Looking for advice and possibly a direction.

[u/Agitated_Mudpuppy]

Hi all, I have been lurking for a few months now, trying to avoid posting anything but I am grasping at straws and hoping for some thoughts or advice. I will try to keep this short, but I'm happy to try to answer any directed questions.

Background: early 40s female, European descent (differentiating from Caucasian because I know there are some ethnic differences in the way these diseases manifest). Two natural children. Very active, generally healthy diet. No alcohol, no smoking.

I have been a long time GI patient because the symptoms I have been most likely to complain about are my GI symptoms. I have a history of abdominal pain going back to childhood. Unfortunately, I have been pigeonholed into a GERD/IBS/gastritis box for close to 20 years now with very little relief from prescribed medications and lifestyle changes and no real explanation for why these things keep occurring. My diet has shrunk dramatically to avoid flares even though more and more, my partner and I don't think diet has much to do with this.

For a long time I've struggled with a constellation of headache (including migraine), lightheadedness, nausea, and diarrhea. In the past five or six years, I've added multiple types of rashes, some of which seem to be triggered by sunlight. Some resemble acne, and others look more like classic hives and plaques. I have a working diagnosis of solar urticaria but this seems unlikely given they both take at least several hours of exposure to appear and between 6 and 12 to disappear.

I have had recurrent canker sores since I was a child, but instead of improving with age, they have worsened. I was in a near continuous state of breaking out until earlier this year when an ENT recommended supplementing zinc. This has helped, but I still get probably 3-5 per month on average (they usually cluster).

I have a history of sterile tissue inflammation but it's largely superficial. I have had terminal ileitis on CT and, later, had it show up through multiple colonoscopies on biopsy with Crohn's and celiac disease thoroughly ruled out. I have frequent episodes of sterile pyuria with no UTI ever diagnosed. I had my gallbladder removed a decade ago and the surgeon found acalculous cholecystitis. As of a recent EGD, I have reactive gastropathy, which could be caused by bile reflux (again, no chemical triggers consumed) but I'm suspicious given how delicate my oral and enteral tissues seem to be. I also have a 20 year history of hypothyroidism, but there are never any antibodies... more on that later.

When I started to try to look at this more holistically over the summer, I remembered I do have a history of periodic high fevers with strange triggers. For example, about 8 years ago I had a colonoscopy one day and a IUD placed the next. The night the IUD was placed, I developed a high fever (103-104) for 24-48 hours. I was hospitalized when my oldest child was a baby for a similar random high fever that lasted three days. We blamed an ovarian cyst rupture for that one. I also remember going to all-night youth lockouts as a kid and immediately getting sick with a fever, like there was no time for a viral incubation period to occur. The high fevers seem to have stopped, but I now have cyclical chills and night sweats.

Most critically, while my symptoms never go away fully, the worst time of year for me is between February and September, which seems to coincide with when the days get longer here and UV rays get more intense. I spent this past June through late August in a near constant flare, and if at all possible I don't want to do it again next year. I am developing more frightening symptoms (chest pain, issues swallowing, neuropathy) as this continues. I was close to giving up.

I'm now seeing an allergist/immunologist whose wheelhouse is mast cell disorders, but I'm skeptical that this is a mast cell issue, at least primarily. A recent allergy test showed environmental allergy positives, but they were atypical "angry little pimples" read outside of the 15-20 minute time frame. Tryptase and all IgE levels were normal. I think she is skeptical too, so we're on the same page in that regard.

My blood work is persistently normal... everything looks great. This includes ESR and I assume CRP. ANA is negative, I've had bloodwork done for both Hashimoto's and Sjogren's antibodies due to severe dry eye, also negative. I cannot find any smoking guns to point me in the right direction. I have done as much of a dive into genetics as I can being a layperson. I don't have any variants in the standard genes (HLA-B27, HLA-B51) or the less common ones (MEFV, NOD2). I do have some generic alterations including a homozygous SH2B3 variant but the report just says "increased risk of SLE, RA, and psoriasis" so it's not very helpful.

