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Year : 2005  |  Volume : 51  |  Issue : 2  |  Page : 104-108

Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological study

Immunology-Rheumatology Unit, Kasturba Medical College, Manipal - 576 104, India

Date of Submission12-Jan-2005
Date of Decision02-Mar-2005
Date of Acceptance06-Apr-2005

Correspondence Address:
Anurag Bharadwaj
Immunology-Rheumatology Unit, Kasturba Medical College, Manipal - 576 104
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Source of Support: None, Conflict of Interest: None

PMID: 16006700

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 :: Abstract 

Background: Mixed connective tissue disease (MCTD) has features common to lupus, scleroderma and myositis with high levels of antibodies to U1 ribonucleoprotein (U1 RNP). Identification of a high incidence of pulmonary artery hypertension (PAH) has changed its prospect. We report the largest series from India. Settings and Design: Rheumatology unit of a tertiary care centre in India; prospective. Materials and Methods: Patients seen between January 2002 and June 2004, satisfying the Kasukawa criteria were enrolled. All patients had a complete laboratory work-up including pulmonary function test, 2-D echocardiography, and Schirmer's test, antinuclear antibodies (ANA) and antibodies to extractable nuclear antigens. HRCT of chest was done where indicated. All patients were given standard treatment and followed up regularly. Results: Out of 1500 patients, thirteen (one male) were diagnosed to have MCTD. The median follow-up period was 18 months [Interquartile range (IQR) 12-22]. The median age of onset of symptoms was 36 years (IQR 22-39) and the median duration of disease was three years (IQR 1.75-4). The most common manifestation was polyarthritis followed by puffy fingers. Sjogren's syndrome, dysphagia and interstitial lung disease, was present in four, three and two patients respectively. Two patients each had myositis and migraine. None had PAH, serositis or renal involvement. Arthritis, puffy fingers and RaynaudÆs phenomenon were the most common manifestations at onset. All patients were positive for ANA and anti U1 RNP. Two patients each had antibodies to Sm and SSA. Response to treatment also was noted. Conclusion: Pulmonary artery hypertension is not common in early MCTD.

Keywords: Overlap syndrome, Interstitial lung disease, Myositis, Scleroderma, Lupus

How to cite this article:
Haroon N, Nisha R S, Chandran V, Bharadwaj A. Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological study. J Postgrad Med 2005;51:104-8

How to cite this URL:
Haroon N, Nisha R S, Chandran V, Bharadwaj A. Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological study. J Postgrad Med [serial online] 2005 [cited 2023 May 29];51:104-8. Available from:

Mixed connective tissue disease (MCTD) was described more than 30 years ago and has clinical features common to systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSS) and inflammatory myositis.[1] There is an antibody response to the spliceosome complex, involved in the processing of pre messenger RNA. [2],[3],[4] An antibody against the uridine-rich U1 ribonucleoprotein (U1 RNP) characterizes the disease.[5] The antibody reacts with two components of the small nuclear ribonucleoprotein (snRNP), U 1 RNA and 70 K polypeptide.[6] This antigen is the ribonuclease-sensitive fraction of the extractable nuclear antigens (ENA), which was identified initially by enzyme denaturation and haemagglutination.[7]

Unlike SLE and PSS, MCTD was considered to have a relatively favourable outcome, good response to low-dose corticosteroids and low incidence of renal manifestations. However, controversies on the very existence of such an entity have come up. [8],[9],[10] Antibodies to U1 RNP have been identified in other connective tissue diseases.[11] The concept of a good prognosis in MCTD has also not stood the test of time.[12],[13] Pulmonary artery hypertension (PAH), reported in an increasing number of patients, is the predominant cause for morbidity and mortality. [14],[15],[16] Up-regulation of intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1 and Class II MHC molecules on pulmonary artery endothelial cells as well as the endothelial cell-binding activity of U1 RNP antibodies are considered to mediate PAH.[17],[18] Anti-endothelial cell antibodies also have been reported to be higher in patients with active disease.[19]

There is very little data on Indian patients of MCTD and it is considered a rare entity here.[20] The studies on MCTD are case record reviews or cross-sectional studies and not fact finding prospective studies.[20],[21] We prospectively examined the clinical and serological profile of patients with MCTD in a tertiary care centre in India.

