APR: Still's Disease & Fever Save
Transcription
This is advanced practice RheumNow. Hi, I'm Jack Cush, executive editor of RheumNow.com. In this review, we'll discuss Still's disease. Still's disease was recently changed from systemic juvenile idiopathic arthritis and adult onset Still's disease to just be Still's disease. It is considered as such by both the ACR and EULAR. Still's disease is defined as a systemic inflammatory disorder usually of children but may extend into adulthood up to age 35. After 35 it becomes suspect.
The disease is characterized by quotidian fevers, evanescent rashes, polyarthritis, sore throat in adults, polyserositis, organomegaly, a really big leukocytosis with left shift and a marked acute phase response with very high sed rates and CRPs. There is no diagnostic test for the syndrome as there are in other autoinflammatory disorders, but not here. Here it's diagnostic criteria that you have to lean on. The disorder is manifest as a systemic onset often with exacerbations over time with long disease-free intervals and in some a chronic polyarthritis ensues.
If you want to understand this disorder in adults, get the papers by Eric Bywaters in Annals of Rheumatic Disease 1971 or Joseph Bujak — B U J A K — in the journal Medicine from 1973. These are the seminal papers that describe what this disorder looks like.
If you're considering Still's disease as a diagnosis, I would urge you to go to StillsNow.com because there you'll find a Still's disease diagnosis calculator and it says, "Do I meet criteria for Still's disease?" And it'll tell you whether you meet the juvenile criteria or the Yamaguchi or Cush criteria for adult disease, and you just check a bunch of boxes and it does all the work for you. There's also a calculator there for disease activity.
My criteria for the diagnosis of Still's disease, much like the Yamaguchi criteria, has major and minor criteria. The Cush criteria 2000 say that for each major you get two points and for each minor you get one point and you need 10 points to have the diagnosis. Major criteria are quotidian fever of greater than 39° centigrade, number two Still's rash, number three simultaneous elevation of both the white count and sed rate, number four seronegativity and number five the last major criterion is carpal ankylosis. If you have all five of those, you got 10 points. For each one of those you are missing, you need two minor at one point.
Onset age under 35, polyarthritis, a prodromal sore throat, elevated LFTs, hepatosplenomegaly, serositis, and then lastly cervical or carpal ankylosis. Meeting criteria is very important. The vast majority of people who throw around this diagnosis don't know the criteria and are far from it if they go to a criteria check.
These patients should be young. As I said, this is usually a juvenile disorder that often starts at age 2, 3, 4 — actually more like 3, 4, 5, 6 — can extend into adolescence, and if you look at adults from age 19 and thereafter about 76% are going to occur with an onset age under 35. Only 9% have an onset age over 50. Hence, if you're considering Still's disease in a febrile patient over the age of 50, you should be considering another diagnosis. Still's affects males and females equally.
To have the diagnosis, to consider the diagnosis, you must begin by having what I call the Still's triad. Number one, you must have quotidian daily spiking fevers for weeks, if not months. A quotidian fever is a fever that returns to baseline every day and has its spike of over 39 degrees centigrade, over 102 degrees Fahrenheit, every day. When they're really bad, they get a double spike, a double quotidian fever, two spikes in a day and a return to baseline, you know, under 99. It has to be daily. It has to be reproducible. The fever follows a circadian pattern. It happens at the same time every day. Late in the day, late in the night, in the middle of the night — late in the night and middle of night is most common.
Criteria number two in the triad is the rash that comes and goes. It's called the Still's rash, the JIA rash, or rheumatoid rash. It is an evanescent, comes and goes, salmon pink faint maculopapular rash on the trunk and usually extensor surfaces of the extremities or the neck. It's never on the face. It's never on the palms and soles.
And lastly, polyarthritis. The most distinctive arthritis you see is wrist arthritis. And that leads to wrist ankylosis, carpal ankylosis seen in 50% of adults. But polyarthritis is required. Monoarthritis not a criterion. Arthralgia not a criterion. The EULAR criteria said instead of polyarthritis you need to have an exuberant inflammatory lab — very, very high inflammation by sed rate, CRP, or ferritin — and that's a criterion with the new EULAR criteria.
