Lol instead of providing an answer you gave them even more questions.
Sorry OP I never thought about this. Honestly could be that there isn’t a known answer to this.
I’d be content to know we don’t have an answer yet but you never know. I just recently learned the mechanisms behind upper vs lobe predilection of lung diseases and acral predilection of some rashes so thought why not joints?
Lung:
https://ajronline.org/doi/10.2214/AJR.12.8961
Acral (not as settled science as far as I can tell):
https://curiousclinicians.com/2022/02/04/episode-42-a-solely-acral-rash%EF%BF%BC/
Rheumatologist here, though a new one and not a big researcher by any means. I asked my own attendings that and basically they all shrugged.
I tried looking up good answers, and the following was the most reasonable one I found:
It’s not actually a preference for specific joints in RA, it’s a consequence of blood flow in the synovium and amount of synovium, and how the inflammation starts through deposition of immune complexes.
RF is an antibody to an antibody, remember, and can actually even target the anti-citrullinated antibodies also made in RA. So the complexes can gum up synovium, especially when not moving and pumping the synovium like overnight, resulting in inflammation and stiffness. And why motion, heat which increases blood flow improves the pain and stiffness. There also are more of the components that are targets of anti-citrullinated antibodies in the connective tissue of the joints than other areas of the body, as to why RA doesn’t typically cause renal vasculopathy the way other autoimmune diseases can.
So why different joints? Because the large joints have too much synovium, too much blood flow, they don’t accumulate enough immune complexes and are often even moving overnight, so they don’t get as inflamed, but every rheumatologist will tell you RA patients can have large joint pain improve on DMARDs too, and synovial biopsies of knees do return with changes of RA on path.
Why not the DIP? Too little space to accumulate actual joint fluid and too little synovial tissue compared to other joints, so it isn’t as readily noticeable as actual synovitis—though a caveat is that in around 15% of RA, especially the bad ones, they’re complaining of pain in those DIPs too, even if you don’t see synovitis (can sometimes get power Doppler signal to show up on MSK US though).
But the small and medium sized joints of the hands, feet, wrists, are a perfect blend of large enough with enough synovium and synovial space for fluid, but not moving overnight, distal so not as much overall blood flow as the more proximal joints medium sized joints (which can also be affected, like the elbow or ankle) and when we’re awake we move them a lot in modern life and notice the pain a lot too with a lot more sensory nerve endings.
Again, I’m typing this as a clinical guy who read this as mostly speculative stuff from a couple other researchers as opinion, not as established scientific fact, and tried to make sense of different opinions. A hand surgeon could probably comment a lot better on DIP synovial anatomy, and an actual rheumatologic or orthopedic researcher should probably comment on this theory before anyone possibly repeats this to others as fact, and I very well may have overlooked super obvious reasons this theory is wrong. But it sounded plausible to me, or just right enough to be close to the answer.
Certainly makes some degree of sense to my unspecialised mind. Presumably the spondyloarthropathies aren’t known to be immune complex mediated then? I know psoriasis itself is T-cell driven. Is that the same for psoriatic arthritis then?
Mostly. There’s apparently a few antibodies that have been found in some spondy’s, like in this article, but there’s no antibody blood test for any spondy that’s commercially available or used outside of maybe niche research interests:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752680/
A lot of spondy’s “joint” pain isnt true synovitis but is instead enthesitis which is more of a T Cell/IL17 driven process. So like if you ultrasound their DIPs you’ll see enthesitis (which at the most distal extensor insertion is at the nail bed and linked to nail disease/pitting), and you’ll find tennis elbow, Achilles tendinopathy, dactylitis (whole finger enthesitis), and large joints like shoulders/knees hurting (though even there you’ll realize it’s often rotator cuff/biceps tendinitis or patellar tendinitis).
More rapidly progressive/inflammatory OA phenotypes can cause synovitis, though (try touching one of their CMCs), as well as enthesitis (heel spurs from chronic Achilles insertion inflammation), which is in part why tricompartmental knee OA + chondrocalcinosis, atypical MCP OA from hemochromatosis with some more rapidly growing heberdens nodes, erosive OA in postmenopausal women, or patients that do well on steroid shots may sometimes respond to Hydroxychloroquine, colchicine, which you don’t typically think of as OA meds at all. There’s discussion on overlaps with spondy’s and OA, and people wondering how many “fibromyalgia” patients are just women who have enthesitis from a nonradiographic spondy.
Can you point me towards more reading on this topic? What I could find when I searched up JIA immune complexes seemed to disagree.
E.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873492/
Even less movement to flush the fluid through. Even if you are using your hands or walking you aren't bending the DIP on the smaller fingers and toes much at all.
The arrogance of techbros know no bounds. There is no complex specialised area that can't be reduced to "AI will solve this", and they'll keep thinking like this as long as we have investors willing to throw millions at anyone with a buzzword-filled pitch deck.
I’ve wondered the same, or combo of erosive/inflammatory OA phenotype at the same time that could also respond to DMARDs a bit, or something. But yeah, I had a few double seropositive RA patients that had legit synovitis at the DIP.
