Rheumatology

SGLT2 Inhibitors Begin to Show Therapeutic Potential in Rheumatology

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Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.

“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.

photo of Dr. April Jorge
Dr April Jorge Credit: Harvard Medical School

In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr Jorge and Dr Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.

There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.

But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr Yokose said.

Research Hints at Gout-Busting Potential

The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”

Dr Chio Yokose

As Dr Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”

These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.

Dr Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.

A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).

What about recurrent gout? In a 2023 study, Dr Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).

“This finding requires further replication in other populations and compared to other drugs,” Dr Yokose cautioned.

Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.

Lower Urate Levels and Less Inflammation Could Be Key

How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr Yokose said, but researchers often excluded patients with gout.

For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs 4.2% of sulfonylurea initiators.

“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”

Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”

In Lupus, Findings Are More Mixed

Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr Jorge of Massachusetts General Hospital and Harvard Medical School. However, ” one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.

Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).

“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”

Dr Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”

However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant…early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.

“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.

Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr Jorge added.

As for mechanism, Dr Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”

Side Effects and Cost: Where Do They Fit In?

According to Dr Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.

Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.

In Dr Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.

She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”

Dr Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”

As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.

“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr Yokose said.

She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”

In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”

As for prescribing the drugs in lupus now, Dr Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”

As for gout, Dr Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.

“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”

Osteoporosis ‘largely ignored’ in older men

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Less than 3% of older men who had experienced an osteoporosis-related fracture had been properly diagnosed and treated, according to findings presented at ACR Convergence 2020.

“Osteoporosis is a debilitating disease and it carries with it significant morbidity and mortality,” Jeffrey R. Curtis, MD, MS, MPH, professor of medicine in the division of immunology and rheumatology at the University of Alabama at Birmingham, said in a press conference. “But it is often misconstrued as a disease that really mainly, if not only, affects Caucasian women, which is, in fact, not the case.”

Fracture hip x-ray 2019
“It is quite clear from these results that men are being largely ignored when it comes to osteoporosis,” Jeffrey R. Curtis, MD, MS, MPH, said in a press conference. Source: Adobe Stock

Some 20% to 25% of osteoporosis-related fractures occur in men, according to Curtis. “The idea here was to figure out [whether] people recognize the risk factors of fractures, falls and the like and doing something about it ahead of time to try to mitigate that risk,” Curtis said.

The group investigated a cohort of 9,876 Medicare fee-for-service male beneficiaries who had experienced a closed fragility or osteoporosis-related fracture over the period between Jan. 1, 2010 and Sept. 30, 2014.

Jeffrey R. Curtis

Eligible participants were aged older than 65 years, had ongoing enrollment in Medicare fee-for-service plans that included parts A, B, D-C medical and pharmacy benefits for a full year prior to the index date and at least one month after.

Baseline data showed that 61% of the cohort was 75 years or older, while 90.3% of participants were white.

Bone mineral density testing with dual energy X-ray absorptiometry in the 2 years before fracture had been performed in fewer than 6% of participants. Similarly, 92.8% of patients with a qualifying fracture did not have a claim for a diagnosis or treatment of osteoporosis at baseline, according to the results.

Curtis and colleagues grouped these older men who had experienced an osteoporosis-related fracture into one of four groups: those who had been diagnosed, those who had been treated, those who had been both diagnosed and treated and those who had neither been diagnosed nor treated.

Results showed that 2.8% were diagnosed but not treated. Only 2.3% were treated but not diagnosed, an outcome Curtis described as “only slightly better than the reverse.”

Overall, just 2.1% of these individuals with osteoporotic fractures were both diagnosed and treated accordingly.

Other findings showed that a history of musculoskeletal pain was reported in 62.8% of the group, while 48.5% had a history of opioid use in the year before their index fracture.

Spine fractures occurred in 31.0% of patients, while 27.9% experienced hip fractures and 9.8% had ankle fractures.

DXA scans declined between 2012 and 2014 among patients aged 65-69 years (from 6.3% to 5.5%), those aged 70-74 years (from 4.7% to 4.0%) and for those aged 75 years or older (from 6.0% to 4.3%). “The underutilization of DXA testing was actually getting a bit worse, not better, over time,” Curtis said.

A further distressing result, for Curtis, was that once patients had been properly diagnosed, the treatment patterns were “not much better.” Just 12% of patients underwent proper BMD testing in the year following their fracture. “Only 9% were treated with an osteoporosis medication,” he said of this period, as well.

“Importantly, about 7% of the men in this cohort went on to have one or more fractures in the next year,” Curtis added.

