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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 2  |  Issue : 2  |  Page : 65-72

Unexplained fever, weight loss, and worsened dyspnea with pulmonary hypertension as the presenting symptoms of mixed connective tissue disease with interstitial lung disease: A case report with review of literature


1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission10-Mar-2022
Date of Acceptance25-Apr-2022
Date of Web Publication17-May-2022

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


DOI: 10.4103/jalh.jalh_9_22

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  Abstract 


Pulmonary manifestations of mixed connective tissue disease (MCTD) include as bronchiolitis, bronchiectasis, and interstitial lung disease with or without pulmonary hypertension. Tuberculosis (TB) is the most common diagnosis in India in the presence of constitutional symptoms such as cough, fever, and weight loss with lung parenchymal abnormality, irrespective of microscopic or nucleic acid amplification test abnormalities due to high tuberculosis prevalent tropical setting. In this case report, a 35 year old female presented with constitutional symptoms and lung parenchymal nodules, interstitial involvement with lung fibrosis and pulmonary hypertension. Mediastinal window documented necrotic mediastinal lymph nodes, without negative mycobacterial microscopic (smear examination) or genome documentation (Gene Xpert MTB/RIF). She had received empirical anti tuberculosis treatment for three months without clinical or radiological response, resulted in progression of disease with clinical and radiological worsening and referred to our unit for further workup. Bronchoscopy guided evaluation for tropical screen including bacterial, fungal and tuberculosis with malignancy was inconclusive. Vasculitis and CTD workup documented antinuclear antibody (ANA) test strongly positive with very highly raised titres, with positive antigen as U1 small nuclear ribonucleoprotein particle, SSA/RO, single strand DNA, and Scl 70. Treatment initiated with systemic steroids, tadalafil, mycophenolate and diuretics, and satisfactory clinical response documented as near complete resolution of pulmonary parenchymal abnormalities in 24 weeks and pulmonary hypertension in 12 weeks. Pulmonary manifestations of MCTD are common, underestimated in the presence of constitutional symptoms, and early pickup of entity in course of illness will have good outcome with excellent prognosis.

Keywords: Dyspnea, mixed connective tissue disease, pulmonary hypertension, unexplained fever


How to cite this article:
Patil S, Gondhali G, Narwade G. Unexplained fever, weight loss, and worsened dyspnea with pulmonary hypertension as the presenting symptoms of mixed connective tissue disease with interstitial lung disease: A case report with review of literature. J Adv Lung Health 2022;2:65-72

How to cite this URL:
Patil S, Gondhali G, Narwade G. Unexplained fever, weight loss, and worsened dyspnea with pulmonary hypertension as the presenting symptoms of mixed connective tissue disease with interstitial lung disease: A case report with review of literature. J Adv Lung Health [serial online] 2022 [cited 2022 Jul 6];2:65-72. Available from: http://www.jalh.com/text.asp?2022/2/2/65/345378




  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-U1 RNP is the characteristic of MCTD. The common feature of these patients is that they possessed anti-U1 RNP in very high titers above 1:1000. All MCTD cases may be anti-Sm antibody negative, and unlike the SLE patients where anti-RNP is positive with lower titres.[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 of 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 Summary Top


A 35 year old female, farmer by occupation, without any addictions, normotensive and nondiabetic, referred to our center by her family physician for constitutional symptoms as persistent fever, cough, and weight loss for 6 months of duration, for which she received symptomatic treatment initially with antibiotics and antipyretics without any clinical response, and further workup with sputum smear microscopy and Gene Xpert MTB/RIF was negative for both smear and MTB genome, and received empirical anti TB treatment for 3 months with progression of illness without clinical and radiological response and finally referred to our center for further workup.

Further clinical details are given below:

  1. Fever – Intermittent, low grade without chills and rigors associated with minimal body ache and headache
  2. Cough – Dry, intermittent, with minimal white sputum production
  3. Loss of appetite and weight loss over a period of 6 months
  4. Weakness and myalgia with fatigability for 2 years
  5. Shortness of breath on exertion for 6 months.


Clinical examination was documented as follows:

  • Thin built, cachexic, pallor+, no cyanosis/icterus/clubbing/lymphadenopathy
  • Hyperpigmented macular areas documented over bilateral malar and forehead areas with frontal baldness and alopecia bilateral eye brows
  • Heart rate - 120/min, respiratory rate: 26/bpm, blood pressure - 110/70 mmHg
  • SpO2: 91%–94% at room air resting and 89%–91% at room air on exertion
  • Respiratory system examination revealed bilateral breath sounds being normal, bilateral crepitation's heard on both lung fields – Velcro type
  • Nervous system examination - Higher functions being normal, no neurological abnormality, cranial nerves being normal, recent and past memory being normal recall
  • Cardiovascular and gastrointestinal systems were normal.


