Approach to Hyperuricemia and Gout

Welcome to MedPOTS, the podcast on topics of internal medicine from the Department of Medicine at AFMC. We are continuing in this series of podcasts with a new topic this time. This topic pertains to hyperuricemia and GAUP, a very common rheumatological disorder often encountered in clinical practice. To discuss this topic today with us, we have Colonel Berghese Koshy, a professor of medicine and rheumatologist in the Department of Internal Medicine at AFMC. The topics that we have chosen over the past few podcasts have had relevance for undergraduates who appeared in their exams to understand the topics better and for postgraduate residents to manage these patients in their outpatient or hospital practice. We will continue to do that in this edition as well and I would request Colonel Koshy to elaborate on various issues that pertain to this topic of hyperuricemia and GAUP as relevant to undergraduates and postgraduates. You would also notice that we have made a change and brought in a new logo for our podcast, the MedPOTS. It is a white background, white which symbolizes purity, clarity and honesty and that is what we stand for here in this podcast and in the Department of Internal Medicine at AFMC. So welcome, Dr. Koshy. Thank you, sir. So what we do in this podcast is to have an interview kind of a session where we would like to ask you certain questions. We would like you to answer it in such a way that our students understand these topics better. So coming to this topic of hyperuricemia, can you explain what hyperuricemia means and how it relates as far as development of this rheumatological condition called GAUP? Mr. Koshy, thank you for the question and hyperuricemia and GAUP are very interesting topics and probably age old as man and uniquely it is a problem for the primates which is there. The rest of the animal kingdom most mammals have a serum-urate level which is roughly in a range between 0.5 and 2 milligram percent whereas the primates have a serum-urate level between 4 and 6 milligram percent. And coming to the direct answer of the question, hyperuricemia is defined as a serum-urate level greater than 6.8 milligram percent which is the limit of unit solubility in serum. So essentially speaking, most of the humans and the primates probably developed higher serum-uric acid levels as an evolutionary process and this was because the primates did not have the uricase enzyme which converts uric acid into allantoin which is water soluble and can be excreted by the kidneys. So to cut a longer process shot, the answer is hyperuricemia is defined as a serum-uric acid level more than 6.8 milligram percent. Okay and this uric acid predominantly comes from the purine metabolism as I understand. Okay, so what are the primary risk factors for developing hyperuricemia and then eventually leading to gout? So again a very interesting question, primarily speaking I mean if we want to use the term primary then we would have to go to the genetic issues which lead to hyperuricemia and these things could result in higher serum-uric acid level even in young activities. But what concerns, those are very rare and what concerns most of us are the other risk factors or associations if it may be put that way. So older age, the male sex and post-menopausal status in women are the important biologic variables which lead to hyperuricemia and association with gout. Here I must mention that all patients with hyperuricemia will not necessarily develop gout arthritis and even the presence of monosodium urate crystals that is the crystallization when the serum-uric acid exceeds 6.8 milligram percent does not mean that an inflammatory process will be triggered and those are the interesting questions that future research will try and answer as to why not all patients with hyperuricemia and monosodium urate crystal formation will develop an inflammatory process. So how prevalent is this condition in general population and do you see a rise in the trend as far as over the past few decades is concerned? Yes, over the last few decades we have seen a more than four times rise in the prevalence in the general population and most rheumatologists in the west would consider gout arthritis as the commonest form of inflammatory deforming arthritis. Whereas in India also it is a common problem but probably because we are still a developing country and the problem is one of plenty where there is a lot of maybe dietary indiscretions and lifestyle indiscretions which result in gout but we are also seeing a rising trend in patients with gout arthritis and hyperuricemia. So when we talk about gout what are the typical clinical manifestations and when we have to differentiate it from the other forms of inflammatory arthritis what is certain peculiar features of this particular type of arthritis that students should know? So that is a very, very important question and a very question which is close to the heart of the rheumatologist and something which probably every MEBS graduate should know about. So the commonest forms of inflammatory arthritis what we see in India are rheumatoid arthritis, these ponlo arthritis subgroup and gout arthritis and