Time Stamps

  • 01:37 Pearl 1: What are the limitations of an ANA test?
  • 03:54 Pearl 2: What Qs do you ask to raise suspicion for autoimmunity?
  • 13:53 Pearl 3: What exam findings raise your suspicion for autoimmunity?
  • 18:07 Pearl 4: What else is on ddx for a positive ANA?
  • 29:30 Pearl 5: After a positive ANA, what are next steps in an evaluation?

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Show Notes

Pearl 1: An ANA does not mean a patient has an autoimmune disease 

  • First, what exactly is an ANA?
    • Autoantibodies to antigens in the nucleus
      • The thought is in autoimmune diseases there is dysregulated apoptosis. When the cells breaks down, the contents inside the nucleus come out of the cell. The dendritic cells can present the nuclear antigens to T cells, which then activate B-cells to create antibodies.
    • Can be obtained by 2 different tests
      • IFA (indirect immunofluorescence assay)
      • ELISA
  • What are some of the challenges of interpreting a +ANA?
    • Studies have found 20% – 32% of the healthy population have a +ANA
    • Poor positive predictive value for connective tissue disorder of less than 10%
    • While a screening test for lupus, also has wide expression in many other rheumatic diseases as well (and other conditions – see Pearl 4!)
  • Does the titer matter? Yes! 
  • The pattern of the ANA is usually non-specific
    • Except for if the pattern centromere in the appropriate clinical setting (Raynaud’s phenomenon, skin changes, esophageal dysmotility) would suggest scleroderma
    • Nuclear dense fine speckled was exclusively seen in healthy individuals in some studies, though other data suggest this can be seen in patients with autoimmune diseases as well
    • “Monospecific DFS70 may help exclude CTD”
  • Keep in mind, ANAs can be positive long before any rheumatological symptoms. 
  • In one study of military recruits that were ultimately diagnosed with lupus, the earliest antibodies before any clinical symptoms were ANA, dsDNA Anti-Ro and Anti-La.
    • They were found between 3 – 9 years before diagnosis. Then, closer to diagnosis of lupus, anti-Smith and AntidsDNA antibodies were found.
  • Experts like Dr. Jonas still counsels patients that the likelihood that developing rheumatological disease with a sole positive ANA is low and counsels regarding symptoms that may need further workup.

Pearl 2: Check an ANA only if suspicion for autoimmune disease, not non-specific pain or fatigue vs. What patient histories should you not get an ANA for and which aspects of the history would raise suspicion for autoimmunity?

  • Do not order for fatigue, diffuse joint pain alone (non-inflammatory history), or other mild nonspecific symptoms that have been ongoing for years.
    • If an ANA is ordered, there is a 1 in 5 chance in a woman that the ANA will be positive.
  • Ask about:
    • Photosensitivity
      • “Do you feel sick when you are in the sun?”
    • Dry eyes or dry mouth
    • Oral ulcers (often painless and on the hard palate = more unique to SLE)
    • History of clots or pregnancy losses
    • Raynaud’s 
  • Symptoms with highest odds ratio for  SLE compared to fibromyalgia:
    • Raynaud’s, rash, fever, easing bruising, hair loss
  • Examples of  more “clear cut” histories that warrant checking an ANA/diagnosis of lupus: 
      • Woman with a positive ANA with a low white blood cell count, anemic, low platelet count and active urinary sediment
      • Prior history of organ involvement such as glomerulonephritis or pericarditis.

Pearl 3: An ANA should be checked only for inflammatory joint pain, which requires a careful history and physical to elicit.

