Autoantibodies associated with Rheumatic disease 류마티스내과 최 지 영 2015.4.16.

Immune system makes an abundance of proteins Made by white blood cells Recognize and combat infectious organisms In autoimmune diseases, autoantibodies may be the actual pathogenic agents of the disease, the secondary consequence of tissue damage, or the footprints of an etiologic agent. The determination of circulating autoantibodies can be used for the following clinical information: Likelihood of an autoimmune disease; Specific diagnosis; Clinical subtype; Disease activity (only possible in a very few cases).

ANA Target: “normal” proteins within the nucleus of a cell Could signal the body to begin attacking itself which can lead to autoimmune diseases A positive ANA test means autoantibodies are present By itself, a positive ANA test does not indicate the presence of an autoimmune disease or the need for therapy Sensitivity and simplicity of an ANA test makes it extremely popular to screen for lupus in particular Nearly all patients with SLE have a positive ANA test (sensitivity of 93% to 95% and a specificity of 57%) 11-13% of persons with a positive ANA test have lupus up to 15% of completely healthy people have a positive ANA test Positive ANA test does not automatically translate into a diagnosis of lupus or any autoimmune or connective tissue disease

What does a positive ANA reading mean? Reported in titers and patterns Positive ANA reading alone dose not indicate an autoimmune disease In healthy individuals 3~15% Strongly age-dependent: ↑10~37% over the age of 65 Viral infection Medications Cancer

Arch Pathol Lab Med 124:71-81, 2000

10% to 15% at a titer of 1:80, and 5% at a titer of 1:160 or greater Arthritis & Rheumatism (Arthritis Care & Research) Vol. 47, No. 4, August 15, 2002, pp 434–444 25% to 30% of healthy persons have a positive test with a titer of 1:40, 10% to 15% at a titer of 1:80, and 5% at a titer of 1:160 or greater ANA titer of 1:40 is seen in 25% to 30% of relatives of patients with rheumatologic disorders

Different types of ANAs

Anti-DNA Antibodies Very useful in the diagnosis of SLE and assessment of disease activity Associated with lupus nephritis Present at some time in the course of the disease as the levels fluctuate and may be absent at times Reported in rheumatoid arthritis, Sjögren's syndrome, scleroderma, drug-induced lupus, Raynaud's phenomenon, mixed connective tissue disease, discoid lupus, myositis, chronic active hepatitis, uveitis, Graves’ disease, anticardiolipin antibody syndrome, women with silicone breast implants

Arthritis & Rheumatism (Arthritis Care & Research) Vol. 47, No. 5, October 15, 2002, pp 546–555 weighted means (weighted according to numbers of patients assessed) for the use of anti-DNA in diagnosing SLE were 57.3% for sensitivity and 97.4% for specificity positive likelihood ratios (LR) for anti-DNA antibodies in the diagnosis of SLE are very high

Anti-Smith Antiribonucleoprotein Antibodies Antibodies directed against small nuclear riboprotein Anti-Smith (anti-Sm): very useful for confirming the diagnosis of SLE Sensitivity for diagnosis of lupus ranges from 24% to 30%, and specificity ranges from 96% to 98% (Arthritis Rheum. 2004, 51: 1030-1044) Antiribonuclear protein (anti-RNP) bind to protein containing U1-RNA coexist with anti-Sm antibodies in many patients with SLE very useful in diagnosing mixed connective tissue disease (sensitivity from 71% to 100%, specificity from 84% to 100%)

Antiribosomal P Protein Antibodies High specific for lupus and associated with neuropsychiatric lupus 10% to 20% of patients with SLE 32 consecutive SLE patients Depression (59.4%), headache (46.9%) and cognitive dysfunction (37.5%) aRP was positive in seven (21.9%) patients, all of whom had one or more NPSLE syndromes 3) significantly higher mean titers of aRP than patients without these disorders Clin Rheumatol (2008) 27:1377–1385