many times there is a confusion as regards as what constitutes gout arthritis? The gold standard for diagnosis of gout would be actually aspiration of the sinusoidal fluid and demonstration of monosodium urate crystals, however this is not always feasible and many times the clinical presentation is adequate for us to distinguish between rheumatoid arthritis or a spondoidal arthritis and gout arthritis. So I will begin with the gout arthritis presentation especially in the beginning when the first few attacks take place the patient usually complains of severe painful joint predominantly involving the lower limb joints and classically the first MTP joint involvement, the metatarsophalangell joint involvement is known as Pudagra and the patient it usually wakes up the patient at night and the patient has severe pain to the extent that he says that even the air from the fan above is causing him pain and that the skin overlying the joint also becomes red and green and the entire peak of the pain results within the first 24 hours. Contrast this with rheumatoid arthritis, the pain is more insidious in onset, it takes a much longer time to reach its peak, it is additive in nature. Especially speaking in the initial beginning of gout the pain is likely to remain localized to this first MTP joint it may also sometimes present with midfoot involvement and the ankle involvement. However polyarthritis form of presentation is unlikely in the beginning but if the patient has come to you on after multiple episodes or attacks it is possible that even a polyarticular form of gout and persistent joint inflammation may take place. Another important characteristic of gout arthritis is that the pain would resolve in about two weeks time. It is very unlikely to rather it is nearly impossible that the pain has persisted so the episodes of arthritis are episodic and the interictal period between the episode the patient is actually asymptomatic till he progresses and develops chronic gout arthritis with a form of chronic cyanobitis which may take place and that would be more difficult to distinguish. However if a careful history is taken we would realize that in the beginning the pain was limited to a particular joint or a few joints especially the lower limbs and would reach a peak within 24 hours and this also forms a part of the classification criteria which is there. However I will probably discuss classification criteria later and subsequent attacks progressive attacks without appropriate intervention in management leads to the states of chronic gout arthritis and TOEFI formation which is subsequent stages without if we do not intervene. So we understand gout is a very traumatic condition often a mono arthritis or oligo arthritis very uncommonly chronic and that also would happen only subsequent to the initial episodes of mono arthritis or oligo arthritis. So I think clinically it would be difficult to miss this if a person is aware of a condition like this and that is what makes it important for the students to understand and be aware and I have a high index of suspicion for this kind of arthritis. Yes absolutely and if I may add one of the differential diagnosis to gout arthritis would obviously be a septic arthritis and they are not mutually exclusive conditions also because the skin and skin over the underlying joint may become red, inflamed and angry which is very uncharacteristic for rheumatoid arthritis or spondyl arthritis and so a septic arthritis will be a differential diagnosis and so all the students and doctors should be aware that one of the differential would be septic arthritis and a joint aspiration might be mandated. Okay so I think we have covered this aspect as well but if you could just put it in two or three lines how do you eventually confirm the diagnosis after having had that clinical suspicion of gout? Yes this is a very good question because finally the gold standard for diagnosis is aspiration of the sinusoidal fluid demonstration of monosodium urate crystals. These crystals can be screened even in light microscopy but it is difficult to distinguish them from the other crystal of arthropathy but if your clinical suspicion and your clinical history and examination is highly indicative of gout so when I say highly indicative this also means that typical patient would be a middle aged male patient who may have other metabolic risk factors in the form of obesity, diabetes, hypertension, cardiovascular disease and who presents with an acute onset severely inflamed metatarsal phalingel joint or maybe an ankle or mid foot joint and in this patient we may not really need an aspiration but the gold standard is an aspiration of the sinusoidal fluid demonstration of monosodium urate crystals on light microscopy and of course the gold standard is polarizing microscopy where we can demonstrate negatively biofringent crystals. So when I say negatively biofringent again it sounds like a lot of physics but in very simple terms it means that the crystals are arranged in such a manner that they have to refractive in dices and they would appear very bright in a polarizing microscope. Okay so having got the clinical suspicion and confirmed the diagnosis