Sjogren’s Disease Part 1: Clinical Presentation, Workup and Diagnosis

Hey guys, thanks for joining me today. In this episode, we're going to be discussing Shogren's disease. Wait Dr. Lidak, you must mean Shogren's syndrome, right? Nope, I mean Shogren's disease, because the name was recently updated. Now, like I was saying, this is part one of two on Shogren's disease. And today, in part one, we're going to discuss everything I think you need to know about the condition other than treatment. So very short snippets on terminology, epidemiology, and pathophys, but really the meat and potatoes is going to focus on clinical presentation, how you would work up a patient with suspected Shogren's disease, and diagnosis, whereas part two is only going to be about management, and that episode will hopefully be coming out shortly after you are. Now, as you're going through this episode, I hope you will realize that Shogren's disease is more than just dryness, fatigue, and pain. It is a systemic autoimmune condition that causes a number of extra glandular manifestations, some of them severe, including lymphoma. The idea that Shogren's disease is just dryness, fatigue, and pain is a common one. Perhaps even the most common opinion, but it is very clearly a misconception. Anyway, that's enough about that, let's get into Shogren's disease. Welcome to Rheumatology for the Royal College, where we aim to bring you reviews that will strengthen your knowledge going into exams and clinical encounters. We hope you'll find it useful and enjoyable, whether you're running, lifting, cooking, grocery shopping, driving, you get the idea. I'm your host, Dr. Karim Ladak, an American trained Canadian rheumatologist. Before we start, my lawyer advised that I should say that the information here only reflects what I have in my personal notes and should not be used in isolation in the management to patients, nor for your boards. I'd like to thank Pfizer and J&J for supporting this podcast through their educational grants. However, it should be noted that they have absolutely no editorial say in its production. If like me, you are not a Gen Z, you may be more familiar with the term "Shogren's Syndrome." However, the terminology has evolved, and we now call it "Shogren's disease." Same thing, new name. You may also recall the terms "primary shogrens" and "secondary shogrens." Primary meant that the clinical manifestations of shogrens happened in isolation, where a secondary shogrens meant that the clinical manifestations occurred with other autoimmune diseases. So for example, we would frequently see secondary shogrens in patients with lupus, rheumatoid arthritis, and scleroderma. Now we just say "Shogren's disease" when we mean primary shogrens, and "Shogren's disease" with overlap when we mean secondary shogrens. So quickly, the new terminology from "Shogren's Syndrome" has become "Shogren's disease," and nowadays we don't really use the terms "primary shogrens" and "secondary shogrens" as much. Those have now evolved into "Shogren's disease" or "Shogren's disease" with overlap when you see it in conditions like lupus, rheumatoid arthritis, and scleroderma. Going forth in this talk, we are referring to "Shogren's disease," i.e. primary shogrens, unless stated otherwise. Epidemiology. Shogrens is a rare disease. You don't need to remember the exact numbers, but for context, it affects one out of every 1700 people. And the classic patient with shogrens is a woman around the age of 50. It can occur in younger patients. It can occur in older patients, but the most common age of onset for shogrens is 50. And 90% of patients are going to be female. Path of physiology. Okay, let's make pathophysiology short, painless, and relevant. So we know that shogrens disease is a chronic autoimmune condition. And at the center of this is B cell hyperactivation. And with all of this B cell hyperactivation, antibodies will be produced. These include the classic anti-row antibody, i.e. SSA, the classic anti-law antibody, i.e. SSB, and others, including rheumatoid factor. And we will also see lymphocytes infiltrate into the salivary and lacrimal glands, i.e. the glands that produce saliva and tears. And with damage to these glands, patients will develop Xeroothalmia, tri-is, and Xeroestomia, dry mouth. There. That's all you have to know. Short, sweet, relevant. B cells are at the center of shogrens. Quick time. Okay, guys, question number one, which immune cell is central to the pathophysiology of shogrens disease? The B cell. And question number two, who is the classic demographic that gets shogrens disease? Please give me the sex and the average age. Then around 50, well done. Clinical presentation. The classic triad of symptoms and shogrens disease. The triad that's present in 80% of patients with shogrens is one, dryness, two, fatigue, and three joint pains. Again, 80% of patients are going to have this classic triad of shogrens, dryness primarily dry eyes and dry mouth, fatigue, and joint pain. However, what some of us forget, or perhaps are not even aware of, is that this triad is not the beginning and end of shogrens disease. No, in fact, that's quite incorrect, because there are also systemic manifestations which are present in at least one third of patients with shogrens. We're talking lung disease, we're talking skin disease, we're talking nerve disease or neuropathies, we're talking kidney disease, we're talking constitutional symptoms. And we are even talking the dreaded and somewhat common complication of shogrens, which is lymphoma. So again, there are extra glandular systemic manifestations that we cannot ignore, and these affect the lungs, the skin, the nerves, the kidneys, they can cause constitutional symptoms, and they can even cause lymphoma. Thankfully though, there's a range of severity which we see in shogrens. Some patients have very mild disease, perhaps they just need eye drops a few times a day, they've got a positive row antibody, and that's it. Bob's your uncle, they're doing great. Whereas on the other end of the spectrum, we can see severe manifestations. We're talking about patients with glandular enlargement, severe sicka, dryness, extra glandular manifestations like lungs, skin, nerves, kidney, constitutional symptoms, and laboratory abnormalities like cryoglobulinemia. But thankfully, these patients make up a minority of those with shogrens. If you look at retrospective cohort studies, it's around 15% of patients that have such bad disease, they require systemic immunosuppression. 