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Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 34-40

Isolated pulmonary hypertension without interstitial lung disease with progressive dyspnea in young female needs connective tissue diseases workup: A case report with review of the literature

Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission24-Apr-2022
Date of Decision12-May-2022
Date of Acceptance20-May-2022
Date of Web Publication12-Aug-2022

Correspondence Address:
Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/japt.japt_11_22

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Obstructive airway disease is the leading cause of breathlessness in young patients and in the absence of atopy or chest radiograph abnormalities such as nontubular heart and enlarged pulmonary artery mandates more workup. Pulmonary manifestations of mixed connective tissue disease (MCTD) range from bronchiolitis and bronchiectasis to interstitial lung disease and pulmonary hypertension. In this case report, a 25 year old female, presented with progressive dyspnoea and received treatment in line of obstructive airway disease with inhaled bronchodilators with inhaled corticosteroids with clinical worsening and no treatment response even after 24 months with good compliance. Radiological workup documented cardiomegaly with enlarged pulmonary artery in chest X-ray, multidetector computed tomography (MDCT) thorax documented grossly enlarged pulmonary arteries with dilated right heart chambers, and echocardiography documented severe pulmonary hypertension with dilated right atrium and right ventricle. Vasculitis and connective tissue diseases (CTD) workup was documented as strongly positive antinuclear antibody (ANA) with very highly raised titers, with other parameters in ANA blot documented positive antigens such as U1-small nuclear ribonucleoprotein particle, SSA/RO, single-strand DNA, and Scl-70. We have started on tadalafil, ambrisentan, and diuretics, and documented clinical response with increased work performance with improved quality of life with stabilization of pulmonary artery pressures on echocardiography at 12 weeks of treatment. We recommend young female genders with progressive dyspnea with nontubular heart on chest radiograph with or without enlarged pulmonary artery needs prompt workup such as high-resolution computed tomography/MDCT thorax, echocardiography, and ANA blot for early pickup of underlying CTD/MCTD to have successful treatment outcome.

Keywords: Connective tissue diseases, interstitial lung disease, mixed connective tissue disease, progressive dyspnea young female, pulmonary hypertension

How to cite this article:
Patil S, Narwade G, Acharya A. Isolated pulmonary hypertension without interstitial lung disease with progressive dyspnea in young female needs connective tissue diseases workup: A case report with review of the literature. J Assoc Pulmonologist Tamilnadu 2022;5:34-40

How to cite this URL:
Patil S, Narwade G, Acharya A. Isolated pulmonary hypertension without interstitial lung disease with progressive dyspnea in young female needs connective tissue diseases workup: A case report with review of the literature. J Assoc Pulmonologist Tamilnadu [serial online] 2022 [cited 2023 Jan 27];5:34-40. Available from: http://www.japt.com/text.asp?2022/5/1/34/353739

  Introduction Top

Mixed connective tissue disease (MCTD) was first described in 1972 by Sharp et al. conducting a study on 25 patients who had clinical characteristics of several rheumatic diseases: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and polymyositis (PM).[1],[2] Extractable nuclear antigen now called ribonucleoproteins (RNPs) are a group of cytoplasmic and nuclear antigens of which anti-U1RNP is the characteristic of MCTD. The common feature of these patients is that they possessed anti-U1RNP in very high titers above 1:1000. All were anti-Smith negative, and unlike the SLE patients were anti-RNP positive but with lower values.[2],[3] Another finding was that there was no renal involvement. Antinuclear antibodies (ANA) had speckled pattern predominance unlike patients with SLE.[1] The epidemiology shows a clear female predominance 5:1.[4] The incidence of cases varies in each region from 0.2 to 0.8 cases per 100,000 people.[5],[6],[7]

  Case Report Top

A 25-year-old female, homemaker, no addiction history, normotensive, nondiabetic, referred to our center by a family physician for shortness of breath which is persistent and progressive of 24-month duration, received symptomatic treatment initially with oral and inhaled bronchodilators with systemic steroids from multiple general physicians consultations during the mentioned period with partial response initially and then shown the progression of symptoms with worsening of daily activities with impaired quality of life. She was evaluated with chest X-ray by multiple consolations and reported as a normal chest radiograph as per the accompanying relatives, and they have shown prescriptions regarding oral and inhaled bronchodilators with other medicines for relief of symptoms.

