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Clinical Review Forum When an ANA test is positive – what next? More selective ordering of ANA can decrease anxiety of patients, write Nick Malone, Claire-Louise Murphy and Paul O’Connell What do you do when faced with a positive ANA (antinuclear antibodies) test? This is a common question encountered by GPs and a frequent cause for referral to rheumatology services. In the course of this article we aim to answer the following: • What’s the meaning of a positive ANA test? • When should an ANA test be ordered? • What questions should be asked when faced with a positive ANA? • When and who to refer? Antinuclear antibody Antinuclear antibodies are autoantibodies directed against a variety of components of the cell nucleus. Most healthy people have a low ANA titre (defined as < 1:80 in Irish laboratories). However, unfortunately about 3% of the healthy population has a positive ANA and this poses a dilemma and difficulty for doctors, especially when the test is ordered indiscriminately. The most common autoimmune disease associated with a positive ANA is connective tissue disease (CTD). What is the meaning of a positive ANA test? A positive ANA reading does not alone indicate autoimmune disease. The prevalence of ANAs in healthy individuals is about 3-15%.1 The production of these antibodies is strongly age-dependent, and increases to about 10-35% in healthy individuals over the age of 65.1 Even healthy patients with viral infections such as infectious mononucleosis can have a positive ANA for a short while. Furthermore, patients with cancer, or patients taking common medications such as beta blockers, can have a positive ANA. It is therefore crucial to take a positive result in the context of clinical history and examination. Some autoimmune diseases are strongly associated with a positive ANA to the extent whereby the test is an intrinsic part of diagnosis as indicated in Table 1. ANAs present different ‘patterns’ depending on the staining of the cell nucleus following immunofluorescent lab preparation and can have a diagnostic value. Speckled and homogenous patterns tend to be nonspecific, while a nucleolar and centromere pattern is specific for scleroderma and CREST syndrome respectively (see Figure 1 and 2). When should an ANA test be ordered? The likelihood that a positive test will provide useful information is proportional to the probability that CTD is present.2 ANA testing is recommended in patients who show signs and symptoms of CTD consistent with systemic lupus Table 1 Conditions associated with a positive ANA Frequency Diseases for which ANA is very useful for diagnosis: SLE (systemic lupus erythematosus) 95-100% Scleroderma 60-80% Diseases for which ANA is somewhat useful for diagnosis: Sjögren’s syndrome 40-70% Dermatomyositis-polymyositis 30-80% Diseases for which ANA is an intrinsic part of diagnosis: Drug-induced SLE 100% Mixed connective tissue disease (MCTD) 100% Autoimmune hepatitis 100% erythematosus (SLE), scleroderma, Sjögren’s syndrome or polymyositis/dermatomyositis. The list below outlines the important questions to ask in search of an underlying CTD and in general a patient with CTD will have two or more symptoms: • Symmetrical small joint inflammatory arthritis • Recurrent mouth ulcers • Malar rash/photosensitive rash • Severe cold sensitivity of the digits with tri-phasic colour change (Raynaud’s, see Figure 3). If positive for Raynaud’s ask about: dysphagia, heartburn, tight skin, finger tip ulcers • Sicca (dry eyes and dry mouth) • Proximal muscle weakness • Alopecia • History of other autoimmune disease (thyroid disease, ITP). Rates of positive ANA are affected by the prevalence of CTD in the population. Specifically, false positive rates will be higher in populations with a low prevalence of CTD, such as in primary care.3 Therefore, ANA should only be obtained in patients with suspicious symptoms as outlined above. It should also be noted that back pain, fatigue and nonspecific musculoskeletal pain alone do not merit an ANA test. ANA is also not useful in diagnosing osteoarthritis. Positive ANA tests do not usually need to be repeated and FORUM February 2011 43 ANA test./NH2* 1 26/01/2011 14:29:30 Forum Clinical Review Figure 1. Stained ANA (speckled and homogenous) Figure 