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ORIGINAL ARTICLE
Year : 2014  |  Volume : 59  |  Issue : 1  |  Page : 35-40
Cutaneous manifestations of mixed connective tissue disease: Study from a tertiary care hospital in Eastern India


1 Department of Dermatology, Venereology and Leprosy, The Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Salt Lake City, Kolkata, India
2 Department of Rheumatology, The Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Salt Lake City, Kolkata, India
3 Department of Pharmacology, The Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Salt Lake City, Kolkata, India

Date of Web Publication23-Dec-2013

Correspondence Address:
Sumit Sen
CG-75, Sector-2, Salt Lake City - 700 091, Kolkata
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.123491

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   Abstract 

Context: Mixed connective tissue disorder is an uncommon disease. Some scientists are reluctant to recognize it as a separate entity. Some others have defined this ailment. Cutaneous features of this condition are unique. Researchers from India have described these features to relate to those described in the studies from other parts of the globe. Aims: This study aims to delineate the skin manifestations of clearly defined mixed connective tissue disease (MCTD) patients, to compare them with those established as overlap syndrome, and to relate them with studies from other parts of the globe. Settings and Design: Successive patients who fulfilled the specific criteria for MCTD presenting in the skin outpatient department of a tertiary care hospital in eastern India were clinically examined from 2009 for 3 years. Materials and Methods: The number of participants was 23 and the dermatological features of these were compared with 22 patients with overlap syndrome. The antibody to uridine-rich U1 ribonucleoprotein was measured for all patients. Statistical Analysis Used: SPSS (Version 17) and MedCalc (Version 11.6). Results: The Male: Female ratio among the MCTD patients was 1:6.67 and that of the overlap syndrome was 1:10. Twenty patients of the MCTD group presented with synovitis as against only seven in the overlap group. Raynaud's phenomenon was present in some of the subjects. Puffy fingers were rare in our study. Facial numbness was reported by four of those suffering from MCTD. Antinuclear antibody (ANA) was essentially of a speckled pattern in this disease Conclusions: Cutaneous indicators of MCTD are distinct from overlap syndrome. Knowledge of these manifestations prevalent in a region may lead to early diagnosis of the disease.


Keywords: Autoimmune disease, inflammatory myositis, mixed connective tissue disease, overlap syndromes, sausage fingers, synovitis


How to cite this article:
Sen S, Sinhamahapatra P, Choudhury S, Gangopadhyay A, Bala S, Sircar G, Chatterjee G, Ghosh A. Cutaneous manifestations of mixed connective tissue disease: Study from a tertiary care hospital in Eastern India. Indian J Dermatol 2014;59:35-40

How to cite this URL:
Sen S, Sinhamahapatra P, Choudhury S, Gangopadhyay A, Bala S, Sircar G, Chatterjee G, Ghosh A. Cutaneous manifestations of mixed connective tissue disease: Study from a tertiary care hospital in Eastern India. Indian J Dermatol [serial online] 2014 [cited 2019 Dec 8];59:35-40. Available from: http://www.e-ijd.org/text.asp?2014/59/1/35/123491

What was known?
Mixed connective tissue disease (MCTD) is a distinct entity, closely resembling overlap syndrome. The skin manifestations of MCTD are different from those of overlap syndrome. There is suboptimal recording of cutaneous manifestations of this disease In India and none from eastern India.



   Introduction Top


Mixed connective tissue disease (MCTD) is a specific condition in which two or more connective tissue disorders are associated with the presence of antibody against a specific uridine-rich U1 ribonucleoprotein (U1RNP). [1] Clinical manifestations are usually those of systemic lupus erythematosus (SLE), scleroderma, and inflammatory myositis. First described by Sharp [2] in 1972, this disease is now known to have characteristic cutaneous features. Overlap syndromes present a combination of at least two collagen vascular diseases without necessarily demonstrating antibody against U1 RNP. MCTD has been observed to eventually develop into scleroderma, SLE, or dermatomyositis by some authors and so they prefer to use the term "undifferentiated connective tissue disease." [3] Others have firmly established the entity as MCTD, setting forth criteria for demarcating this disease. [4] There is a paucity of data regarding the skin manifestations of MCTD from India and none from eastern India. This led to study the predominant skin lesions of this disease prevalent among MCTD patients from this region. A comparison of the dermatological manifestations occurring in overlap syndromes with those of MCTD was another of our objectives. We also sought to evaluate our data with similar research from other parts of our country and that from the West.