So once you have the criteria then you look for the other features that we commonly see: prodromal sore throat, weight loss, myalgias, arthralgias along with the arthritis, hepatosplenomegaly 40%, hepatic dysfunction and LFTs 70%, lymphadenopathy generalized bilateral all over the place, non-painful, is like two-thirds
of patients serositis in 20 to 40% of patients, myocarditis is very rare — I've reported that in one of my patients. But the labs are what usually will stand out. They should have — they usually end up in the hospital at presentation and the labs should stand out. They should all be seronegative. They should all have a high white count greater than 12,000 with a big left shift. The average number is usually around 20 to 24,000. Can be as high as 60, 70,000. Right? When they have that much inflammation, they'll have an anemia of chronic disease. They'll have a very low albumin. What'll happen is as they lose weight, they drop albumin and their anemia develops. All those run in parallel, all due to inflammation.
So, inflammatory labs are very high — sed rate often greater than 90. What is it? 50% of patients have a sed rate greater than 90. 90% of patients have a sed rate greater than 50. They have a very high CRP and they'll have a thrombocytosis. A lot of you have been told hyperferritinemia — ferritin greater than a thousand. It's really ferritin greater than 10,000 that is seen in 10 to 20% of patients. That's not a good sensitivity but it's got a reasonable specificity, but not a great specificity. Ferritin greater than a thousand is seen in only 50% of Still's patients. Don't rely too much on ferritin. Ferritin goes up with iron overload states, polytransfusion, hemochromatosis, liver disease, neoplasia, sepsis, pancreatitis, and mainly the macrophage activation syndrome, also called the hemophagocytic syndrome or HLH.
Pitfalls in the diagnosis of Still's. Number one, not having the triad. People send me cases all the time to comment on or to help them with. My first thing I always find is they didn't have the triad. Why are we even talking Still's disease? Fever, rash, polyarthritis — or fever, rash with a really very very high sed rate and CRP.
Second big mistake is only having intermittent fevers or undocumented fevers greater than 100, not daily quotidian circadian going on for weeks or months. How can you have the diagnosis if you don't have that?
Three, not meeting Cush or Yamaguchi criteria. Sub-bullet: don't make a diagnosis because the ferritin is really high. That's nuts.
Number four, not knowing whether you're treating Still's disease that's systemic or a Still's disease that's articular. 30% of patients or more will develop a severe erosive polyarthritis like RA, like seronegative polyarticular JIA. And that's bad news — disabling. You've got to find that earlier. When you see that, and that is the aftermath of a systemic onset Still's, then you treat them just as if they had really bad RA. But early on in systemic disease — that's the fever, the rash, the lymphadenopathy, splenomegaly, serositis, ferritins, macrophage activation — systemic disease or articular, be clear.
Next big mistake is not recognizing macrophage activation syndrome. Patients with Still's disease don't die unless they get macrophage activation syndrome. And then knowing the complications: macrophage activation syndrome, DIC has been reported in a number of cases. Amyloidosis, especially renal amyloidosis, leading to renal failure or transplant or renal death. And lastly, lung disease is a big problem, often unrecognized, often insidious, and the etiology of that is not known, but it does occur in a minority of people. My feeling in the adult population — less than 5%; in the juvenile population they're worried about it — it could be as much as 20%.
The keys to the diagnosis. Number one, the triad. Number two, daily fevers that are quotidian and circadian. Number three, identifying the evanescent rash — it may happen late at night when you're not seeing them. Next, relying on the sed rate and CRP more so than the ferritin is very key. And if the patients don't meet criteria — Cush, Yamaguchi, or Ular criteria — then you do further testing, and by that I mean genetic panels for auto-inflammatory disorders.
When do you consider an auto-inflammatory disorder? When they don't meet criteria, when they have continued undiagnosed non-daily high fevers, when there's no response to standard of care therapies for systemic JIA or adult onset Still's, and if there's a family history of like disorders. Like febrile disease, you can do genetic panels — look them up, it's in the handout.
There are other febrile disorders in adults. Disorders that cause high fevers in adults: Still's disease, PMR, GCA, vasculitis, macrophage activation syndrome, HLH, hemophagocytic syndrome due to other causes — and that can be other autoimmune disease like lupus or vasculitis, or severe infections or malignancies. Sweet syndrome, Kikuchi-Fujimoto syndrome — that's necrotizing lymphadenitis with fever — lymphoma, leukemia, Crohn's, colitis can do this, septic arthritis and gout. And then there are auto-inflammatory disorders, which are usually in kids and infants, but they can be in adults. This includes Schnitzler syndrome, DITRA, Yao syndrome, cyclic neutropenia, TRAPS, FMF, and Muckle-Wells. How
do you follow patients with stills? If they have arthritis, you follow them just like you do RA or JIA. For the systemic disease, you follow fever, rash, sore throat, hepatosplenomegaly, lymphadenopathy. But the labs that are very useful are the sed rate and CRP much more so than ferritin. I like and have proven to myself and others that aldolase is a great biomarker. It all comes from liver and it's elevated in all the autoinflammatory conditions, especially stills. You could also look at the neutrophil to lymphocyte ratio. Do the math. If it's greater than three, it's bad. If they're greater than five, they're at high risk for MAS. There are other tools that are not available. Treatment is high-dose steroids. And then you emit. If it's systemic disease, you give them an IL-1 inhibitor, IL-6 inhibitor, and full dose. For acute action and steroid sparing, you start them on high doses of steroids and methotrexate if that's — if that — if you can.