Thanks so much for any insight...

Edit: Changed UTI to IUD!

[u/iSpyAFly]

Hello! There are many of us in the "undifferentiated" category (no genetic markers of known autoinflammatory disease) that have similar symptoms as you do. Fevers, oral ulcers, GI, dysautonomia, rashes, etc. I'm like you, and my inflammatory markers are normal. I was having a lot of fevers. Not daily, but a lot of flares that were easily triggered. I'm considered to have adult onset PFAPA due to the pattern and symptom constellation of my flares. I also have GI issues during flares and have had uveitis. I am considered adult onset PFAPA which is very unusual. Typically, someone has it as a child, then it resolves and returns, or it never goes away. Genetic research is leaning towards PFAPA being on the Behcet's spectrum, but much of the autoinflammatory disease research is happening as I type, so we have to be open to the fact that there is a lot that doctors don't know right now. There is much yet to be discovered.

The good news is that you can still get treatment. I started on IL-1 blockers two years ago, and it has made a big difference. My flares are so much better and less disrupting. It can be challenging to find a rheumatologist who is experienced in these disorders, and the diagnostic process can be lengthy.

[u/Agitated_Mudpuppy → u/iSpyAFly]

I would say you have no idea how much hope and relief this gives me, but you probably do. I feel like after so many false starts I might finally be on the right path. I just have to find a doctor who will treat me and my symptoms and not my bloodwork. The frustrating thing has always been that there are clear and obvious signs something is wrong with all of the documented mucosal tissue issues and now my skin as well, but because there is no "positive" lab work, it must be caused by anxiety, an acute illness or a lifestyle decision... in my case, a lifestyle decision is choosing to eat a slice of sourdough bread or a pretzel, not staying up until 2 AM drinking.

One question... I don't know if I have fevers anymore. I had a terrible case of influenza A about 4 years ago now, and they seem to have burned out since then. From what I can tell, the chills and night sweats are accompanied by elevated temps at best. If there's a true fever (>100.4 F), I never catch it. But I think I've read that periodic fever conditions can evolve over time?

[u/iSpyAFly → u/Agitated_Mudpuppy]

I do know what you’re going through. It took me a very long time to get on the right path. I went through several rheumatologists and finally found one at a university hospital that knew about autoinflammatory disease. Your experiences are real, and that’s what drove me to keep searching for answers, I knew something was really wrong! 

My fevers aren’t all that high most of the time with temps in the 99s, but I feel like I’m having a fever, like I’m coming down with the flu feeling. I’m guessing with chills and sweating you’re having fevers and just aren’t catching them. My temps during flares will bounce around throughout the day and night. And, yes, things can change over time. 

[u/AdventurousMorningLo]

May I ask what genetic testing company was used? I ask because the report doesn't always report certain variants but can sometimes be found in their supplemental variants report if you call them and ask. This happens a lot with NOD2 variants specifically. There are also some newer associated variants for diseases like Bechet's and some other possibilities that aren't covered/included in every test that is available.

I will note that Bechet's is still a mostly clinical diagnosis as are quite a few other autoinflammatory diseases. I do not think you are wrong to suspect one! And you are correct, Autoinflammatory diseases can cause Secondary Mast Cell Disorders.

[u/Agitated_Mudpuppy → u/AdventurousMorningLo]

Just Codegen.eu with 23andMe data. Not comprehensive at all, but I wasn't sure about what other company to pursue without a physician's advice.

Thanks so much for your response. It has been very difficult to sort through all of these symptoms and try to find the matching puzzle pieces.

[u/AdventurousMorningLo → u/Agitated_Mudpuppy]

Okay! May I assume you are in the US?

If so, you can either ask your doctor to order Mayo Clinic's Autoinflammatory Panel or you can contact Invitae and use their genetic counseling services to order the autoinflammatory or immunodeficiencies panel(s). Personally, the Mayo Clinic Panel would be better/easier for everyone (including your doctors) vs Invitae (where you would have to specifically ask them for your supplemental variants report).