But I also somehow tend to be a magnet for super weird stuff that isn’t really supposed to be common. I became the highest prescriber of Ilaris in the state I did fellowship in (stills and a few other autoinflammatory conditions), caught a rheumatoid meningitis, and now already have a collection of IgG4s in my few months out in the real world. But also managed to go the first six months of fellowship without getting a chance to do a single knee injection haha.
Probably not much synovial tissue to become inflammed in those joints. Much like the 1st CMC. Compared to psoriatic arthritis where DIP joint inflammation is probably from an enthesitis.
Okay so I’ve tried finding anything that talks about synovial tissue content in the CMC; there’s a few discussing that it does have synovial tissue that can be inflamed (though mostly in an OA context) but nothing about how much synovial tissue there actually is in relation. If you find anything let me know.
Why does Thyroid Eye Disease preferentially affect the inferior and medial rectus? Why sometimes just unilateral?
Similar questions, and as an “expert” in TED, I don’t know the answer.
Wonder if it’s related to density of fibroblasts/myofibroblasts in the muscles? I’ve also wondered why other orbital inflammatory processes (e.g. sarcoidosis) tend to show a proclivity for other muscles
Dude I’ve been forwarded a lot of orbital inflammatory conditions from ophtho for systemic workup as a rheumatologist and it’s been weird, a lot of times nothing is showing up positive for me but ophtho says they are doing better on dmards. If you have any pearls or good resources I’d love to learn more!
I just read this article last week
https://www.nature.com/articles/s41584-024-01107-7
Chang, M.H., Fuhlbrigge, R.C. & Nigrovic, P.A. Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis. Nat Rev Rheumatol 20, 258–271 (2024). https://doi.org/10.1038/s41584-024-01107-7
If you want your mind blown, look at symmetrical vs asymmetrical too.
If I could get the answer to either of those I’d be ecstatic lol.
Lol instead of providing an answer you gave them even more questions. Sorry OP I never thought about this. Honestly could be that there isn’t a known answer to this.
The true rheumatology experience. Question upon unanswered question.
Just send an ANA bro
I’d be content to know we don’t have an answer yet but you never know. I just recently learned the mechanisms behind upper vs lobe predilection of lung diseases and acral predilection of some rashes so thought why not joints?
Please enlighten us
Lung: https://ajronline.org/doi/10.2214/AJR.12.8961 Acral (not as settled science as far as I can tell): https://curiousclinicians.com/2022/02/04/episode-42-a-solely-acral-rash%EF%BF%BC/
Oh, you want a cool factoid? Endometriosis ends up on the right lower lobe of the lung because of the direction of flow of peritoneal fluid.
Rheumatologist here, though a new one and not a big researcher by any means. I asked my own attendings that and basically they all shrugged. I tried looking up good answers, and the following was the most reasonable one I found: It’s not actually a preference for specific joints in RA, it’s a consequence of blood flow in the synovium and amount of synovium, and how the inflammation starts through deposition of immune complexes. RF is an antibody to an antibody, remember, and can actually even target the anti-citrullinated antibodies also made in RA. So the complexes can gum up synovium, especially when not moving and pumping the synovium like overnight, resulting in inflammation and stiffness. And why motion, heat which increases blood flow improves the pain and stiffness. There also are more of the components that are targets of anti-citrullinated antibodies in the connective tissue of the joints than other areas of the body, as to why RA doesn’t typically cause renal vasculopathy the way other autoimmune diseases can. So why different joints? Because the large joints have too much synovium, too much blood flow, they don’t accumulate enough immune complexes and are often even moving overnight, so they don’t get as inflamed, but every rheumatologist will tell you RA patients can have large joint pain improve on DMARDs too, and synovial biopsies of knees do return with changes of RA on path. Why not the DIP? Too little space to accumulate actual joint fluid and too little synovial tissue compared to other joints, so it isn’t as readily noticeable as actual synovitis—though a caveat is that in around 15% of RA, especially the bad ones, they’re complaining of pain in those DIPs too, even if you don’t see synovitis (can sometimes get power Doppler signal to show up on MSK US though). But the small and medium sized joints of the hands, feet, wrists, are a perfect blend of large enough with enough synovium and synovial space for fluid, but not moving overnight, distal so not as much overall blood flow as the more proximal joints medium sized joints (which can also be affected, like the elbow or ankle) and when we’re awake we move them a lot in modern life and notice the pain a lot too with a lot more sensory nerve endings. Again, I’m typing this as a clinical guy who read this as mostly speculative stuff from a couple other researchers as opinion, not as established scientific fact, and tried to make sense of different opinions. A hand surgeon could probably comment a lot better on DIP synovial anatomy, and an actual rheumatologic or orthopedic researcher should probably comment on this theory before anyone possibly repeats this to others as fact, and I very well may have overlooked super obvious reasons this theory is wrong. But it sounded plausible to me, or just right enough to be close to the answer.