how do you go about counseling these patients as far as the non-pharmacological aspects of management like lifestyle modification, diet etc is concerned. Right again a very very important aspect and question and many of us even in the medical fraternity feel that the acute episode is due to something or due to a momentary indiscretion. This is something which we need to understand that the urate levels is a function of the intrinsic urate production due to urine metabolism and balanced exactly by the urate excretion by the body. So the urate levels are entwined with the metabolic issue. So actually we have two distinct pathological processes intersecting with each other. We have a metabolic issue which is hyperuricemia and increased urate levels and we have an inflammatory process and the metabolic aspect of it actually could be an adaptive process and at what point it becomes a pathologic process is what is interesting. And what I would like to highlight is that the dietary aspect and the lifestyle modification is a long term commitment that each and every patient and probably even before you become a patient that you should undertake because the hyperuricemia is inextricably intertwined with the metabolic syndrome with features such as obesity, hypertension, dyslipidemia and of course cardiovascular diseases. So essentially what are modifiable in these aspects? It is the behavioral aspect in terms of obesity. So we do need to lose weight and it has been very clearly demonstrated that weight loss results in sustained lower syrupy acid levels and sustained lower episodes of gout arthritis if at all. So what I am propagating is that patients should take on dietary modifications on a long term basis not as a quick fix. It does not work that way. The total contribution of diet to a single episode of gout is actually only very small it is only one third of the trigger that may have taken place. So various other factors which have accumulated over a period of time would result in this increased syrupy acid and further a purine load in terms of dietary indiscretion like eating a lot of bread meat or sugary drinks would precipitate that gouty episode. So it would not work to just have a fad and decrease the intake of sugary intake for a short period of time and then go back to behavioral pattern which would be contributing to the metabolic syndrome and which would finally result in worsening of the gout in terms of frequency and intensity of the drugs. What about specific fruits and vegetables and what are the advice on that aspect? So the dietary advice like I said the importance of it is that it should be a long term commitment red meat, red wine are clearly complete no and if it is not possible to keep a complete no it should be reduced then even the various dietary aspects like the dash diet and the keto diet which is there. Now in these two diets the keto diet I must state that actually increases the UCRWC acid level whereas the dash diet where which encourages increase in low fat dairy products and increase intake of fruits and nuts helps. The list of vegetables, fruits and the things which may include even such things as tomatoes is very extensive and may not really be practicable to exclude all of them from your diet. So a broader aspect a zoom out aspect where you see you can control the more important aspects like decreasing your red meat intake and decreasing the calorie intake is what I would recommend. Of course the specifics there is a whole list which would be available but might be difficult to practice and here I must say also staying well hydrated is a part of it because the crystallization of the Uric acid crystals take place because of lower temperature and lower pH and why it occurs in the first MTP joint because it is a very peripheral joint temperatures are lower and during night the fluid might go back into the intravascular compartment which leads to a local dehydration and probably precipitation of the crystals there. So on a larger scale what I would advise is that patients should cut out red meat, red alcohol, degrees, dietary fat levels and that is what I would advise but cutting out everything would not really be visible. So it is very dramatic the way the patients present and they are in agony so I think the best difference that you can make to managing such patients is to manage the acute attack well. So I want you to make it very clear to the students what are the drugs that are used for managing an acute attack and it would be nice if you could tell them how they each of them work and how effective they are and then we will go on to the long term management. So again yes this is a very important aspect of the management of an acute attack of gout arthritis. So the question is very specific it is for an acute attack of gout arthritis but I would not be able to answer this entirely without addressing a rather myth which exists that nearly every hyperurethemia is equal to a gout or an acute attack of gout arthritis. This is not true because many times it may be a different issue and the uric acid level above 6.8 milligram percent and between 10 milligram percent is considered by many rheumatologists without an acute