Pulmonary hypertension not a major feature of early mixed connective tissue disease: A prospective clinicoserological studyN Haroon, RS Nisha, V Chandran, Anurag Bharadwaj
Immunology-Rheumatology Unit, Kasturba Medical College, Manipal - 576 104, India
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
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. There is an antibody response to the spliceosome complex, involved in the processing of pre messenger RNA. ,, An antibody against the uridine-rich U1 ribonucleoprotein (U1 RNP) characterizes the disease. The antibody reacts with two components of the small nuclear ribonucleoprotein (snRNP), U 1 RNA and 70 K polypeptide. This antigen is the ribonuclease-sensitive fraction of the extractable nuclear antigens (ENA), which was identified initially by enzyme denaturation and haemagglutination.
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. ,, Antibodies to U1 RNP have been identified in other connective tissue diseases. The concept of a good prognosis in MCTD has also not stood the test of time., Pulmonary artery hypertension (PAH), reported in an increasing number of patients, is the predominant cause for morbidity and mortality. ,, 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., Anti-endothelial cell antibodies also have been reported to be higher in patients with active disease.
There is very little data on Indian patients of MCTD and it is considered a rare entity here. The studies on MCTD are case record reviews or cross-sectional studies and not fact finding prospective studies., We prospectively examined the clinical and serological profile of patients with MCTD in a tertiary care centre in India.
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. 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.
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.
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 %)., 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.,, The prevalence of MCTD depends on the criteria used. In Smolen and Steiner's cohort (Alarcon-Segovia criteria) only 70 % satisfied the Sharp criteria. 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).,,, 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. 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.,,, 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. 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., 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 . 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. Anti-dsDNA positivity of 7.7% and 27% has been reported., 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.
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.
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.
[Table - 1], [Table - 2]