Curtis attempted to explain the findings. One issue is that clinicians are failing to recognize fractures and falls and aren’t screening men appropriately. Another is the “silent” nature of the disease, meaning that it can progress largely unnoticed.

Ongoing prevention is also problematic, according to Curtis. “Even if they break bones, they may just not know enough how to prevent their next fracture,” he said.

“It is quite clear from these results that men are being largely ignored when it comes to osteoporosis,” Curtis concluded.

Sjögren’s syndrome ‘not curable, but certainly treatable’ with available therapies

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 Although not currently curable, the symptoms of Sjögren’s syndrome, like dry eyes and dry mouth, can be effectively managed using a variety of therapies, said a speaker said at the Congress of Clinical Rheumatology East 2022 meeting.

“There are no curative therapies, but we certainly have the tools to palliate these symptoms and prevent complications,” Frederick B. Vivino, MD, MS, of Penn Presbyterian Medical Center, in Philadelphia, said in his presentation.

Eye with cracking, dry skin around it.
“Sjogren’s syndrome, unfortunately, is not curable but it is certainly treatable,” Fredrick B. Vivino, MD, MS, told attendees. Source: Adobe Stock

Vivino noted that although dry eyes and mouth are consistently the most important issues reported by patients, there are options to treat the full range of Sjögren’s manifestations, including lung disease.

Regarding the “all-important” dry eyes, Vivino suggested that multiple options are available, depending on the severity of the complication. These include anti-inflammatory drops, omega-3 fatty acids, punctal plugs and moisture chamber glasses. Steroid eye drops may also be used in certain cases.

“But, of course, after a month, the incidence of glaucoma and cataracts caused by steroids tends to go up,” Vivino said.

Autologous serum tears created from the patient’s own blood are available in severe cases.

“Sometimes that provides the best relief of all,” Vivino said. However, he noted that most insurance companies will not pay for this treatment.

When patients develop eye infections, azithromycin drops may be used, along with antibiotic ointments such as 0.5% erythromycin ocular ointment or oral doxycycline.

“The issue here is that because Sjögren’s is a chronic condition, these infections may recur,” Vivino said.

There can be many causes of Sjögren’s-associated dry mouth, but Vivino stressed that many medications can also cause this complication.

“Sometimes a common-sense approach is to work with primary care and other clinicians to eliminate as many drugs as possible,” he said.

For patients with mild dry mouth, gustatory or masticatory stimulus with sugar-free lozenges is a “perfectly adequate” approach, according to Vivino. As severity increases, secretagogues are an effective option.

“The most important thing is to ignore the manufacturers’ directions for dosing secretagogues,” Vivino said, noting that these recommendations are often too aggressive. “Start low and go slow.”

For still more severe cases, pilocarpine 5 mg or cevimeline 30 mg after dinner may have utility, he added.

“When you try this therapeutic approach, make sure you try both [drugs] before you give up,” Vivino said.

Turning to systemic manifestations of Sjögren’s syndrome, Vivino noted that interstitial lung disease can warrant immediate attention.

“Over the last several years, it has become apparent that ILD has become a source of not only morbidity, but mortality in Sjögren’s,” he said.

That said, there is hope.

“ILD in Sjögren’s is treatable and even curable,” Vivino said. “I would like you to remember that.”

Steroids are the first-line therapy for these patients.

“Patients are almost always steroid responsive, which is very gratifying,” Vivino said.

Next in line are mycophenolate mofetil or azathioprine. If these drugs fail and reassessment is necessary, rituximab (Rituxan, Genentech) or a calcineurin inhibitor is recommended.

“If it is in the fibrotic stage, it is nintedanib (Ofev, Boehringer Ingelheim),” he said.

Vivino urged clinicians to research the full spectrum of complications that can occur in patients with this condition.

“Sjögren’s syndrome, unfortunately, is not curable but it is certainly treatable,” he said. “These patients have syndromes that are worthy of your time and effort as rheumatologists.”

Q & A: Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism

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Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism (EULAR) spoke about the organisation’s ongoing projects and what’s new in rheumatology.

Radha Chitale spoke with Professor Johannes W.J. Bijlsma, president of the European League Against Rheumatism (EULAR), about the organisation’s ongoing projects and what’s new in rheumatology. 

What initiatives within EULAR have been working well and what would you like to continue during your tenure?

I’ve been working with education for quite some time and we’ve produced a lot of materials. We’re in the process of formalizing them into a virtual School of Rheumatology with continuing education materials not only for physicians but for health professionals and patients.

The School of Rheumatology would have different classrooms for different people. For patients the priority is to have lay summaries of all the important EULAR recommendations and publications. For health professionals, we’d like to gather different subspecialties like occupational therapy and physical therapy and see what their activities should be and how to certify them. For medical students, we’d like to establish the minimum things every medical student should know about rheumatology and make a primer available on the Internet.

