Connective Tissue Diseases

Dx
Monitor
Background
Peds
Lab Tests
Algorithm

Diagnosis

Indications for Testing

Patient with systemic symptoms, including arthralgias, arthritis, skin rashes, anemia, renal dysfunction, pleuritis, pericarditis

Laboratory Testing

Nonspecific testing
- CBC – rule out infection
- Erythrocyte sedimentation rate or C-reactive protein – monitor inflammation

ANA testing

Antinuclear antibodies (ANA), IgA, by ELISA

Negative – possible scenarios

No connective tissue disease (CTD) present

False negative result – consider scleroderma (SSc), polymyositis/dermatomyositis (PM/DM), inactive systemic lupus erythematosus (SLE)

If strong suspicion for CTD, consider disease-specific antibody tests or panels

Autoimmune connective tissue diseases and major autoantibodies

Systemic lupus erythematosus	dsDNA, Sm (ENA), cardiolipin, lupus anticoagulant, histone (drug-induced lupus erythematosus)
Rheumatoid arthritis	RF IgM, cyclic citrullinated peptide (CCP)/citrullinated protein antibodies
Scleroderma/systemic sclerosis	Scl-70, centromere, RNA polymerase I/III
Sjögren syndrome	Ro (SS-A), La (SS-B)
Mixed connective tissue disease	RNP
Polymyositis/Dermatomyositis	Jo-1, Mi

Positive – ANA HEp-2, IgG, by IFA (result pattern suggests underlying disease)
- ANA reported patterns and diagnoses
  - Centromere – limited cutaneous scleroderma (lcSSc), CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia)
  - Cytoplasmic – PM, DM, SLE, SSc
  - Peripheral/rim/homogenous – SLE, drug-induced lupus erythematosus (DIL)
  - Nucleolar – SLE, SSc, PM/DM
  - Speckled – antibodies detected
    - Sm+ – SLE
    - SS-A/SS-B+ – Sjögren syndrome, SLE
    - U1RNP+ – mixed connective tissue disease (MCTD) /undifferentiated connective tissue disease (UCTD)
    - Scl-70+ – diffuse cutaneous scleroderma (dcSSc)
    - No specificity – unidentified specificities or markers of low prevalence in CTD
- False-positive results may be induced by age, certain infections, cancers, and drugs
- ANA may be positive in inflammatory diseases such as autoimmune liver diseases
- Titer level has no bearing on diagnosis or disease severity once it is above established normal level

Other testing
- Rheumatoid factor IgM antibodies – if musculoskeletal complaints are present
- If suspicion for connective tissue disease is low, consider drug-induced lupus erythematosus (DIL), chronic autoimmune disease, chronic hepatitis C virus
- Urinalysis – rule out glomerulonephritis associated with connective tissue disease
- ANCA – rule out vasculitis associated with connective tissue disease

Differential Diagnosis

Arthritis
- Rheumatoid arthritis
- Osteoarthritis
- Crystalline arthritis
- Reactive arthritis (Campylobacter spp, Salmonella, Shigella, group A streptococcus)
- Ankylosing spondylitis
- Psoriatic arthritis
- Sarcoidosis
Myositis
- Demyelinating disease (multiple sclerosis, etc)
- Peripheral neuropathy
- Paraneoplastic syndromes
- Guillain-Barré syndrome
- Cushing syndrome
Systemic presentation
- Drug-related autoimmune disorders
- Antiphospholipid syndrome
- Vasculitis
- Malignancy
  - B-cell lymphoma
  - T/NK-cell lymphoma
  - Thymoma
- Endocarditis
Renal
- Acute glomerulonephritis
- Vasculitis
Central nervous system
- Vasculitis
- Stroke
- Migraine
- Infectious meningitis/encephalitis
- Brain tumor
- Malignancy
  - Lymphoma
  - Leukemia (most commonly ALL)
Hematologic
- Autoimmune hemolytic diseases
- Malignancy
  - Infiltrative metastatic tumor
  - Leukemia (ALL and AML)
  - Myeloproliferative neoplasms
  - Myelodysplastic syndromes

Monitoring

Once diagnosis is made, use monitoring tests based on organ involvement
- Urinalysis acceptable screen for renal disease
- If cytopenias present, follow with sequential CBCs
- Certain treatment drugs require liver function testing

Clinical Background

Several autoimmune connective tissue diseases may present with similar features. These diseases include systemic lupus erythematosus, Sjögren syndrome, mixed connective tissue disease, scleroderma (systemic sclerosis), progressive systemic sclerosis, inflammatory myopathies (polymyositis/dermatomyositis [PM/DM]), and undifferentiated connective tissue disease.

Epidemiology

Incidence – 15-50/100,000, depending on disease
Age – onset is 15-40 years; peak onset in 20s
Sex – M<F, 1:6-10

Pathophysiology

Circulating antigen-antibody complexes affect a variety of organs
Multisystem disease presentation

Clinical Presentation

Constitutional – fever, anorexia, weight loss
Musculoskeletal – arthralgias, arthritis, synovitis, myopathy
Dermatologic – skin rashes, Raynaud phenomenon, photosensitivity
Cardiopulmonary – pleuritis, pericarditis, fibrosis, chest pain
Renal – proteinuria, glomerulonephritis
Otorhinolaryngologic – sicca syndrome, oral ulcers
Gastrointestinal – gastroesophageal reflux disease
Neurologic – seizures, encephalopathy
Hematologic – cytopenias (involving neutrophils, erythrocytes, and platelets)

Treatment

Anti-inflammatory therapies – glucocorticosteroids and other drugs (eg, methotrexate and mycophenolate)

Pediatrics