We further asked for more history regarding progression of disease over the last 24 months, her spouse told regarding recurrent low-grade fever and decreased appetite and other constitutional symptoms and multiple consultations for the same. The patient disclosed that she had fatigability with shortness of breath and documented as hypothyroidism as etiology for her manifestations. She was on thyroid replacement therapy for 2 years with no symptomatic relief, and she was started new symptoms as dry cough and recurrent stomatitis. For recurrent stomatitis and dry cough, she consulted many general physicians and received symptomatic treatment for the same without any response. Her breathlessness and cough increased over the last 6 months, and she was diagnosed as sputum-negative pulmonary TB and received anti-TB treatment for 3 months, with no response, hence stopped medicines. Her spouse said that she had small joint pain and throat discomfort for 6 years and received many consultations for the same with partial response.

Laboratory examination was documented as follows:

  • Hemoglobin - 7.6 gm%, total white blood cells - 24,000/mm3, polymorphs - 80%, platelet count - 490,000/μL
  • CRP - 96 mg/L (0–6 mg/L), random blood sugar level - 149 mg%, HbA1c - 5.70%
  • LDH - 880 IU/L (70–470 IU/L), uric acid - 11.4 mg (3.5–7.5 mg/dL)
  • Serum electrolytes: Sodium - 136 mEq/L (135–145 mEq/L), potassium - 3.7 mEq/L (3.5–5.5 mEq/L), ionic calcium - 1.22 mEq/L (1.09–1.36 mEq/L)
  • D-dimer - 590 ng/mL (<500 ng/mL)
  • IL-6-94.75 pg/mL (0.00–7.00 pg/mL)
  • Thyroid functions - Normal
  • Liver and kidney functions - Normal
  • Sputum examination for acid-fast bacilli was negative, and TB Gene Xpert MTB/RIF was negative for MTB genome
  • COVID-19 RT-PCR test results were negative for SARS-CoV-2
  • Chest X-ray done showed enlarged cardiac silhouette with bilateral upper, middle, and lower zone inhomogeneous infiltrates [Figure 1] taken 3 months before and received empirical ATT and showed no response with progression of disease with increased inhomogeneous infiltrates with cardiac silhouette and obliteration of costophrenic angles [Figure 2].
Figure 1: Chest X-ray PA

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Figure 2: Chest X-ray PA

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As clinical findings and chest X-ray were suggestive of bilateral lung pathology, we performed high-resolution computed tomography (HRCT) thorax.

HRCT thorax documented:

  1. Bilateral ill-defined peripheral random nodules with fibrotic areas and consolidation bilateral lower lobes [Figure 3] and [Figure 4]
  2. Bilateral parenchymal bands, increased linear opacities, increased interstitial shadows bilaterally predominantly in the middle and lower lobes [Figure 3] and [Figure 4]
  3. Beaded interlobular septum [Figure 4].
Figure 3: HRCT thorax showing bilateral ill-defined peripheral random nodules with fibrotic areas and consolidation bilateral lower lobes

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Figure 4: HRCT thorax showing Bilateral parenchymal bands, increased linear opacities, increased interstitial shadows bilaterally predominantly in the middle and lower lobes, Beaded interlobular septum

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Computed tomography (CT) pulmonary angiography and multidector (CT) thorax documented:

  1. Enlarged main pulmonary trunk >2.5 cm, documented at carina, i.e., division of trachea in to right and left main stem bronchus [Figure 5] and [Figure 6]
  2. Gross pulmonary hypertension with dilated right atrium (RA) and right ventricle (RV) [Figure 5] and [Figure 6]
  3. Bilateral pleural effusion [Figure 5] and [Figure 6]
  4. Pericardia effusion [Figure 6]
  5. Enlarged mediastinal lymph nodes [Figure 5].
Figure 5: Contrast CT thorax mediastinal window showing Enlarged main pulmonary trunk >2.5 cm at carina

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

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Electrocardiography documented as sinus tachycardia with left ventricular (LV) strain pattern [Figure 7], while echocardiography analysis revealed pulmonary hypertension.
Figure 7: Electrocardiography documented as sinus tachycardia with left ventricular (LV) strain pattern

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Echocardiography reported as [Figure 8]
Figure 8: Echocardiography showing evidence of severe PH RVSP by TR jet 100 mmHg

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  • All valves - Normal
  • Dilated RA and RV with global RV hypokinesia with apical scarring
  • Other chambers - Normal in size
  • Dilated main pulmonary artery
  • IAS (Interatrial septum) and IVS (Interventricular septium) intact
  • Normal LV function, no regional wall motion abnormality
  • LVEF (left ventricular ejection fraction) - 60%
  • Diastolic function grade 1 diastolic dysfunction
  • Evidence of severe PH (pulmonary hypertension) RVSP (right ventricular systolic pressure) by TR jet 100 mmHg, IVC (interventricular septum) dilated and noncollapsing, no evidence of clot/vegetation, or embolus [Figure 8].