If they're going into MAS, and that's the next slide. Next instruction — you make sure that they're on either an IL-1 or IL-6 and steroids and then you use another drug — emapalumab, the gamma interferon monoclonal antibody that's approved for HLH and MAS in stills — calcineurin inhibitors like tacrolimus, cyclosporine, etoposide, and JAK inhibitors are also useful.
Again, macrophage activation syndrome — you suspect it in a systemic disorder that's often a febrile disorder and they now get really high fevers greater than 104 Fahrenheit. They become hypotensive and have CNS manifestations or altered mental status. The big clues on labs are gigantic elevations of LFTs, order of ferritin — it'll be greater than 10,000 and you think uh-oh — and then you'll look at the cell counts and what used to be leukocytosis is now a leukopenia, thrombocytopenia, lymphopenia — bad news. Their CRPs go up, their sed rates which were once high go down, and now you have macrophage activation syndrome with up to a 20 to 40% chance of death. Not good.
Know that there are guidelines for the treatment of systemic JIA. I like the EULAR 2022–23 guidelines. Again, it's in the handout. Look for it. The high points of that is that the new diagnostic triad is fever greater than 39°C, the stills rash, and high inflammation markers. They always say as soon as you make the diagnosis, start with IL-6 or IL-1 inhibitors ASAP. The ACR guidelines say the exact same. When they have this diagnosis, you always worry about MAS, especially if there's a turn of events — they were doing good, all of a sudden they're doing bad. Fevers are back. They're feeling worse. They're throwing up. They have altered mental status. Look at the labs. Again, you treat the MAS aggressively.
And then worry about patients with this diagnosis because most of us don't have experience with this. Difficult stills disease — stills with MAS or lung disease needs to be referred to an expert stills consultant or center. And you know what? The pediatric rheumatologists are great at managing stills, much more so than the adults. That's it for this advanced practice rheumatology.
The disease is characterized by quotidian fevers, evanescent rashes, polyarthritis, sore throat in adults, polyserositis, organomegaly, a really big leukocytosis with left shift and a marked acute phase response with very high sed rates and CRPs. There is no diagnostic test for the syndrome as there are in other autoinflammatory disorders, but not here. Here it's diagnostic criteria that you have to lean on. The disorder is manifest as a systemic onset often with exacerbations over time with long disease-free intervals and in some a chronic polyarthritis ensues.
If you want to understand this disorder in adults, get the papers by Eric Bywaters in Annals of Rheumatic Disease 1971 or Joseph Bujak — B U J A K — in the journal Medicine from 1973. These are the seminal papers that describe what this disorder looks like.
If you're considering Still's disease as a diagnosis, I would urge you to go to StillsNow.com because there you'll find a Still's disease diagnosis calculator and it says, "Do I meet criteria for Still's disease?" And it'll tell you whether you meet the juvenile criteria or the Yamaguchi or Cush criteria for adult disease, and you just check a bunch of boxes and it does all the work for you. There's also a calculator there for disease activity.
My criteria for the diagnosis of Still's disease, much like the Yamaguchi criteria, has major and minor criteria. The Cush criteria 2000 say that for each major you get two points and for each minor you get one point and you need 10 points to have the diagnosis. Major criteria are quotidian fever of greater than 39° centigrade, number two Still's rash, number three simultaneous elevation of both the white count and sed rate, number four seronegativity and number five the last major criterion is carpal ankylosis. If you have all five of those, you got 10 points. For each one of those you are missing, you need two minor at one point.
Onset age under 35, polyarthritis, a prodromal sore throat, elevated LFTs, hepatosplenomegaly, serositis, and then lastly cervical or carpal ankylosis. Meeting criteria is very important. The vast majority of people who throw around this diagnosis don't know the criteria and are far from it if they go to a criteria check.