  • Arthralgia vs. Arthritis 
    • Arthralgia = joint pain without examination findings
    • Arthritis = swelling and localized tenderness of joints
  • Fibromyalgia vs. inflammatory arthritis (overlap up to 22% of patients with SLE have fibromyalgia)
    • Symptoms such as muscle pain, headaches, cognitive problems, paraesthesias, fatigue and abdominal pain more common in fibromyalgia than SLE 
    • Fibromyalgia is characterized by periarticular (around the joints, not at the joints) soft tissue tenderness at characteristic locations: shoulder girdle, lateral epicondyle, etc. 
    • Focal tenderness adjacent to joints (muscles, non-joint areas)
    • Joints may hurt also – but often more diffuse pain, not localized to specific joints
    • No swelling, warmth or erythema
  • Inflammatory arthritis is characterized by articular (joint) pain and tenderness. 
    • Joint swelling (feels boggy, especially in RA)
    • Joint tenderness
  • Inflammatory joint pain
    • Prolonged (>30 mins) morning stiffness and joint pain worse in the AM or after inactivity, which is more common in RA
    • Lupus inflammatory arthritis may not be always have characteristic morning stiffness.
    • Patients with lupus usually have inflammatory arthritis that is symmetric and involves small joints (such as the MCPs, PIPs of the hands), and classically is NON-erosive (i.e. does not cause joint damage).
      • Most inflamed joints in RA and lupus are NOT usually red/warm and can have subtle inflammation (swelling or tenderness)
      • *Gout and sepsis are only conditions where you usually see warm, red joints

Pearl 4: ANA positivity is seen in other non-rheumatic medical conditions and is not unique to autoimmune diseases.

Pearl 5: Once an ANA comes back positive, use a CBC and UA to triage how quickly they need to be seen by a rheumatologist. Monitor DsDNA, CBC and complements level as it correlates with disease activity.

  • Check CBC and urinalysis (and Cr and LFTs) to see if there is any internal organ involvement
    • Cytopenias 
    • Proteinuria / active urinary sediment ( >5 RBCs and >5 WBCs per high-power field (hpf) and/or cellular casts where none previously existed) that may suggest SLE.
  • What does Rheumatology check?
    • Additional autoantibodies on the ENA (extractable nuclear antigen) panel
      • Autoantibodies are not entirely specific as we were often taught in med school:
        • RNP is commonly positive among patients with SLE, though also seen in mixed connective tissue disease (MCTD)
        • SSA/SSB can be seen in primary Sjogren’s Syndrome but also SLE
  • Should the ANA be checked again?
    • No!  There is limited utility in rechecking an ANA once it is a known positive (or negative) in most circumstances, similarly with ENA panel antibodies.
  • What may correlate with disease activity, particularly in lupus?
    • DsDNA antibodies
      • dsDNA antibodies can increase and decrease over time, and may correlate in some patients with disease activity
    • Complement levels 
    • Lymphocytes

Transcript

Dr. Jonas: The patient is looking at a positive result and then they’ve inevitably gone to the internet and looked up lupus and it creates a lot of anxiety.

S: That is Dr. Beth Jonas, a rheumatologist at UNC. Welcome to Core IM 5 Pearls Podcast, bringing you high-yield, evidence based pearls. I am Dr. Shreya Trivedi, a hospitalist at BIDMC. And today I am joined by

Mithu: Hi, I am Mithu, a rheumatologist at Duke University.  

AMK: Hi, I am Ann Marie, a hospitalist at UNC.  

S: Today we are talking about one of the more common causes for a Rheumatology referral, a positive ANA. If you have ever wondered whether you should check that ANA or what to do with a positive result, this episode is for you.  

AMK:  I certainly have some rheum for improvement in this area.

S: Ugg

AMK: I cannot resist a good pun.  

S: Let’s get into those pearls we’ll be covering in the episode. Test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

A: Pearl 1: ANA Titer

 –S: Is a positive ANA always significant? What does the titer mean? Is the pattern of the ANA helpful?

A: Pearl 2: The History 

 –S: What patient histories should you not get an ANA for and which aspects of the history would raise suspicion for autoimmunity?

A: Pearl 3: The Physical Exam

 –S: How can you use the physical exam to assess likelihood of autoimmune disease

A: Pearl 4: Differential for positive ANA

 –S: What are other conditions bedsides autoimmune disease is associated with a positive ANA

A: Pearl 5: Next steps 

 –S: Once an ANA comes back positive, what are the next steps in evaluation?

Pearl 1: Is a positive ANA always significant? What does the titer mean? Is the pattern of the ANA helpful?

S: Ok lets start off with some foundation and maybe start what actually is an ANA? 

Mithu: I don’t know if people make this connection readily. So ANAs are basically autoantibodies against antigens in the nucleus… so things in the nucleus, DNA, RNA, the histones and the like.