Further clinical details

  1. Dyspnea/shortness of breath: progressed over 2 years, initially MMRC Grade I and progressed to Grade IV over 2 years, associated with palpitations and chest discomfort. She was too breathless and complained of breathless during dressing/undressing and routine activities at home
  2. Fatigability for 3 months: she walks for few steps and sits down due to fatigability and later on for few days before hospitalization unable to perform any activity without breathlessness
  3. She was not having fever, weight loss, or decreased appetite

Clinical examination documented as Thin, cachexic built, and pallor present, with no evidence of cyanosis, icterus, clubbing, or lymphadenopathy, and heart rate is 120/min, respiratory rate is 26/breath per minute, blood pressure is 110/70 mmHg, resting room air oxygen saturation (PsO2) is 91%–94%, and 89%–91% on exertion. Respiratory system examination revealed bilateral breath sounds normal and adventitious sounds as bilateral crepitation's heard on both lung fields. Other systemic examinations as central nervous system, cardiovascular and gastrointestinal systems were normal.

We, further ask for more history regarding the progression of disease over the past 24 months, her husband told her regarding joint pain and stomatitis before 5 years of these symptoms, received treatment for the same with steroids, and resolved over 1-year. The patient disclosed that she was having fatigability with shortness of breath, and documented hypothyroidism as etiology for her manifestations and received treatment with thyroid replacement therapy. For recurrent stomatitis and dry cough, she consulted many general physicians and received symptomatic treatment for the same without any response. She was also referred for neuropsychiatric consultations for symptoms as she was not responding to any medicines and her condition is worsening due to decreased appetite. She was never evaluated in the past 2 years with a protocolized approach for breathlessness.

  • Laboratory examination documented as-
  • Hemoglobin −8.6 gm% total white blood cells −9000/mm3 Polymorphs −60%, Platelet count −490000/uL.
  • CRP-48 mg/L (0–6 mg/L), random blood sugar level-141 mg% HbA1C-5.70%.
  • LDH-780 IU/L (70–470 IU/L), Uric acid-10.8 mg (3.5–7.5 mg/dL).
  • Serum electrolytes: Sodium-139 mEq/L (135–145 mEq/L) Potassium-3.8 mEq/L (3.5–5.5 meq/L) Ionic calcium-1.22 mEq/L (1.09–1.36 mEq/L).
  • D-dimer-490 ng/ml (<500 ng/ml).
  • IL-6–29.75 pg/ml (0.00–7.00 pg/ml).
  • Thyroid functions-normal liver and kidney functions-normal.
  • Induced sputum examination for acid-fast bacilli was negative and TB GeneXpert MTB/RIF was negative for MTB genome.
  • COVID-19 RT-PCR (reverse transcription-polymerase chain reaction) test and results documented Negative for SARSCoV2.

Chest X-ray was done and showed an enlarged cardiac silhouette with an enlarged descending pulmonary artery and near-normal bilateral lung fields [Figure 1] electrocardiogram is showing sinus tachycardia [Figure 2].
Figure 1: Chest X-ray PA

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Figure 2: ECG. ECG: Electrocardiography

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As clinical findings and chest X-ray suggestive of cardiomegaly with enlarged pulmonary artery, we have analyzed with echocardiography, high-resolution computed tomography (HRCT) thorax, and multidetector computed tomography (MDCT) thorax to rule out the lung parenchymal and pulmonary vasculature abnormality, respectively.

Electrocardiography was documented as sinus tachycardia with the left ventricular strain pattern [Figure 3], and echocardiography analysis revealed pulmonary hypertension.
Figure 3: Echocardiograph

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Echocardiography reported as-[Figure 3].

  • All valves normal
  • Dilated RA and RV with global RV hypokinesia with apical scarring
  • Other chambers normal in size
  • Dilated main pulmonary artery
  • IAS and IVS intact
  • Normal LV function and no regional wall motion abnormality
  • LVEF‒60%
  • Diastolic function Grade 1 diastolic dysfunction
  • Evidence of severe PH (pulmonary hypertension) right ventricular systolic pressure by TR (tricuspid regurgitation) jet 100 mmHg, IVC dilated and noncollapsing, and no evidence of clot/vegetation or embolus [Figure 3].