episode as asymptomatic hyperurethemia. When I say asymptomatic there are a lot of patients who will come into the OPD and who say they have lots of aches and pains and polyarthralgia they do not qualify as gout arthritis. It is very important to understand and treating you do not have to treat these pains as symptomatic gout arthritis. So I will come back to the original question an acute attack of gout arthritis. So we have multiple modalities this is literally one of the most painful situations the patient is cringing in pain and he needs relief urgently. So the modalities which we have which we can use are non-steroidal anti-inflammatory drugs very easily available not very difficult to access and do not have many contraindications but however a raised serum creatinine level or in the background of a renal failure patient or heart failure patient we will need to exercise caution and they would not be the first line of drugs. In most other patients they can be used as the first line of drugs for example we can use naproxen or hindomethacin. Naproxen can be used at 500 milligrams twice daily till the acute episode of gout resolves and in the past there was also a school of thought which believed that we should definitely not start any urette lowering therapy because the urette lowering therapy which we will come to subsequently can precipitate an acute episode of gout. However if we are giving prophylaxis we do not need to worry about that. So if the patient has a contraindication for non-steroidal anti-inflammatory drugs then we can use colchicin which is again which acts on the microtubules and has an anti-inflammatory action. So the present day belief is that even a low dose of colchicin like one milligram followed one hour later by another one milligram and subsequently 0.5 milligrams once daily till the acute episode subsides is adequate. The only precautions are that colchicin can result in diarrhea and any on the first sign of diarrhea colchicin should be withdrawn. Now if we have further contraindications and the patient is unable to tolerate colchicin and NSAID then we can use systemic corticosteroids. This can be in the form of oral corticosteroids or it can be in the form of injectable corticosteroids or intraarticular corticosteroids. So oral corticosteroids we can use about 35 milligrams of prednisolone which is equivalent to about 500 milligram BDF naproxen or endomethysin 50 milligrams three times daily these would be equivalent doses. So we can give oral prednisolone 35 milligrams OD for a short course even lasting up to 7 to 15 days when we do not need to taper off steroids we can stop the steroids. Now if this also doesn't work then we also have the option of injecting the affected joint with an intraarticular long acting preparation of steroids such as depot withdrawal and which would have a quick effect and give the patient a lot of relief. There is also the availability of a single dose of adrenocortico trophic hormone which also would work which would act by the melanocortin 3 receptor but I must be honest even I have not used that but it is there in the textbooks and it can be used effectively if there are contraindications to NSAID, colchicin and to oral or systemic corticosteroids adrenocortico trophic hormone remains a method to deal with an acute episode of GAUT and what is happening new in the acute episodes of GAUT we can use even interleukin 1 beta blockers such as monoclonal antibodies like anachronoma it has been it has got the approval FDA approval and is being used and I believe it is even available in India now Novartis is the company which produces it Anakindra also another interleukin 1 blocker but probably less effective ok so with these options available I think one can address and I think most of the acute episodes would get treated by at least one of these agents now we know that this disease happens in episodes and it is very important to put the patient on some kind of long term therapy so that these episodes do not occur or if they occur they are of minor type so what are the long term management options to be followed yes with that we will come to the ureth lowering therapy because we should not confuse the acute management of GAUT arthritis episode with the long term goal of decreasing the serum ureth levels to prevent the precipitation of uric acid crystals these are we managing an acute episode of GAUT and so here I must mention with no malice to anyone in particular we have seen a lot of patients being started on ureth lowering therapy by ureth lowering therapy there are a number of classes of drugs that in oxidase inhibitors being the commonest namely Febuzostat and allopurinol being started in acute episodes of GAUT here I would like to reemphasize that a sudden lowering of ureth sometimes actually precipitates an acute episode of GAUT arthritis and it is not a treatment for the inflammatory process so I go back to what I said initially it is an intersection of two pathologic process one is metabolic and one is an inflammatory process and the address of the inflammatory process is kind of diverse and distinct from the metabolic process so the long term management is actually to address