Mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune condition characterized by concurrent features of at least two autoimmune connective tissue diseases, e.g., systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies. The clinical presentation is highly variable and may include Raynaud phenomenon, acrosclerosis, myositis, and esophageal dysmotility in the later stages. Interstitial lung disease (ILD) and pulmonary hypertension are common manifestations and major causes of mortality. Diagnosis is based on suggestive clinical features and the presence of anti-U1 RNP antibodies. Management involves immunosuppressive agents (e.g., glucocorticoids, cyclophosphamide), especially in patients with severe organ involvement.

• Rare (exact prevalence is unknown) ^[1]
• Peak incidence: 30–40 years of age ^[1]
• ♀ > ♂ (∼ 4:1) ^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• The exact cause is unknown.
• Predisposing factors ^[3][4]
  • Viral infections (e.g., COVID-19)
  • Certain drugs (e.g., TNF inhibitors)

Mixed connective tissue disease is characterized by concurrent features of at least two autoimmune connective tissue diseases (e.g., SLE, SSc, idiopathic inflammatory myopathies). ^[1][5][6]

• Initial presentation is often nonspecific, e.g., fatigue, low-grade fever, lymphadenopathy.
• Features of later stages include: ^[1][5][6]
  • Raynaud phenomenon (∼ 90% of patients) ^[1]
  • Acrosclerosis (including sclerodactyly), digital ulcers
  • Puffy fingers
  • Synovitis, myositis
  • Polyarthralgia, polyarthritis
  • Xerostomia and/or xerophthalmia
  • Features of esophageal dysmotility (e.g., GERD, dysphagia)
  • Clinical features of ILD and/or pulmonary hypertension (e.g., dyspnea, cough, inspiratory crackles)
  • Pericarditis, malar rash or discoid rash, peripheral neuropathy (uncommon)

In approximately 25% of patients, MCTD progresses into a specific CTD. ^[1]

General principles ^[1][5]

• Refer all patients with suspected MCTD to a rheumatologist and other specialists as needed (e.g., pulmonologist if ILD or pulmonary hypertension is suspected).
• Diagnosis is based on suggestive clinical features and the presence of anti-U1 RNP antibodies.
• Laboratory studies and cardiopulmonary evaluation are performed to assess organ involvement.
• Some specialists use diagnostic criteria (e.g., Sharp criteria, Kasukawa criteria) to facilitate the diagnosis.

The diagnosis of MCTD is challenging because of the highly variable clinical presentation and overlap with other autoimmune CTDs.

Laboratory studies ^[1][5]

Serology

• Antinuclear antibodies (ANAs)
  • Positive titers (typically > 1:1000)
  • ANA patterns: can help determine the type of autoimmune disease
    • A speckled pattern on immunofluorescence is typical in MCTD.
    • Other ANA patterns can indicate overlap with established autoimmune CTDs. ^[7][8]
• Antigen-specific ANAs
  • Anti-U1 RNP: present in all patients with MCTD
  • Others (e.g., anti-Ro/SSA antibodies, anti-Sm antibodies) may be present.
• Other possible antibodies: rheumatoid factor or ANCA

Routine studies ^[1][5]

• CBC: may show leukopenia, anemia, and/or thrombocytopenia
• Inflammatory markers: CRP and ESR may be elevated.
• Renal function testing
  • Serum creatinine: may be elevated
  • Urinalysis with sediment: may show proteinuria, and/or nephritic or nephrotic sediment
• CMP: ↑ creatine kinase during acute flares of myositis

The absence of severe kidney involvement helps distinguish MCTD from SLE and SSc.

Additional studies ^[1][5]

• Cardiopulmonary evaluation: MCTD is a risk factor for PH and ILD. The following should be obtained for all patients upon diagnosis.
  • Screening for ILD (e.g., PFTs and/or HRCT)
  • Screening for pulmonary hypertension (i.e., echocardiography)
• Further studies may be performed by a specialist (e.g., nailfold capillary microscopy to evaluate for microvascular abnormalities)

• Systemic sclerosis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Undifferentiated connective tissue disease
• Idiopathic inflammatory myopathies

The differential diagnoses listed here are not exhaustive.

General principles

• Refer all patients to a specialist (e.g., rheumatologist, pulmonologist) for management.
• Pharmacological treatment focuses on organ-specific, symptomatic therapy.
• Offer supportive care to all patients as needed.
• All patients should receive long-term follow-up to assess for cardiopulmonary involvement and the development of a CTD.

Pharmacological treatment ^[1][6]

Pharmacological treatment is extrapolated from other autoimmune CTDs.

• Organ-specific symptomatic treatment
  • Treatment of Raynaud phenomenon: calcium channel blockers (e.g., nifedipine)
  • Treatment of lupus-like features (e.g., malar rash): antimalarials (e.g., hydroxychloroquine)
  • Management of GERD: e.g., omeprazole
  • Management of pulmonary hypertension: e.g., endothelin receptor antagonists
  • Management of ILD: methotrexate, cyclophosphamide, and other immunosuppressants
• Disease flares: Glucocorticoids (e.g., prednisone) may be considered.

Supportive care

• Counsel patients on recommended immunizations and ASCVD prevention.
• Cutaneous involvement (e.g., acrosclerosis)
  • Advise patients to use gloves and emollients for skin protection.
  • For symptom-specific recommendations, see the respective articles (e.g., Raynaud phenomenon).
• Pulmonary involvement
  • Refer patients for pulmonary rehabilitation and oxygen therapy if indicated.
  • See “Supportive management” in “ILD.”

• The disease course is usually less severe compared to other CTDs. ^[1][5][9]
• Progression
  • Remission occurs in approx. 45% of patients.
  • In approx. 25% of patients, MCTD progresses into another CTD. ^[1]
• Poor prognostic factors include:
  • ILD and/or pulmonary hypertension
  • Male sex
  • Older age at presentation
  • Presence of anti-Scl-70 or anti-RNA polymerase III antibodies

Pulmonary hypertension and ILD are the main causes of mortality in patients with MCTD.