   Materials and Methods Top


Twenty-three consecutive patients of MCTD attending the Dermatology outpatient department of a tertiary care hospital were enrolled. These patients had to fulfil the criteria laid down by Alarcón-Segovia and Villareal. According to their definition, a case could be designated as MCTD when a patient is serologically positive for U1RNP at a titer of 1:1600 or higher, with the presence of at least three clinical features from among edema hands, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis. The association of edema of hands, Raynaud's phenomenon, and acrosclerosis in any combination requires at least one of the other two clinical features, that is, synovitis or myositis to be present. Swollen hands were considered as a diagnostic parameter only in the absence of edema anywhere in the body. A patient was denoted as having puffy fingers when the fingers were swollen and tapered distally. At the same time, 22 patients of "overlap syndrome" were also examined and documented. Patients were diagnosed to suffer from overlap syndrome when they clinically manifested features of any two connective tissue disease supported by serological positivity and absence of U1RNP positivity. The duration of the study period was 3 years (March 2009 to February 2012). The following were taken as the inclusion criteria:

  1. All patients over the age of 12 years
  2. Patients satisfying the criteria laid down by Alarcón-Segovia for MCTD
  3. Patients diagnosed as overlap syndrome demonstrating the features of at least two connective tissue disorders.


Exclusion criteria included:

  1. Unwilling patients
  2. Patients in the pediatric age group
  3. Pregnant patients.


A rheumatologist's opinion was taken whenever necessary. It was a cross-sectional observational study. Permission of the ethical committee of the institution was taken prior to the start of the research and an informed consent of each participant was obtained.

Patients were subjected to detailed history taking, and a thorough clinical examination was then carried out on each subject with emphasis on the cutaneous system. Routine laboratory investigations including complete hemogram, erythrocyte sedimentation rate (ESR), X-rays of chest and hands, C-reactive protein, rheumatoid factor, estimation of antinuclear antibody (ANA), antitopoisomerase-1, anticentromere antibody, and anti-U1RNP as well as creatinine phosphokinase were performed in all of the cases. Antibody against double-stranded DNA, pulmonary function test, electromyography, echocardiography, histopathology, ultrasonography, Coombs test, high-resolution computerized tomography (HRCT) of the chest, and complement 3 levels were tested when indicated. The ANA was tested using the indirect immunofluorescence technique on HEp-2 cells. Antibody against U1RNP was also measured using the indirect immunofluorescence test. The observed parameters were transcribed to MS Excel from the source. Statistical analysis was done using SPSS version 17 manufactured by IBM, and MedCalc manufactured by MedCalc, version 11.6. The categorical data were described using absolute and relative frequency. The numerical data were observed for the distribution pattern, first using Kolmogorov-Smirnov test (KS test), the parametric data were observed with mean and standard deviation (SD), and nonparametric data were observed with median and interquartile range (IQR). Categorical variables of MCTD and overlap syndromes were compared using the Fisher's exact test and numerical variables of the same were compared using independent sample t test.


   Results Top


Out of the 23 MCTD patients, 20 (86.96%) were females and 3 (13.04%) were males. In comparison, of the 22 recruits of "overlap syndrome," 20 (90.91%) were females and 2 (9.09%) males. The patients' ages ranged from 18 to 41 years in the MCTD group. In this group, the youngest female was only 18 years and the youngest male was 39 years. The overlap syndrome patients were between 15 years and 56 years of age. The youngest female with features of overlap was only 15 years old and the youngest male was 25 years old. Mean age of presentation of MCTD and overlap syndrome participants were 31.22 ± 7.4 years and 34.23 ± 12.3 years, respectively, with no significant difference between the two (P = 0.32). No significant difference existed between mean duration of disease of the patients with MCTD and overlap syndrome on presentation, which was 32.43 ± 25.9 months and 41.95 ± 44.9 months, respectively (P = 0.39).

