The ANA, anti-CCP, RF, and beyond!
We all have ‘rheum’ to grow when it comes to making sense of autoantibodies and common markers. We talk through the nuances with rheumatologist Dr. Matthew B. Carroll (biography here!). Our interview covers physical exam tips for inflammatory arthritis, basic interpretation of rheumatologic testing, and what to do with the dreaded ‘vaguely positive’ speckled ANA!
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Before you hit the order button on sets of inflammatory markers and autoantibodies in a patient with joint pain, consider the chronicity of the patient’s symptoms. Guidelines indicate symptoms persisting for more than 6 weeks is a threshold when you can start to think about a long-term arthritic process (Aletaha 2010). Conducting a thorough physical exam is critical. Dr. Carroll (and the ACR 2010 guidelines) recommends evaluating for signs of synovitis/joint effusion (Aletaha 2010). Findings associated with sclerodactyly (such as joint contractures, tendon friction rubs: ‘leathery’ or squeaky sensation with joint movement, digital ulcers, digital pitting, skin puffing) would also be concerning (Young 2016). Symptoms associated with Raynaud’s symptoms and Sjogren’s Syndrome should also be assessed. Dr. Carroll recommends asking about OTC eye drop usage, frequent water intake, and dentition quality to assess ‘sicca’ symptoms.
Asking about rashes (although a mimic of the malar rash is rosacea, not uncommon in middle-aged patients) PRO TIP: the malar rash should spare the nasolabial folds (Uva 2012).
Finding collateral history or concerning symptoms beyond joint pain can indicate that you are dealing with an antinuclear antibody (ANA)-positive autoimmune condition, which includes lupus, idiopathic inflammatory myositis, Sjogren’s syndrome, mixed connective tissue, and scleroderma (Horimoto 2016; Aguila 2014). Medicine is an iterative process and sometimes these patients may present with an insidious process, so you could consider close repeat follow-up in 6 months to a year (expert opinion).
What does synovitis look and feel like?
Assessing and definitively identifying synovitis can be a challenge even when you are a rheumatologist, per Dr. Carroll. Some tips for your physical exam from Dr. Carroll: feeling a spongy sensation or lack of indentation at joint, loss of skin folds.
For honing in on morning stiffness, Dr. Carroll is more concerned when patients report greater than 30 mins but he does note that sometimes fibromyalgia patients report several hours of morning stiffness.
Initial Evaluation & Testing
Dr. Carroll’s recommended first line of tests for considering rheumatoid arthritis diagnosis would be: ESR, CRP, rheumatoid factor, anti-CCP. If you’re thinking of Sjogren’s Syndrome, consider an anti-SSA/SSB antibody test and potentially pursuing a minor salivary gland biopsy. For Systemic Lupus Erythematosus, check ANA, anti-dsDNA and anti-Smith antibodies as well as complement levels (C3/C4), CBC with differential, BUN/Creatinine, and urine protein-creatinine ratio (Syed 1996, Wielosz 2020). Metabolic panels can be helpful in terms of determining treatments, per Dr. Carroll.
If rheumatoid factor returns in the low positive range (ie: 14-20 IU/ml) it can be an equivocal finding. However, if paired with an elevated anti-CCP (ie: anti-CCP 270 u/ml) that can give you evidence of an inflammatory arthropathy, per Dr. Carroll. When rheumatoid factor is severely elevated (ie: high 200s) that should make you consider HCV and HBV screening (Moll 2019). If those are negative, that alone can be a positive indicator for rheumatoid arthritis, Dr. Carroll reports.
Role of Imaging
Dr. Carroll recommends getting imaging at the outset. Joint x-rays can show erosions at the metacarpophalangeal and/or proximal interphalangeal joints. Chest x-rays can capture interstitial lung disease, but if clinical suspicion remains high with a normal chest x-ray, pursue CT Chest, high resolution, per Dr. Carroll’s expert opinion.
Early Diagnosis is Key!
Rheumatologists want us to try to capture patients with inflammatory conditions early. For example, the rheumatology community is increasingly interested in identifying and treating patients in a ‘pre-RA’ state (Haville 2022). Ideally, we can treat these patients so they don’t develop the debilitating joint and lung damage that prior generations of patients have endured (Paul 2017).
