Antinuclear antibodies (ANA) are present in up to 20% of the healthy population, depending upon the particular lab that is used and in which population. However, it is also important in helping to identify some autoimmune diseases, especially systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), and mixed connective tissue disease.Â
October 2024: The medical newspaper, The Rheumatologist, published my article about “A Practical Guide to Autoantibody Testing in Rheumatic Diseases.” Though it is written for healthcare providers, it gives lots of interesting information about these tests.
Exagen’s CB-CAPS are more accurate and sensitive with a higher positive predictive value for diagnosing SLE than are C3, C4, anti-dsDNA, and anti-Smith antibody.Â
Read on to learn about newer tests that can help get a more accurate and faster diagnosis of lupus for a positive ANA workup
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The Positive ANA Workup Begins the Journey
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If someone is found to have a positive antinuclear antibody (ANA), the doctor will often tell the patient they need a positive ANA workup and that “lupus needs to be ruled out.”
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Lupus is a disease where the immune system of the affected person attacks their own body (called an autoimmune disease). If someone has symptoms suggestive of lupus (fatigue, joint pain, rash, fever, pleurisy, Raynaud’s, mouth sores, etc) the doctor will usually order an antinuclear antibody (ANA, also called FANA) test as depicted in the picture above. This is what the lab technician sees under the microscope when someone’s blood is positive for ANA. This is the initial test done in people who could possibly have systemic lupus erythematosus (SLE) because around 98% to 99% of adult SLE patients are positive for ANA (when both the IFA technique and ELISA lab methods are used). Children, especially young children, with SLE have higher rates of being ANA negative (as high as 15% to 20% in young children).
If positive, the patient is then often referred to a rheumatologist (the doctor who specializes in lupus)
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The Visit to the Rheumatologist: Where the positive ANA workup often begins
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The rheumatologist then does a complete history (asks about symptoms), performs a thorough physical examination, and does a whole bunch of blood work and takes a urine sample to look for lupus. However, since multiple other disorders can cause similar symptoms as lupus and can also cause a positive ANA, he or she will also look for these possibilities. These tests include labs such as anti-dsDNA, anti-Smith antibody, anti-SSA, anti-RNP, rheumatoid factor, anti-CCP antibody, complete blood counts, liver enzymes, kidney function test, C3 and C4 complements, Coombs’ antibody, CH50 complement test, antiphospholipid antibodies, and a urine protein measurement.Â
The list of disorders that can mimic lupus and can have a positive ANA is broad and include (not an exhaustive list):
– Other systemic autoimmune diseases (such as rheumatoid arthritis, scleroderma, Sjogren’s, polymyositis, mixed connective tissue disease, undifferentiated connective tissue disease) – Infections (such as hepatitis C, hepatitis B, parvovirus infection, Epstein Barr virus infection) – Fibromyalgia – Cancer – Medications
Or, the ANA can be a normal finding. It is found in up to 20% of all women. For example, a 55-year-old woman could have joint pains due to a different type of arthritis (such as osteoarthritis, OA), be very tired and fatigued after going through menopause, and have a positive ANA as a normal finding.
If the rheumatologist diagnoses lupus or a related disorder, hopefully, you will be treated immediately. Or, the rheumatologist will find another reason for your problems and the ANA (such as the woman with OA in the above paragraph).
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6 Years for a Diagnosis of Lupus?
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Unfortunately, not everyone is so lucky. In 2014, UK Lupus did a survey of their members. Over 2500 SLE patients responded. The survey showed that it took an average of 6.4 years to get a correct diagnosis. Most ended up seeing multiple doctors before a diagnosis was reached. A few years later, the Lupus Foundation of America did a similar survey and found similar results, it took an average of 6 years. This is a travesty, and a huge unmet need. We need better ways to diagnose lupus.Â
We do have better and more accurate ways, by the way, read onwards! But 1st … why does it take so long?
There are several reasons:
SLE will often start off slowly and add symptoms and problems and blood test results very slowly over time. Someone can actually have the disease lupus, feel miserable, yet not have enough evidence using the typical labs to make the diagnosis. The person often suffers while waiting for new problems to occur before enough evidence is present to properly make the diagnosis. The best solution for this problem is if we can figure out a way to identify the disease process of lupus earlier and faster by identifying an immune system abnormality that is unique for lupus. For example, maybe this could be a certain interferon signature in the blood work. However, we don’t have this luxury yet.Â
Another possible scenario is the person who has enough evidence for a systemic autoimmune disease, but there is not enough to label it as one of them (such as SLE, rheumatoid arthritis, scleroderma, Sjogren’s, or polymyositis). This person has evidence of an autoimmune disease, which we also call connective tissue diseases (CTDs), but it has not “differentiated” into one of the named CTDs. So, we label this person as having an undifferentiated connective tissue disease (UCTD).Â
People in the above situations could heed my advice and see a rheumatologist who does certain procedures to try to get a faster diagnosis (discussed below).