S: Right, that makes a lot of sense. Thats why we get anti-dsDNA antibodies or anti-histone antibodies so its antibodies to all the things in the nucleus   

AMK: That makes a lot of sense, but what doesn’t make sense is how can the body create antibodies to antigens that are actually hidden inside the nucleus?

Dr. Jonas: And it’s always kind of a bit of a head scratcher, right? So if the antigens are inside the nucleus, how does the body see them and create antibody to them? And the reason for that probably has to do with what we think may be one pathogenic process in systemic Lupus and probably a number of other autoimmune diseases. And that is sort of dysregulated apoptosis. So apoptosis is regulated cell death, right? So the cell breaks down and in that process antigens that might be in the nucleus come out of the cell or sit on the surface of the cell and therefore create an immune response, which may include the activation of B cells and producing auto-antibodies. But it really has to do with probably dysregulated cell death.

AMK: Ok so, some disordered cell breakdown triggers the body to create the antibodies.  

S: Right, so does having those autoantibodies against components of the nucleus mean that it’s clinically significant? 

Mithu: To answer that, let’s do a thought experiment: Let’s say that I randomly sent an ANA test on 100 people without autoimmune disease. How many would be positive?

S: A handful? A few? 5? 10?

Dr. Pisetsky: So up to 20% of the otherwise healthy population is ANA positive depending on how the test is done and that dramatically limits its ability to be used as a screening test. Nevertheless, in the right setting, it’s quite informative.

AMK: That’s Dr. Pisetsky, a rheumatologist at Duke who does research on autoantibodies. And again that 20% of the healthy population have positive ANA, particularly if they are women. That is quite a high false positive rate. Proceed with caution.

S: That’s so humbling – What about the titer? Does the titer help? And come to think of it, can we just go over the titer real quick, the last time I sent an ANA, the results showed a titer was 1:160. I always had to pause and remind myself does the second number being high, good or bad? 

Mithu: The way I think about it conceptually is that the higher the second number, the more of that antibody there is, since it takes longer to dilute out.

S: Got it the higher that second number of the titer, the higher risk of autoimmune disease.

Mithu: I’m so glad you hedged and said “higher risk” of autoimmune disease, because this is where the ANA titers starts to get messy.

S: Really? Are there false positives even if the titer is high? What about a titer of like 1:80? That’s not nothing – does that have false positives?

Mithu: But you might be surprised up to 15% of patients are walking around with a titer of 1:80, but don’t have autoimmune disease.

S: What really? What about an ANA titer of 1:160?

Mithu: Yep, even a titer of 1:160. Studies have shown 5% of people have a titer of 1 to 160 but don’t have autoimmune disease.

S: What? Really? What about a crazy high titer like 1:2560

Mithu: It might be hard to believe, but even at a titer of 1:2560, 1% of otherwise healthy people are walking around with that high of a titer!

AMK: Wow so sounds like a higher titer is in general more concerning, but people without autoimmune illnesses can still have a high titer.  So then on the flip side, does a low titer exclude autoimmune disease?

Dr. Jonas: This is also like a little bit of area of a controversy. Someone says to me, what tighter do you consider positive? Well, it really depends on the history and physical. So someone has a really compelling story and physical exam. And the ANA is 1:80. That means something to me.

Mithu: And then on the other hand, if someone has a higher titer, like 1:160 or greater, and has no symptoms and nothing on exam, then I don’t take the titer ratio too seriously. I wish there was a black and white titer threshold you can hang your hat on for what is considered a positive ANA – it would totally make my job easier!

S: I know right…. but sounds like the ANA is just another data point in addition to our history and exam findings but gosh, part of me was hoping there was some clear easy cut off. 

Mithu: Well, I do have to say if we really pressed rheumatologists a lot of them would consider a titer of 1:160 or higher as positive.  But as Dr. Jonas said, you can still have a connective tissue disease with a lower titer if the story fits. 

S: Hmm okay, what about the pattern of the ANA? Does the pattern, say its speckled, nucleolar, homogenous, help us take the ANA more seriously or narrow down what it is going on? 

