The Management of Patients With Hyperuricemia vs Gout
In this video, James Matera, DO, discusses hyperuricemia vs gout, recent studies on the role of lubricin in patients with gout, and a case presentation of a 76-year-old woman with significant hyperuricemia, overt gout, and progressive chronic kidney disease. This is part three of a three-part video series.
For more gout content, visit the disease state hub.
James Matera, DO: Good afternoon. This is Dr. James Matera here. I'm the Senior Vice President for Medical Affairs and Chief Medical Officer at CentraState Medical Center in Freehold, New Jersey, and I'm happy to be talking a little bit about gout and hyperuricemia today for our audience.
Thanks for joining us for our third video in this series. Here I'm going to talk a little bit about hyperuricemia versus gout. Hyperuricemia. Let's remember that we have not had substantial evidence that have shown us that treatment of asymptomatic hyperuricemia is beneficial. We do, however, know that there are some meds and conditions that we should be aware of when it comes to being gout-friendly or gout-unfriendly. Certain things will exacerbate gout and other things are known to be less likely to do that. That's so important because when we go through this list, we're going to see a lot of these medications that are used in various conditions that we see on a daily basis.
A recent New England Journal article actually summarized this in a very good slide that showed the overall effects of hyperuricemia and gout that could lead to potential adverse effects, including cardiovascular disease and chronic kidney disease. If you think of this, everything that we've been seeing through the years is a continuum of trying to reduce cardiovascular risk factors, whether it be associated with chronic kidney disease or not. Along the way, hyperuricemia and gout do play a role. We certainly want to reduce cardiovascular risk factors.
When I look at that slide and I look at that New England Journal article, several points I want to make regarding this. Specific to treatment protocols, when we treat acute flares with the agents that we talked about in the second video, like Colchicine, and IL-1 inhibitors. Those tend to be a little bit more friendly and don't have a larger potential for adverse cardiovascular events.
When we talk about non-steroidals, the story's a little bit different. Non-steroidals can be shown to have some adverse effects on cardiovascular disease. We've known that for a long time. Again, it's shared decision-making and understanding what we want best for our patient in order to lessen their cardiovascular risk. Certainly, as we said in the other video, chronic kidney disease, we have to be very careful with non-steroidal anti-inflammatories. We need to use those with caution.
When you have patients who are on multiple medications for other disease conditions, and who haven't had patients, especially those with gout who have other conditions, particularly diabetes and hypertension, there are certain medications that could be gout-friendly or gout-unfriendly. We look at some that may have a potential benefit or certainly not an increased risk.
Agents such as calcium channel blockers, and fenofibrate. Interestingly enough, Losartan alone, not the ARBs, but Losartan alone as a standalone ARB, has been shown to be in that category. Metformin, and of course now the ever popular, one of my favorite agents, the SGLT2 inhibitors. I think we're just beginning to scratch the surface of what these agents can do as we look at the studies that come out, not just for kidney disease, heart disease, all these different things, and I think we're going to see so much more in the upcoming years on SGLT2 agents.
As far as potential adverse effects that may worsen gout or exacerbate hyperuricemia, here's where we have some of our ACE inhibitors and our ARBs, except for Losartan, and how important are those in managing cardiovascular disease and chronic kidney disease. Aspirin and beta blockers are also important, but yet may have a slight disadvantage when treating gout. Certainly, our loop diuretics, bring into the armamentarium, chronic congestive heart failure patients too.
I do want to take a moment to talk about some increasing research. It just came out this year and it came out of the University of California San Diego. It was an international study, but it looked at joint fluid in particular and deficiencies of proteins that could lead to gout and hyperuricemia. They also found that these deficiencies led to higher joint erosion and damage to the joints, which for our rheumatology counterparts is so, so important.
This protein that they found was called lubricin, and it's become a target now for some more therapeutic possibilities to stop the process in the joint fluid. What they ended up with is they looked at a case of a specific young woman with gout, and they found that there were deficiencies in several proteins in the joint fluid, but it was centered around this joint protein called lubricin. They then went and looked at other patients with atypical gout and found that in several patients there was a defect or a decrease or a deficiency of lubricin, which is basically a joint lubricant. Then they started to look at what that mechanism might be.