15-15%, which is encouraging. Okay, let's get into specific symptoms here, and we'll start with the triad, dryness first. So, sicka symptoms or dryness are the primary symptoms of shogrens disease, but even though they are the primary symptom of shogrens disease, they may not be the first symptom. So even though rheumatologists do this very commonly, they say, "Oh, a patient I'm seeing does not have shogrens because they don't have shicca," that could be incorrect. You might be missing someone with early disease who hasn't yet manifested the dryness symptoms. All right, now, let's get more into dryness. Dryness is a very common symptom. Over 90% of patients are going to feel dry. We're talking dry eyes, zero-automia, dry mouth, zero-stomia, dry vagina, over 50% of patients are going to have this and even dry skin, but we're going to come to that later. And along with dry mouth, some patients are going to have such bad glandular inflammation that you can see swelling of the parodids or sub-mendipular glands. However, that's only about 20% of patients. Now, I should also say that unlike salivary glands swelling, which we can see in shogrens disease, lacrimal gland swelling, swelling of the glands which make tears. This is an uncommon phenomenon in shogrens and it should lead you to look for an alternative diagnosis. Now dry mouth is more than just discomfort. It causes difficulty with speaking, it causes difficulty with swallowing food, and it interferes with sleep. Saliva is also very important for dental health, so patients can have accelerated tooth decay in shogrens disease. Now if you're not sure how to screen for dryness, here are some validated questions you could ask. Does your mouth feel dry daily for more than three months? You're trying to rule out things like seasonal allergies here and really establish chronicity. Have you had swollen salivary glands as an adult, either recurrent or persistent? Do you frequently drink liquids to aid in swallowing dry food, like a cookie? Have you had daily dry eyes again for kurnicity for three months? Do you have a recurrent sense? of sand in your eyes, and do you have to use tear substitutes several times per day? In terms of joint pains with chowgrens disease, patients can have just regular arthritis, i.e. pain without inflammation, or true objective inflammatory arthritis with signovitis. The distribution of these pains is usually symmetric, affecting the PIPs and MCPs and risks. It generally will not cause deformities and is non-erosive. And the last component of the triad is fatigue. Now about 90% of patients are going to report feeling tired, exhausted, or unrefreshed even after a full night's sleep, and this symptom can be disabling. Now while we're on the topic of fatigue in chowgrens, I should also mention fibromyalgia. Fibromyalgia is very common in chowgrens disease. It's only present in 2% of the general population, but it's present in 30% of patients with chowgrens disease. In a quick review here on fibromyalgia, this is a chronic condition characterized by fatigue and widespread pains. It is non-inflammatory, it is more common in patients with inflammatory disease. Common symptoms include, like I said, fatigue, widespread pain, feeling unrefreshed even after a full night's sleep, unclear thinking, sometimes referred to colloquially as fibrophog, headaches, and can be associated with depression or anxiety. So overall, it's a pretty difficult thing to live with. But the interesting thing is that even though it's much more common in chowgrens disease, studies don't show a clear link between the severity of chowgrens and the odds of having fibromyalgia nor its severity. Let me repeat that because it's quite interesting. Several studies show that the level of disease activity in chowgrens does not correlate with the presence nor the severity of fibromyalgia. Alright, that's it for the triad. Dryness, pain, fatigue, dryness, oral, ocular, vaginal, skin. We're going to talk about that later. Pain, arthritis, or arthritis, and fatigue, including fibromyalgia. This triad is present in over 80% of patients with chowgrens disease. So now that that's done, let's look more in depth at the extra glandular manifestations, which remember affect one third of patients with chowgrens disease. And we are talking here about lung disease, skin disease, nervous system disease, kidney disease, constitutional symptoms, and the dreaded complication of lymphoma. And we will start with pulmonary disease. Now, according to some estimates, patients with chowgrens have lung involvement about 12% of the time. But this almost certainly underestimates the true number. Because if you look at one older French study, when chest x-rays and broncs were done on every patient with chowgrens, at least 50% had some kind of abnormality in their lungs. But thankfully, most patients with chowgrens lung disease are going to be asymptomatic. So what kind of damage does chowgrens actually do to the lungs? Well, it can affect the airways or the lung perankama, the actual lung tissue responsible for gas exchange. And airways are probably affected more than the perankama. And the airways can be affected by any of the following mechanisms. Airway dryness, impaired mucosylary clearance that can lead to bronchiactasis, direct inflammation of the airway walls causing things like bronchiolitis, and patients can even get an airway hyperreactivity that resembles asthma, but is distinct because firstly, it's not driven by easinophils, and secondly, because this asthma-like phenotype only responds to inhaled corticosteroids 50% of the time. So that's it for the airways. Dryness, impaired mucosylary clearance, direct inflammation, and this asthma-like picture. How about the perankama? Well, chowgrens can cause ILD. It can cause inflammation and/or scarring of the lung tissue itself, and this will lead to a restrictive pattern on PFTs. Now, the most common radiologic patterns are NSIP followed by UIP. There are others as well, but really NSIP and UIP are the most common. Now, as a reminder, NSIP is ground glass predominant and spares the subplural region, whereas UIP is more fibrotic and it does not spare the subplural region and it can evolve into honeycombing. Now, there is just one more perankama lung pattern that we can see in chowgrens, and that is cystic lung disease, whereby you get cysts that show up in the lungs. And these can occur in isolation, or they can occur as part of a condition called lymphoid interstitial pneumonia. And honestly, I think that's an adequate amount of information on the patterns of lung disease in chowgrens. Clinically, these patients are either asymptomatic or will present with classic symptoms like dry cough and shortness of breath. And from a workup perspective, consensus guidelines suggest that every patient with chowgrens should get a baseline two-view chest x-ray. That's for all comers. Symptoms are no symptoms when you first meet them and they've got chowgrens disease. But if you feel your patient has symptoms of chowgrens lung disease, let's say dry cough, let's say, dysnia, let's say they have crackles on the osculation of their lungs, then you're going to do two tests. The first is PFTs, and that's going to look for a restrictive pattern. And the second is a non-contrast CT to look for those abnormalities we were discussing before. Ground glass changes, fibrosis, honeycombing, bronchiactasis, cystic lung disease. Okay, guys, let's move on to skin disease. Now, unlike lupus, there are no specific chowgrens