The clinical signs and symptoms were recorded for all the individuals [Table 1]. There was a significant difference between synovitis observed in the MCTD group and that in the overlap group (P = 0.000) with as many as 20 (87%) persons presenting with this sign in the MCTD group as against 7 (31.8%) in the overlap group. There was no significant difference in Raynaud's phenomenon in the two groups. However, a trend toward statistical significance (P = 0.065) was noticed. MCTD group had 18 patients (78.3%) who complained of Raynaud's phenomenon and the overlap group presented 11 patients (50%) with this occurrence. Out of those diagnosed with MCTD, swollen hands, acrosclerosis, and myositis were found in 9, 17 and 12 individuals, respectively. Number of patients with swollen hands, acrosclerosis, and myositis were 4, 13, and 11, respectively, in the overlap group. Puffy fingers [Figure 1] were demonstrated by one patient from the MCTD group. There was no such finding in those in the overlap syndrome group. Malar rash [Figure 2] was a significant finding in five patients in the MCTD group and in four subjects in the overlap group. Erythema and ulceration of the palmar surface of the hands and dorsal surface of the right leg [Figure 3] suggesting vasculitis was noticed in another MCTD patient as an incidental finding. One patient from each group suffered fingertip gangrene. One woman from the MCTD group was noticed with scattered patchy hypopigmentation of the face and fingers with tightened and contracted digits [Figure 4]. She had generalized hyperpigmentation. Tightening of face was observed in eight patients of MCTD and all of them had tightening of fingers. Tight face was noticed in only three of those with overlap syndrome. A discoid lupus erythematosus-like rash was present over the scalp in one case and another near the frontal hairline in two cases of MCTD. An interesting finding was paresthesia of face, especially the perioral area in four of the study group of MCTD but none in the overlap group. One person showed telangiectasia of the nail folds and there was one patient each with calcinosis cutis and photosensitive rash, all in the MCTD group. Two of those, within the MCTD group alone, displayed erythema multiforme-like lesions of the extremities. Two persons were diagnosed as suffering from restrictive lung disease (RLD) and three from interstial lung disease (ILD) among those in the MCTD group. There were four ILD patients and one RLD patient in the overlap group. Twenty persons among those with MCTD tested positive for ANA [Table 2] and the pattern was solely speckled while 14 of those suffering from overlap syndrome tested positive for ANA, the pattern being homogeneous. The findings of this research were compared with previous studies to assess for differences between the observed signs and symptoms [Table 3].
Figure 1: Puffy fingers in a patient with mixed connective tissue disease

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Figure 2: MCTD subject with erythematous malar rash in butterfly distribution

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Figure 3: Vasculitic lesions over hand and foot in another MCTD patient

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Figure 4: Tightened and contracted digits with patchy hypopigmentation in MCTD patient

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Table 1: Clinical signs and symptoms of MCTD and overlap syndrome

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Table 2: Serological parameters in patients with MCTD and overlap syndrome

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Table 3: Clinical features and serological parameters in comparison to historical control

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   Discussion Top


Cutaneous manifestations of MCTD may be the presenting signs of the disease. These have been included by researchers as important markers while defining criteria to identify this disease. Overlap syndromes are a combination of signs and symptoms of at least two connective tissue diseases with specific serological parameters. Antibody to RNAse-sensitive extractable nuclear antigen is rarely found in overlap disorders in contrast to MCTD. This antigen has been identified as polypeptides on the U1 ribonuclear protein component of the splicesosome (U1RNP). [5] The U1 small nuclear ribonucleoprotein element (snRNP) is a target of autoreactive B cells and T cells in MCTD. [6]

The exact pathogenesis of MCTD is not known. It appears to be an autoimmune disease. Individuals who express the human leukocyte antigens (HLAs), HLA-DR4 or HLA-DQB1, are genetically predisposed. This genetic background in MCTD is different from that in SLE and scleroderma. Persons with SLE have been seen to have increased frequency of HLA- B8,-DR3,-A1, DR-2, and HLA DQ antigens while those with scleroderma have an increased incidence of HLA-B8. Such observation can perhaps partly explain the difference in clinical presentations between MCTD and other connective tissue disorders such as SLE, scleroderma, and the overlap syndrome. Specific nature of the HLA associations that occur in relationship with MCTD differ with the ethnicity of the populations studied and may account in part to the variability of cutaneous features. [7]

