Results from the MIRROR RCT trial, presented at the 2022 American Society of Nephrology’s Kidney Week demonstrate that estimated glomerular filtration rate (eGFR) did not decrease after oral methotrexate initiation in combination therapy with pegloticase.1 These findings suggest that combination therapy with methotrexate did not negatively impact renal function in MIRROR RCT trial participants.


 

Advanced disease develops in approximately 15% of patients with gout2 and is characterized by subcutaneous nodules composed of monosodium urate (tophi), unremitting articular inflammation, and potential joint erosion and deformity.

Patients with chronic kidney disease (CKD) have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes urate, and efficacy is not impacted by CKD stage. Immunomodulator combination therapy with pegloticase has improved treatment response rates over phase 3 monotherapy trials by attenuating anti-drug antibodies. The MIRROR RCT trial met its primary endpoint treating uncontrolled gout in renal insufficiency patients with pegloticase and methotrexate.3 The updated data presented at Kidney Week  by Abdul Abdellatif, MD, FASN, nephrologist at Baylor College of Medicine and at CLS Health, showed increased urate-lowering response rate (71.0% vs 38.5% during month 6) and lower infusion reaction rate (4% vs 31%) in patients who received methotrexate over placebo in combination with pegloticase. In particular, the investigators measured eGFR changes in MIRROR RCT from 100 patients randomized to pegloticase with methotrexate compared with 52 patients treated with pegloticase with placebo.

In both treatment arms, eGFRs were stable during methotrexate or placebo run-in period and after pegloticase initiation (Day 1). At week 24, eGFR had increased mildly in both groups, with a difference of  +5.3 ± 1.3 and +4.3 ± 2.3ml/min/1.73m2 in the methotrexate (N=70; 69 responders) and placebo (N=19; 19 responders) groups, respectively, which was not significant. There were no differences in effect between subgroups of patients characterized by eGFR less than 60 versus 60 or higher in either arm. The authors concluded that combination therapy with methotrexate was safe and effective for patients with and without pre-therapy eGFR less than 60ml/min/1.73m2; there was no evidence for negative impact on renal function in MIRROR RCT trial participants.

Physician’s Weekly spoke with study senior author Bradley Marder, MD.

 

PW: How should we interpret the new MIRROR RCT findings?

Dr. Marder: I would say that the era of using pegloticase monotherapy for patients is over. We found that you can get much better efficacy and much better safety using pegloticase with an immunomodulator medication like methotrexate. For patients with a kidney function that might not be able to tolerate methotrexate, physicians really need to look at other evidence for other immunomodulator medications like mycophenolate mofetil, which has also been studied to prevent the development of anti-drug antibodies.

Likewise, gout is not just a disease of intermittent inflammation in peripheral joints. Gout is a disease with which monosodium urate does not just crystallize in the joints, but in just about every body tissue. It is found in more than 80% of coronary arteries and thoracic aortas of patients with gout, and that illustrates the systemic and progressive nature of gout. Putting all the data together gives us an urgency to identify patients who have gout and to make sure they are treated effectively, whatever is needed.

What about patients who cannot tolerate methotrexate? 

The MIRROR RCT study was not in just patients with kidney transplants or with CKD, but basically for patients with all kidney diseases and uncontrolled gout. The inclusion criteria for that trial were that a participant had serum uric acid above 7 mg/dL, failure to achieve the treat-to-target goal of 6 mg/dL of uric acid on oral urate-lowering therapy, and some symptoms of gout, which could be two or more gout flares per year. In addition, we enrolled patients who were characterized by unresolving tophaceous disease, or with chronic gout with arthritis. All patients were randomized into the trial in a 2:1 format to either receive methotrexate 15 milligrams orally once a week or a placebo. We then studied the patients for a full year of IV pegloticase 8 mg every 2 weeks.

Notably in this trial, patients who had an eGFR less than 40 ml/min were excluded, not because you cannot use pegloticase in patients with CKD, but because there was an abundance of caution to use methotrexate in patients with chronic kidney disease. Methotrexate is is cleared by the kidney, and if you have chronic kidney disease, methotrexate concentrations can build up and cause a higher risk for either kidney injury or other kinds of adverse events due to the accumulation of the medicine. But there were a sizable number of patients—roughly one-third—who had mild-to-moderate chronic kidney disease, or eGFRs of 40-60 mL/min.

What is the take-home message of the presentation at Kidney Week?

The primary outcome data were reported at the EULAR congress this last summer. At Kidney Week, we wanted to focus on participants who had CKD.

In particular, we wanted to focus on the impact of pegloticase and methotrexate on patients’ kidney function and safety profile for those patients with CKD. New data presented were not just that the medication was effective for these patients, but that the use of pegloticase and methotrexate actually did not negatively impact these patients’ kidney function. We focused on eGFR levels before treatment, while they were in the run-in period with methotrexate, and for the 24 weeks of pegloticase therapy.

I always think of gout as being treated in two ways. One approach is addressing what to do with the inflammation and pain that patients experience. Often, that inflammation is treated with anti-inflammatory medications, which are often either not effective in patients with CKD or are contraindicated, such as with NSAIDs, for fear that they will negatively impact remaining kidney function. As a result, treating the inflammatory aspect of gout for most patients with moderate-to-severe CKD is limited to steroids. We would all agree that steroids are not a good medicine for patients over a prolonged period due to a high risk for side effects. For tackling inflammation, we do not really have a lot of options for patients with CKD.

For the chronic treatment of gout, which requires the lowering of serum uric acid levels, there also are few great options for patients with CKD. Diet can help reduce serum uric acid levels a bit but maybe 1-2 mg/dL. But the reason patients with CKD have high serum uric acid levels really does not have as much to do with diet but that their kidneys do not have sufficient function to excrete uric acid. Many medications to reduce serum urate levels are not effective or can be even dangerous to use in patients with CKD for fear that uric acid concentrations within the renal tubule will increase and cause crystallization of uric acid leading to kidney stone development.

Unfortunately, for patients with CKD, febuxostat and allopurinol remain their only choices. However, with febuxostat getting a black box warning due to cardiovascular events, real-world evidence has shown that allopurinol is primarily the only oral urate-lowering therapy that a lot of patients with CKD receive. All in all, that means that particularly for patients with CKD who have such a high prevalence of gout, there are not a lot of options available. I believe that this is why a lot of patients who end up with uncontrolled gout will require some kind of biologic therapy, like pegloticase.