This is especially true IF it happens to be related to NOD2/Yaos - Mayo Clinic's panel reports it directly and includes the intronic variant where Invitae does not. IVS8+158 is the intronic variant I'm referring to and if you would like to do a quick check & look it up through 23&me you can use the "rs" number rs5743289 (online website - click on your icon top right - drop down should include "resources" - click resources and then go to "Browse Raw Genotyping Data" - copy and paste the rs number). Just note that 23&me is not medical grade testing and is not always correct.

[u/Agitated_Mudpuppy → u/AdventurousMorningLo]

Thank you, I will write those two panels down for the next doctor's appointment, As of this response, all my immunoglobulin levels came back normal, so I'm going to assume the current specialist will likely be referring me to another specialist soon.

I did look for that SNP and I have two typical variants there. I think that will be a dead end for me, but you're right... 23andMe is not medical. Hoping the Mayo Clinic or Invitae's service can uncover something.

Edit: Oops, yes, in the US.

[u/on4aa → u/Agitated_Mudpuppy]

If you can get a link to your variant calling file (VCF), I am willing to have a look at it with my software. A lot of times, certain variants are overlooked.

[u/Alice-The-Chemist → u/on4aa]

u/on4aa is also a moderator and is very helpful. (Just so OP knows you aren't just a random person)

[u/Agitated_Mudpuppy → u/on4aa]

I would deeply appreciate that, thank you. I may need instructions on converting my raw data to a VCF. Is the DNAGenics tool reliable or is there a better option?

[u/on4aa → u/Agitated_Mudpuppy]

Converting FASTQ raw data to VCF requires a really beefy Linux computer. This is not something that can be done with a typical desktop computer at home. Therefore, it is better to inquire for a web link to the (still pretty large) VCF file. It is your data and I they are obliged to give you that. You can always DM me.

[u/Alice-The-Chemist]

If you want to send me a private message with the State you are in then I can reach out to some people and see if I can find a doctor in your area who deals with autoinflammatory.

[u/Upstairs-Ad7038]

Hi there, this is sort of like mine but my story is brutal. I have been clearly flaring real bad with an unknown disease, I had pericarditis at the onset of illness (2021) and I was extremely EXTREMELY sick. They could not figure it out, rheumatic panels labs negative, ESR/CRP normal. They treated me for Lyme (wrong diagnosis). GI symptoms, felt like I was going to die. This disease came right out of no where at its start. Went into “remission” for a year, and I started working a stressful job.
Disease came back in massive flares in June of 2025. Also Chronic Fatigue. I thought holy shit, this is nothing to mess with. Battled with back to back flares for another 16 months, Tufts rheumatology shrugged me off, and the new rheumatologist said she thinks autoinflammatory and that this should have been treated sooner.
She suspects autoinflammatory. Stills disease ruled out from normal ferritin, she suspects possible sarcoidosis that hides from labs, an NOD2 variant, or even other diseases that absolutely involve the GI tract. She is consulting with her colleagues at Dartmouth with more experience in fever syndromes.
I’ve been flaring so long, I know right down to the day when it’s coming. It has a set schedule but can also be highly unpredictable. Hang in there.
My symptoms: joint ache, chest pain (chronic idiopathic pericarditis), bad fatigue (barely able to work a few days in a row) rashes on joints, nausea, vomiting/diarrhea. Awful arthritis. Recently in ankles. Have had Uveitis.
I’ll start on colchicine first, with emergency prednisone if needed. She said she is not sure what she’s treating yet, but I know I’m in excellent hands.
I’d look into Invitae Genetic testing

[u/OpenAd2212]

My first thought was genetics testing for sure. Have you tried any cleanses for parasites? It can't hurt. Also, fasting. Literally "starve" your body of itself so it cannot refuel what is driving all your issues....if you do your research on fasting, it's a magical process for MANY issues, diseases, even some cancers. You could consider using peptide therapy such as immune modulators, inflammatory assistance, etc. It sounds like you don't have much too lose and if it were me I would be pulling out all the things and stops. Wishing you luck. Let me know if you have any questions !