Epidemiology

• Defined by presence of features of SLE, polydermatomyositis, and Scleroderma (and occasionally Sjogren’s Syndrome)
• MCTD may differentiate into other rheumatologic diseases: differentiation appears to be genetically determined
• Incidence: 1 in 10k persons
• Sex: F:M is 9:1
• Peak Age: 30’s

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Physiology

• Vasculitis of Small Arterioles and Large Arteries (Pulmonary, Coronary, Renal)
  • Immunologic mechanism

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Diagnosis

Serology

• Anti-U1-RNP (targets small nuclear proteins): usually positive at >1:1600 (at >1:10,000 titer, this is almost diagnostic of MCTD), but not in all cases
  • May be positive in scleroderma and SLE also
• Anti-U2-RNP: may be positive in myositis-overlap syndromes
• Anti-GBM: negative

Other

• Erythocyte Sedimentation Rate (ESR): usually elevated

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Clinical Manifestations

Dermatologic Manifestations

• General Comments: almost always involved
• Alopecia
• Cutaneous Lupus
• Dyspigmentation
• Periungual Telanigectasia
• Photosensitivity
• Sclerodactyly

Gastrointestinal Manifestations

• Esophageal Dysfunction: dysmotility occurs in 80% of cases

Hematologic Manifestations

• Hypercoagulability (see Hypercoagulable States, [[Hypercoagulable States]])
• Iron Deficiency Anemia (see xxxx, [[]]): usually present
• Leukocytosis (see Leukocytosis, [[Leukocytosis]])
• Lymphadenopathy (see Lymphadenopathy, [[Lymphadenopathy]])

Neurologic Manifestations

• Central Nervous System Involvement
• Fatigue (see Fatigue, [[Fatigue]])

Pulmonary Manifestations

General Comments

• Occur in 20-85% of cases

Interstitial Lung Disease (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])

• Epidemiology
  • Interstitial lung disease is the most common pulmonary manifestation
  • Sex: F: M ratio is 8:1
  • Race: no race predilection
• Diagnosis
  • CXR Pattern
    • Interstitial Infiltrates (lower-lobe predominance): seen with chronic disease or recurrent DAH
      • May mimic the appearance of IPF
  • Chest CT Pattern
    • Ground-glass infiltrates
    • Subpleural micronodules
    • Non-septal linear opacities
    • Honeycombing: small cystic changes (seen best in lower fields) seen late in course
  • PFT’s: restriction with decreased DLCO
  • Lung Biopsy
    • Proliferative vasculopathy (prominent): medial hypertrophy with intimal thickening of pulmonary arteries and arterioles or plexogenic angiopathy
    • Interstitial fibrosis
• Clinical
  • Presents with dyspnea, pleuritic chest pain, cough, bibasilar rales, increased P2, absence of clubbing
  • 33% of cases are asymptomatic: 75% of these cases have CXR or PFT abnormalities and resting hypoxemia
  • Interstitial lung disease is often subclinical (usually detected only by CXR or PFT’s)
• Treatment: corticosteroids + cytotoxic (cyclophosphamide or azathioprine)

Acute Lung Injury-ARDS (see Acute Lung Injury-ARDS, [[Acute Lung Injury-ARDS]])

• Pathology: diffuse alveolar damage
• Diagnosis: HRCT -> diffuse ground-glass infiltrates and/or consolidation, reticular infiltrates, honeycombing (mimics accelerated idiopathic pulmonary fibrosis)
• Clinical: acute respiratory deterioration
  • May occur as the initial presentation of the disease (without pre-existing lung manifestations)
• Treatment and Prognosis: most cases die within months, despite steroid therapy
  • Case reports describe the use of cyclosporin A + either prednisolone or cyclophosphamide

Pleurisy/Pleural Effusion (see Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])

• Epidemiology
  • Occurs in 35-40% of cases
  • May be the first manifestation of MCTD
• Diagnosis
  • Pleural Fluid: exudate
  • CXR/Chest CT
    • Pleural effusion: seen in some cases
    • Pleural thickening is seen in only 3% of cases
• Clinical
  • Pleural effusion
  • Pleurisy/pleuritic chest pain
• Treatment
  • Usually small and resolve spontaneously
  • Occasionally require corticosteroids

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

• Physiologic Mechanisms
  • Vasoconstriction: due to hyperreactive pulmonary vasculature)
  • Proliferative Vasculopathy: vascular medial hypertrophy with intimal fibrosis (not a true pulmonary vasculitis though)
  • Plexogenic Angiopathy
  • CTEPH:
  • Advanced ILD:
• Clinical: usually insidious onset
• Prognosis: may be fatal in some cases

Chronic Aspiration Pneumonia (see Aspiration Pneumonia, [[Aspiration Pneumonia]])

• Epidemiology: common
• Physiology: may be due to esophageal dysmotility

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])

• Epidemiology: uncommonly complicates MCTD
  • Most cases are associated with co-existing systemic vasculitis
  • One case reported with isolated lung vasculitis [Chest 1998; 113: 1609-1615]
  • Most cases of alveolar hemorrhage occur after the primary diagnosis of MCTD
• Diagnosis
  • CXR/Chest CT: diffuse or patchy alveolar infiltrates
  • PFT’s: increased DLCO during alveolar hemorrhage
  • Lung Biopsy: pulmonary capillaritis

Respiratory Muscle Weakness with Acute/Chronic Hypoventilation (see Acute Hypoventilation, [[Acute Hypoventilation]] and Chronic Hypoventilation, [[Chronic Hypoventilation]])

• Physiology: myopathy
• Clinical
  • Atelectasis with small lung volumes may occur

Renal Manifestations

• Renal Disease

Rheumatologic Manifestations

• Arthralgias/Arthritis (see Arthritis, [[Arthritis]]): most cases
• Myalgias/Myositis (see Myositis, [[Myositis]])
• Raynaud’s Phenomenon (see Raynaud’s Phenomenon, [[Raynauds Phenomenon]])
• Swollen Hands
• Vasculitis (see Vasculitis, [[Vasculitis]])

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Treatment

• Steroids/Immunosuppressives: indicated early for ILD (although no studies show prevention of progression to fibrosis)

Treatment of Pulmonary Hypertension

• Usually difficult to treat

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Prognosis

• Disease course seems to follow that connetcive tissue disease that MCTD most resembles
• Survival is better if anti-U1-RNP is present

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References

• Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum 1999; 42:899-909
• Diffuse Alveolar Damage: Uncommon Manifestation of Pulmonary Involvement in Patients With Connective Tissue Diseases. Chest 2006; 130:553–558
• Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 2008;58:521-31