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

• 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

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)

Clinical Background

Epidemiology

• Incidence – varies by disease but lower than in adults
• Sex – M<F for most disorders
• Age – presents more often >10 years

Clinical Presentation

• Constitutional – fever, anorexia, weight loss (most common)
• Musculoskeletal – arthralgias, arthritis, synovitis, myopathy, weakness
• Dermatologic – skin rash, Raynaud syndrome, photosensitivity
• Cardiopulmonary – chest pain, pericarditis, pleuritis
• Gastrointestinal – abdomen pain, diarrhea, hepatitis

Diagnosis

Indications for Testing

• Appropriate clinical presentation, including arthritis, arthralgias, skin rashes, anemia, pleuritis, pericarditis

Laboratory Testing

• Nonspecific testing
  • Refer to Diagnosis tab
• ANA testing
  • Refer to Diagnosis tab and Connective Tissue Disease Testing algorithm
• Other testing
  • Rheumatoid factor IgM antibodies – rule out juvenile idiopathic arthritis if musculoskeletal complaints are present

Differential Diagnosis

• Polyarthritis
  • Juvenile rheumatoid arthritis
  • Juvenile ankylosing spondylitis
  • Infectious arthritis
  • Psoriatic arthritis
  • Vasculitis
  • Growing pains
  • Reactive arthritis (Campylobacter spp, Salmonella, Shigella, group A streptococcus)
• Renal
  • Acute glomerulonephritis
  • Vasculitis
• Central nervous system
  • Vasculitis
  • Migraine
  • Brain tumor
• Rash
  • Kawasaki disease
  • Scarlet fever
  • Parvovirus
• Systemic presentation
  • Vasculitis
  • Malignancy
  • Endocarditis
  • Acute rheumatic fever
  • Sarcoidosis
• Myositis/weakness
  • Muscular dystrophies
  • Guillain-Barré syndrome
  • Cushing disease
  • Mitochondrial diseases
  • Metabolic disease
  • Infections
    • Toxoplasma gondii 
    • Enterovirus (polio)
    • Trichinella spiralis (trichinosis)
• Hematologic
  • Autoimmune hemolytic diseases
  • Malignancy
    • Infiltrative metastatic tumors
    • Leukemia
    • Myeloproliferative neoplasms
    • Myelodysplastic syndromes

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis. 2010; 69 (8) :1420-1422.PubMed
• Tozzoli R, Bizzaro N, Tonutti E, Villalta D, Bassetti D, Manoni F, Piazza A, Pradella M, Rizzotti P. Guidelines for the laboratory use of autoantibody tests in the diagnosis and monitoring of autoimmune rheumatic diseases. Am J Clin Pathol. 2002; 117 (2) :316-324.PubMed

General

• Fritzler MJ. The antinuclear antibody test: last or lasting gasp?. Arthritis Rheum. 2011; 63 (1) :19-22.PubMed
• Ghirardello A, Bendo R, Rampudda ME, Bassi N, Zampieri S, Doria A. Commercial blot assays in the diagnosis of systemic rheumatic diseases. Autoimmun Rev. 2009; 8 (8) :645-649.PubMed
• Haugbro K, Nossent JC, Winkler T, Figenschau Y, Rekvig OP. Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: the role of analytical diversity. Ann Rheum Dis. 2004; 63 (4) :386-394.PubMed
• Kumar TS, Aggarwal A. Approach to a patient with connective tissue disease. Indian J Pediatr. 2010; 77 (10) :1157-1164.PubMed
• Liu CC, Ahearn JM. The search for lupus biomarkers. Best Pract Res Clin Rheumatol. 2009; 23 (4) :507-523.PubMed
• Mammen AL. Dermatomyositis and polymyositis: Clinical presentation, autoantibodies, and pathogenesis. Ann N Y Acad Sci. 2010; 1184 :134-153.PubMed
• Schulte-Pelkum J, Fritzler M, Mahler M. Latest update on the Ro/SS-A autoantibody system. Autoimmun Rev. 2009; 8 (7) :632-637.PubMed
• Singh S, Mehra S. Approach to polyarthritis. Indian J Pediatr. 2010; 77 (9) :1005-1010.PubMed
• Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, Barros R, Santos MJ, Sousa E, Barcelos A, Ines L. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009; 28 (8) :915-921.PubMed

Cryoglobulinemia
Inflammatory Myopathies
Mixed Connective Tissue Disease
Rheumatoid Arthritis
Scleroderma
Sepsis
Sjögren Syndrome
Systemic Lupus Erythematosus
Thiopurine Methyltransferase Activity