disease rashes, but they can get a variety of them. We'll just mention four. One super common one, one less common, but very important prognostically, and two others that I think you should know about. These are the common one, Xerosis, or dry skin, the less common, but prognostically, very important one, cutaneous vasculitis, and the two others, levidoreticularis, and Raynode's phenomenon. So let's start with Xerosis, i.e. dry skin, because it is by far the most common cutaneous manifestation present in over half a patient with chowgrens disease. It is worse in cold climates. It is worse in low humidity, and it is worse after long, hot showers. If your patient has dry skin, here are some easy suggestions you can offer for them to implement. Firstly, shower modification. Patients with dry skin should limit themselves to one 10 minute lukewarm shower per day. In the shower, they should be using gentle soaps like dove sensitive. And when they're finished, they should not towel vigorously, but pat dry. No aggressive toweling. And immediately when that's done, they should apply moist drizzers. And ointments like Vaseline are the best. Number two, in terms of addressing the itch, which is very common with dry skin, I would recommend one of two products. The first is Sarna original lotion, S-A-R-N-A, Sarna original lotion. It's easy to get in the States. It's harder to get in other countries like Canada. And so if you can't get your hands on Sarna, the other very good product is La Roche Lipicar Bomb. L-I-P-I-K-A-R Lipicar Bomb. La Roche Lipicar Bomb and Sarna original lotion. And to get even more effect for your patients with dry skin and itch, they can consider putting the lotion in the fridge before they use it to give an almost immediate cooling and relieving effect to itchy skin. Now, the La Roche Lipicar Bomb is a little bit pricier. And in the current geopolitical environment, gas is stretching everybody's budget. So the good old blue chip brands like SeraVee and Cetaphil have completely reasonable options as well, including SeraVee moisturizing cream and the Cetaphil Restore Derm moisturizer. And that is more than I ever thought I would know about dermatology. Okay. So dry skin. For 50% of patients with chowgrens, we've got some good solutions there like shower modification and some products you can recommend to patients to relieve their itch. Now, let's move on to the second manifestation we want to discuss, which is less common, but quite significant. And that is cutaneous vasculitis. This is a much less common manifestation in patients with chowgrens, less than 10% of patients are going to have cutaneous vasculitis. But something you should be aware of because it's a poor prognostic sign and suggests a higher risk of serious internal organ involvement and a higher risk of lymphoma. It looks just like most typical cutaneous, small vasculitis, most commonly presenting as palpable perpera on the lower extremities. Okay. cutaneous vasculitis. Now moving into the last two cutaneous manifestations, levito reticularis, the lacy or modeled appearance of skin, secondary to altered blood flow, and ray notes phenomenon. Ischemic color changes of the fingers and toes, particularly triggered in the cold. And that's it for skin. Number one, Xerosis or dry skin. Number two, cutaneous vasculitis, way less common, but very important prognostically, and two others to be aware of levito reticularis and ray notes phenomenon. And this brings us to the next extra glandular manifestation of showgrens, which is constitutional symptoms. We see these in about 10% of patients with showgrens disease, and they include fever, weight loss, night sweats, and we're going to group lymph adenopathy and here as well. That's it for constitutional. So now we've covered the extra glandular manifestations in the lungs, in the skin, and constitutional manifestations. Let's move into the neurologic diseases of showgrens. Both the peripheral and central nervous system can be affected in showgrens disease, though peripheral disease is much more common than central. In terms of peripheral manifestations, about 6% of showgrens are going to have a peripheral neuropathy, and what makes this tricky is that in one third of these cases, the neurologic manifestations will precede the sicka manifestations. In other words, in one third of cases, of peripheral neuropathy caused by showgrens disease, the neuro manifestations will come before the sicka symptoms, and this is going to make your life a little bit more challenging when it comes to correctly diagnosing the condition. Now, there are many different forms of peripheral neuropathy and showgrens disease, and depending on which study you look at, their relative proportion varies, but let's just mention a few that I think it's very important for you to know about. And these are small fiber neuropathy, distal, axonal, sensory neuropathy, autonomic neuropathy, trigeminal neuropathy, and mononuritis multiplex. I'm going to say that at least one more time. Small fiber sensory neuropathy, distal, axonal, sensory neuropathy, autonomic neuropathy, trigeminal neuropathy, and mononuritis multiplex. And we are quickly going to elaborate on each of these. The first is small fiber neuropathy. This is the one we're going to hone in on because small fiber neuropathy is one of the most common ones you'll encounter in your patients with showgrens disease. Typically, it presents with a chronic burning or prickling pain, alidinia, or hyperalgesia. And it can be in a glove and stalking distribution, affecting the fingers and toes, but it can also be more proximal as well. Because it's a small fiber condition, the nerve conduction studies are usually normal. They are not sensitive enough to capture small fiber abnormalities. Instead to make this diagnosis, you will require a skin punch biopsy that'll show you reduced nerve density. I normally send this to neurology to do for me, but if you're going to do it yourself, you generally need a biopsy in two spots to show a proximal to distal gradient. Okay, small fiber sensory neuropathy, one of the most common neuropathy is in patients with showgrens. Again, they present with a chronic burning and tingling, hyperalgesia type pattern. It can be glove and stalking, but it can also be more proximal. All right, the second neuropathy we're going to discuss is the distal axonal sensory poly neuropathy. This is another very common form of peripheral neuropathy in showgrens disease. This is another chronic, slowly progressive neuropathy, and it presents in a glove and stalking distribution, affecting the fingers and toes first. And it causes negative symptoms like parasthesia and numbness. So if you're comparing both of these common peripheral neuropathy in patients with showgrens disease, and you're not sure which one is causing neurologic manifestations in the fingers and toes of your patient, small fiber neuropathy is more likely to cause positive symptoms like chronic burning or prickling or hyperalgesia, whereas the distal