What EULAR projects are planned for the coming year?

Another important thing to have would be more awareness for rheumatic disease in the public and a greater possibility for patients to visit a health professional.

We know that the most gain you can get in treating rheumatism is not only in the first year but in the first months, and improving the knowledge of general physicians and health professionals about rheumatic disease, and who they should refer patients to, will help let those patients into practices earlier on.

Next year, for the 70th meeting of EULAR in Madrid, Spain, we will launch a “time is joint” campaign, which says that if you make an early RA diagnosis, you can preserve the joints. But we also want to help people with joint problems to have good an easy access to people who can help them – a “joint over time” approach. I think that will keep me quite busy for the coming years.

What have been the most exciting developments in rheumatology in the last few years, and what will be the major themes in treatment and care moving forward?

More early diagnosis, which has been possible with new imaging and lab techniques, and also more personalized treatment. For the individual patient, checking them more often than we did in the past to see if they are doing well and adapting treatment modalities accordingly. We have more drugs, biologics and others, and so have more possibilities to act on those findings and improve patients at that moment.

We see different mechanisms, not just for RA, but for spondyloarthritis and there is a start in the fields of osteoarthritis and osteoporosis of new ways of treatment based on increased knowledge of the pathogenesis and the possibility to make targeted therapies. There’s been a lot of new drug development in the last 5 years, for example, new pathways targeting interleukin-17, that will benefit a lot of new patients.

But making the most optimal use of existing drugs and combinations of existing drugs before we go to other drugs is also important. Ten to 15 years ago we used only 7.5 mg of methotrexate per week because we were afraid to increase the dose. But when we started increasing the dose, instead of getting 20 percent of patients in good condition, we got 70 percent. You can gain a lot by looking at how patients are responding and adapting the dose.

Gout Guidelines From ACR Include New Drugs, Diet.

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New gout guidelines from the American College of Rheumatology are meant to improve gout management by providing clinicians with clear, readily implemented guidance on urate-lowering therapy (including diet and lifestyle changes), chronic tophaceous gouty arthropathy (CTGA), analgesic and antiinflammatory management of acute gouty arthritis, and drug prophylaxis of acute attacks.

The guidelines, reported in the October issue of Arthritis Care & Research in two parts, and include guidance on the new drugs febuxostat and pegloticase, recently approved for gout management and not yet addressed in the European League Against Rheumatism or British Society for Rheumatology gout guidelines.

Senior author Robert Terkeltaub, MD, told Medscape Medical News,”This is the first time in the 78-year history of ACR that there have been guidelines for the management of gout. This indicates how seriously people in rheumatology take this and how common the problem has become, with more than 8 million cases in the US, affecting 3.9% of adults. What we have here is a disease that is very well understood but ridiculously poorly managed.” Dr. Terkeltaub is chief of rheumatology at the Veterans Affairs Medical Center in San Diego, California, and professor of medicine and associate division director at the University of California in San Diego.

Old Disease, New Management

Part 1 of the guidelines focuses on hyperuricemia and CTGA. The top recommendation is for more intensive education of patients on diet, lifestyle choices, treatment objectives, and management of concomitant diseases; this includes recommendations on specific dietary items to encourage, limit, and avoid.

“We provide a comorbidity check-list for the clinician that I expect will be very useful in day-to-day practice,” Dr. Terkeltaub said. “We have also provided a cohesive set of diet and lifestyle recommendations. This has been a problem because of the fact and fiction mixed in to diet and lifestyle approaches to gout. The guideline is an advance because it provides a more actionable set of recommendations for physicians to talk about with their patients.”

Table. Comorbidity Checklist for Patients with Gout

Obesity, dietary factors
Excessive alcohol intake
History of urolithiasis
Chronic kidney disease
Potential genetic or acquired causes of uric acid overproduction (inborn error of purine metabolism, psoriasis, myeloproliferative or lymphoproliferative disease)
Lead intoxication

 

Dr. Terkeltaub added, “Many patients feel that diet and moderation alone should be sufficient to manage their gout. Diet is important, but what is really important is getting the serum urate to a target appropriate for that patient. At a bare minimum it should be < 6 mg/dL. In clinical practice the serum uric acid level is no longer part of the routine metabolic panel, but it is inexpensive and should be monitored regularly in gout patients.”

Dr. Terkeltaub noted that dietary or alcohol excess can increase uric acid and trigger acute gout attacks in susceptible individuals, but he said that dietary restrictions alone may not reduce serum urate levels enough to prevent joint damage in gout patients.