Dr. Jonas: If you get your ANA and they tell you it’s a centromere pattern, particularly if it’s in a high titer, that’s very, very helpful. But short of that, I don’t generally pay a lot of attention to the pattern at all.

AMK: Got it, so a centromere pattern can suggest scleroderma especially if the patient has reflux, skin thickening, or Raynaud’s but otherwise the ANA pattern is pretty non-specific. 

S: Oh gosh, I’m really appreciating this dive thinking about the ANA titer and how much importance I should place on a particular lab finding because I am often toying between if I should send the patient to rheum or not and want to feel confident in the test.

Dr. Pisetsky: So it is by no means unusual that in one laboratory, the patient has a positive result and in another laboratory they have a negative result, or the pattern comes out differently. It’s very confusing, both for the provider and also for the patient because they saw one provider and they said, oh, I’m worried about you. You may have a connective tissue disease or rheumatic disease. Cause your ANA is positive, send ’em on to a rheumatoid. And what happens is now the test is negative and they go, what happened? Uh, so probably a different kit.

AMK: Oh wow, things got more confusing! Variation just based on the kit is such a letdown to hear.

S: I did not know kit variation was a thing! Maybe at least we can counsel your patient not to hang their hat too much on the ANA because maybe they’ll go to rheum and it’ll be negative!

Mithu: It is really annoying and one reason may be for the variation because there are actually two ways to test the ANA, an IFA and Elisa.  The good news is that most places use the IFA which is more sensitive but sometimes I’ve seen labs sent using Elisa and that may contribute to some of the lab discrepancies…

S: Okay one last Q, it sounds like there is a good chunk of patients that are walking around otherwise healthy with a positive ANA, im curious how  autoimmune symptoms just not declared themselves? If so how long can it take for AI symptoms to declare themselves after a positive ANA…

Dr. Jonas: Interesting study. They looked at military recruits, like I think about a hundred and in 150 military recruits who were ultimately diagnosed with lupus. And because when you’re in the military, you donate your blood every so often and they bank it somewhere. They went back in those patients to see what was going on years before the diagnosis of Lupu. And what they found was that in many of those patients, there were auto antibodies present in the blood for years. The ANA were there and the earliest antibodies tend to be ANA and anti-row and the anti-law. And then as they got closer to the diagnosis of lupus, things like Smith antibody and double stranded DNA.  

S: Wow, I can’t believe that some cases had positive ANA’s for 9 years before they had any symptoms at all! 

Dr. Jonas: What we really don’t know is of the X percent of patients who have an Ana who are completely and utterly asymptomatic, what percentage of those patients are gonna go on to develop disease. So that, that stem didn’t really answer that question. Um, not in any appreciable way.So what I generally tell my patients is the vast majority of people with an a today are probably never going to have an autoimmune disease but then we’re left with this marker that at least in some studies suggests that you might have one in the future. And I can’t say with a hundred percent certainty that you won’t, but what I can say is that the likelihood is low. And if you have a change in your and symptoms, that’s the kind of thing we need to look at.

S: OK, let’s do a quick recap. Having a positive ANA is not the same as having an autoimmune disease.  And I can’t believe 1/5 of adults who are healthy are walking around with a positive ANA, this is especially true in women.  As a general rule of thumb, the higher the titer, the more likely there is an autoimmune disease, but a low titer does not exclude it, especially if the history and physical fit, which is what we will delve into in pearl 2 and 3.

Pearl 2: What patient histories should you not get an ANA for and which aspects of the history would raise suspicion for autoimmunity?

S: Now that we covered the nuances of the actual ANA test and know that so much of how much weight to put on the test goes back to the clinical picture, let’s unpack the different histories that may make your antennas go up and or down about sending an ANA. If we start with the low-hanging fruits, it’s really easy when there is a classic textbook story or clear organ involvement, then sending the ANA makes a lot of sense.

Dr. Jonas: Obviously, if you have somebody who has much more severe disease, they’ve got glomerulonephritis, they’ve got pericarditis, they’ve got other things that we generally associated with associate with lupus or autoimmunity. Then the test is gonna be very, very helpful to you.