New Testing On the Way
One new inflammatory marker to consider is the 14-3-3 eta/14-3-3η protein (Wang 2020). A value of 0.2 nanograms per milliliter or higher is considered positive, but when it returns as 0.2-0.4 it can be a bit equivocal. 0.8 or higher is highly abnormal and consistent with an inflammatory disorder (Maksymowych 2014, Alashkar 2022).
Dr. Carroll interprets in the setting of other labs. For example, all negative labs with signs of osteoarthritis and a 14-3-3η protein of 0.4 might be something he watches over time, but a patient with high rheumatoid factor and 14-3-3η protein of 0.2, would not rule out rheumatoid arthritis.
Anti-CarP antibody is another new, promising marker of rheumatoid arthritis (Yee 2015). Neither of these are part of the clinical classification criteria, per Dr. Carroll.
Uh-oh – the vaguely positive speckled ANA!
“You got a 1:80 speckled pattern that’s probably just reflective that she’s a[…]human on planet earth,” says Dr Carroll.
If a patient has a mildly elevated ANA titer, with a speckled pattern, it is a common finding. Studies show between 15-30% of adult females can have a mildly positive ANA (Tan 1997, Blumenthal 2002, Parks 2014, Slater 1996).
As a note: the way ANA levels are reported is based on the last serial dilution which it can be detected, towards how many dilutions it takes to *not* find ANA (ie: a high titer means it can be detected even with a very large dilution).
What about a positive ANA and nothing else?
America’s Internist Paul Williams mentions that many times the ANA is ordered during a hospital work-up for another systematic process as part of an orderset or battery of rule-out tests for kidney and liver function. Dr. Carroll’s expert opinion is that in these cases of visceral end-organ damage (ILD, proteinuria, pleurisy) it is not unreasonable to check ANA.
In Dr. Carroll’s expert opinion: if a patient has an isolated ANA of a lower titer level, you can monitor (eg: 1:80). However, if it’s a higher titer (eg: 1:640),you can consider additional testing such as anti-DNA, anti-Smith, etc. Any additional testing needs to be based on the patient’s current symptoms, physical exam findings, and available lab data. For example, an anti-centromere antibody is not needed if the pre-test probability is low for scleroderma, but an anti-dsDNA antibody would be very appropriate for a patient with lymphopenia, a malar rash, and synovitis.
If a patient has a positive ANA, but no rheumatologic disease, other considerations on the differential are autoimmune hepatitis, autoimmune thyroid disease, PBC, idiopathic pulmonary hypertension, and multiple sclerosis (Sur 2018).
Basics of ANA testing
Originally, ANA testing used to involve an indirect immunofluorescence. More recently the testing modality involves solid phase assays, which is faster. Solid phase assay ANA tends to enhance the specificity but forfeit some of the sensitivity, per Dr. Carroll (Bizzaro 2018).
Dr. Carroll recommends understanding what technique your local lab is using so you can better interpret results. Usually, when the lab is reporting a titer and pattern, that means the lab is utilizing indirect immunofluorescence.
Dr. Carroll says cutoffs based on titers can be nuanced. Titers of 1:320 or more are suggestive of inflammatory disorders. ANA can also be elevated in other conditions (such as Hashimoto’s Thyroiditis). Anti-centromere pattern of ANA is associated with scleroderma (Vlachoyiannopoulos 1993).
Listeners will recognize appropriate situations for autoantibody testing.
After listening to this episode listeners will…
Dr. Carroll reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Carroll MB, Garbitelli BC, Williams PN, Watto MF. “#399 Wisely Ordering Autoantibodies – ACP IM2023”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast June 12, 2023.
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Showrunners, Hosts, Producers and Writers: Matthew Watto MD, FACP; Paul Williams MD, FACP
Show Notes, Infographic, Cover Art: Beth Garbitelli MD
Reviewer: Emi Okamoto MD
Technical Production: PodPaste
Guest: Matthew B. Carroll MD
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