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

Abstract

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.
Rheumatology unit of a tertiary care centre in India; prospective.
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.
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 Raynaud's 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.
Pulmonary artery hypertension is not common in early MCTD.

Full text

Page 1

104
J Postgrad Med June 2005 Vol 51 Issue 2
?
?
Pulm onary hypertension not a m ajor feature of earlyPulm onary hypertension not a m ajor feature of early
Pulm onary hypertension not a m ajor feature of earlyPulm onary hypertension not a m ajor feature of early
Pulm onary hypertension not a m ajor feature of early
m ixed connective tissue disease: A prospectivem ixed connective tissue disease: A prospective
m ixed connective tissue disease: A prospectivem ixed connective tissue disease: A prospective
m ixed connective tissue disease: A prospective
clinicoserological studyclinicoserological study
clinicoserological studyclinicoserological study
clinicoserological study
Haroon N, Nisha RS, Chandran V, Bharadwaj A
Original Article
ABSTRACTABSTRACT
ABSTRACTABSTRACT
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 Raynaud’s 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.
KEY WORDS: Overlap syndrome, Interstitial lung disease, Myositis, Scleroderma, Lupus
ixed connective tissue disease (MCTD) was described
more than 30 years ago and has clinical features com-
mon to systemic lupus erythematosus (SLE), progressive sys-
M
temic sclerosis (PSS) and inflammatory myositis.[1] There is
an antibody response to the spliceosome complex, involved in
the processing of pre messenger RNA.[2-4] An antibody against
the uridine-rich U1 ribonucleoprotein (U1 RNP) character-
izes 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 haemaggluti-
nation.[7]
Unlike SLE and PSS, MCTD was considered to have a rela-
tively 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.[8-10] 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]
Immunology-Rheumatol-
ogy Unit, Kasturba
Medical College, Manipal
- 576 104, India
Correspondence:
Anurag Bharadwaj,
E-mail:
anurag_bharadwaj@hotmail.com
Received: 12-01-05
Review completed : 02-03-05
Accepted: 06-04-05
PubMed ID: 16006700
J Postgrad Med 2005;51:104-8
www.jpgmonline.com
Pulmonary artery hypertension (PAH), reported in an increas-
ing number of patients, is the predominant cause for morbid-
ity and mortality.[14-16] 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 anti-
bodies 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 find-
ing 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
This prospective study was conducted in the rheumatology clinic of
a tertiary care centre in southern India, a major referral centre for

Page 2

105
J Postgrad Med June 2005 Vol 51 Issue 2
?
?
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 myosi-
tis and arthritis. A blanket serology of all patients was not done. Pa-
tients 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 diffu-
sion 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. Pulmo-
nary 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) test-
ing 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 labora-
tory 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. My-
ositis 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
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 pa-
tients satisfied the inclusion criteria at presentation and de-
veloped 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 af-
ter 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 inter-
stitial lung disease (ILD) and HRCT in both showed honey-
combing and increased septal thickness in the basal regions of
both lungs. Dysphagia was present in three patients. Two pa-
tients 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 anae-
mia (Haemoglobin < 120 g/L). One patient each had monon-
euritis 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 phenom-
enon 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 spe-
cific drugs were prescribed for the same and no surgical proce-
dures were done. Myositis and ILD were not presenting mani-
festations 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 posi-
tive in six patients (46.15%), all of whom had arthritis.
Discussion
MCTD formed 0.87% of patients with rheumatism at our cen-
tre. The prevalence of MCTD among patients with rheuma-
tism 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
Table 1: Diagnostic criteria for mixed connective tissue
disease
Common symptoms
1. Raynaud’s Phenomenon
2. Swollen fingers or hands
Presence of Anti U1 RNP
Mixed findings
A. SLE like
Polyarthritis
Pericarditis/pleuritis
Lymphadenopathy
Facial erythema
Leucopenia/thrombocytopenia
B. Scleroderma like
Sclerodactyly
Pulmonary fibrosis
Esophageal dysmotility
C. Polymyositis like
Muscle weakness
High CPK
Myopathic EMG
Requirement for diagnosis: At least one common symptom, with
positive U1 RNP antibodies and one or more findings in at least two of
the three categories A, B and C.
Haroon et al: Pulm onary hypertension in m ixed connective tissue disease