axonal sensory poly neuropathy is more likely to cause negative symptoms like parasthesia and numbness. And if you're to do an EMG, you will see the distal axonal sensory poly neuropathy, but you will miss the small fiber neuropathy. Instead, the small fiber neuropathy requires a skin biopsy to make the diagnosis. And the last peripheral neuropathy, which I think it's important for you to know about in patients with showgrens disease, is autonomic neuropathy. This is very common in showgrens. Symptoms can include those related to orthostatic hypotension, those related to gastroparesis, those related to abnormal sweating and bladder dysfunction. It is very common for your patients with showgrens to tell you they feel dizzy when they stand up. It's very common for your patients with showgrens to describe GI symptoms like early satiety or nausea. It's very common for your patients with showgrens to describe that they sweat abnormally, and it's very common for your patients with showgrens to describe bladder dysfunction. And these could very well be coming from autonomic neuropathy in your patient. Okay, now the central nervous system is a little bit different. It will present much less frequently than peripheral neuropathy in showgrens disease. However, virtually all parts of the CNS can be involved. We are talking the optic nerves causing optic neuritis. We're talking the brain hemispheres, causing MS-like demyelinating lesions, and we're talking the spinal cord with transverse myelitis. Additionally, cognitive deficits are also common in showgrens disease. These include things like poor memory, attention, visiospatial dysfunction, and sometimes patients can feel very frustrated about this or down on themselves. And it's our responsibility as their care providers as the experts to reassure them this is not something wrong with them. This is part of their disease. So they don't feel ghastlet and they don't feel despondent about themselves. Okay, good. So to summarize so far, we have talked about the classic triad of showgrens disease, dryness, pains, fatigue, and we've sort of lumped fibromyalgia into that. We've talked about some extra glandular manifestations, including pulmonary disease, both airway and perencomal. We've talked about cutaneous manifestations, particularly Xerosis, dry skin, but also cutaneous vasculitis, and others. We've talked about constitutional manifestations, and now we've also discussed that showgrens can cause neurologic complications, including primarily peripheral neuropathy. We are talking small fiber sensory neuropathy. We're talking distal axonal sensory poly neuropathy. We are talking autonomic neuropathy. And in terms of the CNS, you now know that there are central nervous system complications, which can be seen on MRI, like demilinating lesions of the brain and transverse myelitis of the spinal cord. But they are also relatively invisible, radiologically invisible cognitive deficits, like poor memory, inattention, and visiospatial dysfunction that patients need to be educated about. And so this brings us to the last extra glandular manifestation, which I think we should discuss, and that is renal disease. Renal disease occurs in about 5% of patients with showgrens, so it is a minority of patients who get this, but it's classic and important to know about it. And this is a tubulointerstitial nephritis. This is not like laminal nephritis, which we see in lupus. It is a tubulointerstitial nephritis. The urinalysis will usually be normal, or only show mild protein urea or sterile pyurria. But this interstitial nephritis can lead to electrolyte and acid-based abnormalities, the classic one being type 1 renal tubular acidosis, where the kidneys cannot effectively excrete acid, and patients end up with hypochalemia, and nephrogenic diabetes insipidus. I want to bring up just one more clinical manifestation. And I'm not even going to call it an extra glandular manifestation. I should more accurately term it a complication of showgrens disease. And that is lymphoma. Now we know already that patients with autoimmune disease have an increased risk of lymphoma, in rheumatoid arthritis, in systemic lupus, in celiac disease. But the risk of lymphoma in showgrens disease is pronounced. And that translates to about a 15 to 20 times higher risk of lymphoma compared to the general population. In other words, about 5 to 10 percent of your patients with showgrens are going to end up with lymphoma. And this is directly related to chronic B cell activation. And therefore, it makes sense that the most common lymphoma we see and showgrens is the B cell non-Hodgkin's lymphoma, especially malt lymphoma, and malt stands for mucusa associated lymphoid tissue. Now you may remember from medical school or your internal medicine residency that malt lymphomas are most common in the stomach, but in showgrens disease, we see them particularly in the salivary glands, and features which should get your spidey senses tingling for the development of malt lymphoma, are B symptoms, fevers, night sweats, unexplained weight loss, as well as plenamegaly. Okay, that's it, great job. You've finished the clinical manifestations of showgrens disease. Now you may have come into this episode thinking, the triad, the classic triad of showgrens, which is present in 80% of patients, dryness, fatigue, pain, was the B all and end all. But hopefully now you also appreciate that one third of patients will get extra glandular manifestations, and in fact, probably even more than that, with disease being present in the lungs, both the airways and the perencoma. In the skin, particularly like dry skin, but even the harbinger from more severe disease, mutaneous vasculitis, constitutional symptoms, neurologic symptoms, more so peripheral manifestations than central manifestations, but these include things like small fiber sensory neuropathy, distal axonal sensory poly neuropathy, and autonomic neuropathy, as well as CNS disease. Of course there's the classic renal manifestation of interstitial nephritis causing type 1 renal tubular acidosis, and lastly the dreaded complication of showgrens, which is lymphoma. Very high risk of this present in up to 5% or 10% of patients with showgrens disease over the course of their lifetime. So well done, you've digested all of that. So a question might arise in your mind, if a patient is sitting in front of me, and I'm looking at them, and I'm looking at their labs, is there some way for me to prognosticate how likely it is this patient is going to have severe disease versus mild disease? And yes, absolutely there is. Let me provide you with some of the most telling clinical signs that your patient may end up with severe disease activity. These include recurrent glandular swelling, palpable perperate representing cutaneous vasculitis in the lower extremities, lymph adenopathy. These clinical features should tell you your patient is higher risk for systemic disease and potentially even lymphoma. From a laboratory perspective, the presence of a positive