Dr. Pisetsky: Let’s just say was ANA positive, woman, low white count anemic, low platelet count, active urinary sediment, creatinine bit up. I want to know anti-DNA, I want to know compliment. I really wanna know what’s going on. 

AMK: Yeah, sometimes it is super clear. But most of the time in clinic it was patients with fatigue or joint pain and they would ask if they could have lupus, in those cases it was hard to decide when you should send that ANA. 

Dr. Jonas: If the  symptoms have been going on for 10 years or more you, and they’re mild, and there’s nothing specific, I probably would not order an ANA cause there’s nothing more organ specific, than you. You’re gonna end in a place where you’re not gonna know what to do, and there may be nothing to do

S: Yeah nothing to do, or lead you and your patient down a rabbit hole. 

AMK: I feel like I particularly struggle with differentiating if this is more fibromyalgia or an autoimmune disease or both.  

S: One thing that was helpful is asking about the things that have highest odds ratio for lupus compared to fibromyalgia is asking about rash, fever, easy bruising, hair loss and coming in at the highest odds ratio of around 3 is asking about Raynaud’s.

Mithu: Yeah so I usually ask patients about Raynaud’s phenomenon by asking them something like “do you notice in the cold, your fingers turning different colors, such as white or blue?” 

AMK: That’s a cool approach. Let’s go through some other high-yield questions to ask.

Dr. Jonas: A couple of things that I think are helpful on that is sun sensitivity? Do you get sick when you’re in the sun? And that sometimes will make somebody’s eyes go wide and go, oh yeah, you know, that definitely happens. That’s a clue… I always ask about Sicka complex. So dry eyes and dry mouth, most patients will not associate that with their arthritis or their autoimmune syndrome, but it’s very frequently associated with lupus, with rheumatoid arthritis and other autoimmune syndromes. I always ask about oral ulcers and you know, one of the things about oral ulcers particularly in lupus is that they can be relatively asymptomatic. You know, I always ask about clotting history. Um, so that may not, that may have been something in someone might have had a pregnancy loss in the first or second trimester. You wanna make sure you’re asking about that.

AMK: Yeah I’ve definitely stopped at just no history of clots and not dug into other ways antiphospholipid syndrome can present. 

S: Yep have been there too – ok let’s summarize this quick pearl of high-yield history, one big takeaway is don’t check an ANA for non-specific symptoms like fatigue or arthralgias since, as we learned in pearl 1, up 25% of healthy women have a positive ANA. Symptoms such as photosensitivity, sicca symptoms, oral ulcers, Raynaud’s,or hx pregnancy loss  can make you feel a bit confident about sending that ANA.

Mithu: And of course, go ahead and send the ANA with more severe organ inflammation like glomerulonephritis or pericarditis.

Pearl 3: An ANA should be checked only for inflammatory joint pain, which requires a careful history and physical to elicit.

S: Okay now that we did a bit of history, let’s get into the ever so humbling physical exam.

AMK: Okay, back to the clinic. SO many patients have joint pain due to things like osteoarthritis or fibromyalgia. But when to send an ANA for a patient with joint pain is the bane of my existence. 

Dr. Jonas: Arthralgia is such a common presenting complaint that if you send an Ana for arthralgia alone, you’re gonna end up with a lot of ANA’s you’re not gonna be able to really unpack.

Mithu: Exactly, so this is a little bit of semantics but technically arthralgias refers to a complaint or symptom of joint pain, which can be from any cause, whereas inflammatory arthritis is where the money is at and what we are really looking for on exam.

Dr. Pisetsky: An inflamed joint is tender and it’s the ability to elicit tenderness in a distribution that’s indicative of an inflammatory disease. 

Mithu: So that inflamed joint distribution in most ANA-associated autoimmune diseases will look symmetric and typically affect smaller joints, like the hands.

Dr. Pisetsky: You’re looking for joint swelling, but swelling for the joint has sort of at least two explanations. One is there’s more Sonofy present. The other is actually there’s fluid present a lot of time, especially for rheumatoid arthritis. It’s more cellular it’s in extra tissue. So it feels different. It coul It could be boggy there’s texture there. So normal snow, you, you can’t feel, but an RA you’re getting the sense that there’s soft tissue present

Mithu: Yeah trying to figure out if there is more swelling can be hard but the more you examine, the easier it gets! AND If the joint is really inflamed, we might see limited range of motion of a joint, joint effusion and less commonly redness or warmth of the joint.