2. Stained ANA (nucleolar and centromere pattern) Figure 3. Raynaud’s changes in ANA titre do not correlate with disease activity. Only if there is a strong suspicion that the patient may have an evolving CTD should a repeat ANA be considered. When and who to refer? Under the majority of circumstances, an ANA titre of ≤ 1:100 is enough to rule out connective tissue disease and can be disregarded.4 Titres < 1:160 outside of liver disease is rarely significant and unless signs and symptoms suggest CTD, can be disregarded. Titres between 1:200 and 1:320 require clinical assessment for CTD. Only if clinical assessment is positive for CTD is further testing necessary. Should further testing subsequently reveal signs and symptoms of CTD, referral should be made to a rheumatologist. Titres of > 1: 400 are significant and need careful evaluation for CTD followed by further blood testing. A positive ANA is rarely an emergency and there is time to complete further blood work prior to referral. A renal, bone, liver, thyroid, complete blood count and inflammatory marker screen is necessary to assess the extent of organ involvement. Double-stranded DNA should be considered as it is highly specific for SLE. ENA (extractable nuclear antigen) serology are also useful; these are nuclear and cytoplasmic components that are antibody targets. They include Anti-Ro, Anti-La, Anti-RNP, Anti-Sm, Anti-Scl 70 and Anti Jo-1 antibodies all of which are helpful in sub-classifying patients with an established diagnosis of autoimmune disease. It is worth noting that ANA titres are included in the diagnostic criteria for autoimmune hepatitis. The IAHG (International Autoimmune Hepatitis Group) includes an ANA ≥ 1:80 in its scoring system. Therefore, in the context of abnormal LFTs, the presence of raised IgG and absence of viral hepatitis, this is also a possibility and should be kept in mind when faced with a positive ANA. Selective ordering To conclude, many diseases cause a positive ANA and many healthy patients have a positive ANA. The higher the ANA, the more significant it becomes. Patients should be evaluated for signs and symptoms of connective tissue disease before ordering an ANA. A positive clinical assessment for CTD with a positive ANA requires referral. A negative ANA with signs and symptoms of CTD should prompt evaluation for another diagnosis and consultation with a rheumatologist can be considered. More selective ordering of ANA can decrease anxiety among patients with a positive result and reduce the chances of misdiagnosis. Nick Malone is rheumatology house officer, Claire-Louise Murphy is rheumatology SpR and Paul O’Connell is consultant rheumatologist at Beaumont Hospital, Dublin References 1. American College of Rheumatology Practice Management: ANA. 2010 2. Thomas C, Robinson JA. The antinuclear antibody test. When is a positive result clinically relevant? Postgrad Med 1993; 94(2): 55-66 3. Gill J, Quisel A, Rocca P, Walters D. Diagnosis of Systemic Lupus Erythematosis, American Family Physician, Dec 2003 4. Tan E, Cohen A, Fries J, Masi A, McShane D, Rothfield N. The 1982 revised critieria for the classification of SLE. Arthritis Rheumatology 1982; 25: 1271-7127 Stress reduction and mindfulness training for GPs An eight-week programme (24 contact hours) designed to make a positive contribution to your own life as well as improve the quality of your patient care • A proactive and preventative training programme specifically tailored to the occupational health needs of GP’s in Irish contexts • The programme comprises four integrated components: Contemplative and Reflective practices, Discursive exercises with peers and relevant Didactic input to support effective responses to recognised stressors such as burnout Places are limited to 15 participants – early booking is advisable Dates: Wednesday, February 23 to Wednesday, April 13 Cost: e350 (includes eight weekly classes full day workshop and CDs/course workbook for home practice) Venue: Catherine McAuley Centre, Baggot Street, Dublin 2 Contact: Debbie Correll at [email protected] for booking or further information The ICGP’s Health in Practice Programme endorses this mindfulness course and will post details of the course on the website at www.icgp.ie/hip 44 FORUM February 2011 ANA test./NH2* 2 26/01/2011 14:29:38