rheumatoid factor, a positive cryoglobulin, low complement particularly C4. These are also risk factors for systemic disease activation and potentially lymphoma. And this will come in handy because if a patient is in your clinic and says hey doc, I looked up that showgrens can cause lymphoma, am I at risk? And you can give them some sense of that very truthfully based on the clinical presence of recurrent parodid swelling, lymph adenopathy, and palpable perperate, and the laboratory features of positive rheumatoid factor, positive cryoglobulins, and a low C4. Next time. All right guys, great job. That was a lot of clinical manifestations, both glandular and extra glandular. Let's see how much of what I said made sense. Seven questions for you here. Question number one. What is the classic triad of showgrens disease that's present in 80% of patients with this condition? All right. Fitness, particularly dry eyes and dry mouth, fatigue, and joint pain. Question two. Remember that one third of patients will develop extra glandular manifestations of showgrens. Which organ systems can be involved? Okay, the lungs, the skin, the peripheral and central nervous system, and the kidneys. If you also mentioned constitutional symptoms, that's great. And if you said lymphoma as part of the hematologic system, that's a bonus. Question three. What is the typical pattern of arthritis in showgrens disease? Okay, it is a symmetric polyarthritis affecting the PIPs, MCPs, and risks, and it's generally non-erosive. Question four. What are the two most common patterns of ILD in showgrens disease? In which pattern of ILD is associated with cystic lung disease? All right, NSIP, followed by UIP, and cystic lung disease can happen in isolation or can be associated with lymphocytic, interstitial pneumonia, aka, LIP. Okay, nice job, more than halfway. Question five. Please list at least three subtypes of peripheral neuropathies that we see in showgrens disease. We talked about five. I'm asking you to just list three. Okay, small fiber sensory neuropathy, distal axonal sensory polyneuropathy, autonomic neuropathy, trigeminal neuropathy, and mononuritis multiplex. Again, small fiber sensory neuropathy, distal axonal sensory polyneuropathy, autonomic neuropathy, trigeminal neuropathy, and mononuritis multiplex. And a little follow-up question, almost like a part B, question five part B, which of these sensory neuropathies is usually only seen on skin biopsy? And which sensory neuropathy is typically detectable on EMG or nerve conduction studies? The small fiber sensory neuropathy is usually going to have a normal EMG, but skin biopsy will give you the diagnosis. Whereas a distal axonal sensory polyneuropathy can be detected on EMG nerve conduction studies. Two more questions to go. Question number six. What is the classic renal manifestation of showgrens disease? Two below interstitial nephritis that can lead to type one renal tubular acidosis. Question lastly, question number seven. Which three clinical features and three laboratory features are associated with the higher risk of lymphoma in your patients with showgrens disease? Three clinical, three laboratory that increase the risk of multiple lymphoma in your patients with showgrens disease. Okay, from a clinical perspective, recurrent parotid swelling, lymphadenopathy, and cutaneous small vasculitis causing palpable perprar usually on the lower extremities. So parotid swelling, lymphadenopathy, cutaneous vasculitis repalpable perprar, these are the clinical features associated with a higher risk of lymphoma, from a laboratory perspective, positive rheumatoid factor, positive cryoglobulins, and hypocomplimentemia, particularly a low C4. Nice job. That was a lot of information. Let's take a bird's eye view of the workup of showgrens disease, and then we'll hone in. So a practical workup of showgren starts with a good history and physical exam. Again, you are looking for the classic triad, of course, dryness of the eyes, dryness of the mouth, dryness of the vagina, pain, and fatigue, including features of fibromyalgia. And then you delve into the extra glandular manifestations. So pulmonary disease of the airways or the lung perencoma, cutaneous manifestations like dry skin, and the harbinger cutaneous vasculitis, you assess for constitutional manifestations, fevers, night sweats, etc., neurologic disease like peripheral neuropathy or CNS disease, and renal manifestations. And once you are done your excellent clinical evaluation, now you go into laboratory testing and objective glandular testing of the salivary gland and/or the lacrimal cleanse. In terms of your labs, there are four key auto-antibodies you're looking for. T-Row SSA Antilaw SSP. A&A and rheumatoid factor. Those are the four key auto antibodies. There are other labs though you should also obtain, and these are more to support your diagnosis or understand prognosis a little better. These are ESR, CBC, quantitative immunoglobulins, compliments, particularly C4, and your analysis to look for renal involvement. And when you are completed your laboratory testing, you move into objective glandular testing. This is either with a salivary ultrasound, a minor lip biopsy or minor salivary gland biopsy, the Schirmers test, ocular surface staining, or the unstimulated salivary flow rate. It's important for you to know or be familiar with some of the names of the special tests, like Schirmers testing, ocular surface staining, or the unstimulated salivary flow rate. But in reality, for the general rheumatologist who doesn't specialize in connective tissue disease or doesn't work in a center with a dedicated children's program, the main glandular testing you are going to start with is probably salivary gland ultrasound or the minor salivary gland lip biopsy. Okay, let's delve into each of these. And briefly, we will start with examination of the prodiglins. When you are looking for the prodiglint, they sit between the masseter, which is the chewing muscle in the jaw and the ear, and normally you should not be able to feel this gland. However, in showgrens, they can become enlarged. And if you want to find them, you can ask the patient to clinch their jaw so you can identify the masseter and palpate right behind it in front of the ear. You can do it on yourself right now, too, if you want, clinch down on your jaw. You feel the masseter tense up, move just posterior to it, and that's where your prodigts sits, and you should not be able to feel it usually. And actually, with enough glandular enlargement, the prodiglint can drop below and behind the angle of the mandible. Okay, in terms of lab testing, there are four key auto-antibodies you should be requesting. Anti-row, SSA, anti-law, SSB, ANA, and rheumatoid factor. The row and law are available as part of the ENA panel. And of all of these, the anti-row is the most helpful one, because while both anti-row and anti-law are common in showgrens disease, we see them in 70% of patients with showgrens. Anti-law is actually not specific