Chronic gout is characterized by hyperuricemia, inflammation, and the deposition of monosodium urate (MSU) crystals in the joints and other tissues.¹ Deposition of MSU crystals progresses to chronic synovitis, bony erosions, cartilage damage, and tophi.² Over time, untreated or suboptimally-treated patients with hyperuricemia progress to severe pain, limited mobility, functional disability, and loss of productivity.¹ Furthermore, gout is associated with diabetes mellitus, hypertension, cardiovascular disease, kidney disease, and an increased risk of death.^2-4

The prevalence of gout increases with age (Figure)¹ and is reported to be higher in men. Approximately 9.2 million people in the United States have gout, representing 3.9% of the adult population.¹ The reported world prevalence of gout is between 1% to 4%.^2,4

Xanthine oxidase inhibitors, primarily allopurinol and febuxostat, are the mainstay of treatment. The goal of chronic gout management includes lowering serum urate levels to below 6 mg/dL.⁵ Overall, the clinical goals of therapy are directed towards reducing tophus burden, functional disability, work disability, pain, and joint inflammation as well as improving health-related quality of life and global patient health status.⁶ By lowering serum urate levels below the MSU saturation point, therapy leads to the dissolution of urate crystals which reduces acute flares and joint damage and improves overall disease outcomes.² 

Several urate-lowering therapies (ULTs) have emerged over the years. However, approximately 2% of patients who have been treated with ULTs fail to reach clinical target goals and progress to refractory gout, defined as a serum urate level above 6 mg/dL with ongoing symptoms of recurrent flares, arthritis, and increased tophi despite maximum recommended or tolerated doses of ULTs.⁷ The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) recommend pegloticase for treating gout that is refractory to conventional therapy.^5,8

Challenges Associated With Pegloticase for the Treatment of Refractory Gout

Uricase metabolizes urate to allantoin, which is water-soluble and easily excreted by the kidneys. However, uricase has a short half-life. Rasburicase, a recombinant uricase from Aspergillus flavus, was developed for the short-term management of hyperuricemia and may be administered intravenously for up to 7 days. The rasburicase molecule is not PEGylated; PEGylation increases the half-life of uricase and is moderately successful in mitigating immunogenicity. Pegloticase, a pegylated mammalian recombinant uricase, has a half-life between 6.4 days and 13.8 days and is administered as a twice-monthly infusion.⁹
Available evidence demonstrates the effectiveness of pegloticase in the treatment of gout. A study of 225 participants treated with pegloticase had their serum urate levels normalized within 24 hours of receiving the first infusion. Additionally, treatment with pegloticase resulted in tophi resolution, reduced pain, and improved physical function and quality of life.^10-12 However, response waned over time, as only 42% of patients on biweekly pegloticase infusion achieved a serum urate level below 6 mg/dL.¹⁰

Pegloticase is indicated in patients who fail to achieve the serum urate level target and have at least 2 gout flares each year. Similarly, patients with nonresolving tophi also are eligible for pegloticase therapy.⁵ 

Similar to other ULTs, there is an increased risk of flares during treatment with pegloticase, with the highest risk occurring in the first 3 months of initiating treatment.¹² There is a significant reduction in flares 4 to 6 months into treatment, necessitating flare prophylaxis with nonsteroidal anti-inflammatory drugs, colchicine, or steroids when treating patients with pegloticase.¹⁰ Another major challenge in using pegloticase is that between 41% to 60% of patients who receive treatment develop antibodies to the drug, resulting in increased clearance and reduced response to the medication.^12,13 Antipegloticase antibodies increase the risk of drug and infusion reactions. Flushing, vomiting, urticaria, and hypotension have been reported.¹² Patients also can stop responding to the urate-lowering effect of pegloticase before a first infusion reaction is evident. Serum urate levels should be checked before the next infusion.

