The development and use of biologic agents have brought about many changes in how we treat a range of challenging rheumatologic conditions. However, while these treatments offer relief and hope to many patients, they are far from a panacea. Historically, we have seen that for some patients, treatment with biologics can trigger the immune system to develop antidrug antibodies (ADAs), which can reduce the effectiveness of therapy.1

The coadministration of biologic agents with immunomodulating therapies has been shown to prevent or minimize ADA development, improve response, and lengthen therapy duration. Clinical rheumatologists have been increasingly employing this approach.

Recently, a team of researchers, including myself, examined the success and progress being made in combining immunomodulatory agents with pegloticase, a biologic agent to treat uncontrolled gout.2 Our assessment was guided by the identification of immunogenicity as the primary factor leading to a loss of response in phase 3 randomized controlled trials (RCTs) of pegloticase and evidence demonstrating improvement due to prevention of ADA formation using antiproliferative agents.


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Understanding the Damage Caused by Gout

Uncontrolled gout constitutes a significant percentage of the 9.5 million individuals with gout in the United States who are unresponsive to oral treatments designed to lower serum urate levels. These patients typically experience a wide range of symptoms, which may include severe pain, tophi, and disability associated with bone and joint destruction.

John Botson, MD, RPh, CCD, is the president of the Alaska Rheumatology Alliance and a rheumatologist at Orthopedic Physicians Alaska.

Advanced imaging, like dual-energy computed tomography (DECT), has enabled us to better understand the overall urate burden among patients with gout. As clinicians, we know there is more urate deposition than what is seen on the skin and that for every tophus identified clinically, there can be up to 4 times as many that we don’t see.3

While gout is called the most common form of inflammatory arthritis, we rarely discuss its resultant systemic inflammation. Studies have shown us that there is local inflammation and fibrosis adjacent to urate deposition in organs even outside of the joints.4,5,6 Moreover, patients with gout are also affected by chronic, systemic inflammation, which may be compounding the effects.

Looking beyond the impact to the bones and joints, we should appreciate the urgency to reduce the burden of urate and view uncontrolled gout as a systemic disease linked to increased rates of comorbidities, hospitalization, and mortality.

The Case for Immunomodulatory Agents

Today, we have 1 medication approved, pegloticase, to treat uncontrolled gout. Patients with uncontrolled gout often face significant disease burden, which is why it is critical that we maximize the effectiveness and response rate of pegloticase. These are what make the use of immunomodulatory agents an exciting and promising avenue for clinicians to explore.

Multiple case reports, studies, and ongoing clinical trials have examined the combination of pegloticase with immunomodulatory agents including methotrexate, azathioprine, leflunomide, and mycophenolate mofetil. Research has shown that these medications can limit the production of ADAs, leading to an increased response rate for pegloticase for many patients with uncontrolled gout.7,8  

In the expert opinion piece published in Current Rheumatology Reports,2 we looked at the evidence that exists on pegloticase and immunomodulation, including open-label studies and RCTs, as well as a meta-analysis on how providers treating gout are using the combination. Collectively, these studies included 10 publications (describing 82 cases) using immunomodulation; the research demonstrated a markedly improved response rate with pegloticase plus immunomodulation compared with pegloticase alone (82.9% vs 42%) in the original pivotal clinical trials of pegloticase monotherapy.2

Overall, evidence suggests that patients with gout will have the best possible chance for the medication to work by using immunomodulation.

Because this is currently our last-line therapy, we must maximize the opportunity to lessen the burden of disease and improve health outcomes in this patient population.

Partnering in Continued Research

Being one of the many authors who worked on this editorial2 was very rewarding. Each contributor had a piece of the puzzle and their own experiences; by bringing everyone together, we were able to provide clinicians who are less familiar with pegloticase and immunomodulation a path forward. We knew that, with the current evidence available, this was the right time to convene experts in gout – not just researchers in academic institutions, but also private physicians treating uncontrolled gout – to bring this information to light.

For me, this paper provides hope for patients and clinicians. There is nothing more devastating in my clinic than having to tell a patient with refractory gout that “there is nothing I can do,” or “the last medication stopped working.” As I began using pegloticase and immunomodulation, I started seeing patients not only being able to complete treatment but gain control of their condition and change their lives. 

Looking to the Future of Uncontrolled Gout Treatment

Gout treatment continues to evolve, supporting more aggressive approaches as seen for other rheumatic diseases such as rheumatoid arthritis (RA). For example, previously in RA, patients were initiated on treatment with less aggressive treatments and care was escalated only when these were considered ineffective, which delayed obtaining an effective response and increased the risk of ongoing joint damage. Now, more aggressive approaches are used upfront to achieve remission and later reduced with an improvement in symptoms. I hope that, with the growing body of data, we will continue to see an evolution of care for patients with gout, because there are more effective and safer alternatives when oral therapies aren’t enough.

The good news is that immunomodulatory agents are widely available and familiar to rheumatologists, many of whom are already putting this into practice in the treatment of uncontrolled gout.

Because it has been proven that immunomodulatory agents can make pegloticase a more effective treatment, it should be considered a routine clinical practice for uncontrolled gout.

References

  1. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8
  2. Botson JK, Baraf HSB, Keenan RT, et al. Expert opinion on pegloticase with concomitant immunomodulatory therapy in the treatment of uncontrolled gout to improve efficacy, safety, and durability of response. Curr Rheumatol Reports. 2022;24:12-19. doi:10.1007/s11926-022-01055-9
  3. Choi HK, Al-Arfaj AM, Eftekhari A, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis. 2009;68(10):1609-1612. doi:10.1136/ard.2008.099713
  4. Frustaci A, Russo MA, Sansone L, et al. Heart failure from gouty myocarditis: a case report. Ann Intern Med. 2020;172(5):363:365. doi:10.7326/L19-0486
  5. Nickeleit V, Mihatsch M. Uric acid nephropathy and end-stage renal disease – review of non-disease. Nephrol Dial Transplant. 1997;12(9):1832-1838. doi:10.1093/ndt/12.9.1832
  6. Pattanaprichakul P, Bunyaratavej S, McLain PM, Varothai S. Disseminated gouty panniculitis: an unusual presentation of extensive cutaneous tophi. Dermatol Pract Concept. 2014;4(4):33-35. doi:10.5826/dpc.0404a05
  7. Albert JA, Hosey T, LaMoreaux B. Increased efficacy and tolerability of pegloticase in patients with uncontrolled gout co-treated with methotrexate: a retrospective study. Rheumatol Ther. 2020;7(3):639-648. doi:10.1007/s40744-020-00222-7
  8. Berhanu AA, Krasnokutsky S, Keenan RT Pillinger MH. Pegloticase failure and a possible solution: immunosuppression to prevent intolerance and inefficacy in patients with gout. Semin Arthritis Rheum. 2017;46(6):754-758. doi:10.1016/j.semarthrit.2016.09.007