when present in isolation, and therefore, if you see a patient who just has anti-law positivity, SSB, this is unhelpful for your diagnosis of showgrens disease. This is not a specific finding. I'll say it again, anti-law SSB in isolation is not helpful in the diagnosis of showgrens disease, because that is not a specific finding. I should also mention that a minority of us practice in places where the lab will break down anti-row into anti-row 60 and anti-row 52. Most of us do not practice in labs where we have access to that kind of differentiation. If we do though, if you are one of the lucky few, then anti-row 60 is the more specific antibody. If you have access to the anti-row 60, that makes your life much easier when it comes to diagnosis versus anti-row 52 is less specific. You can see it in ILD. You can see it in myocytus. You can even see it in cancer. I'm just going to quickly mention three caveats around the anti-row antibody. Caveat number one. Immuno assays nowadays are much more sensitive, and in this case less specific than they used to be. If you see a very mildly elevated anti-row antibody, don't automatically make the diagnosis. Be a little cynical. Note number two. You can see row and law in other conditions as well. So don't automatically diagnose showdowns just on the basis of seropositivity. For example, 1% of the healthy population will be positive for anti-row. And I just told you that sometimes the labs that we see are picking up anti-row 52, which we can get in things like ILD, myocytus, and even cancer. And caveat number three. Remember that 70% of your showgrounds patients are going to be seropositive for row and law. But this means that 30% are going to be zero negative. In other words, I'm going to reiterate this. Being zero negative does not exclude the diagnosis of showgrounds disease. 30% of patients with showgrounds are going to be negative for row and law. And that's enough for row and law. That's what I want you to know. Let's move on to other lab tests. Let's start with the ANA. This is commonly seen in showgrounds disease present in at least half of patients. But the ANA should not be used, absolutely not be used as a screening test for showgrounds because you can totally be ANA negative and anti-row positive. Room and toyed factor is another antibody you should be ordering in your patients with showgrounds disease because it predicts higher disease activity and it also confers a higher risk of lymphoma. For other supporting labs, get a CBC because you might see Lucopenia with showgrounds. Get quantitative immunoglobulins and ESR because both of these may be elevated. Obtain a C4 because if low, it can suggest higher disease activity and a higher risk of lymphoma. And the last lab is cryoglobulins because they are associated with the higher disease activity and a higher risk of lymphoma. And truly your serologic pattern matters. We know, for example, that in patients with all four of the classic auto antibodies, row, law, ANA, rheumatoid factor, these patients are going to have a more active disease course, more likely to get extra glandular manifestations and they have a higher lifetime risk of lymphoma. Whereas those with just an anti-row or seronegative patients tend to be older at presentation with a less severe clinical course. And like we said earlier, certain serologic profiles predict lymphoma risk. For example, rheumatoid factor positivity, cryoglobulin positivity, and a low C4. Okay, now let's move into objective evaluation of the salivary and lacrimal glands. And the test that I want to pitch at you as potentially your go-to is the salivary gland ultrasound. This has become an established central tool for the diagnosis of shogrens. It is increasingly used in patients who we suspect to have shogrens such that it is now the first line imaging modality. And we can use it both on the prodids or the sub-mendipular glands. Early on, signs of inflammation include hypoechoic areas, and as time progresses, the glands start to show hyper-echoic bands, cysts, and calcifications. And we know that ultrasound findings correlate very nicely with salivary gland positivity, and reduce salivary flow rate. According to a recent meta-analysis, the sensitivity of salivary gland ultrasound is 86% and its specificity is 87%. So overall, a great test. And it is widely available. It's cheap, and there's no radiation exposure. It is an excellent first-line test to evaluate the glands in your patients with suspected shogrens disease. But let's see if I can prove to you that this is an excellent imaging modality with data. In 2021, there was a paper published by Dr. Xavier Merriott's group. And Dr. Merriott is one of the world's foremost experts on shogrens disease. This group concluded that salivary gland ultrasound can be an excellent rule-out test in combination with a negative anti-row antibody, such that if a patient does not have at least moderate changes on their salivary gland ultrasound and a negative anti-row antibody, then the diagnosis of shogrens disease is very improbable, and you can likely avoid a salivary gland biopsy. In their study of over 250 patients, they found that the negative predictive value of a negative salivary gland ultrasound and a negative anti-row combined with each other, this dual-finding negative ultrasound, negative anti-row, the negative predictive value was 92%. It's not perfect, but it's pretty darn good. And a newer development now in the salivary gland ultrasound world is the use of power doppler, which looks for abnormal, high-vascular signals. And it's something that even inexperienced anographer seemed to be able to do reasonably well. And this doppler mode can look for evidence of active inflammation as opposed to just damage. And the data now for salivary gland ultrasound is so good that they recently released British Society for rheumatology guidelines on the management of shogrens disease, specifically recommend against additional imaging modalities over and above ultrasound in the routine assessment of shogrens disease. If you want other imaging, it's acceptable, for example, MRI to look at the salivary ducts, but it is not needed in the majority of patients being worked up for shogrens. Okay, that was glandular test number one, which I encourage you to consider as your first line glandular evaluation when. assessing patients for shogun's disease in your practice. This salivary gland, ultrasound. Okay, that's test number one. The second practical test that you will likely order from time to time is the salivary gland biopsy. This has been a key test in the diagnosis of shogun's disease, particularly important when patients are seronegative. Generally, the biopsies we do are called minor salivary gland biopsies, aka lip biopsies. They're minor procedures. They're done as outpatients under local anesthetic with no more than a one centimeter incision where the surgeon can remove four to six glands. Don't worry, your patient has between 600 and 1,000 of them so they won't notice the four