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Musculoskeletal Ultrasound can look inside the Joints right in the Rheumatologist’s Exam Room
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Many, but not most, rheumatologists can perform an ultrasound exam of the joints right in the examination room. In the photo above, I am doing an exam of the big toe joint in a patient. You can see a very nice picture of the joint ultrasound image on the screen. The vertical blue line in the middle cuts right between the two bones of the toe (that is where the cartilage of the joint exists). The horizontal bright white line going to the right is one toe bone (the middle phalanx) and the left line that starts out as a hump is the other (the first metatarsal bone).Â
90% of adult SLE patients have inflammatory arthritis. They typically have pain in the joints and stiffness that is worse when they first wake up from sleep. The middle joints of the fingers, the knuckles, elbows, and knees are some of the most common joints affected. It can be very difficult to tell on physical examination (PE) when some SLE patients have inflammatory arthritis. They often will not have swelling of the joints on the PE. An ultrasound exam can be invaluable to diagnose arthritis accurately in these individuals. I’ve seen quite a few patients who were told they have fibromyalgia (which is not an arthritis) or arthralgias (joint pains without inflammatory arthritis) yet turn out to actually have lupus inflammatory arthritis easily seen on ultrasound.
Below is one of my SLE patient’s ultrasound results of the wrist (I have her permission to use her image). Note the horizontal white line in the center between the red and yellow arrows. Those are two bones of her wrist (bright white = bone). Just above it is an oval dark area (the red arrow points at it). That is swelling and fluid inside of her wrist joint (fluid shows up as black). This is diagnostic of arthritis. Yet, more telling is the orange blotches that are on the rim of the joint swelling (yellow arrow). That is actual lupus inflammation of the joint. This ultrasound result made it very easy to prove she has lupus inflammatory arthritis.
​(by the way, the upper orange blotch is blood in the vein just below the skin of her her hand. Look at the top of your hand. See those blue veins? Your veins would look like this under ultrasound).Â
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Finding a Rheumatologist Certified in Musculoskeletal Ultrasound (rhMSUS)
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So, first, you can search out a rheumatologist who does ultrasound in his or her office. You can figure this out by going to the American College of Rheumatology’s website and look for a rheumatologist in your area who is certified to do these exams:Â https:///www.rheumatology.org/Learning-Center/RhMSUS-Certification/RhMSUS-Designees
You can then look up the names of doctors in your area to see if they are on the list. These rheumatologists can put the initials rhMSUS after the MD of their name (rhMSUS stands for Musculoskeletal Ultrasound Certification in Rheumatology). My partner (Dr. Yevgeniy Sheyn, MD) and I were in the very first group of doctors to earn this prestigious certification.Â
The second best option is to call up rheumatology offices in your area and ask if their doctors do ultrasound exams. Most rheumatologists who perform ultrasound are not certified (and are not on this list), yet many of them are still excellent ultrasonographers. Ask the phone personnel who they would see in that office to get an US exam if they might have lupus. That is always a good question to ask. Office staff usually know who the best doctors to see in their practice are.Â
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Exagen Diagnostic’s AVISE Lupus Test and AVISE CTD Test for the “Positive ANA Workup”
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The second test that can be very helpful is to get newer and more accurate labs done. A company called Exagen specializes in lupus lab tests. A type of blood test called Cell-Bound Complement Activation Products (CB-CAPs) is more sensitive and accurate than standard tests in diagnosing lupus compared to the usual commercial insurance labs (LabCorp and Quest) that most doctors order from. Exagen put these valuable labs in two helpful tests called the AVISE Lupus Test and the AVISE CTD test. Anyone can get these tests done, yet only around 25% of rheumatologists order them.
Why do so few rheumatologists order these tests if they are so accurate in diagnosing SLE?
Previously, to order these tests, a rheumatologist had to have a lab technician in the office that could draw the blood, process it correctly, then send it to the Exagen labs in California. This is a lot of work. Most rheumatologists do not have the capability to do this, or do not want to put forth the extra effort and work to implement these tests in their office. (It can be a lot of hassle ordering new types of labs, fill out a lot of paperwork, and fight with the insurance companies to cover the lab costs for patients… so I can certainly understand why they would not want to do them!)
Below is an example of a patient who has a positive AVISE Lupus Test. The orange oval at the top left highlights this patient’s positive result and the middle circle highlights it on the graph. The bottom orange oval highlights her positive CB-CAPS (EC4d and BC4d) that gave her the positive results. The value of this test is that CB-CAPS become positive due to activation of and consumption of complements (important immune system proteins). This is a key problem in SLE (complement activation and lower C3 and C4). Most rheumatologists order C3 and C4 complements on standard tests hoping to see low C3 or C4 to help diagnose SLE. However, this only occurs in 20% to 30% of SLE patients because the liver will often times produce a whole bunch more C3 and C4, which ends up normalizing the blood levels. CB-CAPS (EC4d and BC4d) results are not interfered with by this liver over production of C3 and C4.
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​You can imagine how this test could simplify things.Â
HOWEVER: a word of caution! … if you happen to get this test done, please do not assume that a positive AVISE Lupus Test automatically means you have lupus. On the other hand, a negative result does not mean you do not have it. The test result increases or decreases the likelihood of having lupus. For example, if the patient with test result above started off with a low likelihood of having SLE, this result may not be enough to say she has SLE. However, if the result was much further on the right of the graph (such as a Tier 1 positive test), then that could be enough to say she has SLE. Â
So how can you get this valuable test done?
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How to get the AVISE Lupus Test or AVISE CTD Test
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It is now much easier to get the AVISE Lupus Test done. If you are interested in doing this. Follow my advice. Doctors are much more likely to do something if you make it as easy for them to do as possible. All doctors are overworked these days. So, if you make it easy, then it is a cinch.
