Mixed Connective Tissue Disease (MCTD)

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

Physiology

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

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

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

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]])

Treatment

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

Treatment of Pulmonary Hypertension

  • Usually difficult to treat

Prognosis

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

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