Pegolase + methotrexate has become the "nemesis" of refractory gout?

*For medical professionals only to read and reference Gospel for patients with refractory gout ~ On March 7, 2022, Horizon Therapeutics announced that the U.
S.
Food and Drug Administration (FDA) has granted pegloticase (polyethylene glycol recombinant uricase) supplementation Priority review eligibility for a Biologics License Application (sBLA) seeking the use of pegloticase in combination with methotrexate to treat patients with uncontrolled gout
.

Pegloticase is a drug for the treatment of gout, which was approved by the FDA in 2010 for adults with chronic gout who are ineffective or intolerable to conventional treatment
.

 As soon as this news came out, the rheumatology community was full of joy.
Don't look at these two short sentences, but they contained important information
.

Is refractory gout really that tricky to treat? Gout is a crystal-related arthritis caused by the deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and/or decreased uric acid excretion, including acute gouty arthritis, chronic Tophi gout, gouty nephropathy,
etc.

Common acute attacks of gouty arthritis can generally be relieved by clinical use of non-steroidal anti-inflammatory drugs, colchicine or glucocorticoids
.

However, gout is often accompanied by hyperlipidemia, hypertension, type 2 diabetes, cardiovascular disease or co-infection, etc.
Some patients also have multiple tophi and gouty nephropathy throughout the body, which brings difficulties to clinical treatment
.

 In recent years, there are not a lot of studies on gout, but there are few reports on refractory gout [1]
.

The definition of refractory gout and its treatment principles are currently the focus of the majority of clinicians, and there is still no consensus at home and abroad so far
.

In recent years, a number of clinical studies on refractory gout have defined baseline serum uric acid (SUA) ≥480 μmol/L and at least one of the following clinical features as refractory gout: (1) In the past 18 months, gout attacks 3 (2) At least 1 tophi; (3) Persistent joint pain or joint damage associated with gout on imaging; (4) Allopurinol treatment is contraindicated, or the maximum dose of allopurinol is used for 3 months SUA is still not up to the standard at the time of the above
.

 There are many reasons for refractory gout, most of which are related to the following factors: 1.
Delayed uric acid-lowering therapy; 2.
Poor compliance of patients with uric acid-lowering therapy; 3.
Other reasons such as renal insufficiency and poor tolerance to uric acid-lowering drugs 4.
A small number of patients cannot achieve the SUA target even if they use sufficient therapeutic doses of drugs
.

 Therefore, there are still many problems in clinical refractory gout that need to be solved urgently
.

 The "new favorite" of gout - pegloticase refractory gout treatment principles mainly include two points: reducing the level of SUA and improving clinical symptoms.
In terms of reducing the level of SUA, pegloticase has a good effect on most refractory gout, and its pharmacokinetics Kinetics are not affected by age, gender, body weight, and creatinine clearance, and can be used for refractory gout that is ineffective with conventional uric acid-lowering therapy [2-3]
.

Pegloticase is produced by Escherichia coli and has been modified by genetic engineering to produce uricase
.

The cDNA encoding of uricase is based on mammalian sequences.
Uricase in many mammals catalyzes the oxidation of uric acid to the more water-soluble purine metabolites, allantoin, CO2, and H2O2.
Allantoin is a water-soluble It is a sex molecule that can be easily excreted through the urine, and its renal excretion is 10 times more efficient than the normal excretion of uric acid
.

However, during human evolution, the expression of uricase was lost, so the level of uric acid in the human body was 10 to 50 times higher than that of other animals, and this artificial uricase could make up for this defect [4]
.

Pegloticase extends half-life and reduces antigenicity by pegylation
.

This drug only needs to be injected once every 2 weeks, which not only alleviates adverse reactions, but also rapidly reduces the level of SUA and dissolves tophi, providing an important new option for adults with refractory or intolerable chronic gout
.

However, existing data show that the 6-month response rate of pegloticase in patients with refractory gout is only 42%, which undoubtedly cannot meet the needs of patients with refractory gout
.

 Can methotrexate treat gout? In addition to pegloticase, the effect of methotrexate, a "classic old drug" in rheumatism, on gout should not be underestimated
.

 Methotrexate is a dihydrofolate reductase inhibitor, which can inhibit the synthesis of folic acid in cells and affect cell proliferation, thereby exerting anti-inflammatory and immunosuppressive effects
.

Studies have confirmed that in inflammatory arthritis such as rheumatoid arthritis, methotrexate can not only reduce swelling and pain, increase joint mobility, improve inflammatory indicators [5], but also prevent bone destruction and reduce The residual rate is as high as 94% [6]
.