Page 3

106
J Postgrad Med June 2005 Vol 51 Issue 2
?
?
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 repre-
sentative 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 co-
hort (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, Neth-
erlands and the United Kingdom (UK).[21,23,24,27] However Ray-
naud’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 sig-
nificantly 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 pa-
tients 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 fol-
low–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%) pa-
tients had sicca symptoms. Of these only two had SSA anti-
bodies, 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 dis-
ease-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 re-
ported 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 fol-
low-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
MCTD is not a rare entity in India. PAH and ILD are not com-
mon early in the course of MCTD. Long-term prospective stud-
ies with immunogenetic assays are needed for analysing the
differentiation of MCTD in Indian patients.
References
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.
2. Hassfeld W, Steiner G, Studnicka-Benke A, Skriner K, Graninger W, Fischer I,
et al. Autoimmune response to the spliceosome. An immunologic link be-
tween rheumatoid arthritis, mixed connective tissue disease and systemic
lupus erythematosus. Arthritis Rheum 1995;38:777-85.
3.Sharp PA. Splicing of messenger RNA precursors. Science 1987;235:766-
71.
4.Newman A. RNA splicing. Activity in the spliceosome. Curr Biol 1994;4:462-
4.
5.Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin
Rheumatol 2000;12:386-90.
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, longi-
tudinal study. Arthritis Rheum 1986;29:986-96.
7.Sharp GC, Irvin WS, May CM, Holman HR, McDuffie FC, Hess EV, et al. Asso-
ciation of antibodies to ribonucleoprotein and Sm antigens with mixed con-
nective tissue diseases, systematic lupus erythematosus and other rheu-
matic diseases. N Engl J Med 1976;295:1149-54.
8.Citera G, Lazaro MA, Maldonado Cocco JA. Mixed connective tissue dis-
ease: fact or fiction? Lupus 1995;4:255-7.
9. Isenberg D, Black C. Naming names! Comment on article by Smolen and
Steiner. Arthritis Rheum 1999;42:191-6.
10.Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be?
Arthritis Rheum 1998;41:768-77.
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.
12.Nimelstein SH, Brody S, McShane D, Holman HR. Mixed connective tissue
disease: a subsequent evaluation of the original 25 patients. Medicine (Bal-
timore) 1980;59:239-48.
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.
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.
15. Jones MB, Osterholm RK, Wilson RB, Martin FH, Commers JR, Bachmayer
JD. Fatal pulmonary hypertension and resolving immune-complex glomeru-
lonephritis in mixed connective tissue disease. A case report and review of
Table 2: Comparison of clinical profile of patients with past studies
Clinical featureOur Study (India) Nedumaran (India) Burdt (USA) de Rooij (Netherlands) Gendi (UK)
n=13n=8n=47 n=18n=39
Arthritis11 (84.62) 8 (100) 45 (96) 18 (100)31 (80)
Raynaud’s phenomenon9 (69.23) 8 (100) 45 (96)18 (100)39 (100)
Sclerodactyly 8 (61.54)8 (100) 23 (49) 10 (56)17 (44)
Interstitial lung disease2 (15.38) 6 (75) 31 (66) 9 (50)10 (26)
Myositis2 (15.38)6 (75) 24 (51) 8 (44) 9 (23)
Pulmonary artery hypertension 0 2 (25) 11 (23) NA NA
Keratoconjunctivitis sicca 4 (30.8) NA NA 3 (17)16 (41)
Values indicate number (%), NA: not available
Haroon et al: Pulm onary hypertension in m ixed connective tissue disease