A rising serum urate level is a surrogate for antidrug antibodies (ADAs), associated with the loss of lowering serum urate levels and a risk for infusion reactions, which would eventually lead to failure of treatment.¹³ Discontinuing pegloticase in patients with elevated preinfusion serum uric acid levels above 6 mg/dL while on therapy can minimize or avoid most infusion reactions. Data from 3 clinical trials of pegloticase showed that only 2 of 22 patients would have had infusion reactions if pegloticase had been discontinued after a single preinfusion serum urate level above 6 mg/dL.¹⁴ It is recommended to stop pegloticase if serum urate levels rise above 6 mg/dL, especially when there are 2 consecutive instances of serum urate levels higher than 6 mg/dL.¹⁵ Pegloticase should not be prescribed with other ULTs to avoid masking the loss of its urate-lowering ability.

Currently, pegloticase is the only approved therapy for refractory gout. Therefore, patients who develop ADAs will experience drug reactions that lead to failure of treatment. The coadministration of pegloticase with immunosuppressive agents has been shown to minimize the development of ADAs.¹⁶ Consequently, immunomodulation has been explored as a strategy to reduce the immunogenicity of pegloticase and improve clinical outcomes, thereby offering patients with an effective treatment against refractory gout.^16,17

Immunomodulation and Enzyme Therapy for Improved Efficacy

Concomitant administration of an immunosuppressive agent with pegloticase can improve the response rate in patients with uncontrolled gout. This combination should be considered as an option for minimizing drug intolerance and lowering the risk of adverse events.^18,19 A systematic review of 10 publications evaluating pegloticase use combined with an immunomodulatory agent found that patients experienced an overall response rate of 82.9%, comparatively higher than the patients who received pegloticase monotherapy (42%).¹⁹  

The immunosuppressive agent of choice requires careful consideration of the patient’s medical profile, including comorbidities, contraindications, or factors that may increase the risk of adverse events. While evidence-based recommendations are not available on combined immunosuppressive agents and pegloticase therapy, several studies have explored different immunomodulation protocols (Table 1).^20-26

In the exploratory open-label MIRROR trial (ClinicalTrials.gov Identifier: NCT03635957), 11 of 14 patients who received oral methotrexate, folic acid, and pegloticase maintained serum urate levels below 6 mg/dL more than 80% of the time.²⁰ The study demonstrated that treatment with a methotrexate/pegloticase combination resulted in a greater response than pegloticase alone. Similarly, in a retrospective study of 10 patients with uncontrolled tophaceous gout, a methotrexate/pegloticase combination with preinfusion prophylaxis resulted in a superior response compared with pegloticase alone.²¹

Other studies have found similar results. A case series of 7 patients treated with a methotrexate/pegloticase combination achieved lower serum urate levels and completed treatment without having adverse effects such as infusion reactions.²² In an observation case series, all 10 patients showed superior response to a combination therapy of methotrexate/pegloticase with no infusion reaction or methotrexate dose adjustment.²³ In another study, 1 patient who had 73 MSU-affected joints, identified with a dual-energy computed tomography scan, had their affected joints reduced to 4 at the end a 52-week treatment period with pegloticase/methotrexate combination therapy, and MSU volume decreased by 99%.²⁷

A supplemental biologics license application was submitted in January 2022 to the US Food and Drug Administration (FDA) to expand the approved indication for pegloticase plus methotrexate for patients with uncontrolled gout.²⁸ The supplemental biologics license application is primarily supported by the MIRROR randomized controlled trial results, showing that 71% (n=71/100) of patients randomly assigned to receive pegloticase plus methotrexate achieved a complete serum urate levels response, defined as serum urate levels below 6 mg/dL at least 80% of the time during month 6.²⁸

The side effects of concomitant methotrexate plus pegloticase treatment are fatigue, gastrointestinal toxicity, and liver toxicity.²⁹ In the MIRROR study, 1 patient experienced leucopenia and elevated liver enzymes. These adverse effects were managed by lowering the dose of methotrexate and the patient was able to successfully continue treatment throughout the 6-month study duration.²⁰ 