As HRCT showed lung parenchymal abnormality with predominant nodules bilaterally, we have performed fiberoptic video-bronchoscopy with oxygen supplementation as she is having gross pulmonary hypertension and as sputum examination was inconclusive and contrast HRCT thorax showed necrotic mediastinal lymph nodes.

Bronchoscopy examination revealed hyperemic mucosa at lower trachea, carina, and purulent secretions coming out from bilateral main stem bronchial lumens, increased rugosity in segmental bronchial openings, no evidence of endobronchial growth, gross visible abnormality and also no evidence of submucosal or peribronchial abnormality. BAL (bronchoalveolar lavage) was collected after 100 ml saline instillation and four aliquots were sent for cytology, Gene Xpert, bacterial, and fungal culture.

  • BAL cytology was suggestive of acute inflammation, negative for malignant cell
  • BAL AFB - Negative
  • BAL Gene Xpert MTB/RIF (mycobacterium tuberculosis/Rifampicin) - Negative
  • BAL bacterial culture - No growth
  • BAL fungal culture - No growth.


As tropical workup was negative and she is having very typical facies for CTD suspicion, we sent blood sample for vasculitis workup. CTD (connective tissue disease) facies - [Figure 9]. Hyperpigmented macular areas documented over bilateral malar and forehead areas with frontal baldness and alopecia bilateral eye brows.
Figure 9: CTD facies -Hyperpigmented macular areas documented over bilateral malar and forehead areas with frontal baldness and alopecia bilateral eye brows

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Connective tissue disease and vasculitis workup documented:

  • MPO-ANCA (myleoperoxidase antinuclear cytoplasmic antibody) (P-ANCA) - 0.86 RU/ml (normal range 0–20 RU/ml)
  • PR3-ANCA anti-proteinase 3 antinuclar cytoplasmic antibody (C-ANCA) - 0.90 RU/ml (normal range 0–20 RU/ml)
  • ANA - strongly positive, 1:1000 titer; pattern - homogenous, grade +++


ANA blot reported:

  • U1 small nuclear ribonucleoprotein particle (U1-snRNP) - Positive
  • SSA/RO - Positive
  • Single-strand DNA - Positive
  • Scl-70 - Positive


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

Spirometric analysis were showing restrictive pattern with FVC 69%.

DLCO analysis was not done. Six-minute walk test distance was 85 m at entry point with desaturation below 81% on room air.

We have stopped anti TB treatment, and started injection meropenem 1 g intravenous (IV) 8 hourly for 10 days and injection methylprednisolone 40 mg IV 8 hourly for 7 days with oral medicines as tablet mycophenolate Mophetil 500 mg OD and dosages increased to TDS over 3 weeks and continued for additional 12 weeks, tablet dytor plus LS 10 OD for 12 weeks, tablet tadalafil 20 mg OD 12 weeks, and tablet clopidogrel 75 OD for 12 weeks, with advise for oxygen supplementation during rest and ambulation for first 3 weeks and then continued during night for 12 weeks after documentation of oxygen saturation above 90% at rest and during ambulation, and symptomatic treatments as antipyretics for fever control, with advise for conservative oral liquids intake, and regular monitoring of serum electrolytes, kidney functions tests and liver functions tests as per institutional protocol. After 1 week, injectable methylprednisolone has been shifted to oral and dose decrease from 40 mg TDS to oral 48 mg and tapered over 12 weeks. The patient was hospitalized for 4 weeks, and oxygen saturation monitoring during rest and ambulation were done, and decision to step down oxygen therapy has been taken after clinical recovery and monitoring oxygen saturation during rest and ambulation. We have added trimethoprim sulfamethaxazole (160/800) OD for 1 month for necrotic mediastinal nodes as prophylaxis during steroid treatment for prevention of bacterial and pneumocystis pneumonia. As per institutional protocol, strict monitoring of hemogram, renal and liver function tests were done weekly for 1st month and then monthly till 3 months and or documentation near complete resolution of lung parenchymal abnormalities in chest radiograph [Figure 10] and satisfactory clinical response.
Figure 10: Chest x-ray PA vies showing near-complete resolution of lung parenchymal opacity

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After 3 months, we have continued oral disease-modifying agents as mycophenolate mophetil 500 mg OD with tadalafil 20 mg OD, dytror plus LS 10 OD, and clopidogrel 75 mg OD as a maintenance therapy with 3 monthly follow-ups.