Entity of MCTD is more common among women. In a pioneering study by Sharp, [2] 21 (84%) were females and 4 (16%) were males out of 25 patients recognized as suffering from MCTD. Haroon and associates noticed only 1 male and rest 12 (92.30%) females among their set. [8] These figures corroborated with our research (86.96% females). The age group that is usually affected is 30-50 years. Median age of onset of disease was 36 years in a study from south India. [8] The age range in the original study from the West [2] was 13-66 years with a mean of 36 years. This was similar to our study (mean = 31.22). All were adults (youngest respondent was 18 years) in our group of MCTD subjects. The mean age at diagnosis of adult-onset MCTD was found to be 37.9 years by others. [9] MCTD has been identified in children by Tiddens. [9]

Edema of hands, Raynaud's phenomenon, and acrosclerosis can all manifest together in scleroderma. [4] Existence of these features thus needs the presence of either myositis or synovitis (arthritis) for fulfilment of the criteria we used to diagnose a case as MCTD. The frequency of synovitis detected in our MCTD group was consistent with previous studies of the same type. [8],[10],[11] Our group noted 87% of synovitis, the Nedumaran et al., study noted 100%, and the Haroon et al., study 84.62%. Alarcón-Segovia et al., noted synovitis in 98% of patients and Burdt noted 96% of patients suffering from synovitis. Low recording of RA factor among our patients of synovitis compared identically to the study done by Nedumaran et al., who could not demonstrate any RA factor positivity in spite of noting synovitis in all the cases. A distinct difference was nonetheless present in the finding of synovitis among the MCTD group and the overlap group in our research. Raynaud's phenomenon involves intermittent blanching followed by cyanosis and finally rubor on exposure to cold. This entity often characterizes as the earliest manifestations of MCTD. [12] A significant number (78.3%) in our MCTD group manifested this, similar to studies from the USA and the Netherlands. [11],[13] This finding was significantly less than the figure of 96% of the Alarcón Segovia a study. Nedumaran et al., documented all patients of MCTD suffering from this phenomenon in their study. [11] Edema of the hands was found in 9 (39.1%) persons in our sample and was statistically diverse from the figure of 77 (96%) as found by Alarcón-Segovia. Acrosclerosis, which is tightening, thickening, and loss of elasticity of the fingers, was noted by Nedumaran et al., in all of their eight cases of MCTD. Seventeen subjects (73.9%) demonstrated this sign in our research, but the difference from the above study was statistically insignificant (P = 0.2976). Myositis was seen to be present in 12 (52.2%) of our cases. Proximal muscles of both upper extremities were the most common group to be affected.

The number was comparable (P = 0.412) to that of study conducted by Nedumaran et al., [10] who noted in six (79%) patients such feature but was in contrast to another south Indian study, which reported only two such patients. [8] Discovery of a single case of puffy finger in our study was in stark contrast (P = 0.001) to the work done by Haroon and co-workers, who found 10 of their total number of MCTD patients displaying this sign. Burdt et al., noted a period of 3 years as the mean duration of presentation in their study. Puffy fingers were not a significant finding in their investigation. [11] The classical puffy finger of MCTD does not show features of sclerodactyly. [14] The clinical and serological markers of MCTD take time to develop. [11],[15],[16] Period of illness among those with MCTD in our group ranged from 7 months to 120 months. The median duration (there was no record of the mean) of MCTD in Haroon et al., study [8] was 36 months (IQR = 1.75-4 years) and the mean of our study was 24 months (IQT = 18-36 months). The duration in case of the overlap syndrome group was between 6 months and 192 months. Patients with MCTD can have other cutaneous features such as photosensitivity, livedoid vasculitis, and calcinosis. [17] One woman diagnosed as a case of MCTD displayed calcinosis cutis of her right buttock region. Increasing generalized calcinosis cutis with MCTD in the form of large calcified plaques just 1 year after the onset of the disease has been described from Europe. [18]

Uncommon features such as edema of the forehead, trigeminal neuralgia, and juxta articular calcinosis may suggest possibility of MCTD. [4] Periorificial numbness was seen in four of our patients due to trigeminal neuralgia. Others have noted this sign in a patient with MCTD who was also suffering from Sjogren's syndrome. [19] None of those in the overlap group complained of this difficulty. Two of our MCTD cases presented with discoid erythematosus (DLE) like rash. One lesion over the scalp had been present for 4 years and the other over the forehead was present for 2 years. Both were positive for ANA and anti-U1RNP. Similar lesions of DLE were observed by other scientists studying the cutaneous features of MCTD, but in their research one individual was found to have developed MCTD 10 years after onset of a DLE rash. [20]