If you go back to mouse models of this, they found that preventing inflammation by using lubricin or having lubricin available in the joint, also lessened the whole cascade of the inflammatory process that we talked about in video one. I think this is a high area coming out now. This literature came out around March of this year from the UC San Diego group that was leading this international effort.
When we look at percentages of gout, what percentage of the population has hyperuricemia, what percentage of the population has actual gout? Let's go back to the first video. Recall the definitions that we talked about. Six milligrams per deciliter in women and seven milligrams per deciliter in men. When we look at the difference between hyperuricemia and overt gout, the literature shows that about 3.9% of the population will have actual gout, and up to 15% percent of the patients may have hyperuricemia when you use these definitions.
If we take that 15% that has hyperuricemia, about a third of them will go on to develop overt gout. This is a subgroup of patients that has to be followed. That is also going to increase with CKD. Remember, in CKD, you reduce the excretion of uric acid. It stays around longer, therefore it can cause all these things. We didn't really have time to talk about uric acid nephrolithiasis, but that also plays a role. It's very important to take hyperuricemia and overt gout very significantly and seriously.
I'd like to end these conversations with a little bit of a case study of a patient that I've had that really had significant hyperuricemia, overt gout, and progressive chronic kidney disease and what we did for this patient. This is a 76-year-old patient who I followed for years. Interesting family. She came to me because of a family history of tuberous sclerosis, where her offspring had a lot of the manifestations of tuberous sclerosis, including angiomyolipomas and chronic kidney disease as well as renal cell carcinoma.
This patient herself did not have overt tuberous sclerosis, but she did have factor V Leiden deficiency, which led to some hypercoagulable issues including chronic DVT. She had stage four chronic kidney disease with a creatinine up to 2.6. That did seem to fluctuate with her hyperuricemia. The higher her uric acid levels were, the higher the creatinine was. She had tubulointerstitial nephritis, likely related to gout hyperuricemia and hypertension.
She was coming along, but she started to have significant gout flares and it wasn't just located in the feet. It was located in the ankles, and the knees, and at one point her uric acid peaked at a level of about 13. Despite her chronic kidney disease, we started her on urate-lowering therapy. She couldn't take non-steroidals of course, so we used steroids in her for acute flares.
But I started her on Allopurinol, and unfortunately, she had a pretty significant allergic reaction to Allopurinol with massive skin reaction and leukopenia, so we had to discontinue that. We then tried Febuxostat, but she simply could not tolerate that. Ultimately, we were then left without any real significant ability to treat her hyperuricemia with any urate-lowering drugs.
I did not try Probenecid or the IL-1 inhibitors, but I did choose to use the injectable Pegloticase on her, and we dosed it at eight milligrams every two weeks. One of the things you have to be very careful about with the use of that drug is you can have precipitous drops in the uric acid levels, so you have to be very careful about that.
What we did find is that when I was able to get her urate levels down to seven, I never actually got her down to six, but I got her down from 13 to seven. Her symptoms, number one did improve. She had far less gout, and interestingly enough, her serum creatinine went from a peak of 2.6 down to about 2.0 and stayed that way through the use of Pegloticase. We now treat her every four weeks with a dose or an injection of this, and she's been doing very well on that.
I think that's an interesting case to show how shared decision-making ultimately needs to continue to look at that. I do want to make one comment though before we end on Febuxostat and the relative contraindications of cardiac disease. A black box warning came out in 2018 based on what was called the CARES trial. The CARES trial there showed that there was a higher incidence of cardiovascular events in patients who took Febuxostat, so that led to a black box warning. A lot of people then shied away from it and went back to Allopurinol, which ultimately proved to be the best move anyway.
But then what we call the FAST trial or Febuxostat versus Allopurinol Streamlined Trial came out, which didn't show those same things. The black box warning can be taken as it is, but again, shared decision-making. I think Febuxostat at this point is not always the first line of therapy. People do get concerned about the use of Allopurinol. I think again, treatment to target and dose adjustments are your key factors.
Well, I hope this talk on hyperuricemia and gout sheds a little bit of light on this disease. It is a chronic disease that we do need to pay attention to, and as I said, I think we're just in that phase where we're going to start to see some more benefits of our SGLT2 agents, and maybe next time we talk about this, they'll be part of the armamentarium as well.
Thank you for your attention and for listening.