to six that go missing. Now, the whole thing takes less than 15 minutes. And the pathologist, when they receive the samples, can very easily identify the degree of inflammation using something called the focus score, which is the number of lymphocyte aggregates per four millimeter squared. And the magic number, the focus score which we think is positive for shogun's disease is a focus score of one. The salivary gland biopsy is relatively safe, very well tolerated, and the side effects are typically minor and uncommon. About 5% of patients will get prolonged numbness after the biopsy, but this tends to improve after a few months. The sensitivity of salivary gland biopsy for shogun's disease is about 85%, and the specificity is even higher. It's a great test, but since salivary gland ultrasound has proven itself, and it's non-invasive, many experts are now ordering a salivary gland ultrasound before the minor lip biopsy. Okay, those are the first two glandular tests, and there are three more to go. These are special clinical exam maneuvers in a way. The first is the unstimulated salivary flow rate, whereby patients drool into a tube for five minutes. They don't spit, they drool into the tube for five minutes, and the volume of saliva they produce is measured. A normal flow rate is more than 0.1 milliliters per minute. And so after five minutes, your patient should have more than 0.5 milliliters in the tube. It's easy to do in clinic. I would say it does not take particular skill. However, the most accurate way to do this is with a digital scale, where you can measure the before and after weight of the tube, after the patient's had a chance to drool. But my gut feeling is that the majority of us do not have digital scales just laying around in our offices. Special glandular exam number two is the Schirmers test, whereby a thin filter paper is placed on the lower eyelid for five minutes. And if less than five millimetres of that paper is wet after five minutes, it suggests deficient to your production, and that is considered significant for Shoghrin's disease. This is something I usually ask the eye doctors to do for me, but you can totally do it in your clinic. And the last of the five special glandular tests is the ocular surface staining. This is to obtain something called a sicka score. It's carried out also by an eye doctor, where the surface of the eye is temporarily stained with special drops and examined with a slit lamp. And the eyes are scored from zero to 12 per eye. The higher the score, the more severe the dryness. A score of five or more is considered significant for Shoghrin's disease. And that's it. That's the workup of Shoghrin's disease. Again, bird's eye view, you start with an excellent history and exam, including examination of the prodids. You get the four key auto-antibodies. Rho, ideally Rho 60, but most of us don't have that luxury. So Rho, La, A&A, rheumatoid factor, supporting lab tests like an ESR, quantitative immunoglobulins, CBC for leukopenia, C4 for hypo complementemia, urinalysis, and objective gland testing. I think the salivary gland ultrasound is great to reach for. You can also obtain a minor lip biopsy, and then there are the special examination maneuvers, the shirmers test, the ocular surface-staining score, and the unstimulated salivary flow rate. - Quiz time. - Okay, guys, five questions for you here. Question one, what are the four key antibodies we order when we suspect Schogren's disease? Okay, anti-row, SSA, anti-law, SSB, A&A, and rheumatoid factor. Again, that's the anti-row, AKA SSA, anti-law, AKA SSB, A&A, and rheumatoid factor. Anti-row, anti-law will come standard as part of your E&A panel, and if you're one of the lucky few who have access to an anti-row 60, I highly recommend you order that. Question two, true or false? A negative A&A rules out anti-row positivity. False, very much false, a patient can totally be A&A negative and anti-row positive. Question three, why should we be cautious about isolated anti-law, AKA SSB, positivity, meaning anti-law positive, anti-row negative? Because an anti-law in isolation is not specific and therefore not helpful diagnostically. Question four, which objective glandular test am I emphasizing as especially useful? I'll give you a hint, it is widely available, relatively cheap and does not have any radiation risk on the patient. Yes, you guessed it, the salivary gland ultrasound. And lastly, question five, what are the three objective tests of dryness that we classically talk about in showrooms disease? Okay, the two I ones that I usually send to the I doctor are the ocular staining score and the Schirmer test. And the one that you can do in your own office, but is ideally done if you have a digital scale is the unstimulated whole salivary flow rate, the unstimulated whole salivary flow rate, where a patient drools into a tube for five minutes. And the result is positive if they only make the 0.1 milliliters per minute or less. In other words, if they have five minutes to drool, they only make 0.5 milliliters or less, that's a positive test. So the three objective tests that we do for dryness and showrooms disease, which are part of the classification criteria, are number one, the ocular staining score, number two, the Schirmer test, and number three, the unstimulated whole salivary flow rate. Diagnosis. Honestly, I find diagnosing showrooms disease to be challenging sometimes. You know, it's one thing if you have a patient who's got a sky high anti-row anti-law, positive RNA, positive rheumatoid factor, elevated immunoglobulins, some leukopenia, high ESR, and a positive salivary gland ultrasound or minor lip biopsy. Combined with the classic symptoms of dry eyes, dry mouth, fatigue, and articular pains, those cases are easy peasy, lemon, squeezy, slam dunk, done. But I think the nuances make it difficult. And so when the diagnosis of this condition, you want to do two things. Firstly, you want to demonstrate that the lacrimal and salivary glands are dysfunctional. And secondly, you want to prove that it's from an autoimmune etiology, and you need to rule out differential diagnoses. So how do we do this? Well, in terms of proving dysfunctional or damaged lacrimal and salivary glands, you can obtain a salivary gland ultrasound or you can do objective special testing to prove dryness. That's the Schirmer test, the ocular surface staining, an unstimulated salivary flow rate. And when it comes to proving autoimmune causes for this damage, you do that by demonstrating the presence of an anti-row antibody or a positive minor salivary gland biopsy that shows lymphocytic infiltration into the glandular tissue. So again, for diagnosis, you want to prove that there's objective lacrimal or salivary gland dysfunction or damage. And then you need to prove number two that there's likely an auto immune cause for this. And so in practice, my personal approach starts with a thorough history and exam then relies heavily on doctor Xavier Marriott's initial strategy, which is testing the