 :: Materials and Methods Top

This prospective study was conducted in the rheumatology clinic of a tertiary care centre in southern India, a major referral centre for rheumatic diseases in the region, during the period January 2002 to June 2004 after obtaining permission from the institutional Ethics Committee. Patients satisfying the diagnostic criteria proposed by Kasukawa et al [Table - 1] who gave a written consent were included in the study.[22] Patients presenting with the common symptoms of puffy fingers or Raynaud's phenomenon were screened serologically for anti U1 RNP and clinically for features of SLE, PSS, inflammatory myositis and arthritis. A blanket serology of all patients was not done. Patients who had a past history suggestive of MCTD but not satisfying the diagnostic criteria presently were excluded. However, a close watch was kept for the development of additional features in these patients. The onset of any one of the two common symptoms was considered the time of onset of disease.

All patients had a complete hemogram, clinical chemistry including muscle enzymes, thyroid function tests, urine examination, chest radiograph and electrocardiography (ECG) done at baseline. The hemogram, chemistry and urine examinations were repeated every three months. The chest X-ray and ECG were repeated annually or earlier if needed. A pulmonary function test (PFT) including diffusion capacity of lung with carbon monoxide (DLCO), 2-D echocardiography (2DE), Schirmer's test and tear film break-up time were done for all patients at baseline and annually thereafter. Pulmonary hypertension was defined as a resting mean pulmonary artery pressure above 20 mm Hg. High resolution CT scan (HRCT) of the chest was done where indicated. Antinuclear antibody (ANA) testing was done by indirect immunoflourescence (IIF) on HEp-2010 and mouse liver cell lines using commercially procured composite slides (Euroimmun, Germany). Antibodies to U1 RNP, Sm, dsDNA, SSA (Ro), SSB (La), centromeric, Ribosome P, Jo-1, Histone and Scl-70 were done by immunoblot (Euroimmun, Germany). Rheumatoid factor (RF) was tested by latex agglutination. All clinical and laboratory details as well as the follow-up visits were noted in individual proformas, starting from baseline.

All patients were given aspirin (150 mg/day) and hydroxychloroquine (HCQ) in a daily dose of 400 mg to be reduced to 200 mg after two months. Malaise, fatigue and arthralgia were managed with naproxen 500 mg twice daily. Patients with Raynaud's phenomenon were given calcium channel blockers (CCB). Arthritis not responding to HCQ and naproxen was managed with the addition of methotrexate. Myositis was managed with steroids at a starting dose of one mg/kg and tapered based on the symptoms. All patients were followed up monthly for 6 months, three-monthly for a year and then every 6 months.

 :: Results Top

Out of 1500 patients who attended our rheumatology clinic during the study period, 13 patients (one male) were diagnosed to have MCTD. The median follow-up period was 18 months with an interquartile range (IQR) of 12-22 months. All patients satisfied the inclusion criteria at presentation and developed additional features on follow-up. None of the subjects had a past history suggestive of MCTD. Till the last day of follow-up, there were no patients who satisfied the criteria after presenting with an incomplete picture. No patients were lost to follow-up.

The median age of onset of symptoms was 36 years (IQR 22-39) and the median duration of disease was three years (IQR 1.75-4). The most common manifestation was non-erosive, non-deforming polyarthritis (11/13) followed by puffy fingers (10/13). PSS was present in 4 patients. Two patients had interstitial lung disease (ILD) and HRCT in both showed honeycombing and increased septal thickness in the basal regions of both lungs. Dysphagia was present in three patients. Two patients each had myositis (myalgia, muscle tenderness and raised muscle enzymes), alopecia and sub clinical hypothyroidism. Four patients had recurrent oral ulcers (at least twice in the past year). Eight patients had normochromic normocytic anaemia (Haemoglobin < 120 g/L). One patient each had mononeuritis multiplex and trigeminal neuralgia. Two patients had migraine without aura, which responded to amitryptilline. None of the patients in our cohort had PAH, serositis or renal involvement.

Looking at the temporal profile of the different manifestations, we found that arthritis, puffy fingers and Raynaud's phenomenon were the most common manifestations at onset. These features diminished with treatment. Keratoconjunctivitis sicca, ILD and myositis appeared later in the course, of which only myositis showed a good response to treatment. Remarkably, dysphagia responded well to systemic management. No specific drugs were prescribed for the same and no surgical procedures were done. Myositis and ILD were not presenting manifestations in any patient.

Serology: All patients were positive for ANA and anti U1 RNP. Two patients each had antibodies to Sm and SSA. RF was positive in six patients (46.15%), all of whom had arthritis.