2. Fill out the form completely with all your information and the doctor’s information.
3. In Step 2 circle the diagnosis D89.89
4. Check the boxes that say “AVISE CTD Test” and the one underneath it that says “Add AVISE SLE Prognostic regardless of AVISE Index Result” and the “Add anti-Histone”
5. On page 3 print and sign your name. Fill out the last page if appropriate (sometimes you will get the test for free)
6. Make an appointment with your rheumatologist. Very tactfully ask, “Could I possibly get this lab test done for lupus called the AVISE test? I already filled out all the paperwork and I can get it done at a local lab”. Then just have him or her write in their NPI number upper right side and sign anywhere on the first page.
Also (important) ask them to add the diagnostic code D89.89 to the clinic visit note for that day.Â
8. Type in your zip code to find the closest lab that can do the test.Â
9. Call Exagen at 888-452-1522, option 3. Tell them you’d like to get the test done and you have the paperwork. Ask them how much it will end up costing you with your insurance. Most people pay a copay of $0 to $45. If you have no insurance, I believe it is $100 as of 2020. Then ask them what your next steps are.
10. Go to the lab to get your lab drawn, then see your rheumatologist a couple of weeks later to discuss the results.Â
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There is no such thing as a “false positive ANA”
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Positive ANAs are one of the most common reason for referrals to rheumatologists. Since up to 20% of the healthy population can be positive for ANA, most referred patients do not have an identifiable systemic autoimmune disease, like lupus.
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Sometimes, “false positive ANA” is put down as the diagnosis. I am not a fan of this “diagnosis.” It implies that the ANA is “normal” for the person and not associated with any disease.
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The problem with this, is that ANA can show up a decade before the symptoms of lupus show up. The timeline of events for developing something like lupus begins with having the genes that predisposes someone to have lupus, then a trigger causes activation of these genes to cause the immune system to become more active than normal but is not causing any symptoms or problems yet. This period of time is sometimes labeled “benign autoimmunity,” and this is the period when autoantibodies, like ANA and anti-SSA, can emerge.
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If an ANA is positive in this person during a “benign autoimmunity” stage, labeling it as a “false positive” is incorrect. This ANA is associated with the person eventually developing a systemic autoimmune disease, like lupus. The only way to know is in hindsight. However, no rheumatologist has a crystal ball where they can predict that a disease will not occur in the future after the ANA is found to be positive.Â
I strongly believe that people get better healthcare when they are proactive in their healthcare. If you have a positive ANA, have symptoms that could potentially be caused by lupus, had a thorough workup, yet you feel like you don’t have a good answer, take my advice.
– Find a rheumatologist who can do an ultrasound of your joints – And get the AVISE CTD or AVISE Lupus test done
if you do this, then you can be confident that you have done everything that you can with today’s modern technology. I hope in the future that I can report on even better tests. A lot of research is being done looking into this, and I will certainly report on it when it becomes available.
I would love to hear from you about your experience. Write comments below under “LEAVE A REPLY”. If you have lupus, how long did it take? Was it frustrating? What ended up being the key in getting your diagnosis correct? Also, if anyone has any questions, I’ll also be glad to answer them.
Please SHARE with anyone who is struggling to get a proper diagnosis after being ANA positive.
NOTE: I am on the Speaker’s Bureau for Exagen. I do believe strongly in how their tests improve patient care. Note, that the Lupus Foundation of America has also partnered with them to support their help for lupus patients.Â
CB-CAPS became a reality partially due big efforts and funding from The Lupus Foundation of America. Please join in you have lupus and are not a member. It is a wonderful organization fighting for your health!
Positive ANA result, referred by GP to a rheumatologist. Further labs showed B2GP and anticardiolipin antibodies, anti ds dna antibodies, pancytopenia, and low C3 and C4. First rheumatologist said “I’m not convinced it’s lupus, just keep an eye on all the labs.” Went to two more rheumatologists for opinions and just got notes saying “very perplexing 27-year old, currently at a loss as to the underlying etiology despite extensive workup for autoimmune, inflammatory, or connective tissue disease that might be associated with this manifestation.” Frustrated, flew across the country to a tertiary care center for a fourth opinion. The rheumatologist there said, “I don’t think you’re that perplexing, this is definitely rheumatic disease. You meet the criteria for SLE and likely will meet the scleroderma criteria as well within the next couple years. You need to be on hydroxychloroquine, and I’m very sorry no one has put you on it in the last two years.” I am persistent, highly educated, and have the resources to spend a lot of time and money getting a diagnosis. Yet it still took two years. Something needs to change.
So sorry to hear that, ARW, that should never happen! I’m glad you finally found a good rheumatologist, but that should have occurred at the first visit from what you are describing. I hope you are doing better.
I’ve had Lupus for over 30 yrs and over the last several years have begun to really struggle with joint involvement in my hands. Rheumy thinks it’s more from Osteoarthritis. How do you determine if it’s coming from Osteo or your lupus?