Dr. Pisetsky: Joints in RA and lupus are not usually red, they’re not hot, but they are tender and they are swollen. So it’s easy for an internist to miss arthritis, especially if he or she is looking for a red hot joint, except for gout and sepsis, most joints are not red and hot, but just tender and a bit swollen. I always object to the pictures. The show of arthritis and textbooks. And they say, ah, that’s what RA looks like. That’s what RA looks like after 30 years. It’s not what it looks like when it starts. It may look nothing just like a normal hand. It’s just tender and you can feel swelling.

S: This nicely brings up that sometimes we don’t see much in our exam at all, which just adds to how tough it can be to tease out which patients we should send ANAs on or not.

AMK: The struggle is real. Let’s switch gears and compare those inflammatory arthritis findings to what we would expect from non-inflammatory joint pain.

Mithu: Generally, non-inflammatory arthritis will not have swelling or pain in specific joints.  But, it’s not a hard and fast rule: you can get effusions or swelling with OA but usually it’s in large joints like the knees (we don’t see OA causing effusions in small joints of the hands).

S: Ok well what about fibromyalgia? what on physical exam will help us differentiate fibromyalgia from autoimmune disease.

Dr. Jonas: Fibromyalgia is a syndrome of widespread joint and muscle pain, and it’s often very chronic. Number one is they have soft tissue tenderness in fairly characteristic locations, shoulder girdle, hip girdle, lateral epicondyles. So lots of soft tissue tenderness. They often have sleep disturbance and patients will often tell you it’s very chronic. It may be associated with anxiety and depression. 

M: And I just wanna point out a quick tangent – I have seen over and over again that by addressing their sleep disturbance, their anxiety and their depression their pain gets better.

Dr. Jonas: I always look for fibromyalgia tender points, but I’m gonna really palpate the large muscle groups to just get a sense of how much soft tissue rheumatism is part of the, of this arthralgia myalgia complaint complex that we often see in patients with lupus. And then I would say pain out of proportion to the physical findings, also characteristic of fibromyalgia.

S: I really like that as differentiator to point towards fibromyalgia, seeing if there was pain outside of the joints, in some of the muscle areas like the forearms or thighs.

AMK: With that squared away, any other exam pearls for the general internist, Dr. Jonas?

Dr. Jonas: You really wanna do a very careful skin exam and there may be findings in places that the patient doesn’t know some rashes and lupus like to hide in the ear, particularly discoid. And so I always am looking in the ear.

S: Thank you Dr. Jonas! So let’s recap the physical exam, particularly the skin and musculoskeletal exam, that can help you prioritize autoimmune disease on differential. You are looking for tenderness when you palpate joints, especially small joints on both sides and if there is any new swelling in those joints. So you wanna ask about if there is joint stiffness in the morning that lasts for more than 30 mins and gets better with activity but that is more of a rule of thumb and might not be present in all AI disease

AMK: And with fibromyalgia, you wanna do your best to see if there is tenderness not only at the joints, but next to the joint areas and in large muscle groups.

Pearl 4: ANA positivity is seen in other non-rheumatic medical conditions and is not unique to autoimmune diseases.

S: So say we have a theoretical patient, Ms. Smith whose fingers do turn whitish in the cold, had hair loss in a dermatomal distribution, and has some sensitive skin in the sun and we decide to order an ANA. What conversation should we have with her when sending off an ANA?

Dr. Jonas: I would say to the patient, we are gonna order this test. This is a screening test. It is not going to make the diagnosis of lupus. The diagnosis of lupus is made based on many, many other factors, but it may give us some clue and direction that we are gonna go in next to try to understand what’s happening with you. 

AMK: I really appreciate how she sets expectations. So then what if the ANA comes back positive? What should we be thinking about then? 

Mithu: Its important to keep a broad differential for a positive ANA. I see referrals in my clinic where a patient has been told they have lupus because they have a positive ANA, but it ends up being something entirely different like thyroid disease. 