 :: Discussion Top

MCTD formed 0.87% of patients with rheumatism at our centre. The prevalence of MCTD among patients with rheumatism has been reported to be low in India by Malaviya et al (0.3%) and Nedumaran et al . (0.125 %).[20],[21] This is the only large and prospective series on MCTD patients reported from India, with a median follow-up period of 18 months. The clinic was established in 2002 and all patients enrolled were newly diagnosed. This is the reason for the relatively short duration of disease in our cohort. There could also be a sampling error as patients in a new specialty clinic may not be truly representative of the population.

Most studies use the Kasukawa et al criteria as they do not exclude patients with Sm positivity, and quantitative values for U1 RNP are not needed.[21],[23],[24] The prevalence of MCTD depends on the criteria used.[10] In Smolen and Steiner's cohort (Alarcon-Segovia criteria) only 70 % satisfied the Sharp criteria.[10] If we had used the Sharp criteria, two patients who were Sm-positive would have been excluded.

Arthritis and Raynaud's phenomenon were the most common clinical features noted in our cohort. This was in concordance [Table - 2] with the studies from Chennai, North America, Netherlands and the United Kingdom (UK).[21],[23],[24],[27] However Raynaud's phenomenon was not present in all patients. Erosive arthritis was not seen in our study while 7/39 patients (17.9%) had the same in the UK study.[23] Due to the short duration of disease in our cohort the prevalence of ILD and PAH was significantly low in our study. It has been observed that clinical and serological features of MCTD evolve over time.[10],[23],[24],[25] In the study from North America (Burdt et al ), only 9% of patients had pulmonary hypertension at the time of diagnosis (mean duration of 3 years from onset of symptoms) while 23% cumulative cases [Table - 2] were present during 15 years of follow-up.[24] HRCT and cardiac catheterization were not done in all patients, possibly, resulting in missing a few cases of sub clinical ILD and PAH.

The prevalence of sicca symptoms has been reported to be more than 40% in most studies.[23],[26] In our cohort 4/13 (30.8%) patients had sicca symptoms. Of these only two had SSA antibodies, which was similar to the results of the study by Setty et al .[26] Renal manifestations were notably absent. Apart from anti-Sm antibodies, present in two patients, none of the disease-specific antibodies were positive in our cohort. None of the patients were positive for anti-dsDNA antibodies as was seen in the Nedumaran et al study.[21] Anti-dsDNA positivity of 7.7% and 27% has been reported.[23],[25] The higher values reported in studies are cumulative values over the study period, ten years on an average. Anti-dsDNA, Sm and U1 RNP were not done using ELISA, a better technique for them and used in most studies.[27]

MCTD has been shown to evolve over many years and a follow-up study is warranted to identify the same in our patients. The present study gives us an insight in to the clinical and serological features of early MCTD patients from India and the similarities and differences with those from other ethnicities.

 :: Conclusion Top

MCTD is not a rare entity in India. PAH and ILD are not common early in the course of MCTD. Long-term prospective studies with immunogenetic assays are needed for analysing the differentiation of MCTD in Indian patients.