We have documented as

  1. Improved exercise capacity and now she can walk up to 450 m with nil to minimal breathlessness (improved 6-min walk test parameters)
  2. Pulmonary artery pressures decreased to less than 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


Mixed connective tissue disease (MCTD) was initially described by Sharp et al. MCTD was first reported as a mild overlap disease with features of different autoimmune CTDs namely SSc, PM/dermatomyositis, and SLE in patients with antibodies targeting the U1 small nuclear RNP particle (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 because of its characteristic association with conditions such as pulmonary arterial hypertension, aseptic meningitis, and trigeminal neuropathy.[8],[9],[10],[11]

In 1986, the MCTD criteria was 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 Mixed Connective Tissue Disease 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 are given below:[14]

  1. Common manifestations


    1. Raynaud's phenomenon
    2. Puffy fingers and/or swollen hands


  2. Immunological manifestation Positivity for anti-U1 ribonucleoprotein antibody
  3. Characteristic organ involvement


    1. Pulmonary arterial hypertension
    2. Aseptic meningitis
    3. Trigeminal neuropathy


  4. Overlapping manifestations


    1. SLE-like manifestations


      1. Polyarthritis
      2. Lymphadenopathy
      3. Malar rash
      4. Pericarditis or pleuritis
      5. Leukopenia (4,000/lL or less) or thrombocytopenia (100,000/lL or less)


    2. SSc-like manifestations


      1. Sclerodactyly
      2. Interstitial lung disease (ILD)
      3. Esophageal dysmotility or dilatation


    3. PM/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 clinical setting by judgment based on 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 pulmonary hypertension with interstitial involvement with parenchymal fibrosis and managed with steroids, pulmonary vasodilators, diuretics, and disease-modifying agents' mycophenolate mofetil. Most common pulmonary presentations of MCTD are interstitial pneumonia, pulmonary fibrosis, pulmonary hypertension, pulmonary consolidation pattern on chest imaging, and pleural effusion, while other rare presentations are pulmonary thromboembolism, aspiration pneumonia, pulmonary vasculitis, pulmonary hemorrhage, pulmonary nodules, obstructive airway disease, mediastinal lymphadenopathy, and diaphragmatic dysfunction.

Key learning points from this case report are as follows:

  1. MCTD is a complex overlap disease with features of SSc, PM/dermatomyositis, and SLE in patients with antibodies targeting the U1 snRNP particle
  2. Thoracic manifestations of MCTD are diverse with involvement of airways, lung parenchyma, interstitium, pulmonary vasculature, and pleura
  3. Many cases with MCTD are having ILD with pulmonary hypertension, as in our case
  4. MCTD is usually missed and underestimated in the presence of constitutional symptoms, and TB is the most common etiological factor in tropical setting
  5. Constitutional symptoms such as cough, fever, and weight loss with lung abnormality on HRCT thorax may mislead towards empirical treatment without documentation on microscopy and nucleic acid amplification tests
  6. Pulmonary hypertension with lung parenchymal interstitial disease is “radiological clue” to rule out CTD/MCTD
  7. 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.
  8. HRCT thorax with CT pulmonary angiography is important tool in workup of these cases with either enlarged cardiac silhouette with enlarged pulmonary artery or echocardiography showing pulmonary hypertension with dilated RA and RV.
  9. Steroids are cornerstone of treatment of MCTD with lung involvement shown excellent response to steroids with mycophenolate with pulmonary vasodilators with diuretics.



  Conclusion Top


We recommend all cases with constitutional symptoms and negative workup for tropical disease including tuberculosis should undergo prompt evaluation to rule out underlying MCTD as the etiological factor in the background of radiological signs of ILD with pulmonary hypertension.

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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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
    
2.
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
    
3.
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
    
4.
Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. 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
    
5.
Kaipiainen-Seppänen 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
    
6.
Weckmann AL, Granados J, Cardiel MH, Andrade F, Vargas-Alarcón G, Alcocer-Varela J, 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
    
7.
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
    
8.
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
    
9.
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
    
10.
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
    
11.
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
    
12.
Kasukawa R. Mixed connective tissue disease. Intern Med 1999;38:386-93.  Back to cited text no. 12
    
13.
Cappelli S, Bellando Randone S, Martinović D, Tamas MM, Pasalić 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
    
14.
Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro Y, Fujio K, et al. 2019 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
    


    Figures

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



 

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