 Pegloticase + Methotrexate, a powerful combination? However, if pegloticase catalyzes the oxidation of uric acid to allantoin, free radicals such as CO2 and H2O2, which are generated at the same time, have potential to damage DNA if they accumulate in the body
.

In addition, some patients treated with pegloticase developed antibodies against the drug, limiting the effectiveness of the treatment
.

At the same time, the response rate of pegloticase in patients with refractory gout is low
.

These problems all show that the current single use of pegloticase still cannot meet the needs of patients, so whether it can be combined with other gout drugs is the focus of research in recent years
.

 At present, a large number of studies have confirmed that pegloticase combined with methotrexate will not have a significant impact on the pharmacokinetics of each other.
The two can fully play a synergistic and complementary role and effectively relieve the clinical symptoms of patients.
Less reaction and high safety
.

 ■ Research Support Trial - MIRROR trial evaluated the efficacy and safety of pegloticase (8 mg biweekly infusion) combined with methotrexate (15 mg/week) in patients with refractory gout.
The primary endpoint was the proportion of responders, defined as SUA < 6 mg/dl during ≥ 80% of the 6th month
.

Results showed that patients receiving methotrexate in combination with pegloticase achieved a higher proportion of sustained SUA levels <6 mg/dl, a lower incidence of infusion reactions, and no new safety concerns during the 6-month treatment period [ 7]
.

 Figure 1A SUA levels before infusion during pegloticase + methotrexate treatment, Figure 1B Liver function test II at week 24 The latest data show that pegloticase combined with methotrexate can help prevent the production of anti-drug antibodies and help more patients get Durable treatment response
.

 A recent randomised controlled trial (RCT) of MIRROR has again yielded positive results
.

In the trial, 152 patients with refractory gout were randomized to receive methotrexate or placebo for 4 weeks, followed by pegloticase plus methotrexate, or pegloticase plus placebo for 52 weeks
.

The primary endpoint was the proportion of SUA complete responders
.

Trial results showed that 71% (n=71/100) of patients treated with pegloticase + methotrexate and 40% (n = 21/52) of patients randomized to receive pegloticase + placebo met the primary endpoint with no new safety findings Sexual issues
.

These results show that the combined use of methotrexate improves the response rate of pegloticase [8]
.

 Another study from the MIRROR trial in Trial 3 showed that pegloticase in combination with methotrexate improved bone remodeling (reduced erosion area, increased sclerosis, or new bone formation) in addition to reduced MSU deposition during treatment [9]
.

 Figure 2 Serial dual-energy computed tomography (DECT) imaging of the right foot/ankle of patient 1 (A) and patient 2 (B) Note: Green indicates MSU deposition
.

Patient 2 discontinued treatment early due to suboptimal urate lowering efficacy
.

During the treatment period, the total MSU volume in patients 1 and 2 was reduced by 99% and 58%, respectively, and the bone erosion of the first metatarsal head of patient 1 and the bone erosion of the fifth metatarsal head of patient 2 improved (indicated by arrows) ( Significant reduction in erosion area, increased sclerosis, or new bone formation)
.

During treatment, other joints also exhibited reduced MSU volume and bone erosion remodeling (C), with mean reductions in joint MSU of 99% ± 1% and 63% ± 18% in patients 1 and 2, respectively
.

 The above results show that pegloticase combined with methotrexate in the treatment of refractory gout is indeed a powerful combination! Summary Refractory gout has a significant impact on the daily life of patients, and there is a high risk of complications.
Therefore, it is urgent to reduce the urate burden of this group.
Since pegloticase has not yet been listed in China, the existing treatment in China It has not yet been included in the programme
.

It is believed that with the progress of more clinical studies in the future, the efficacy of pegloticase can be improved to ensure that more patients can benefit from the treatment
.

Expert Comments With the improvement of people's living standards, the prevalence of hyperuricemia and gout is increasing year by year, and the trend of younger people is obvious
.

At present, the widely used SUA-lowering drugs at home and abroad include allopurinol and febuxostat, which inhibit the production of SUA, and benzbromarone and probenecid, which promote the excretion of uric acid
.

The symptoms of most patients can be completely controlled by taking the above-mentioned uric acid-lowering drugs, and the SUA can be maintained at an ideal level, but there are still a few patients whose SUA cannot reach the standard, and even suffer from complications such as severe bone destruction and/or renal insufficiency
.