Sharri: Osteoarthritis is usually easy to diagnose on physical exam. We find bony swellings of the finger joints (the end joints and middle joints, but usually not the knuckles). For early OA, an ultrasound exam can be helpful if the bone spurs as too small to feel. X-rays can help in more advanced OA. The inflammatory arthritis of SLE is very different. It causes more prolonged stiffness in the AM and more severe than OA and on physical exam we find soft tissue rubbery feeling swelling of the middle joints, knuckles and wrists, but not the end joints … I hope that helps. btw… I am a strong believer in taking pharmaceutical grade glucosamine sulfate for OA as it may slow down the progressive loss of cartilage over time. Don’t take glucosamine hydrochloride (doesn’t work) nor poor quality brands (most are)… WynnPharma makes pharmaceutical grade products. I take their InvigoFlex AMPM: https:/www.wynnpharm.com/invigoflex-glucosamine-and-chondroitin-supplements/
Over 30 years to get a diagnosis and this was from a General MD, formally an ER MD, turned Wholistic after a bout with cancer. Many years of flares, days off work, depression and pain lost jobs therefore loosing medical insurance. Not till Obama Care received insurance, part time work and out of the pocket to pay for this ER MD with a great reputation for actually helping people with unusual issues. He opted out of medical facilities to help his patience more. Fortunately I was able to push exercise, very healthy eating and pursued Traditional Chinese Medicine all these 30 plus years that helped me. Metabolically very healthy, many doctors still do not believe I have Lupus, RA, Sjogren’s, Raynard’s plus. Yet Avise, other blood tests and symptoms prove positive. All the many doctors I saw throughout the years surmised that I was depressed due to the depression and pain I had. Simple dismissal and no blood tests by doctors who regardless of being over worked, were negligent. I refuse to give up, I eat healthy, mainly an anti-inflammatory diet, exercise, and still pursue Chinese Medicine with hydroxychloroquine from France now. Do not trust doctors till proven ethical, conscientious and worthy of respect. Read your book twice, I continue to study everything I can regarding these conditions, including the immune system, gastro issues, hormones, and drugs. I am my best expert and trump any RA doctor with any amount of years of experience. I am the one who is intimate with what works and what does not and the idiosyncrasies of this complex disfunction.
Malka: Thanks for sharing your story, for persevering and being so proactive in your care. Hopefully, your drive will rub off on others, and I’m sure you do!
I was 16 at the first onset of symptoms. I was a gymnast. I had to quit due to no strength and pain in my hands. I started noticing I had no strength to hold the bars. Then the pain set in with no swelling in my hands. This was all attributed to training. Once I quit training, the swelling started in my ankles and knees.
Then in my twenties, I started to experience pains in the sternum area. I had made 3 different trips to the ER over a span of my adult life thinking it was a heart attack. Everything came back ok and was told they were probably a panic attack. I have dealt most of my life with sternum pain. I also experienced dark bruises on my body.
My turning point came when my husband passed when I was 52. I was thrown into the worst flare of my life without knowing it was a flare. I was told I was depressed and needed counseling to help deal with the grief. The sad part on this is my husband knew something was wrong with me. It was sad that he didn’t live long enough to find out what the diagnosis is. He saw me struggle with the pain, the swelling and dark bruising.
When I couldn’t stand and my PCP wasn’t able to assist, I made an appointment with a rheumatologist on my own. It was a nine month wait to get in to see her.
My first appointment consisted of her looking at each joint, touching, feeling the heat of my joints and asking so many questions my head was spinning. She concluded this appointment by telling me she believes we are dealing with one of 3 things…Gout, RA or Lupus. She set me up for labs and gave me a prescription for a high dose of NSAIDS then had me come back in a month to go over the findings.
By my next appointment, I was feeling so good, I figured I was ok. She walked in the room and told me it was what she had expected, “You have Lupus.” I started crying. Not because I had Lupus. I really didn’t know what Lupus was. It was the fact that a doctor believed my pain was real. I was 52 years old. Thirty-six years I went from doctor to doctor with each one telling me to lose weight, go to counseling and then making me believe it was all in my head.
I am a huge advocate now for Lupus. I don’t want anyone else to go thirty-six years in pain. I now have a fantastic PCP that does primary care for autoimmune patients. She is on the same portal as my rheumatologist. This in turn makes sure I have the best care possible. One thing my PCP does is have me to speak to medical students that come through her office about my Lupus. She is doing everything she can to inform new doctors how important it is to listen to a patient. I’m so very thankful for this.
My vision is to see that every Lupus patient isn’t turned away without the help and resources he/she needs to walk the Lupus journey.
Thanks for sharing your story! I’m glad you finally found someone who believed you. I often hear the same from new patients. Lupus truly is an “invisible disease” even to some doctors and with many of the labs we use. Please keep up the advocacy, it is so important
Love all your content, thank for you being such a valuable resource to this community. I’m curious of your thoughts on this recent paper published in Nature “High titers of antinuclear antibody and the presence of multiple autoantibodies are highly suggestive of systemic lupus erythematosus” by Hejun Li, etc al. 2022 which concluded, “A high titer of ANA (≥ 3 +) was Highly specific for SLE (96.52%) with a high specific likelihood ratio (19.6), enough to predict the diagnosis of SLE. These data clearly indicate that when a high titer of ANA is present, the diagnostic accuracy of clinicians can be improved, and there is no need for too many tests to distinguish SLE from other diseases, which can reduce unnecessary economic costs, since the possibility of a false positive with a high titer of ANA is minimal.” … While it’s new research, that statement seems almost heretical from everything I’ve learned about diagnosing SLE. Obviously more data than a high ANA is needed, but 96% specificity? Seems pretty wild, eh?