In our study, most persons among those with MCTD tested positive for ANA and the pattern was solely speckled while those of overlap syndrome group had positive ANA of homogeneous pattern. This pattern of ANA found in our study was in accordance with a study by Grant et al. [21] Another study has shown that patients with MCTD have very high titer of ANA with specificity for an RNAse-sensitive component of ENA. [22]


   Conclusions Top


This research from eastern India recording the dermatological expressions of MCTD reveals similarities and differences with studies from south India and also from other countries. Synovitis was present in a large number of our survey group, edema of hands distinctly less so. Sample size in our study was a limitation factor and further larger studies are required to characterize the cutaneous manifestations of MCTD.

Our work demonstrates differences in cutaneous features between overlap syndrome patients and MCTD subjects emphasizing the existence of the rare entity that is "mixed connective tissue disease."


   Acknowledgement Top


We acknowledge Dr. Chinmay Halder and Dr. Nidhi Choudhury for their help in literature search while preparing this manuscript.

 
   References Top

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6.Kattah NH, Kattah MG, Utz PJ. The U1-snRNP complex: Structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev 2010;233:126-45.  Back to cited text no. 6
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7.Swartz RA. Hematologic manifestations of mixed connective tissue disease. Available from: http://emedicine.medscape.com. [Last accessed on 2012 June 6].  Back to cited text no. 7
    
8.Haroon N, Nisha RS, Chandran V, Bharadwaj A. Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological study. J Postgrad Med 2005;51:104-7.  Back to cited text no. 8
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10.Nedumaran, Rajendran CP, Porkodi R, Parthiban R. Mixed connective tissue disease - clinical and immunological profile. J Assoc Physicians India. 2001;49:412-4.  Back to cited text no. 10
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11.Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC. Long-term outcome in mixed connective tissue disease: Longitudinal clinical and serologic findings. Arthritis Rheum 1999;42:899-909.  Back to cited text no. 11
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12.Grader-Beck T, Wigley FM. Raynaud's phenomenon in mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:465-81.  Back to cited text no. 12
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14.Oh YB, Jun JB, Kim CK, Lee CW, Park CK, Kim TY, et al. Mixed connective tissue disease associated with skin defects of livedoid vasculitis. Clin Rheumatol. 2000;19:381-4.  Back to cited text no. 14
    
15.Smolen JS, Steiner G. Mixed connective tissue disease: To be or not to be? Arthritis Rheum 1998;41:768-77.  Back to cited text no. 15
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16.Gendi NS, Welsh KI, Van Venrooij WJ, Vancheeswaran R, Gilroy J, Black CM. HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic followup of 46 patients. Arthritis Rheum. 1995;38:259-66.  Back to cited text no. 16
    
17.Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005; 31:519-33.  Back to cited text no. 17
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18.Bäurle G, Hornstein OP. Generalized cutaneous calcinosis and mixed connective tissue disease. Dermatologica 1979;158:257-68.  Back to cited text no. 18
    
19.Alfaro-Giner A, Penarrocha-Diago M, Bagan-Sebastian JV. Orofacial manifestations of mixed connective tissue disease with an uncommon serologic evolution. Oral Surg Oral Med Oral Pathol 1992;73:441-4.  Back to cited text no. 19
    
20.Gilliam JN, Prystowsky SD.Conversion of discoid lupus erythematosus to mixed connective tissue disease. J Rheumatol 1977;4:165-9.  Back to cited text no. 20
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21.Grant KD, Adams LE, Hess EV. Mixed connective tissue disease - a subset with sequential clinical and laboratory features. J Rheumatol 1981;8:587-98.  Back to cited text no. 21
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What is new?
This is the first study from eastern India recording the various unique dermatological manifestations of MCTD. Certain skin manifestations of MCTD such as synovitis are more common than others in this part of the country. ANA pattern has been shown to be chiefly of speckled pattern in this disease.


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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