While methotrexate is an effective immunotherapy, contraindication in some patients requires alternative immunotherapy. Cyclosporine and mycophenolate mofetil have been explored in this context. Treatment with cyclosporine prior to pegloticase infusion in a patient with liver disease successfully lowered serum urate levels from 8.9 mg/dL to below 1.5 mg/dL after the first infusion. The reduction was maintained for the remainder of the treatment course with no infusion reaction.²² Similarly, 32 patients treated with mycophenolate mofetil and pegloticase achieved a serum urate level below 6 mg/dL in 86% of the patients compared to 40% of patients treated with pegloticase alone (P =.01).³⁰ Azathioprine and leflunomide also have shown promising results.^25,26

It should be noted that the adverse effects of immunomodulation can be potentially serious and require monitoring (Table 2).^31-35 Nevertheless, available data show promising results for efficacy and safety, suggesting that combined enzyme immunomodulation therapy is a worthwhile practice. However, there is a need for more robust evidence from clinical trials and standardized treatment guidelines. Until consensus recommendations are available, consideration should be given to comorbidities and contraindications when choosing an immunomodulatory agent.

Psoriatic arthritis (PsA) is among the subset of seronegative autoimmune rheumatic diseases collectively referred to as spondyloarthritides (SpAs). This subset also includes ankylosing spondylitis (AS), which is the radiographic manifestation of axial spondyloarthritis (axSpA). A heterogeneous inflammatory musculoskeletal disease, PsA is the most common comorbidity of psoriasis, affecting 30% to 33% of people with psoriasis.^1,2 

These statistics suggest a subset of patients with psoriasis who are at increased risk for progression to PsA, an erosive disease affecting peripheral and axial joints.⁵

Progression to axial involvement has been reported in 25% to 70% of patients with PsA, potentially leading to fusion of the vertebrae, with pain, structural damage, and significant functional limitation.⁵ Data from the Consortium of Rheumatology Researchers of North America registry reveal that compared with patients who have PsA without axial involvement, patients who have PsA with axial involvement exhibit characteristics of significantly worse overall disease activity. This is reflected in their higher scores on the Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index, an elevated level of C-reactive protein, and more significant impairment of quality of life.⁶ 

The mechanism by which psoriasis, an inflammatory skin disease, progresses to PsA with axial involvement is unknown. It is thought that interleukin (IL)-17 is a critical cytokine, and that elevated levels of IL-17 in patients with skin psoriasis with arthralgia are at increased risk for PsA. Therefore, targeting IL-17 inhibition is a reasonable strategy to prevent progression of psoriasis to PsA.
 
This strategy was demonstrated in a small-scale study of 20 patients with psoriasis who presented with arthralgia, inflammatory lesions on magnetic resonance imaging, and synovitis or enthesitis.⁷ The study found that treatment with the IL-17 inhibitor secukinumab over 24 weeks resulted in significant improvement in symptoms of arthralgia and synovitis. No progression in joint erosion or enthesophytes was reported; there was significant improvement in bone mass.⁷ This study suggests that targeting IL-17 inhibition might effectively treat psoriasis and prevent both progression to PsA and axial manifestations. The demonstrated pathophysiological relationship between psoriasis and PsA suggests that dermatologists can play a critical role in preventing the progression of psoriasis to PsA; therefore, collaboration with rheumatology has the potential to improve patient outcomes. 

What is the evidence for the role of IL-17 in PsA?

Animal models of chronic inflammation and studies of patients with radiographic axSpA support a role for overexpression of the IL-23/IL-17 pathway in chronic inflammatory disease. IL-23 is essential to promoting IL-17 production; although inhibiting IL-23 in patients with axSpA had no significant effect on clinical manifestations of disease, inhibiting IL-17 did significantly alleviate axSpA signs and symptoms^8,9—suggesting that IL-17 is a critical player in the pathophysiology of axSpA.
 