Dr. Jonas: Number one is thyroid disease… autoimmune thyroid thyroid disease, like Hashimoto thyroid and Grave’s disease. These patients often have ANA. So if you are seeing somebody who’s got thyroid disease or somebody who may have undiagnosed thyroid disease and they come with an ANA and remember, you know, thyroid disorders may present with a fatigue and all the usual sort of nonspecific things that we see in early multisystem, autoimmune disease.

 S: Wow good old thyroid mimicking even in our lab tests. You know, I really didn’t know antinuclear antibodies were NOT unique to rheum diseases until I saw Mithu’s RheumOnePager on Twitter 

AMK: Agreed. What other things should we be considering, Mithu?

Mithu: Well some of the most interesting consults I have seen in the hospital presented as a mimicker of SLE with a +ANA and we went down a wild goose chase and turned out to be a hematologic malignancies (lymphoma) and lymphoproliferative disorders

S: Oh interesting and I guess that makes sense. Patients with malignancy can have a lot of vague complaints and have cytopenias like seen in lupus, so I can imagine why the ANA can be sent. But what about drugs being associated with positive ANAs? I feel like I’ve seen medications in the differential for everything.

Dr. Jonas: Hydralazine is one drug that, you know, it’s out there and, and it’s often associated with ANA, there’s a whole laundry list of drugs. A lot of the anti-epileptic medicines of been associated with ANA’s, um, you know, drug induced, lupus syndromes, um, some of the antipsychotics have been associated with that. The anti-TNF drugs often associated with ANA, even in the absence of a drug-induced lupus. 

AMK: Add that to the list of reasons why I hate using  hydralazine. 

S: Lets not get Ann Marie started on a rant! Why don’t we move to the LAST big bucket that gives us ANA positivity — infections! 

Dr. Pisetsky: So malaria has been associated with, uh, ANAs. Tuberculosis is associated with ANAs.

Mithu: I have seen ANAs with other infections including new diagnoses of syphilis, HIV, and other bacterial infections including endocarditis!  

S: Mithu I feel rheumatologists are the real Dr. House that keep getting positive ANAs and have to figure what other diseases could also be giving that ANA.

Mithu: Yeah I totally feel like Dr. House sometimes.  I’ve seen patients referred to me for positive ANAs  and that actually ended up being multiple sclerosis.

AMK: Wow, I think it is wild  that a lot of the “great mimicker” diseases also have an ANA!  This really hammers the point home about expanding our differential beyond rheumatology when we see a positive ANA, especially since incidence of ANA positivity is rising.

Dr. Pisetsky: And there’s a study published relatively recently that the frequency of Ana positivity in the population is rising. And it’s a well done study. So in the general population frequency of ANA’s going up now, what could that be from? Well, you could say infection, environmental exposures, ​​what else?

S: Really interesting observation if the percentage of health population ANAs are going up and even more why we should cement this away that ANA is just screening test, NOT a diagnostic test. And we have to remember at least 3 big buckets of OTHER things that are associated positive ANAs: Heme malignancy, infections and certain medications like hydrazine, antipsychotics and anti TNFs and antiepileptics could all be at play.

Pearl 5: Once an ANA comes back positive, what are the next steps in Evaluation?

AMK: Ok back to our theoretical patient, Ms Smith with a positive ANA. What other evaluation should I send while waiting for the referral? 

Dr. Jonas: If you think someone has an autoimmune disease and you’re gonna get an ANA, please get a CBC and a U analysis. Because I think that tells us a lot when you’re sitting in front of a patient who you think might have an autoimmune syndrome, they may have a positive ANA, but if their urinalysis is perfectly fine, i.e. they have no protein or cells. Then at least we know they don’t have lupus nephritis now. And if their CBC is normal, they’re not anemic. They don’t have lymphopenia, they don’t have thrombocytopenia. They’re probably not gonna have any other major organ involvement that you have to be particularly worried about. Um, and, and the reason I mention that is because a as, as many of you know, there’s a worldwide shortage of rheumatologist. So when you’re sitting in your clinic and you’ve got this patient, you’re worried about who has a positive ANA, and you pick up the phone to call you a rheumatology colleague and they tell you, you know, I can see your patient six weeks, eight weeks in some places, six months from now, your job is to really try to figure out how sick might this patient be. And if you’ve got a normal CBC and a normal urinalysis, I think everybody can breathe.