Thanks for your kind comments and for reading my blog posts, I am glad they are helpful. Thank you for pointing out this paper. I am not real crazy about it because they used “non-SLE rheumatic diseases” as one of the main comparator groups and in that category they include non-ANA disorders such as OA, metatobolic joint disease and spondylos. When we have high positive ANA we are usually trying to distinguish amongst ANA+ systemic autoimmmune diseases (RA, Sjogren’s, scleroderma, etc), cancer, and infection (all can cause high positive ANA). If there were large numbers of patients with those disorders, then it could be useful, and I would predict the results would have been very different. I’m kind of surprised it made it into the journal “Nature.”
Thank you for that explanation. Also it seems like if what they were claiming was actually true it would have been discovered a long time ago. I was surprised it made it into Nature too.
Hello,
Symptoms of SLE for 25 years. Positive ANA 1.160 speckled. Dsdna 40 . Labs over kast few ueara show high CRP, and other inflammation markers. Malar rash and redness joint pain in hands and feet and knees, hips. Several Rhuemetologists, sadly they told me nothing is wrong or they think it was a false positve. That was 7 years ago and they are still coming up positive. Latest Rhueme has never once even put a hand on my body except to listen to my heart. Ive kept a list of symptons, and photos of nalar rash and raynauds. Showed them to her. She says UCTD on my chart but told me SLE in the room. Shes dismissive, tild me my internal medicine Doc who has done every test under the sun to rule out other possibilities isnt qualified like her to tell me SLE im suffering in pain and am experiencing autonomic disruptions regularly. ER Dox thinks ots Lupus and its attaking my Autonomic nervous system. W on addition both My mother and her mother, my grandmother had Lupusas well as two cousins on that side of family. O want to see another Rhueme but my derm has told me that unfortunately that is a part of why im being gaslit at my appts, because I have seen a few . Wht do I do?
Dear Claire: So sorry to hear of your difficult journey. Just another example of our need for better diagnostic tests. I always like to tell people what I would do if I were in their place.
1. It is wonderful you finally have a rheumatologist who agrees you have a systemic autoimmune disease. UCTD is a real thing, just as SLE is. If I were a patient, had symptoms like fatigue and joint pain, I would absolutely ask the diagnosing rheumatologist to put me hon hydroxychloroquine. It has been shown to help these symptoms plus decrease the risk of evolving to severe systemic lupus. Takes anywhere from 3 months to 12 months for the full effect. See my HCQ blog post here: https://www.lupusencyclopedia.com/how-do-antimalarial-drugs-work-for-lupus/
2. I suspect you are keeping all lab results from all docs. If not, get all of them. It will make like easier if you give all these to all docs.
3. Consider asking your rheumy to check the AVISE Lupus and CTD tests along with the AVISE Prognostic test and SLE Monitor test. It may cost you $45 copay with insurance, but could be well worth it. Just download and print out and fill out the paperwork, ask your doc to sign, take to a lab on their “locator“: https://avisetest.com/telavise-draw-site-locator/
I wish you all the best in health and life… let us know how you do.
BTW: the above is NOT meant to be medical advice, simply what I would do if I were in these circumstances as described.
I’m at a loss here with my symptoms. I started getting “cold sores” in my lower lip right side. No sore but my lip would swell 3 times it’s size around the year 2000. In 2003, I had limbic encephalitis. In 2010 I was diagnosed with hypogammaglobulinemia. In 2018 I developed eczema. In 2019 I had an angioedema episode. In 2021 I started get joint pain and joint swelling. My GP sent me to a rheumatologist. All my x-rays and blood work came back normal, except I had a positive ANA ELISA screen. The ANA ifa came back normal at a titer of 1:80. I went to have a US of my wrist (although I had no pain or swelling at that time), so that was normal. Did a f/u with rheumatologist who said, for lack of dx, I had RA and I started Meloxicam (which is doing great for my pain) and hydroxychloroquine. Went to rheum #2 about 2 months later who said it was not RA and took me off the hydroxychloroquine. Did more blood work because he felt it was sjorgrens. Again, bw normal. The PA was having a hard determining what could be the issue. I told them that I have hypermobile joints, but she indicated that’s not a factor.
In October of 2022 had another bout of angioedema. Went to allergist/immunologist. He noticed and asked about my facial flushing. I get this all the time, but it doesn’t go across the bridge of my nose. He did more bw. Again normal and this bw shows that my igg subclass 2 was normal. If I didn’t have the visible swelling, I would think I was a hypochondriac. I have a follow up with allergist next week and was going to discuss his thoughts on possible lupus. I came across the AVISE test and was reading up on it. But I wonder if I’m just reaching for a dx at this point.
I am 32-year-old male, and still is the diagnosed process (currently labeled UCTD with rheum leaning towards Lupus). Have raynauds, and have had some off and on hand joint pain / swelling, but nothing that warranted medication just yet. I find it interesting how many tests there are available yet were not suggested to me. C3/C4 has been the main indicator leaning towards Lupus (though that isn’t specific to Lupus).
Couple questions. Inflammatory arthritis – is that specific to Lupus in the early stages? Compared to something like scleroderma?
What is your take on mixed ANA patterns? I had two high titers, one with a very rare pattern 1:640 (Centriole), and 1:320 (Speckled). My Rheumatologist seemed to just brush the pattern off (as he ran panels for all the main conditions associated with my symptoms). Do patterns provide you very useful information, or are they just helpful hints to utilize when needed?