A proinflammatory cytokine, IL-17 plays an essential role in acute inflammation by stimulating macrophages, fibroblasts, and epithelial and endothelial cells to release cytokines and chemokines involved in promoting inflammation and osteoclastogenesis.^7,10 Evidence supports the complex role of IL-17 in enthesitis, neuropathic pain, and bone modulation, including bone formation and erosion—all common in axSpA.⁹ Given that PsA is a subset of SpA (to which axSpA also belongs), it is reasonable to speculate that IL-17 also plays a vital role in the axial manifestations of PsA. Elevated levels of innate and adaptive cells thought to be involved in IL-17 production have been identified in the blood and synovia of patients with PsA.⁹ An increased level of these cells has also been found in skin lesions and the blood of patients with psoriasis. Furthermore, IL-17A receptors are expressed on the surface of skin keratinocytes, providing a rationale for progression to PsA.⁷ Understanding the relationship between IL-23, IL-17, and the role of IL-17 in early PsA provides a rationale for targeting IL-17 in the treatment of PsA.

Why is IL-17 an essential therapeutic target in PsA?

IL-17 targets various cells, including endothelial cells, fibroblasts, and macrophages that promote chronic inflammatory disease, including PsA. IL-17 is, in fact, a superfamily of 6 isoforms (IL-17A to IL-17F). Although the etiology of PsA in patients with skin psoriasis is not well-defined, some evidence suggests that IL-17A is the critical isoform common to both psoriasis and PsA, and is involved in recruiting inflammatory cells and stimulating the innate immune system inflammatory response that leads to clinical manifestations of PsA.^11,12 IL-17A involvement in the pathogenesis of PsA has been demonstrated in randomized controlled trials of the effectiveness of IL-17A inhibition in improving clinical outcomes in patients with plaque psoriasis (PsO) and PsA.^13-17 

Upon binding to a receptor, IL-17A upregulates inflammatory genes implicated in promoting bone formation and regeneration by facilitating osteoblast differentiation and proliferation.¹⁸ The effects of IL-17A are augmented by other inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-α). Synergistic effects of IL-17A and TNF-α on keratinocytes maintain a positive feedback loop for increased production of TNF-α and other mediators, as well as upregulation of genes involved in psoriasis.¹¹
 
Inhibition of IL-17A has been shown in clinical studies to affect several manifestations of PsA, including skin and nail findings, peripheral arthritis, axial disease, dactylitis, and enthesitis,⁹ suggesting that targeting IL-17A might alleviate symptoms of psoriasis and PsA while preventing progression to axial manifestations. This evidence supports clinical development of IL-17A inhibitors for the treatment of PsA with axial involvement.

Which treatments target IL-17A for PsA with axial involvement?

In the past, treatment of PsA with axial involvement was adapted from studies of AS and based on international guidelines developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; the European League Against Rheumatism; Assessment of SpondyloArthritis international Society; and the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network.^19-21 

MAXIMISE (ClinicalTrials.gov Identifier: NCT02721966) was the first randomized controlled study to investigate the safety and efficacy of a biologic agent in patients with PsA. Patients with axial PsA and an inadequate response to nonsteroidal anti-inflammatory drugs were randomly assigned to secukinumab 300 mg, secukinumab 150 mg, or placebo. Secukinumab provided rapid and significant improvement in axial function and symptoms vs placebo; the percentage of patients achieving an ASAS20 response at Week 12 was 63.1% with secukinumab, 300 mg, and 66.3% with secukinumab, 150 mg—vs 31.3% with placebo (P <.0001).²²
 
The demonstrated efficacy of targeting IL-17A inhibition has resulted in the approval of 2 agents, secukinumab and ixekizumab, for the treatment of psoriasis and PsA, as well as AS.^23,24
 
Secukinumab, a fully human IgG subclass 1 monoclonal antibody, selectively inhibits IL-17A. The phase 3 FUTURE5 study (ClinicalTrials.gov Identifier: NCT02404350) evaluated the efficacy of subcutaneous secukinumab in improving clinical signs and symptoms and radiographic progression in 996 patients with active PsA. Patients were randomized to receive secukinumab (300 mg or 150 mg, with or without a loading dose) or placebo. Compared to placebo, secukinumab, at all dosages investigated, significantly improved signs and symptoms and inhibited radiographically observed structural progression.¹⁴
 