anti-row. Ideally, anti-row 60, but most of us don't have access to that luxury and a salivary gland ultrasound. My algorithm looks like this. If I have a positive positive anti-row and a positive salivary gland ultrasound, the diagnosis is strongly supported. If I have a negative anti-row and a negative salivary gland ultrasound, the diagnosis is very unlikely, not impossible, but very unlikely, with a negative predictive value of 92%. If the patient has an anti-row, which is positive, but a negative salivary gland ultrasound, meaning potential evidence of autoimmunity, but no evidence of glandular damage on ultrasound, then I need to prove or disprove glandular damage in other ways. That is with objective testing, like ocular staining or the Schirmers test at the eye doctor, or trying the unstimulated salivary flow rate, where I have patients drool into a tube for five minutes and see if at the end of that five minutes they've made more than 0.5 milliliters of saliva. And lastly, if the patient has a negative anti-row, but a positive salivary gland ultrasound, meaning they have no evidence of systemic autoimmunity based on the anti-row, but their ultrasound does show damage, I need to look for other ways to prove an autoimmune etiology for that glandular dysfunction, and that's with a lip biopsy. Now please don't think this is the be-all and end-all way to work up Schogren's disease. It's not, there's more than one way to skin a cat, and different groups have published their experiences as well. So for example, the University of Toronto Schogren's clinic recently published that you can largely make the diagnosis of Schogren's based on laboratory testing, Schirmertest, and the unstimulated salivary flow rate alone. But again, my personal approach relies heavily on the row antibody and salivary gland ultrasound, because ultrasound is an easily accessible test at my center, and there's plenty of data supporting its use. And because if I'm being honest, putting dry paper on someone's lower eyelid when they're already complaining about sand in their eyes feels deeply unnatural to me. Differential diagnosis. It is also important to consider some key differentials when you're working up a patient for Schogren's disease who complains about dryness. The main differentials to think about are age-related sicka, it's very common in older adults, especially women, anticholinergic medications, IgG-4-related disease, which is more likely to present in men than women, and more likely to cause prominent lacrimal gland enlargement compared to Schogren's where we don't usually see lacrimal enlargement, sarcoidosis, which can involve both the parodid gland and the lacrimal glands, and lastly Hepatitis C and HIV, both of which can look like Schogren's, can cause sicka, can cause inflammation of the salivary glands, and can have extra glandular manifestations. So if there's any risk for Hepatitis C or HIV, just go ahead and test for those. Again, your key differential diagnoses for sicka when you're working up a patient for Schogren's disease are age-related sicka, anticholinergic medications, IgG-4-related disease, sarcoidosis, Hepatitis C and HIV, Classification, all right guys, great job. Last section, here we go. We as rheumatologists generally do not have diagnostic criteria. We have classification criteria. These are used for research purposes to create homogeneous populations which we can include in trials, not for diagnosis, however, these classification criteria are still frequently used as clinical guides. For Schogren's disease, we have the 2017 ACR-ULAR classification criteria which use five objective tests that are weighted differently. They don't all count for the same. These five tests are the anti-row antibody SSA, a positive salivary gland biopsy focused score of at least one, Aucular staining score of five or more, Schirmers testing less than five millimeters on that piece of paper, and an unstimulated salivary flow rate of less than or equal to 0.1 milliliters per minute. Again, the five features that are part of the 2017 ACR-ULAR criteria for Schogren's disease are an anti-row antibody or SSA, a positive salivary gland biopsy, an Aucular staining score greater than or equal to five, Schirmers testing less than five millimeters, and an unstimulated salivary flow rate of less than or equal to 0.1 milliliters per minute. You will notice that the anti-law antibody SSB, the rheumatoid factor, and ANA are excluded from the classification criteria because they are much less specific for Schogren's disease unlike the anti-row antibody. All right, guys, great job getting through this episode, just four questions before you go. Number one, what two things do you generally want to prove or demonstrate in the majority of Schogren's patients to make the diagnosis? What two things do you want to prove to make the diagnosis of Schogren's disease in the majority of patients? To make the diagnosis, the first part is to prove they have glandular dysfunction, specifically lacrimal or salivary gland dysfunction. The second part of your diagnosis is to prove that the glandular dysfunction is autoimmune in origin. Question two, true or false, a combination of a negative salivary gland ultrasound and the negative anti-row antibody is excellent for ruling out Schogren's disease. Negative anti-row, negative ultrasound is excellent for ruling out Schogren's disease, true or false. True. The combination has a negative predictive value of 92%. Both my own approach and the British Society of Rheumatology's guidelines on the management of Schogren's disease support salivary gland ultrasound as an excellent, first-line imaging modality in the assessment of Schogren's disease. Question three, we rheumatologists do not have diagnostic criteria. We have classification criteria, but these classification criteria can still be used as a clinical guide toward diagnosis. Each five items are part of the classification criteria of Schogren's disease. I'll give you a few seconds here to think of all five. Okay, number one, the anti-row antibody. Number two, a positive minor salivary gland biopsy. Number three, the ocular staining score, number four, the Schirmer test, and lastly, number five, the unstimulated salivary flow rate. And that brings us to the last question of the day, number four. Can you name four or five differential diagnoses for sicker symptoms that you should think about when assessing a patient for Schogren's disease? Four or five differentials. Age, anticolynergic medications, hepatitis C, IgG-4 related disease, and sarcoidosis. And that's it for today, guys, great job of making it through this topic. You deserve a well-earned break. If you enjoyed today's session, please subscribe. I would also tremendously appreciate your feedback in the form of an Apple Podcast review or feel free to email me with suggestions for future episodes, content, accuracy, or sound issues. My email is room for the RC, that's R-H-E-U-M-F-O-R-T-H-E-R-C at gmail.com. Have a great one. (gentle music)