Dear Russell: Keep in mind that UCTD is a true diagnosis. It does mean you have a systemic autoimmune disease, it just doesn’t satisfy classification criteria for on of the other CTDs like lupus, RA, scleroderma, Sjogren’s etc. Some patients can misinterpret it as not a real diagnosis when it actually is. I usually treat my patients with UCTD with hydroxychloroquine which can reduce progression.
There are over 100 causes of arthritis, and systemic lupus is only one of those causes. When we get someone with arthritis, our job is to figure out the cause then give the right treatment based on the cause (like antibiotics for Lyme arthritis, urate-lowering drugs for gout, and immunosuppressants for lupus arthritis).
Patterns are rarely that useful, however, sometimes they can help. Centriole pattern is commonly seen in our patients who have Raynaud’s phenomenon. It is also more commonly seen in scleroderma and patients with pulmonary hypertension. So, in my patients, I’d be monitoring the skin of the fingers to ensure no skin thickening, and I’d consider getting an echocardiogram and pulmonary function tests as screening tests for pulmonary hypertension.
Thank you so much for your response and the details provided. UCTD seemed like a sort of a transit waiting room, but I understand it being a standalone condition.
My hesitation for starting treatment with hydroxychloroquine was due to my age (which may sound silly, as I’m not that young) and the fact that I really am not struggling with symptoms yet. I seem to read of a lot of experiences where people often cannot stay on hydroxychloroquine for years and years to come. It may be that I only read of the negative experiences more so than the positive that I do not see as often. It’s not the fear to take medication, it is more of the fear that if I start taking this now, will I just become more dependent on stronger medication in a few years. The more I read, the more it seems like it may be a good idea to potentially thwart future issues – it just seems to go against my nature since I feel fine right now (knock on wood).
I saw various studies for the centrosome/centriole pattern (most were very small) and saw the one regarding PAH that you referenced (which scared me enough to request an echo and PFT which is underway). The largest one I found seemed to associate this pattern more so with UCTD (study was called “uncommon patterns of antinuclear antibodies recognizing mitotic spindle apparatus antigens and clinical associations”). SLE was the second most common associated with that pattern (in that study). It all makes a layman very confused – as you see other studies as you referred to that suggest the pattern “harolds” scleroderma. Probably further proves the point you mention that patterns are rarely useful.
Your blog is excellent – I have been following an extremely anti-inflammatory diet since December. Your blog regarding the diet aligns very well to what I have been doing – and I was glad to find it. I wish more rheumatologists were as knowledgeable and open as yourself.
One last question if you do not mind. Why is C3/C4 often associated with Lupus more so than other CTD’s? They have checked my C3/C4 each time I go into my rheumatologist – Each time my C3 has been low, and C4 has been low twice. I read that C3/C4 is not specific to Lupus – so why is it more associated with it than other CTD’s?
Low C3 and C4 are much more associated with SLE than the other CTDs. But it is not 100%. Sjogren’s and vasculitis patients can also get it. When we look at UCTD patients, low C3 or C4 is one of the markers that increases the chances for that patient progressing to SLE.
Re HCQ… I would not hesitate in starting it myself. Once people start to feel badly, permanent organ damage is already going on. HCQ has been shown to be a disease modifying agent, reduces the risk for organ damage, reduces the risk for UCTD to progress to severe SLE, and is the only drug proven to prolong survival in SLE. Our eye screening tests are so excellent that for those who are bound to get eye problems from it (retinopathy), we catch it way before the person would notice anything. Few people with SLE have the luxury of catching it in the very early stages (like UCTD) … that is when you want to act…. just my 2 cents worth, but it is important to understand the pros and cons of starting HCQ vs not doing so.
Good luck and I hope you do well… you really read the literature well, so I know you’ll make a well-educated decision.
I’m a 29 y/o female. A lot of people on my dads side of the family suffer with autoimmune diseases. I have had symptoms for the last 6 years. Fatigue, fever, stiff/tingling fingers and toes, butterfly rash, terrible memory issues, etc. Rheumatologist retired in December, never gave me a diagnosis. ANA was always negative. Sent me to oncology and everything was clear. Visited new rheumatologist yesterday and she diagnosed me with fibromyalgia. Due to family history and butterfly rash and symptoms, she sent in AVISE test to double check for any autoimmune. I go back on 3/30/23 for results. Is it possible for me to keep getting negative ANA in the office but a positive from AVISE?
The Exagen Lab who does AVISE is an incredibly high-quality immunology lab. Studies by Pisetsky et al show that lab quality for ANAs varies greatly. I am glad you are being persistent… to make sure… because a study in Oklahoma showed that some ANA-negative family members of SLE patients did develop SLE. So a negative ANA test does not predict not having SLE in the future.
I hope your AVISE test is negative.
I just wish we have better fibromyalgia treatments.
I was diagnosed with MCTD 6 yrs ago at clevleand clinic with pos ANA speckled and RNP . Labcorp and Quest along with Mayo Clinic all positive . I was started on Plaquenial and saw some relief to leg pains, rash and arm pains. Sjrogens and sle were always negative . Aps markers have been low pos or neg on numerous occasions. Before starting plaquenial my alk phos was high and since starting plaquenial it dropped to normal . No Rheumo or physician has been able to explain why my Alk phosphate was high or why it is normal now . 2 month s ago I went to see a new rheumo who did an advise panel and said I am negative for everything . He said my use of plaquenial would not alter the results Advise panels in the past have been negative too . My question is how are Mayo , clevleand clinc, hopkins , quest and labcorp all positive and Advise is negative ?