Similarly, the efficacy of secukinumab in patients with psoriasis was demonstrated in 2 phase 3, double-blind trials: ERASURE (ClinicalTrials.gov Identifier: NCT01365455) and FIXTURE (ClinicalTrials.gov Identifier: NCT01358578). In both trials, secukinumab was superior to etanercept and placebo in achieving 75% or more reduction from baseline in the psoriasis area-and-severity index score.¹³ A pooled analysis of long-term treatment with secukinumab for as long as 5 years in a total of 7355 patients (5181 with PsO, 1380 with PsA, and 794 with AS—representing, respectively, 10,416.9, 3866.9, and 1943.1 patient-years), demonstrated a favorable safety profile.²⁵ These studies further validated IL-17A as a therapeutic target in both PsA and psoriasis, supporting US Food and Drug Administration (FDA) approval of secukinumab for the treatment of SpA, including psoriasis, PsA, and nonradiographic axial SpA.²³

Ixekizumab is a humanized IgG subclass 4 monoclonal antibody approved for the treatment of psoriasis, PsA, and AS.²⁴ The efficacy of ixekizumab for the treatment of patients with active PsA was demonstrated in the double-blind, randomized phase 3 SPIRIT-P1 clinical trial (ClinicalTrials.gov Identifier: NCT01695239). Overall, in patients with active PsA naive to a biologic, treatment with ixekizumab resulted in improvement in disease activity and physical function and inhibition of progression of structural damage.¹⁷ The UNCOVER series of clinical trials (ClinicalTrials.gov Identifiers: NCT01474512 [UNCOVER-1], NCT01597245 [UNCOVER-2], and NCT01646177 [UNCOVER-3]) also demonstrated the efficacy of ixekizumab in patients with moderate to severe PsO,¹⁶ including efficacy and safety in long-term treatment extension through 5 years.²⁶

Approval of secukinumab and ixekizumab by the FDA supports the role of IL-17A in advanced PsA with axial involvement. These agents’ FDA indication for psoriasis suggests that treating a patient with psoriasis or PsA early might slow or prevent disease progression. In support of this hypothesis, data from the IVEPSA study (an arm of the PSARTROS program; ClinicalTrials.gov Identifier: NCT02483234) suggest that very early treatment of PsA, particularly in high-risk patients, can result in a comprehensive reduction in skin symptoms, pain, and subclinical inflammation.⁷ It also offers the opportunity for other agents in this class to be used for the treatment of PsA. Indeed, several investigational agents targeting IL-17A are in mid-stage or late-stage clinical development (Table), potentially expanding options for PsA treatment.¹⁰

These preclinical and clinical studies support the role of IL-17A in the pathophysiology of psoriasis and PsA. It is essential that dermatologists and rheumatologists are knowledgeable about the role of IL-17A in psoriasis and PsA pathology and work collaboratively to achieve optimal patient management.

Rheumatoid arthritis (RA) is one of the most common inflammatory autoimmune rheumatic diseases, with a global prevalence of 0.24% according to the Global Burden of Disease 2010 study.¹ However, the incidence and prevalence of this condition vary substantially among geographic areas.^1,2 A US study reported a higher annual RA incidence in women compared with men.² Furthermore, a moderate increase in the incidence of RA in women was reported during 1995-2007.²

Although RA is associated with significant morbidity, the increasing number of effective drugs and modes of action has improved the disease outcome. Currently, several US Food and Drug Administration (FDA)-approved therapies are available for RA: synthetic disease-modifying antirheumatic drugs (DMARDs) — which include conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDS) such as Janus kinase (JAK) inhibitors, and biological DMARDs (bDMARDs) such as tumor necrosis factor (TNF)-α inhibitors — interleukin (IL)-6 receptor antagonists, a T-cell costimulation blocker (abatacept), and an anti-CD20 B-cell-depleting monoclonal antibody (rituximab).