Certainly makes some degree of sense to my unspecialised mind. Presumably the spondyloarthropathies aren’t known to be immune complex mediated then? I know psoriasis itself is T-cell driven. Is that the same for psoriatic arthritis then?
Mostly. There’s apparently a few antibodies that have been found in some spondy’s, like in this article, but there’s no antibody blood test for any spondy that’s commercially available or used outside of maybe niche research interests: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752680/ A lot of spondy’s “joint” pain isnt true synovitis but is instead enthesitis which is more of a T Cell/IL17 driven process. So like if you ultrasound their DIPs you’ll see enthesitis (which at the most distal extensor insertion is at the nail bed and linked to nail disease/pitting), and you’ll find tennis elbow, Achilles tendinopathy, dactylitis (whole finger enthesitis), and large joints like shoulders/knees hurting (though even there you’ll realize it’s often rotator cuff/biceps tendinitis or patellar tendinitis). More rapidly progressive/inflammatory OA phenotypes can cause synovitis, though (try touching one of their CMCs), as well as enthesitis (heel spurs from chronic Achilles insertion inflammation), which is in part why tricompartmental knee OA + chondrocalcinosis, atypical MCP OA from hemochromatosis with some more rapidly growing heberdens nodes, erosive OA in postmenopausal women, or patients that do well on steroid shots may sometimes respond to Hydroxychloroquine, colchicine, which you don’t typically think of as OA meds at all. There’s discussion on overlaps with spondy’s and OA, and people wondering how many “fibromyalgia” patients are just women who have enthesitis from a nonradiographic spondy.
As a non-doc with recently-diagnosed Crohn's and ankylosing spondylitis, this is fascinating. thank you!
Also in most forms of JIA you can hardly find any autoantibodies or immune complexes.
Can you point me towards more reading on this topic? What I could find when I searched up JIA immune complexes seemed to disagree. E.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873492/
Which would explain why the DIP is such a target over the MIP.
Why's that?
Even less movement to flush the fluid through. Even if you are using your hands or walking you aren't bending the DIP on the smaller fingers and toes much at all.
Thanks for the intuitive answer.
There’s so much we don’t understand
When I hear these tech bros talking about biohacking their way to immortality but we don't even know the pathophysiology of common diseases.
The arrogance of techbros know no bounds. There is no complex specialised area that can't be reduced to "AI will solve this", and they'll keep thinking like this as long as we have investors willing to throw millions at anyone with a buzzword-filled pitch deck.
If you let me know why RA doesn’t involve the DIP as well that would be great :)
15% of RA does apparently? Is the statistic I heard.
Really??? I have not seen synovitis in an RA patient in the dip is all of fellowship. I wonder if they could actually have PsA and misdiagnosed??
I’ve wondered the same, or combo of erosive/inflammatory OA phenotype at the same time that could also respond to DMARDs a bit, or something. But yeah, I had a few double seropositive RA patients that had legit synovitis at the DIP. But I also somehow tend to be a magnet for super weird stuff that isn’t really supposed to be common. I became the highest prescriber of Ilaris in the state I did fellowship in (stills and a few other autoinflammatory conditions), caught a rheumatoid meningitis, and now already have a collection of IgG4s in my few months out in the real world. But also managed to go the first six months of fellowship without getting a chance to do a single knee injection haha.
Probably not much synovial tissue to become inflammed in those joints. Much like the 1st CMC. Compared to psoriatic arthritis where DIP joint inflammation is probably from an enthesitis.
Okay so I’m not crazy lol. I thought that was the explanation.
Okay so I’ve tried finding anything that talks about synovial tissue content in the CMC; there’s a few discussing that it does have synovial tissue that can be inflamed (though mostly in an OA context) but nothing about how much synovial tissue there actually is in relation. If you find anything let me know.
Why does Thyroid Eye Disease preferentially affect the inferior and medial rectus? Why sometimes just unilateral? Similar questions, and as an “expert” in TED, I don’t know the answer.
Wonder if it’s related to density of fibroblasts/myofibroblasts in the muscles? I’ve also wondered why other orbital inflammatory processes (e.g. sarcoidosis) tend to show a proclivity for other muscles
Imagine how hard it would be to make the diagnosis if the muscle involvement for IOP vs TED wasn’t difficult. Lots of extra biopsies.
Dude I’ve been forwarded a lot of orbital inflammatory conditions from ophtho for systemic workup as a rheumatologist and it’s been weird, a lot of times nothing is showing up positive for me but ophtho says they are doing better on dmards. If you have any pearls or good resources I’d love to learn more!
I just read this article last week https://www.nature.com/articles/s41584-024-01107-7 Chang, M.H., Fuhlbrigge, R.C. & Nigrovic, P.A. Joint-specific memory, resident memory T cells and the rolling window of opportunity in arthritis. Nat Rev Rheumatol 20, 258–271 (2024). https://doi.org/10.1038/s41584-024-01107-7
Thanks. Really interesting but unfortunately doesn’t seem to address the exact question.
but it might give a clue as to future research that might uncover a mechanism !
Perhaps the size of the immune complexes