Paula:
1. I always review all diagnoses of MCTD with scrutiny. Many rheumatologists diagnose MCTD in the wrong situations. For example, anti-RNP is very common in systemic lupus and we can see it with other connective tissue diseases. I have also seen it accidentally used in patients who are really UCTD. This includes docs at major medical centers (there is a wide range of expertise even at the Cleveland Clinic).
2. ANA and low titer antibodies can become negative on good treatment in our lupus and UCTD patients.
3. Exagen AVISE is a very high quality lab. If anti-RNP is negative with them, it would make me reevaluate the diagnosis (which connective tissue disease caused the ANA and anti-RNP) even more. MCTD is associated with very high anti-RNP antibodies, and I’d be surprised to see it go away (but nothing is impossible).
4. I disagree with the last part. HCQ absolutely can interfere with the AVISE test… but primarily with the ANA and low level autoantibodies. 20% to 30% of systemic lupus patients become ANA negative on good treatment. Becoming ANA negative on treatment is a good prognostic finding as they are much less likely to flare. Make sure you gave your new rheumatologist all your old records. I’d want to see all the original study and lab results.
5. High alk phos can be incredibly nonspecific (all cells of the body have alk phos). Though it is most helpful when very high (eg > 200) in evaluating people with possible liver or bone disease. Today, I have probably seen several slightly elevated alk phos levels that are not important clinically.
Those are my thoughts from the information you gave and I hope it helps.
I have always suffered from fatigue, headaches, joint pain, and tenderness to touch. I never thought anything of it until my 6 year old daughter started having issues. Her ANA was 1:1280 so we were referred to a pedi rheumatologist. 3 years have now gone by and we still don’t have a diagnosis besides hypermobility and bilateral hip arthritis. I decided to get tested and ANA was positive as well as high values on my anticardiolipins. I just received my Avise results and my rheumatologist wants to start treatment. My question is..I was only tier two positive with an index of 0.2. I feel like this is barely positive so is it that concerning? My ANA was 1:1280 with discrete nuclear dots and speckled pattern. Also my anticardiolipin IgG was really high at 159. I guess I am just having a hard time accepting it. Was not expecting it at all.
Sorry to hear that Ashley:
– I am unable to venture a guess to your diagnosis (takes a complete history and physical and looking at all labs)
– You are correct that a slightly positive Lupus AVISE test slightly increases the chances that someone has lupus compared to what the doctor thought before the test… but it can be enough to make the diagnosis in some cases.
– Being antiphospholipid antibody positive in someone with a probable connective tissue disease (eg undifferentiated connective tissue disease) increases their chances of evolving to SLE.
– Joint pain with tenderness to touch actually meets one of the classification criteria for SLE. So, from your note, you already probably have 3 (ANA, APLA, arthritis)… most rheumys would at least label this UCTD and recommend hydroxychloroquine (decreases the risk of evolving to severe SLE)
First, I appreciate the content you have here, and your reddit contributions. Second, I have been very tempted to try and get an appointment with you and become your patient, which would give me an excuse to take a small vacation to Maryland (I live in Kentucky). I’m not sure if you see out of state patients, but I may inquire about it.
Thirdly, I am a male in my 30’s, and the past year has been quite a ride for me. It started with raynauds a while back, then a bout of arthritis in my hands, which led me to a rheumatologist. I have very high ANA, low c3/c4, low WBC, and borderline platelets. I have had a butterfly rash for many years on my face, but I am not certain if it is related (as it often has flaky skin, but never really hurts). I also have a family history of Lupus, so it really isn’t a far stretch. Honestly, right now, besides occasional raynauds, I feel healthy, which I am thankful for, and partly attribute to the anti-inflammatory diet I started once this all hit (which btw, I appreciate your blog on).
One of my questions relates to blood markers that you see on a CBC test that potentially point to Lupus (like low WBC). In your experience, do these sorts of markers often present themselves early in the condition?
For your patients with raynauds – do you normally prescribe them anything during the winter months if they struggle with raynauds? I saw in your lupus secrets you mention taking low dose aspirin daily, which I know isn’t specifically for raynauds, but potentially would benefit this. Curious if you have ever prescribed cialis or calcium channel blockers?
For your patients that don’t quite meet the criteria for Lupus, but is leaning in that direction, what bloodwork do you normally recommend upon their checkup visits?
Thank you for creating such informative content for those of us struggling to find answers. My question is my blood work repeatedly shows positive for dsDNA but negative ANA. Is dsDNA not a type of ANA? My doctors seem to write me off without having the ANA show positive regardless of all of my symptoms. I have been considering seeing other doctors but also just wonder if I’m wasting my time and there is truly nothing to be worried about. Appreciate any words of wisdom, thank you!
Kelsey:
1. This is a complicated issue and you are not wasting your time. This is just a good example about how poor our current diagnostic tests are and how we need better testing. It is no wonder that the average time to diagnosis of a systemic lupus patient is 4-6 years (ie patients who have lupus being told they do not have lupus only to be correctly diagnosed way after symptoms start), and on the other hand patients are told they have lupus but they actually do not and then they are treated with strong meds they do not need.
2. If the ANA was by ELISA or solid phase, those methods are missing a large number of the antigens/proteins seen in the nucleus and can lead to this scenario.