Page 4

107
J Postgrad Med June 2005 Vol 51 Issue 2
?
?
the literature. Am J Med 1978;65:855-63.
16.Fagan KA, Badesch DB. Pulmonary hypertension associated with connec-
tive tissue disease. Prog Cardiovasc Dis 2002;45:225-34.
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-ribonucleopro-
tein. Clin Exp Immunol 1999;116:174-80.
18.Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Takaono M, Iwasaki K, Kinoshita
M, et al. Endothelial cell-binding activity of anti-U1-ribonucleoprotein anti-
bodies in patients with connective tissue diseases. Clin Exp Immunol
2001;126:345-54.
19.Bodolay E, Csipo I, Gal I, Sipka S, Gyimesi E, Szekanecz Z, et al. Anti-en-
dothelial cell antibodies in mixed connective tissue disease: frequency and
association with clinical symptoms. Clin Exp Rheumatol. 2004;22:409-15.
20.Sood A, Kumar A, Pande I, Malaviya AN. Does mixed connective tissue dis-
ease exist in India? Br J Rheumatol 1995;34:539-41.
21. Nedumaran, Rajendran CP , Porkodi R, Parthiban R. Mixed connective tissue
disease-clinical and immunological profile. J Assoc Physicians India
2001;49:412-4.
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.
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.
24.Burdt MA, Hoffman RW, Deutscher SL, Wang GS, Johnson JC, Sharp GC.
Long-term outcome in mixed connective tissue disease. Longitudinal Clini-
cal and Serologic Findings. Arthritis Rheum 1999;42:899-909.
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.
26.Setty YN, Pittman CB, Mahale AS, Greidinger EL, Hoffman RW. Sicca symp-
toms and Anti-SSA/Ro antibodies are common in Mixed Connective Tissue
Disease. J Rheumatol 2002;29:487-9.
27.de 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 measure-
ment of antibodies in mixed connective tissue disease: a longitudinal follow
up of 18 patients. Ann Rheum Dis 1990;49:391-5.
Haroon et al: Pulm onary hypertension in m ixed connective tissue disease
Im portance of screening and early detection of pulm onary hypertension and current Im portance of screening and early detection of pulm onary hypertension and current
Im portance of screening and early detection of pulm onary hypertension and currentIm portance of screening and early detection of pulm onary hypertension and current
Im portance of screening and early detection of pulm onary hypertension and current
treatm ent options treatm ent options
treatm ent optionstreatm ent options
treatm ent options
Expert’s Comments
have an improved long-term survival with the use of calcium
channel blockers.[3] Prostacyclin derivatives (epoprostenol (IV),
treprostinil (subcutaneous), iloprost (inhaled), beraprost
(oral)) are potent vasodilators with antiplatelet aggregatory
effects that have been shown to primarily improve exercise
tolerance and survival to a lesser extent. Endothelin antago-
nists (bosentan, sitaxsentan, ambrisentan) block endothelin-
1, which is a potent vasoconstrictor and smooth-muscle mi-
togen that might contribute to the increase in vascular tone
and the pulmonary vascular hypertrophy associated with
PAH.[4] Other agents that are currently being evaluated include
phosphodiesterase inhibitors such as dipyridamole and
sildenafil, inhaled nitrous oxide and arginine supplementa-
tion.[5] Surgical techniques including lung transplant remain
the mainstay of treatment for patients with PHT who are un-
responsive to medical management.
Mohan N
University of South Dakota School of Medicine,
Sioux Falls, South Dakota, USA.
E-mail: nmohan@pol.net
References
1.Burdt MA, Hoffman RW, Detuscher 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.
2.McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA. Screen-
ing, early detection and diagnosis of pulmonary arterial hypertension. ACCP
evidence-based clinical practice guidelines. Chest 2004;126:14S-34S.
3. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel
blockers on survival in primary pulmonary hypertension. N Engl J Med
1992;327:76-81.
4.Kim H, Yung GL, Marsh JJ, Konopka RG, Pedersen CA, Chiles PG. Endothelin
mediates pulmonary vascular remodelling in a canine model of chronic em-
bolic pulmonary hypertension. Eur Respir J 2000;15:640-8.
5.Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G.
Medical therapy for pulmonary arterial hypertension. ACCP evidence-based
clinical practice guidelines. Chest 2004;126:35S-62S.
Pulmonary hypertension (PHT), usually a late-stage compli-
cation, is the most common cause of death in mixed connec-
tive tissue disease (MCTD), occurring in up to 38% of pa-
tients.[1] Since PHT does not become clinically manifest until
advanced, even mild elevations in pulmonary arterial pressure
reflect diffuse and extensive vascular damage. Through the
mid-1980s median survival from the date of diagnosis was ap-
proximately 2.8 years. However, several novel therapeutic
agents developed in recent years, have made early detection
and monitoring imperative for improving long-term progno-
sis. ECHO with Doppler ultrasound is the commonest screen-
ing tool and should be performed to establish a baseline at
initial diagnosis of MCTD.[2] Pulmonary function testing (PFT)
including diffusing capacity of the lung for carbon monoxide
(DLCO) is a necessary part of the evaluation of all patients,
primarily to exclude or characterize the contribution of un-
derlying airway or parenchymal lung disease. A fall in DLCO
in a patient with scleroderma/MCTD and normal lung vol-
umes is suggestive of the early development of pulmonary ar-
terial hypertension. PFTs with DLCO should be performed
periodically (every 6-12 months) to improve detection of pul-
monary vascular or interstitial disease with ECHO every 1-2
years, especially if the patient has had symptoms of connec-
tive tissue disease for more than 10 years. Formal assessment
of exercise testing, typically 6-min walk test helps determine
disease severity, response to therapy and progression.[2]
Once the diagnosis of PHT has been established, general ap-
proaches to treatment include supplemental oxygen for
hypoxemia to maintain oxygen saturations >90% at all times,
continuous positive airway pressure therapy and treatment of
other contributing factors such as chronic thromboembolic
disease with warfarin, right ventricular failure with diuretics
and digitalis etc. Patients who respond to vasodilator testing