The advent of pegloticase has brought light to these refractory gout patients with comorbidities, and preliminary studies of the drug have shown that it can rapidly reduce SUA and dissolve SUA crystals
.

However, because pegloticase is prone to allergic reactions and some patients express anti-drug antibodies, the clinical application of this drug is limited
.

In order to solve the above problems, relevant experts tried to combine it with immunosuppressants such as methotrexate, and achieved good results in clinical practice
.

In the future, the combined application of uric acid-lowering drugs and immunosuppressive agents in the treatment of refractory gout will become a new and effective treatment method
.

Expert Profile Prof.
Zhang Xuewu Professor, Chief Physician, MD, Doctoral Supervisor, Clinical Immunity Center/Institute of Rheumatology, Peking University People's Hospital, National Standing Committee Member, Rheumatology Branch, Chinese Medical Association, Chinese Physician, Standing Committee Member, Beijing Rheumatology Branch, Chinese Medical Association National Standing Committee Member of the Rheumatology Branch of the Association and Secretary General of the Osteoporosis Group Vice Chairman of the Beijing Rheumatology Branch of the Chinese Medical Doctor Association Vice Chairman of the National Standing Committee of the Bone and Joint and Rheumatology Branch of the Chinese Association of Rehabilitation Medicine The main research direction is autoimmune diseases pathogenesis and immunotherapy
.

He has deep knowledge in the diagnosis and treatment of rheumatoid arthritis, systemic lupus erythematosus, secondary osteoporosis, Sjögren's syndrome and gouty arthritis.
In 2001, he cooperated in the research on the pathogenesis of osteoarthritis and osteoporosis in Zurich, Switzerland.
The research results have participated in the exchange of academic conferences such as the American Rheumatology Annual Conference, the Asia-Pacific Region, the National and Beijing Rheumatism Annual Conference, etc.
, and have made several conference speeches.
Basic Concept In 2011, it was first proposed at the American Rheumatology Annual Meeting that biologics can be safely used in rheumatoid arthritis patients previously infected with hepatitis B virus.
With the accumulation of years of clinical experience, he took the lead in affirming the efficacy and safety of low-dose cyclophosphamide in the treatment of systemic lupus erythematosus.
In the past ten years, he has published more than 80 papers in SCI and core journals.
Now he is the corresponding editorial board member of "Chinese Journal of Rheumatology", and the reviewer of "Internal Journal of Rheumatic Disease", "Chinese Medical Journal (English version)" and other journals Human reference[1]Zhuang Yu, Lv Zhifen, Chen Yuhang, etc.
Clinical treatment of 30 cases of refractory gout.
Guangzhou Medicine, 2019, 50(01):89-93.
[2]Sundy JS, Ganson NJ, Kelly SJ, et al.
al.
Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout [J] .
Arthritis Rheum, 2007, 56(3):10211028.
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1002/art.
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[3]Soskind R, Abazia DT, Bridgeman MB.
Updates on the treatment of gout:including a review of updated treatment guidelines and use of small molecule therapies for difficult to treat gout and gout flares[J] .
Expert Opin Pharmacother, 2017, 18 ( 11 ): 11151125.
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1080/14656566.
2017.
1349099.
[4 ] Han Ying, Feng Yufei.
Pharmacological and clinical evaluation of polyethylene glycol recombinant uricase.
China Journal of New Drugs, 2012, 21(05): 498-501.
[5] Wang Fang, Ren Hanqiang, Shen Xiaobo.
Hydroxychloroquine combined with methyl methacrylate Clinical efficacy of methotrexate in the treatment of senile gouty arthritis.
Practical Geriatric Medicine, 2017, 31(01):50-53.
[6] Li Xing, Liu Jianfeng, Zhao Guoqin.
Zhu Danxi gouty formula combined with methotrexate in the treatment Clinical observation of rheumatoid arthritis.
Anhui Medicine, 2015, 36(08):995-998.
[7]Botson J, Tesser JHR, Bennett R, et al.
Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter , Open-label Study (MIRROR).
J Rheumatol.
2021;48(5):767-774.
doi: 10.
3899/jrheum.
200460.
[8]National Institutes of Health.
Study of KRYSTEXXA® (pegloticase) Plus Methotrexate in Patients With Uncontrolled Gout (MIRROR RCT).
https:// Accessed Sept 13,2021.
[9]Dalbeth N, Becce F, Botson JK, Zhao L, Kumar A.
Dual-energy CT assessment of rapid monosodium urate depletion and bone erosionremodelling during pegloticase plus methotrexate co-therapy.
Rheumatology (Oxford), 2022 .