3. Though uncommon, there are anti-dsDNA positive, ANA-negative SLE patients out there. I am not an anti-DNA expert so I do not know how to explain this phenomenon.
4. There has to be a reason on why you were tested for ANA and anti-dsDNA in the first place. If no other good explanation has been found, then certainly seeking another opinion is important. I know I would. If you have not had the AVISE Lupus test and AVISE CTD tests, those are a good place to start (by finding a rheumatologist who orders them)… you can call Exagen and ask who in your area. Got to http://www.exagen.com
5. Note that there are people who have a “false-positive” anti-dsDNA in this sort of scenario. The path to figuring this out can be long and frustrating. I tend to err on the side of “keep looking, following, and testing” as I hate to miss something important.
I wish you all the best and hope you and your docs figure this out
In 2017 I had what they initially thought was a stroke, decided it was a migraine (I had never had migraines), positive ANA that turned negative. Tested for every autoimmune disease and MS. They told me I had functional neurological disorder. Learned to manage the burning muscle pain and stiffness, learned to rest when I felt bad. Two weeks ago, 90 degrees, went on my usual run/walk and all the burning muscles came back plus more. Bedridden for 2 days. PCP did ANA, positive with speckled pattern and dns70 antibodies. Other labs show AST slightly elevated. All other labs fine. Now I have to wait for 6 months to see a rheumatologist. Any suggestions because I have to figure out how to live until then. Thank you.
If you meant anti-DFS-70 … when ANA and DFS-70 are positive but all other autoantibodies are negative, it is much less likely to have a systemic autoimmune disease like lupus. However, it is not impossible.
A trick in getting seen faster: Every morning call up the office and ask if they have any last minute cancellations you could take … we love it when a cancelled slot is filled
I am a 39-year-old female. I went to see a GP last month in hopes of getting to the bottom of a chronic atrial arrhythmia. I underwent an ablation for AVNRT in May of 2023. I have not had an episode of SVT since, but I do experience episodes of “supraventricular ectopy” that last 8-12hours, multiple times per month. While there are definite triggers, even when I avoid the triggers, I cannot seem to prevent these episodes from occuring. They are absolutely debilitating, and my EP’s only answer to my questions is a shrug of the shoulders, an “I don’t know” and a recommendation to increase and/or change medications. I am now resigned to undergoing a second ablation.
In the meantime, I went to see a GP who somehow unearthed all of these other symptoms I’ve been having for years that I had always assumed were normal (e.g. extreme fatigue, joint and muscle pain, generalized painful inflammation, swollen lymph nodes, peripheral neuropathy and edema, chronic headaches, periodic low grade fevers, constant gastrointestinal discomfort, tendinitis, heat intolerance, chronic insomnia, tinnitus, nasal sores and persistent inflammation and post-nasal drip, depression, mood swings, etc.). I have experienced “flare ups”, particularly in the hot summer months and when I am nearing my period.
She ordered a whole battery of tests, including hormones, cbc, esr, crp, and ana. Everything came back normal, except for the ANA, which was positive, with the result being “homogeneous 1:320” (I am also mildly anemic and my estrogen was low for the point in my cycle). The doctor then ordered tests that really made very little sense to me (SMA, SSA SSB, a duplicate RF panel that had already come back negative). She didn’t order any of the tests affiliated with a potential SLE diagnosis. My faith in her is very shaken, and I am not entirely sure what to do. Should I request tests be performed (e.g. anti-dsDNA, antiphospholipid ab, anti-Sm, RNP, etcetera)? Or should I simply request a referral? Am I jumping to conclusions here? I am actually a slightly fearful of a negative diagnosis; it will mean starting from scratch again.
I began reading up on Lupus following the positive ANA and, in spite of being dismissed by this GP, as well as my EP, I am almost convinced that something is afoot. I ended up descending the internet wormhole and discovered the “well known” connection between Lupus and cardiac arrhythmias! What am I to make of this? Why is there such a dismal lack of curiosity on the part of doctors these days? They don’t mind throwing pills at you, but try to get to the bottom of anything? Ridiculous! I am fluctuating between desperation and despair, frustration and exhaustion. I cannot do this by myself; I didn’t go to medical school. I merely inhabit this malfunctioning body. Although I do have a background in medicine, I’m certainly no md. I rely on people who can’t be bothered.
I apologize for the rant. Thank you for this article.
Brynne: so sorry you are going through this. To put it into perspective, I’ve done this sort of work up for conditions such as arrhythmia dozens of times over the decades and they usually end up ruling out SLE. However, it is important to make sure. Most of the time, we do not know the reason for SVT etc (but searching for treatable causes like SLE is important). The labs I usually do are urinalysis, urine protein:creat, CBC, chemistry, anti-dsDNA, ENA, C3, C4, CH50, direct Coomb’s antibody, anticardiolipin antibody, lupus anticoagulant, RPR with reflex, beta-2-microglobulin-1, IgM parvovirus, IgM EBV, HIV, Lyme Western blot, anti Smith and RNP, anti-SSA and SSB, TSH, ESR, CRP. You can always feel free to show this list to your doctors. Most docs are completely open to these sorts of things. For example, though I specialize in lupus, I may need assistance in making sure I order the right tests for another disorder and hearing it from another specialist is important and a learning experience.
Good luck with your workup and treatment and I hope your docs get you on a path of recovery and get your life back
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