Computed tomography pulmonary angiography and multidetector computed tomography thorax documented as-[Figure 4], [Figure 5], [Figure 6], [Figure 7]
Figure 4: Contrast CT thorax mediastinal window showing Enlarged main pulmonary trunk >2.5 cm at carina

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Figure 5: Contrast CT thorax showing grossly enlarged pulmonary arteries with dilated right atrium (RA) and right ventricle (RV)

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Figure 6: Contrast CT thorax showing Gross pulmonary hypertension with dilated right atrium (RA) and right ventricle (RV)

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Figure 7: Contrast CT thorax showing enlarged pulmonary arteries with segmental and subsegmental branches with normal contarst uptake without any filling defect

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  1. Enlarged main pulmonary trunk >2.5 cm, documented at the carina, i.e., division of trachea into the right and left main stem bronchus [Figure 4] and [Figure 5]
  2. Gross pulmonary hypertension with a dilated right atrium and right ventricle [Figure 4] and [Figure 5]
  3. No pleural effusion [Figure 4], [Figure 5], [Figure 6], [Figure 7]
  4. Minimal pericardia effusion [Figure 6]
  5. No obvious pulmonary embolism, i.e., near-complete or partial filling defect or areas of hypoattenuation in the main pulmonary trunk, main pulmonary arteries (right and left), lobar, segmental, or subsegmental pulmonary arteries on both sides [Figure 7]
  6. No mediastinal lymphadenopathy [Figure 4] and [Figure 7]
  7. The left atrium and left ventricle normal [Figure 5] and [Figure 6].

High-resolution computed tomography thorax documented

  1. Airways, trachea, and main stem bronchi appear to be normal and no intraluminal or extraluminal abnormality [Figure 8]
  2. Lung parenchyma appears to be normal on both lungs in the upper, middle, and lower lobes [Figure 9]
  3. Overall lung window findings are normal. [Figure 9]
Figure 8: HRCT thorax with normal lung parenchyma and enlarged pulmonary arteries.

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Figure 9: HRCT thorax with normal central airways and normal lung parenchyma in both lungs in all lobes

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As the workup is proceeding toward pulmonary hypertension as the underlying pathology for her symptoms and worsening of breathlessness, we have evaluated CTD workup.

Connective tissue diseases and vasculitis workup as

  • MPO-ANCA (C-ANCA) ‒ 0.86 RU/ml (normal range 0–20 RU/ml)
  • PR3-ANACA (P-ANCA) ‒ 0.90 RU/ml (normal range 0–20 RU/ml)
  • antinuclear antibody (ANA) ‒ strongly positive, 1:1000 titer pattern-homogenous, grade +++.

Antinuclear antibody blot reported as

  • U1-small nuclear RNP particle (U1-snRNP) = Positive
  • Single strand DNA = Positive
  • Scl-70 = Positive.

(Other target antigens such as Jo-1, SSA/RO, SS-B/La, RNP-A, RNP-C, RNP-68, SmB, SmD, centromere B, centromere A, PL-7, PL-12, ribosomal protein P0, PCNA, histones, and dsDNA).

We have stopped previously ongoing inhaled steroids with bronchodilators and started rational treatment as pulmonary vasodilators with tablet tadalafil 20 mg OD, ambricentan 5 mg OD for 12 weeks with mycophenolate mofetil in starting dose of 500 mg OD and increased to 500 mg TDS over next 3 weeks and continued it for 12 weeks. We have also added furosemide with aldactone (20 + 50) OD and tablet clopidogrel 75 OD for 12 weeks, with oxygen supplementation given during rest and ambulation for first 3 weeks, assessed and documented benefit and then continued oxygen supplementation during the night for 12 weeks, with monitoring of serum electrolytes, kidney and liver function tests. Strict monitoring of hemogram and renal and liver function tests were done weekly for the 1st month and then monthly till 3 months, and we have assessed with chest radiograph [Figure 10] and echocardiography at 12 weeks was documented with satisfactory clinical response.
Figure 10: Chest X-ray

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Chest X-ray is showing the decreased size of enlarged cardiac silhouette with enlarged right descending pulmonary artery [Figure 10].