the metabolic process and I will not delve into the management of the metabolic syndrome back because that is a bit out of the mandate for today my main mandate would be to convey how do we manage lowering of serum uric acid levels to what level should we manage it and like I said serum uric crystals would crystallize beyond can crystallize beyond a concentration of 6.8 milligram percent so the target level when we start ureth loading therapy is 6 milligram percent for those patients who have a single episode of GAUT or minor forms of GAUT and this part whether it is minor or major is left a little bit to the discretion of the physician but in more simpler and objective terms if a patient has TOFI or has a chronic form of chronic inflammatory form of GAUT arthritis that is persistent joint inflammation or even deformities and damage to the joints then they would be classified as most severe forms of GAUT arthritis so these most severe forms of GAUT arthritis the target serum uric acid is 5 milligram percent and so how do we go about decreasing so you have multiple methods I mean multiple classes of drugs one of them is these antinoxidase inhibitors which I have already mentioned they prevent the formation they are they prevent the formation of ureth so allocornal is actually the first drug of choice and you should start just with about 100 milligrams per day especially in those who do not have any decreased creatinine clearance for those who have any decreased creatinine clearance again a myth is that allocornal is completely contraindicated this is false we can start at 50 milligram per day and gradually increase by 50 milligrams every two weeks to bring it up to the maximum possible dose the maximum dose is about 800 milligrams per day and this is titrated against the serum uric acid. Febuzostat is one of the newer drugs which has come in again as antinoxidase inhibitor maximum dose is 120 milligrams per day we usually will start at 40 milligrams per day the many of some of us rheumatologists would not be very fond of Febuzostat because there was a trial where it demonstrated increase in cardiovascular mortality and there is a belief that it increases all cause mortality so Febuzostat would not be the first choice that I would prescribe but however this can this is opinion based issue can be addressed then there are uricosuric agents which would promote excretion of uric acid so we have Probenicin, Benz, Bromarone and Lesinuride. Lesinuride has not come into America and has no FDA approval and cannot be used as an independent uric lowering therapy it has to be always combined with a xanthinoxidase inhibitor. What about Rasbure case what is its role in managing patients with hyperibusine? So Rasbure case in the situation that we are not able to achieve the serum uric levels in spite of using these available classes of drugs we can use Rasbure case it is essentially a recombinant uricase enzyme which would convert uric acid into allantoin which can be excreted. Fine I think we have had a very comprehensive discussion right from starting the basics to the management of long term chronic therapy. So coming towards the end are there any recent advances do we have any new molecules in the offering that we can be expecting to have in the near future? Yes sir basically I already mentioned two molecules canacidimab and anacindamab has already been approved it is US FDA approved in the use of acute gouty arthritis and I would not call it very new but what will probably come up in the future is drugs which are going to help which are uricosiric in nature arhalofinate which is a PPR gamma ligand that promotes uric acid secretion by urat 1 inhibition and this is likely to come up in the future in the management of serum uric levels and we also have very new rad this is a potent urate 1 inhibitor again which can be combined with xapenthenoxidase inhibitors and likely we are likely to see this in the future and here I must mention it is not just the novel treatments there is a movement to reclassify gout as an auto inflammatory syndrome. So we may be looking at that aspect also where we manage the inflammatory zones drugs which affect the inflammatory zones are probably what we would look at and at the present moment the there is no consensus whether asymptomatic hyperurusemia should be treated or not but in the future it is likely that we will develop consensus towards treating asymptomatic hyperurusemia patients also. So I think we have come to the end of this podcast it is been very comprehensive it is a topic of great clinical relevance and I think students need to understand it better because I think if you really want to make a difference in the patient's life we need to manage the acute attacks better we need to prevent the acute attacks and we need to manage the chronic management or long term suppression also better. I think with this we conclude I would request the students to go through the podcast come back to us with their feedback any doubts or clarification that they would have we would address it to the community and we must thank you for having spared your time and I am sure the students have benefited a great deal. Thank you. Thank you.