Page 5

108
J Postgrad Med June 2005 Vol 51 Issue 2
?
?
Delayed developm ent of pulm onary hypertension in m ixed connective tissue diseaseDelayed developm ent of pulm onary hypertension in m ixed connective tissue disease
Delayed developm ent of pulm onary hypertension in m ixed connective tissue diseaseDelayed developm ent of pulm onary hypertension in m ixed connective tissue disease
Delayed developm ent of pulm onary hypertension in m ixed connective tissue disease
tients to those reported in other ethnic groups. Thus far, it is
remarkable that across multiple ethnic groups and multiple
investigators, the prevalence of individual clinical manifesta-
tions in MCTD seems generally similar (at least given the wide
confidence intervals that small sample sizes bring). This sug-
gests that MCTD seen around the world is likely to be linked
by common pathophysiology. If pHTN remains less common
in Indian patients than has been reported in Caucasian and
Japanese cohorts over time,[2,7] immunologic and genetic stud-
ies of this group may help elucidate the factors leading to pHTN
in MCTD. Thus, findings from this new cohort in India are
likely to continue to be of interest to the worldwide MCTD
community.
Greidinger EL
University of Miami Miller School of Medicine and VAMC,
1400 NW 10th Avenue, Suite 602, Miami, FL 33136, USA
Correspondence:
Eric L. Greidinger, E-mail: egreidinger@med.miami.edu
References
1.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;51:104-8.
2.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.
3.Greidinger EL, Hoffman RW. The appearance of U1 RNP antibody specificities
in sequential autoimmune human antisera follows a characteristic order that
implicates the U1-70 kd and B’/B proteins as predominant U1 RNP
immunogens. Arthritis Rheum 2001;44:368-75.
4.Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Kinoshita M, Sumiya M. Increase
of cytokine production by pulmonary artery endothelial cells induced by
supernatants from monocytes stimulated with autoantibodies against U1-
ribonucleoprotein. Clin Exp Rheumatol 1999;17:705-12.
5.Suzuki E, Tsukada H, Ishida T, Ishizuka O, Hasegawa T, Gejyo F. Correlation
between the numbers of gammadelta T cells and CD4+ HLA-DR+ T cells in
broncho-alveolar lavage fluid from patients with diffuse lung disease. Tohoku
J Exp Med 2002;196:231-40.
6.Greidinger EL, Foecking MF, Magee J, Wilson L, Ranatunga S, Ortmann RA,
Hoffman RW. A major B cell epitope present on the apoptotic but not the
intact form of the U1-70-kDa ribonucleoprotein autoantigen. J Immunol
2004;172:709-16.
7.Sasaki N, Kurose A, Inoue H, Sawai T. A possible role of anti-endothelial cell
antibody in the sera of MCTD patients on pulmonary vascular damage relat-
ing to pulmonary hypertension. Ryumachi 2002;42:885-94.
Expert’s Comments
The paper, “Pulmonary hypertension not a major feature of
early mixed connective tissue disease: A prospective
clinicoserological study” published in this issue describes the
clinical manifestations of 13 recently diagnosed patients who
satisfy standard classification criteria for Mixed Connective
Tissue Disease (MCTD), from a cohort of 1500 patients seen
at a rheumatology referral centre in India between 2002 and
2004.[1] Consistent with prior reports that go on to find that it
is ultimately the leading cause of death from MCTD,[2] the
authors find that pulmonary hypertension is seldom present
early in the course of MCTD.
Since the immune response in MCTD has been found to evolve
over time,[3] one potential explanation for the late and incon-
sistent development of pulmonary hypertension in MCTD is
that anti-lung autoimmunity emerges late in the course of the
disease. Reactivity between some RNP autoantibodies (and
other MCTD-associated autoantibodies) and the respiratory
tract has been observed.[4] T cell infiltrates are also seen at
sites of MCTD end organ injury including the lung.[5] The
specificities and evolution of any such anti-lung-specific re-
sponse in MCTD remain to be further defined, however.
The recent development of an animal model of MCTD-like
perivascular and interstitial lung disease after immunization
with an RNP peptide may lead to further insights.[6] In the
mouse model, as has been reported in humans,[7] perivascular
pulmonary inflammatory infiltrates can be observed frequently,
even in the absence of clinical evidence of pulmonary hyper-
tension, and even at time points early in the disease. Thus,
although a lag exists between the clinical expression of pHTN
and other MCTD manifestations, this may be attributable to
the extent of lung injury that must occur before pHTN be-
comes clinically apparent, as opposed to possible delays in the
development of an anti-lung-specific component of the MCTD
immune response.
As their number and duration of follow-up grows, it will be of
relevance to continue to compare the manifestations, pulmo-
nary and otherwise, seen in this cohort of Indian MCTD pa-
Haroon et al: Pulm onary hypertension in m ixed connective tissue disease