These patients should be young. As I said, this is usually a juvenile disorder that often starts at age 2, 3, 4 — actually more like 3, 4, 5, 6 — can extend into adolescence, and if you look at adults from age 19 and thereafter about 76% are going to occur with an onset age under 35. Only 9% have an onset age over 50. Hence, if you're considering Still's disease in a febrile patient over the age of 50, you should be considering another diagnosis. Still's affects males and females equally.
To have the diagnosis, to consider the diagnosis, you must begin by having what I call the Still's triad. Number one, you must have quotidian daily spiking fevers for weeks, if not months. A quotidian fever is a fever that returns to baseline every day and has its spike of over 39 degrees centigrade, over 102 degrees Fahrenheit, every day. When they're really bad, they get a double spike, a double quotidian fever, two spikes in a day and a return to baseline, you know, under 99. It has to be daily. It has to be reproducible. The fever follows a circadian pattern. It happens at the same time every day. Late in the day, late in the night, in the middle of the night — late in the night and middle of night is most common.
Criteria number two in the triad is the rash that comes and goes. It's called the Still's rash, the JIA rash, or rheumatoid rash. It is an evanescent, comes and goes, salmon pink faint maculopapular rash on the trunk and usually extensor surfaces of the extremities or the neck. It's never on the face. It's never on the palms and soles.
And lastly, polyarthritis. The most distinctive arthritis you see is wrist arthritis. And that leads to wrist ankylosis, carpal ankylosis seen in 50% of adults. But polyarthritis is required. Monoarthritis not a criterion. Arthralgia not a criterion. The EULAR criteria said instead of polyarthritis you need to have an exuberant inflammatory lab — very, very high inflammation by sed rate, CRP, or ferritin — and that's a criterion with the new EULAR criteria.
So once you have the criteria then you look for the other features that we commonly see: prodromal sore throat, weight loss, myalgias, arthralgias along with the arthritis, hepatosplenomegaly 40%, hepatic dysfunction and LFTs 70%, lymphadenopathy generalized bilateral all over the place, non-painful, is like two-thirds
of patients serositis in 20 to 40% of patients, myocarditis is very rare — I've reported that in one of my patients. But the labs are what usually will stand out. They should have — they usually end up in the hospital at presentation and the labs should stand out. They should all be seronegative. They should all have a high white count greater than 12,000 with a big left shift. The average number is usually around 20 to 24,000. Can be as high as 60, 70,000. Right? When they have that much inflammation, they'll have an anemia of chronic disease. They'll have a very low albumin. What'll happen is as they lose weight, they drop albumin and their anemia develops. All those run in parallel, all due to inflammation.
So, inflammatory labs are very high — sed rate often greater than 90. What is it? 50% of patients have a sed rate greater than 90. 90% of patients have a sed rate greater than 50. They have a very high CRP and they'll have a thrombocytosis. A lot of you have been told hyperferritinemia — ferritin greater than a thousand. It's really ferritin greater than 10,000 that is seen in 10 to 20% of patients. That's not a good sensitivity but it's got a reasonable specificity, but not a great specificity. Ferritin greater than a thousand is seen in only 50% of Still's patients. Don't rely too much on ferritin. Ferritin goes up with iron overload states, polytransfusion, hemochromatosis, liver disease, neoplasia, sepsis, pancreatitis, and mainly the macrophage activation syndrome, also called the hemophagocytic syndrome or HLH.
Pitfalls in the diagnosis of Still's. Number one, not having the triad. People send me cases all the time to comment on or to help them with. My first thing I always find is they didn't have the triad. Why are we even talking Still's disease? Fever, rash, polyarthritis — or fever, rash with a really very very high sed rate and CRP.
Second big mistake is only having intermittent fevers or undocumented fevers greater than 100, not daily quotidian circadian going on for weeks or months. How can you have the diagnosis if you don't have that?
Three, not meeting Cush or Yamaguchi criteria. Sub-bullet: don't make a diagnosis because the ferritin is really high. That's nuts.
Number four, not knowing whether you're treating Still's disease that's systemic or a Still's disease that's articular. 30% of patients or more will develop a severe erosive polyarthritis like RA, like seronegative polyarticular JIA. And that's bad news — disabling. You've got to find that earlier. When you see that, and that is the aftermath of a systemic onset Still's, then you treat them just as if they had really bad RA. But early on in systemic disease — that's the fever, the rash, the lymphadenopathy, splenomegaly, serositis, ferritins, macrophage activation — systemic disease or articular, be clear.