After 3 months, we have continued oral disease-modifying agents such as mycophenolate mofetil 500 mg OD with tadalafil 20 mg OD, ambrisentan 5 mg OD, Dytor plus LS 10 OD, and clopidogrel 75 mg OD as maintenance therapy with 3-month follow-ups.

We have documented as-

  1. Improved exercise capacity and now she can walk up to 450 meters with nil to minimal breathlessness
  2. Pulmonary artery pressures decreased to <50 on echocardiography
  3. No pericardial effusion
  4. Improved quality of life
  5. Able to perform all routine activities with no breathlessness
  6. Resting heart rate, oxygen saturation, and respiratory rate are normal with acceptable increase in parameters with exercise.

  Discussion Top

MCTD was initially described by Sharp et al. MCTD was first reported as a mild overlap disease with the features of different autoimmune connective tissue diseases (CTDs) namely, SSc, poly/dermatomyositis, and SLE in patients with antibodies targeting the U1-snRNP.[1]

Although MCTD was previously considered a subtype of SSc, it has recently been recognized as an independent disease entity in terms of organ involvement due to its characteristic association with conditions such as pulmonary arterial hypertension, aseptic meningitis, and trigeminal neuropathy.[8],[9],[10],[11]

In 1986, the MCTD criteria were first proposed by Kasukawa as representatives of the research committee for MCTD of the Ministry of Health and Welfare in Japan during an International Symposium on MCTD and anti-nuclear antibodies.[12] However, in Europe and the United States, the disease concept of MCTD is sometimes far from being sufficiently acknowledged. Furthermore, in cases of changing pathological conditions over the clinical course, no consensus has been reached on to what extent pathological changes are included in the concept of MCTD, and whether the overlapping manifestations of SLE and MCTD are acceptable.[13]

Diagnostic criteria for MCTD 2019, from the Japan Research Committee of the Ministry Of Health, Labor, and Welfare for systemic autoimmune diseases:[14]

I. Common manifestations

1.Raynaud's phenomenon

2.Puffy fingers and/or swollen hands.

II.Immunological manifestation Positivity for anti-U1 ribonucleoprotein antibody

III. Characteristic organ involvement

1.Pulmonary arterial hypertension

2.Aseptic meningitis

3.Trigeminal neuropathy.

IV.Overlapping manifestations

A.Systemic lupus erythematosus-like manifestations



3.Malar rash

4.Pericarditis or pleuritis

5.Leukopenia (4,000/lL or less) or thrombocytopenia (100,000/lL or less).

B.Systemic sclerosis-like manifestations


2.Interstitial lung disease

3.Esophageal dysmotility or dilatation.

C.Polymyositis/Dermatomyositis-like manifestations

1.Muscle weakness

2.Elevated levels of myogenic enzymes

3.Myogenic abnormalities on electromyogram.

The treatment of MCTD shares many aspects in common with that of SLE, SSc, and PM/dermatomyositis, such that therapeutic components specific to MCTD are limited.[8],[9],[10],[11] This is also attributable to the small number of articles on MCTD because some rheumatologists in Europe and the United States do not acknowledge the disease concept of MCTD.[14] Thus, the diagnosis of MCTD is often made in a clinical setting by judgment based on the expertise of physicians. Meanwhile, with the exception of pulmonary arterial hypertension, the prognosis of MCTD is better than that of SLE and PM/dermatomyositis associated with interstitial pneumonitis. There are even some cases in which bolus corticosteroid therapy is not essential. The treatment of MCTD also shares many aspects with other CTDs.

In the present case report, we have documented MCTD and treated its thoracic manifestations as isolated pulmonary hypertension without lung parenchymal involvement with pulmonary vasodilators tadalafil with ambrisentan, diuretics, and disease-modifying agents' mycophenolate mofetil.