The Role of IL-6 in RA

Although the pathophysiology of RA is complex, there is no doubt that inflammation plays a major role in the associated damage to the articular cartilage. ⁵ Numerous proinflammatory cytokines are involved in the disease process, and studies have suggested that IL-6 also has a significant impact on the development of RA.⁵
 
The pleiotropic cytokine IL-6 mediates a wide range of immunologic responses during host infection and inflammatory disease.⁵ Prompt and transient synthesis of IL-6 in response to infections and tissue injury is beneficial and contributes to host defense, but persistent dysregulated expression of IL-6 may be involved in the pathogenesis of various chronic inflammatory and autoimmune diseases, including RA.⁶
 
Studies have suggested that in patients with RA, dysregulation of IL-6 production occurs in the synovial cells, and the pleiotropic mediator can cause persistent synovial inflammation and associated damage to the articular cartilage and underlying bone.⁶
 
More than 2 decades ago, Straub et al reported that a decrease in IL-6 is a potential prognostic marker for clinical outcome in patients with RA treated with DMARDs.⁷

IL-6 Receptor Antagonists in RA

Although the 2020 American College of Rheumatology guidelines for the management of RA are pending publication, the European League Against Rheumatism (EULAR) recently released updated recommendations for the management of RA with synthetic and biological DMARDs. ⁸
 
There is a consensus that csDMARDs are the mainstay of RA treatment, and the 2019 update of the EULAR recommendations supported the use of methotrexate as the first-line DMARD.⁸ If there is insufficient response to the initial csDMARD or if the patient is not suitable for these medications, bDMARDs or tsDMARDs should be considered.
 
Inhibitors of IL-6 action can target either the IL-6 ligand itself or the IL-6 receptor.
Currently, tocilizumab (Actemra^®) and sarilumab (Kevzara^®) are IL-6 receptor antagonists that have been approved by the US Food and Drug Administration (FDA).^9,10 Sirukumab, a human monoclonal antibody that targets the IL-6 cytokine rather than the IL-6 receptor, was rejected for approval by the FDA due to safety concerns, as data suggested an imbalance in deaths among the trial patients taking the drug.¹¹

Tocilizumab

Tocilizumab is a humanized monoclonal antibody targeting the IL-6 receptor that was approved by the FDA in 2010 as an intravenous formulation for the treatment of RA; it was later approved as a subcutaneous formulation.
 
Tocilizumab is indicated for adult patients with moderately to severely active RA who have had an inadequate response to a csDMARD. It can be given in combination with a csDMARD or as monotherapy. Tocilizumab also received FDA approval for the treatment of giant cell arteritis, polyarticular or systemic juvenile idiopathic arthritis, and cytokine release syndrome associated with chimeric antigen receptor T cells. ⁹
 
In the United States, the recommended intravenous dosage of tocilizumab is 4 mg/kg every 4 weeks, followed by an increase to 8 mg/kg every 4 weeks based on clinical response. Tocilizumab at a dose of 8 mg/kg was found to be more effective than a dose of 4 mg/kg.¹² Recommended adult subcutaneous dosage depends on weight: patients weighing <100 kg should be treated at a dosage of 162 mg every 2 weeks, followed by an increase in dosing frequency to a weekly dosage, based on clinical response; patients weighing ≥100 mg should be treated at a dosage of 162 mg every week.⁹ The MUSASHI study compared subcutaneous vs intravenous tocilizumab monotherapy in patients with RA with previous DMARD failure, reporting the subcutaneous formulation was noninferior to the intravenous infusion.¹³ The SUMMACTA study (ClinicalTrails.gov Identifier: NCT01194414) supported comparable efficacy of weekly tocilizumab 162 mg subcutaneous and tocilizumab 8 mg/kg intravenous when given in combination with DMARDs.¹⁴

Several studies have supported the favorable efficacy of tocilizumab in patients with RA, including DMARD-naive patients and those with an inadequate response to treatment with csDMARDs or TNF inhibitors. Tocilizumab was found to be effective both as monotherapy and in combination with csDMARD in patients with RA.