Next big mistake is not recognizing macrophage activation syndrome. Patients with Still's disease don't die unless they get macrophage activation syndrome. And then knowing the complications: macrophage activation syndrome, DIC has been reported in a number of cases. Amyloidosis, especially renal amyloidosis, leading to renal failure or transplant or renal death. And lastly, lung disease is a big problem, often unrecognized, often insidious, and the etiology of that is not known, but it does occur in a minority of people. My feeling in the adult population — less than 5%; in the juvenile population they're worried about it — it could be as much as 20%.
The keys to the diagnosis. Number one, the triad. Number two, daily fevers that are quotidian and circadian. Number three, identifying the evanescent rash — it may happen late at night when you're not seeing them. Next, relying on the sed rate and CRP more so than the ferritin is very key. And if the patients don't meet criteria — Cush, Yamaguchi, or Ular criteria — then you do further testing, and by that I mean genetic panels for auto-inflammatory disorders.
When do you consider an auto-inflammatory disorder? When they don't meet criteria, when they have continued undiagnosed non-daily high fevers, when there's no response to standard of care therapies for systemic JIA or adult onset Still's, and if there's a family history of like disorders. Like febrile disease, you can do genetic panels — look them up, it's in the handout.
There are other febrile disorders in adults. Disorders that cause high fevers in adults: Still's disease, PMR, GCA, vasculitis, macrophage activation syndrome, HLH, hemophagocytic syndrome due to other causes — and that can be other autoimmune disease like lupus or vasculitis, or severe infections or malignancies. Sweet syndrome, Kikuchi-Fujimoto syndrome — that's necrotizing lymphadenitis with fever — lymphoma, leukemia, Crohn's, colitis can do this, septic arthritis and gout. And then there are auto-inflammatory disorders, which are usually in kids and infants, but they can be in adults. This includes Schnitzler syndrome, DITRA, Yao syndrome, cyclic neutropenia, TRAPS, FMF, and Muckle-Wells. How
do you follow patients with stills? If they have arthritis, you follow them just like you do RA or JIA. For the systemic disease, you follow fever, rash, sore throat, hepatosplenomegaly, lymphadenopathy. But the labs that are very useful are the sed rate and CRP much more so than ferritin. I like and have proven to myself and others that aldolase is a great biomarker. It all comes from liver and it's elevated in all the autoinflammatory conditions, especially stills. You could also look at the neutrophil to lymphocyte ratio. Do the math. If it's greater than three, it's bad. If they're greater than five, they're at high risk for MAS. There are other tools that are not available. Treatment is high-dose steroids. And then you emit. If it's systemic disease, you give them an IL-1 inhibitor, IL-6 inhibitor, and full dose. For acute action and steroid sparing, you start them on high doses of steroids and methotrexate if that's — if that — if you can.
If they're going into MAS, and that's the next slide. Next instruction — you make sure that they're on either an IL-1 or IL-6 and steroids and then you use another drug — emapalumab, the gamma interferon monoclonal antibody that's approved for HLH and MAS in stills — calcineurin inhibitors like tacrolimus, cyclosporine, etoposide, and JAK inhibitors are also useful.
Again, macrophage activation syndrome — you suspect it in a systemic disorder that's often a febrile disorder and they now get really high fevers greater than 104 Fahrenheit. They become hypotensive and have CNS manifestations or altered mental status. The big clues on labs are gigantic elevations of LFTs, order of ferritin — it'll be greater than 10,000 and you think uh-oh — and then you'll look at the cell counts and what used to be leukocytosis is now a leukopenia, thrombocytopenia, lymphopenia — bad news. Their CRPs go up, their sed rates which were once high go down, and now you have macrophage activation syndrome with up to a 20 to 40% chance of death. Not good.
Know that there are guidelines for the treatment of systemic JIA. I like the EULAR 2022–23 guidelines. Again, it's in the handout. Look for it. The high points of that is that the new diagnostic triad is fever greater than 39°C, the stills rash, and high inflammation markers. They always say as soon as you make the diagnosis, start with IL-6 or IL-1 inhibitors ASAP. The ACR guidelines say the exact same. When they have this diagnosis, you always worry about MAS, especially if there's a turn of events — they were doing good, all of a sudden they're doing bad. Fevers are back. They're feeling worse. They're throwing up. They have altered mental status. Look at the labs. Again, you treat the MAS aggressively.
And then worry about patients with this diagnosis because most of us don't have experience with this. Difficult stills disease — stills with MAS or lung disease needs to be referred to an expert stills consultant or center. And you know what? The pediatric rheumatologists are great at managing stills, much more so than the adults. That's it for this advanced practice rheumatology.
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