and immune parameters across the country .