S: Hah yes triaging with a CBC and UA so we can all breath – SO in addition to the CBC and urinalysis, should we also be sending another ANA titer for trending? 

Dr. Jonas: So the ANA go up and down for a lot of reasons. I think the degree to which your body makes the auto antibodies probably changes over time. And you might send it to a different lab that has a different, you know, as they and different standards, this happens all the time. And so truthfully, once I’ve got a positive Ana in a patient that I diagnosed with lupus, I really don’t care what it is in the future. It does not matter. Don’t check it again. Somebody will always check it again. It doesn’t matter, please. Don’t, you know, try hard not to do that because it’s not helpful. 

AMK: Yikes! I can think of quite a few times a patient who has a well-established rheum diagnosis comes into the hospital and sure enough, an ANA gets sent with their workup.  But what other laboratory test sare actually helpful to follow over time, especially in lupus?

Dr. Jonas: Now I will say the antibodies to double stranded DNA are a different story. These do go up and down and in some patients, not all patients correlate with disease. The same is true for complement levels. So we follow complement because someone’s compliment has been, you know, doing okay and you measure it, and then it drops. That’s a sign. Things might be starting to act up. And the same is true in your CBC for lymphopenia. If you start to see worsening lymphopenia, that might be a sign that the lupus is starting to become more active. 

S: That’s really helpful. As someone whose favorite tab is the trend tab on the EMR, it’s good to know to look at the dsDNA, complement and lymphocytes to get a sense of how a patient with lupus has been doing with their illness and where are they now.

AMK: Hashtag dsDNA is trending on Shreya’s EMR. I am curious what about the other autoantibodies we check after a positive ANA?  I feel like sometimes after someone’s ANA is positive we turn into vampires and take a crazy amount of blood from patients to send off for every autoantibody I once learned about in med school. 

S: Yeah I feel like we are taught to send Ro and La antibodies it’s slam dunk for Sjogrens, and if you see a positive antiRNP it’s mixed connective tissue disease. Does that much does that actually hold up in practice?

Dr. Jonas: Some of the other auto antibodies, the RNP antibodies, um, may be present in lupus. It may also be present in other autoimmune syndromes, such as mixed connective tissue disease or systemic sclerosis. It’s not really, um, very specific in very high titer. We tend to associate it with mixed connective tissue disease, but that’s not universally true antibodies to law can be seen in lupus, in rheumatoid arthritis and systemic explosives in a lot of different things. They tend to be associated with primary Sjogren’s syndrome. Um, but they also are associated with many, many other autoimmune diseases

Mithu: The big thing to remember is these autoantibodies often overlap between different autoimmune diseases.  Even the classic anti-histone antibody that we think and learn is so specific for drug-induced lupus, but can be seen in plain old lupus! It’s so humbling… I feel like we learn these rules, which makes sense you have to start somewhere – but then when you are in practice, medicine is more messy and you have to unlearn them in terms of knee-jerk association

AMK: Yeah, especially in rheum. There were so many  nuances to unpack even with this episode! Hydral is not off the hook though. 

S: Yes! So to recap this pearl on what happens after you get back a positive ANA, do send a CBC, creatinine and UA to help you triage how urgently your patient needs to see rheum or get more immediate care. 

Mithu: Yes and if concerned for an autoimmune disease, you can go ahead and send off other autoantibodies, keeping in mind there may be crossover between the autoantibodies and different autoimmune diseases. 

AMK: And lastly, you don’t have to recheck the ANA, especially once you have a known rheum diagnosis. And if the diagnosis is lupus, checking a DsDNA, complement and lymphocytes often correlate with disease activity.

S: And that’s a wrap for today’s episode.  This episode counts for CME credit with the ACP, click on the link in the show notes and answer 3 Qs and get CME credit. If you found this episode helpful, please share with your team and colleagues. Thank you to our peer reviewers Dr. Jason Kolfenbach and Dr. Jacob Meindertsma

Thank you to Daksh Bhatia for the audio editing and Dr. Lyla Atta for the accompanying graphics. As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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