Sjögren's Syndrome Antibodies Clin Rheumatol (2006) 25: 341–346 The Sjögren's syndrome A antigen (anti-SSA/Ro) consists of 52- and 60-kDa proteins (called Ro52 and Ro60) complexed with Y1-Y5 RNAs Should be checked in patients with sicca symptoms Anti-SSA 50% to 60% of patients with primary Sjögren's syndrome and rarely in healthy persons Other autoimmune disease: RA, SLE, polymyositis - 35% to 40% of patients with SLE have anti-SSA antibodies 10~15% of secondary Sjögren's syndrome Associated with development of extraglandular features

Algorithm for the use of antinuclear antibodies (ANAs) in the diagnosis of connective tissue disorders

1997 Update of the 1982 ACR Revised Criteria for Classification of SLE This classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person must have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation (1).The modifications to criterion number 10 were made in 1997 (2). Arthritis Rheum 1997;40:1725

SLICC† Classification Criteria for SLE Arthritis Rheumatism 2012;64(8);2677-86

Rheumatoid Arthritis

Rheumatoid factor Directed against the Fc portion of IgG Most commonly measured RF is IgM Rheumatoid arthritis (sensitivity: 50% to 80%, specificity: 85% to 90%) May be negative in the early stages of rheumatoid arthritis, and positivity increases over time 15% to 20% of patients with rheumatoid arthritis never have RF positivity 2% to 10% of healthy persons are RF positive Correlation between higher RF concentrations and more-severe disease and poor prognosis RF in monitoring disease activity is unclear

Anti–cyclic citrullinated peptide antibodies Directed against citrulline residues formed in post-translational modification of arginine often elevated in patients with rheumatoid arthritis (sensitivity of 30% to 60% and a specificity of 95% to 98%) Presence of anti-CCP antibodies in early-phase rheumatoid arthritis anti-CCP antibodies can appear in the circulation several years before the onset of rheumatoid arthritis presence of anti-CCP antibodies in early disease is highly predictive for more-rapid radiographic progression of disease anti-CCP antibodies have significantly more joint damage DDx with Patients with chronic hepatitis C virus infection sometimes have high titers of RF

ACR 1987 classification criteria for RA

Systemic Sclerosis

Anticentromere antibodies Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 3, June 15, 2003, pp 399–412 associated with limited cutaneous systemic sclerosis, previously called CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangectasia) rarely found in patients with other connective tissue diseases or in healthy persons highly specific for diagnosing systemic sclerosis (Sensitivity 31% and Specificity 97%) very useful in distinguishing patients with limited systemic sclerosis from patients with diffuse systemic sclerosis or with primary Raynaud's phenomenon

Anti-Scl-70 Very useful in diagnosing systemic sclerosis Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 3, June 15, 2003, pp 399–412 Anti-Scl-70 Very useful in diagnosing systemic sclerosis 20.2 % of patients with systemic sclerosis highly specific (100%) for diffuse disease useful in predicting a greater likelihood for the development of diffuse cutaneous involvement and radiographic pulmonary fibrosis with an abnormal pulmonary function test

Antiphospholipid Antibodies

Antiphospholipid antibodies include antibodies directed against phospholipid-associated proteins Most common measured: lupus anticoagulant, anticardiolipin antibody Others: anti-beta 2 glycoprotien1, anti-prothrombin, the “false-posotive” test for syphilis aCL and LAC are the only autoantibodies which are used as criteria for the diagnosis of APS, other autoantibodies can also be detected in patients’ plasma, and these also have clear relationship with the clinical manifestations of APS primary tests for diagnosis of APS include aCL and LAC if these autoantibodies cannot be found but yet the clinical picture is highly suggestive of APS, other autoantibodies should be searched for, such as anti-b2GPI and other aPL.

Lupus anti-Coagulant (LAC) inhibit phospholipids-dependent coagulation tests in vitro surprisingly are associated with increased risk for coagulation and formation of thrombosis Anti-Cardiolipin Autoantibodies (aCL) most frequently used for the diagnosis of APS the IgG isotype is the most frequent found very sensitive test for diagnosis of the syndrome (Since aCL is found in 80%–90% of patients having APS) signifies an increased risk for venous thrombosis, arterial thrombosis and myocardial infarction Anti-b2-Glycoprotein-I (b2GPI) Antibodies serum protein which binds to negatively charged molecules, including phospholipids aCL actually binds to b2GPI which is linked to cardiolipin found in 40%–90% of APS patients

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