“The average age gout patient in our clinical trials has a serum uric acid level between 9.5 and 10 mg/dL. Even ideal diet and alcohol intake will likely lower that by only 10% to 15%, which will not bring the typical gout patient to a serum uric acid of 6 mg/dL. Often people need urate-lowering drugs to get them to the target level and keep them there. People feel that if they have fewer gout attacks, they are better, but the disease will progress unless serum uric acid is reduced to a level where deposits of urate crystals in the joint tissues will disappear,” Dr. Terkeltaub said.

Start Low, Go Slow With Allopurinol

The ACR guidelines recommend treating patients with a xanthine oxidase inhibitor, such as allopurinol, as the first-line pharmacologic urate-lowering therapy approach. The recommended goal is to reduce serum urate to less than 6 mg/dL, and the initial allopurinol dosage should be no greater than 100 mg/d, the guidelines say. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with chronic kidney disease.

“Clinicians often start allopurinol at doses that are too high but maintain allopurinol at doses that are too low,” Dr. Terkeltaub said. “We give specific guidance on start low, go slow dose escalation.”

To avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For CTGA, the guidelines recommend combination therapy, with 1 xanthine oxidase inhibitor (allopurinol or febuxostat) and 1 uricosuric agent, when target urate levels are not achieved. They advise using probenecid as an alternative first-line urate-lowering drug in the setting of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (except in patients with creatinine clearance below 50 mL/min). They also recommend pegloticase in patients with severe gout disease who do not respond to standard, appropriately dosed urate-lowering therapy.

“We provide guidance for dose-escalation of urate-lowering therapy for specific case scenarios of mild, moderate, and severe disease including for patients with destructive joint disease that is chronic to their gout. These provide ways to assess the patient in an office setting on clinical findings alone, with serum uric acid. Pictorial representation of most severe patients should help identify who needs more intensive uric acid-lowering therapy,” Dr. Terkeltaub said.

Acute Gout Requires Prompt Treatment

Part 2 of the guidelines covers therapy and prophylactic antiinflammatory treatment for acute gouty arthritis. These guidelines recommend initiating pharmacologic therapy within 24 hours of onset of acute gouty arthritis attack while continuing urate-lower therapy without interruption.

Nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are the recommended first-line treatment for acute gout, and combinations of these medications can be used for severe or unresponsive cases.

To prevent the acute gout flares that may accompany the early stages of urate-lowering therapy, the guidelines recommend oral colchicine or low-dose NSAIDs as long as there is no medical contraindication or lack of tolerance.

Dr. Terkeltaub advised caution with colchicine dosing. “One of the major problems in quality of care is that people were getting drowned in colchicine for acute gout. We assessed the evidence and decided to go with the FDA [Food and Drug Administration]-approved regimen of low-dose colchicine for early acute gout flare. That is a major recommendation. When people get drowned in high doses of colchicine for a long time for acute gout, the rate of adverse events is quite high.”

The recommendations were prepared during a 2-year project by an ACR task force panel that included 7 rheumatologists, 2 primary care physicians, a nephrologist, and a patient representative. The draft guidelines then went through 3 rounds of peer review, Dr. Terkeltaub said.

“I’d like to see better education of physicians and other primary caregivers, including nurse practitioners and physician assistants, and then better education of gout patients. If we only accomplish that, we’ll have accomplished a lot. There has been a systematic failure of both quality of care and patient education in gout,” Dr. Terkeltaub said.

Doug Campos-Outcalt, MD, scientific analyst for the American Academy of Family Physicians, reviewed the new guidelines for Medscape Medical News. Dr. Capos-Outcalt is chair of the Department of Family Medicine at the University of Arizona College of Medicine in Phoenix.

Dr. Campos-Outcalt said, “This is a reasonable, limited number of guidelines that are implementable. You don’t like to see guidelines that have 50 recommendations. The ACR guidelines also present, from a family physician perspective, no major changes in standard-of-care.” However, Dr. Campos-Outcalt suggested that a broader effort to disseminate the guidelines to primary care physicians will be needed because few of them regularly read the journal in which the guidelines appear.

Dr. Campos-Outcalt told Medscape Medical News that the guidelines seem reasonable but that before being influenced by them, he would like to take a closer look at the level of evidence each recommendation is based on. “We don’t like to see recommendations based on low-level evidence,” he said. Only about 20% of the ACR recommendations were based on top-quality “level A” evidence (supported by more than 1 randomized clinical trial or meta-analysis). About half of the recommendations were based on level C evidence (consensus opinion of experts, case studies, or standard of care).

Source: Mescape.com