 :: References Top

1.Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective issue disease: An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen. Am J Med 1972;52:148-59.  Back to cited text no. 1  [PUBMED]  
2.Hassfeld W, Steiner G, Studnicka-Benke A, Skriner K, Graninger W, Fischer I, et al. Autoimmune response to the spliceosome. An immunologic link between rheumatoid arthritis, mixed connective tissue disease and systemic lupus erythematosus. Arthritis Rheum 1995;38:777-85.  Back to cited text no. 2  [PUBMED]  
3.Sharp PA. Splicing of messenger RNA precursors. Science 1987;235:766-71.  Back to cited text no. 3  [PUBMED]  
4.Newman A. RNA splicing. Activity in the spliceosome. Curr Biol 1994;4:462-4.  Back to cited text no. 4  [PUBMED]  
5.Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol 2000;12:386-90.  Back to cited text no. 5  [PUBMED]  
6.Pettersson I, Wang G, Smith EI, Wigzell H, Hedfors E, Horn J, et al . The use of immunoblotting and immunoprecipitation of (U) small nuclear ribonucleoproteins in the analysis of sera of patients with mixed connective tissue disease and systemic lupus erythematosus: a cross-sectional, longitudinal study. Arthritis Rheum 1986;29:986-96.  Back to cited text no. 6    
7.Sharp GC, Irvin WS, May CM, Holman HR, McDuffie FC, Hess EV, et al . Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective tissue diseases, systematic lupus erythematosus and other rheumatic diseases. N Engl J Med 1976;295:1149-54.  Back to cited text no. 7    
8.Citera G, Lazaro MA, Maldonado Cocco JA. Mixed connective tissue disease: fact or fiction? Lupus 1995;4:255-7.  Back to cited text no. 8  [PUBMED]  
9.Isenberg D, Black C. Naming names! Comment on article by Smolen and Steiner. Arthritis Rheum 1999;42:191-6.  Back to cited text no. 9  [PUBMED]  
10.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. 10  [PUBMED]  
11.McHugh N, James I, Maddison P. Clinical significance of antibodies to a 68 kd U1 RNP polypeptide in connective tissue diseases. J Rheum 1990;17: 1320-8.  Back to cited text no. 11  [PUBMED]  
12.Nimelstein SH, Brody S, McShane D, Holman HR. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine (Baltimore) 1980;59:239-48.  Back to cited text no. 12  [PUBMED]  
13.Bodolay E, Gaal J, Vegh J, Soltesz P, Szodoray P, Lakos G, et al. Evaluation of survival in mixed connective tissue disease (MCTD). Orv Hetil. 2002;143:2543-8.  Back to cited text no. 13  [PUBMED]  
14.Sullivan WD, Hurst DJ, Harmon CE, Esther JH, Agia GA, Maltby JD, et al . A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine 1984;63:92-107.  Back to cited text no. 14    
15.Jones MB, Osterholm RK, Wilson RB, Martin FH, Commers JR, Bachmayer JD. Fatal pulmonary hypertension and resolving immune-complex glomerulonephritis in mixed connective tissue disease. A case report and review of the literature. Am J Med 1978;65:855-63.  Back to cited text no. 15  [PUBMED]  
16.Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002;45:225-34.  Back to cited text no. 16  [PUBMED]  
17.Okawa-Takatsuji M, Aotsuka S, Fujinami M, Uwatoko S, Kinoshita M, Sumiya M. Up-regulation of intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and class II MHC molecules on pulmonary artery endothelial cells by antibodies against U1-ribonucleoprotein. Clin Exp Immunol 1999;116:174-80.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Takaono M, Iwasaki K, Kinoshita M, et al. Endothelial cell-binding activity of anti-U1-ribonucleoprotein antibodies in patients with connective tissue diseases. Clin Exp Immunol 2001;126:345-54.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Bodolay E, Csipo I, Gal I, Sipka S, Gyimesi E, Szekanecz Z, et al. Anti-endothelial cell antibodies in mixed connective tissue disease: frequency and association with clinical symptoms. Clin Exp Rheumatol. 2004;22:409-15.  Back to cited text no. 19  [PUBMED]  
20.Sood A, Kumar A, Pande I, Malaviya AN. Does mixed connective tissue disease exist in India? Br J Rheumatol 1995;34:539-41.  Back to cited text no. 20  [PUBMED]  
21.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. 21  [PUBMED]  
22.Soriano ER, McHugh NJ. Overlap syndromes in adults and children. In Issenberg DA, Maddison PJ, Woo P, Glass D and Breedveld FC (Editors.): Oxford textbook of rheumatology (3rd Edn.). Oxford:OUP; 2004, p. 998-1010.   Back to cited text no. 22    
23.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 follow up of 46 patients. Arthritis Rheum 1995;38:259-66.  Back to cited text no. 23  [PUBMED]  
24.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. 24  [PUBMED]  
25.Hoffman RW, Cassidy JT, Takeda Y, Smith-Jones EI, Wang GS, Sharp GC. U1-70kd Autoantibody-positive mixed connective tissue disease in children. A longitudinal clinical and serological analysis. Arthritis Rheum 1993;36:1599-602.  Back to cited text no. 25  [PUBMED]  
26.Setty YN, Pittman CB, Mahale AS, Greidinger EL, Hoffman RW. Sicca symptoms and Anti-SSA/Ro antibodies are common in Mixed Connective Tissue Disease. J Rheumatol 2002;29:487-9.  Back to cited text no. 26  [PUBMED]  [FULLTEXT] Rooij DJ, Habets WJ, van de Putte LB , Hoet MH, Verbeek AL, van Venrooij WJ. Use of recombinant RNP peptides 70K and A in an ELISA for measurement of antibodies in mixed connective tissue disease: a longitudinal follow up of 18 patients. Ann Rheum Dis 1990;49:391-5.  Back to cited text no. 27  [PUBMED]  


[Table - 1], [Table - 2]

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