⛄️Winter is coming, time for a 2nd 🧵 on cryoglobulins!
❄️What's a cryoglobulin?
❄️What causes cryos to form?
❄️When to suspect cryos are the culprit?
#medtwitter #meded @HRheuminations #immunology #vasculitis
❄️What's a cryoglobulin?
❄️What causes cryos to form?
❄️When to suspect cryos are the culprit?
#medtwitter #meded @HRheuminations #immunology #vasculitis
Cryoglobulins are antibodies that:
❄️precipitate at temps less than 37 degrees C
🌟dissolve after rewarming
(the last 🧵 demonstrates, it's not just temps that cause precipitation, but also changes in concentration, salinity and ph)
Why do they do this? We're not sure!
❄️precipitate at temps less than 37 degrees C
🌟dissolve after rewarming
(the last 🧵 demonstrates, it's not just temps that cause precipitation, but also changes in concentration, salinity and ph)
Why do they do this? We're not sure!
3 types!
but to make life easier:
❄️Type 1 driven by underling malignancy
❄️Type 2 and 3 (mixed): infection or rheumatologic condition
but to make life easier:
❄️Type 1 driven by underling malignancy
❄️Type 2 and 3 (mixed): infection or rheumatologic condition
Type 1-cryos
Lymphoproliferative diseases
❄️Waldenstroms macroglobulinemia
❄️Multiple myeloma
Primarily a concentration problem! lots and lots of cryos floating through the blood, clogging up vessels
❄️ digital ischemia
Hyper viscosity (headaches, retinal hemorrhages)
Lymphoproliferative diseases
❄️Waldenstroms macroglobulinemia
❄️Multiple myeloma
Primarily a concentration problem! lots and lots of cryos floating through the blood, clogging up vessels
❄️ digital ischemia
Hyper viscosity (headaches, retinal hemorrhages)
What about mixed type?
Before discovery of Hep C most mixed cryos were considered "essential" meaning it was unclear what caused them
Interestingly, chronic liver disease was thought to be CAUSED by the cryos because so many people with mixed cryos had liver problems
Before discovery of Hep C most mixed cryos were considered "essential" meaning it was unclear what caused them
Interestingly, chronic liver disease was thought to be CAUSED by the cryos because so many people with mixed cryos had liver problems
It wasn't until Hep C was discovered in 1989, that it was realized Hep C was DRIVING the cryos AND causing the liver problems.
So what's different about Mixed cryos compared to Type 1?
Mixed cryos driven by
chronic infections:
❄️Hep C, less so Hep B and HIV
Rheumatologic conditions:
❄️Sjogren syndrome
Mixed cryos driven by
chronic infections:
❄️Hep C, less so Hep B and HIV
Rheumatologic conditions:
❄️Sjogren syndrome
Mixed Cryos:
NOT driven by concentration and plugging up blood vessels (ie type 1)
Mixed cryos form IMMUNE COMPLEXES, trigging the CLASSICAL complement cascade
Causing an immune complex mediated vasculitis
NOT driven by concentration and plugging up blood vessels (ie type 1)
Mixed cryos form IMMUNE COMPLEXES, trigging the CLASSICAL complement cascade
Causing an immune complex mediated vasculitis
IgM binding to IgG
What does that make?
Rheumatoid Factor!!!!!
❄️Most patients with Mixed Cryos are Rheumatoid Factor ➕
❄️ another big hint is the C3 (normal or mildly low) and C4 (very low)
from the complement cascade activation
What does that make?
Rheumatoid Factor!!!!!
❄️Most patients with Mixed Cryos are Rheumatoid Factor ➕
❄️ another big hint is the C3 (normal or mildly low) and C4 (very low)
from the complement cascade activation
So when to suspect Mixed Cryos?
Meltzer's triad
❄️new palpable purpura on extremities (50-90%)
❄️joint pains (arthralgias in 50-75%)
❄️new peripheral neuropathy (60%)
but also...
❄️new glomerulonephritis (20%)
especially in a patient with history of Hep C or Sjogren syndrome
Meltzer's triad
❄️new palpable purpura on extremities (50-90%)
❄️joint pains (arthralgias in 50-75%)
❄️new peripheral neuropathy (60%)
but also...
❄️new glomerulonephritis (20%)
especially in a patient with history of Hep C or Sjogren syndrome
How to test for it?
It's complicated and can take up to a week! Not all labs can perform the test.
So if you suspect mixed cryos check RF and C3 and C4
It's complicated and can take up to a week! Not all labs can perform the test.
So if you suspect mixed cryos check RF and C3 and C4
How to treat and how do patients do?
Depends on severity and cause (hep C for example, treat the hep C)
Vasculitic manifestations seem to do well with B cell depletion.
Depends on severity and cause (hep C for example, treat the hep C)
Vasculitic manifestations seem to do well with B cell depletion.
Silva F, Pinto C, Barbosa A, Borges T, Dias C, Almeida J. New insights in cryoglobulinemic vasculitis. J Autoimmun. 2019
Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990;162:569–70.
Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990;162:569–70.
Meltzer, M. Franklin, E.C. Cryoglobulinemia-A Study of twenty-Nine Patients American Journal of Medicine 1965
VIta et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012
VIta et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012
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