Key learning points from this case report are

  1. Isolated pulmonary hypertension without lung parenchymal abnormality with progressive dyspnea needs aggressive workup to differentiate between pulmonary embolism to CTD-related pulmonary arteriopathy
  2. Thoracic manifestations of MCTD are diverse with the involvement of airways, lung parenchyma, interstitium, pulmonary vasculature, and pleura
  3. Many cases with MCTD are having interstitial lung disease with pulmonary hypertension, and isolated pulmonary hypertension is very well described in MCTD and SSc
  4. Although obstructive airway disease is the most common cause of shortness of breath or dyspnea in young patients, progressive nature with enlarged cardiac silhouette with enlarged pulmonary artery indicates underlying pulmonary hypertension
  5. Radiological marker of pulmonary hypertension over chest X-ray shows nontubular heart or enlarged cardiac silhouette with enlarged right descending pulmonary artery
  6. Radiological marker of pulmonary hypertension over contrast CT thorax or MDCT suggestive of enlarged pulmonary trunk diameter > 2.5 cm or diameter equal or more to the diameter of ascending aorta measured at carina level CT section.
  7. Pulmonary hypertension without lung parenchymal abnormality with enlarged pulmonary artery is a radiological clue to rule out CTD/MCTD and echocardiography is a simple bedside noninvasive test to document pulmonary hypertension with dilated right heart chambers as the right atrium and right ventricle
  8. ANA is simple, sensitive test and high titers signify toward underlying CTD, also it will help in guiding to workup CTD panel for exact typing of CTD which will help in differentiating and planning treatment.
  9. Although steroids and mycophenolate mofetil are the cornerstone of the treatment of MCTD with intestinal lung disease with pulmonary hypertension, isolated pulmonary hypertension can be managed with pulmonary vasodilators such as PDE5 inhibitors such as tadalafil and endothelin receptor antagonists such as ambrisentan with antiplatelets.
  10. We recommend young female genders with progressive dyspnea with nontubular heart on chest radiograph with or without enlarged pulmonary artery needs prompt workup such as HRCT/MDCT thorax, echocardiography, and ANA blot for early pickup of underlying CTD/MCTD to have successful treatment outcome.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Sharp GC, Irvin WS, LaRoque RL, Velez C, Daly V, Kaiser AD, et al. Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest 1971;50:350-9.  Back to cited text no. 1
Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52:148-59.  Back to cited text no. 2
Hoffman RW, Sharp GC, Deutscher SL. Analysis of anti-U1 RNA antibodies in patients with connective tissue disease. Association with HLA and clinical manifestations of disease. Arthritis Rheum 1995;38:1837-44.  Back to cited text no. 3
Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, et al. Epidemiology of mixed connective tissue disease, 1985-2014: A population-based study. Arthritis Care Res (Hoboken) 2016;68:1843-8.  Back to cited text no. 4
Kaipiainen-Seppanen O, Aho K. Incidence of rare systemic rheumatic and connective tissue diseases in Finland. J Intern Med 1996;240:81-4.  Back to cited text no. 5
Weckmann AL, Granados J, Cardiel MH, Andrade F, Vargas-Alarcón G, et al. Immunogenetics of mixed connective tissue disease in a Mexican Mestizo population. Clin Exp Rheumatol 1999;17:91-4.  Back to cited text no. 6
Gunnarsson R, Molberg O, Gilboe IM, Gran JT; PAHNOR1 Study Group. The prevalence and incidence of mixed connective tissue disease: A national multicentre survey of Norwegian patients. Ann Rheum Dis 2011;70:1047-51.  Back to cited text no. 7
Dima A, Jurcut C, Baicus C. The impact of anti-U1-RNP positivity: Systemic lupus erythematosus versus mixed connective tissue disease. Rheumatol Int 2018;38:1169-78.  Back to cited text no. 8
Gunnarsson R, Hetlevik SO, Lilleby V, Molberg Ø. Mixed connective tissue disease. Best Pract Res Clin Rheumatol 2016;30:95-111.  Back to cited text no. 9
Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: An overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol 2012;26:61-72.  Back to cited text no. 10
Tani C, Carli L, Vagnani S, Talarico R, Baldini C, Mosca M, et al. The diagnosis and classification of mixed connective tissue disease. J Autoimmun 2014;48-49:46-9.  Back to cited text no. 11
Kasukawa R. Mixed connective tissue disease. Intern Med 1999;38:386-93.  Back to cited text no. 12
Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. “To be or not to be,” ten years after: Evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 2012;41:589-98.  Back to cited text no. 13
Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro Y, Fujio K, et al. Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases. Mod Rheumatol 2021;31:29-33.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]


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