Monotherapy. The AMBITION study (ClinicalTrials.gov Identifier: NCT00109408) supported improved efficacy of tocilizumab monotherapy over methotrexate monotherapy in patients who responded to treatment with methotrexate or bDMARDs, with rapid improvement in RA signs and symptoms.¹⁵ The SAMURAI (ClinicalTrials.gov Identifier: NCT00144508) and SATORI (ClinicalTrials.gov Identifier: NCT00144521) studies have also supported the superiority of tocilizumab monotherapy over methotrexate.^16,17
 
The ACT-RAY study (ClinicalTrials.gov Identifier: NCT00810199) reported that in patients with previous DMARD failure, the combination of tocilizumab with methotrexate was not superior to tocilizumab monotherapy; hence, there was no benefit for an add-on strategy over the switch to tocilizumab monotherapy in patients with an inadequate response to methotrexate.¹⁸ Similarly, the FUNCTION (ClinicalTrials.gov Identifier: NCT01007435) and the U-ACT-Early (ClinicalTrials.gov Identifier: NCT01034137) studies showed no added benefit with the combination of methotrexate with tocilizumab over tocilizumab monotherapy for csDMARD-naive patients with early RA.^19,20
 
Patients with early or newly diagnosed RA are potential candidates for tocilizumab, as the FUNCTION and the U-ACT-Early studies have shown that tocilizumab is more effective than methotrexate in patients with early RA, with higher remission rates and better protection from structural joint damage.^19,20
 
In the ADACTA study (ClinicalTrials.gov Identifier: NCT01119859), patients who were intolerant of methotrexate or for whom methotrexate was inappropriate were randomly assigned to receive adalimumab or tocilizumab.  Results of the study showed superiority of tocilizumab over adalimumab monotherapy for reduction of signs and symptoms of RA.²¹ Tocilizumab monotherapy was also found to provide radiographic benefit compared with csDMARD monotherapy.^16,22
 
Combination Therapy. Several studies have supported the efficacy of combination treatment with tocilizumab and csDMARDs in patients with previous DMARD failure.^23-26 In addition, in patients with previous failure of TNF inhibitors, the combination of tocilizumab with methotrexate was found to be effective.²⁷
 
In recent EULAR recommendations for the management of RA, the task force stressed that although in clinical practice many patients are taking bDMARD monotherapy, combination therapy may be more effective for all bDMARDs and tsDMARDs, and combination therapy is advantageous with respect to immunogenicity for all bDMARDs.⁸

Sarilumab

Sarilumab is a fully human monoclonal antibody against the IL-6 receptor that was approved by the FDA in 2017 for the treatment of adults with moderately to severely active RA who had an inadequate response or intolerance to a csDMARD.
 
Sarilumab can be used as monotherapy or in combination with another csDMARD. However, due to the possibility of increased immunosuppression and increased risk of infection, it is recommended to avoid using sarilumab with bDMARDs.
 
The recommended dosage of the subcutaneous injection is 200 mg once every 2 weeks. The dosage may need to be reduced to 150 mg once every 2 weeks to help manage neutropenia, thrombocytopenia, and/or elevated liver transaminases.
 
Sarilumab has greater affinity for the human IL-6 receptor than tocilizumab and it has a prolonged half-life, but the overall efficacy and safety of tocilizumab and sarilumab seem to be comparable.²⁸
 
The MOBILITY study (ClinicalTrials.gov Identifier: NCT01061736) investigated the efficacy and safety of sarilumab in combination with methotrexate for the treatment of patients with moderately to severely active RA who had inadequate response to methotrexate.  Sarilumab in both approved doses in combination with methotrexate was well tolerated and provided significant clinical and radiographic improvement.²⁹ The TARGET study (ClinicalTrials.gov Identifier: NCT01709578) investigated the outcomes of sarilumab with csDMARDs in patients with moderately to severely active RA who had an inadequate response to or were intolerant of a TNF-α inhibitor. Both doses of sarilumab in combination with csDMARDs were associated with clinical improvement.³⁰ In both studies, a greater proportion of patients treated with sarilumab plus csDMARD compared with placebo achieved low level of disease activity and higher response rates.
 
The MONARCH study (ClinicalTrials.gov Identifier: NCT02332590), which was a comparable study to ADACTA, compared sarilumab with subcutaneous adalimumab. This study demonstrated superiority of sarilumab monotherapy to adalimumab monotherapy in patients with active RA who have had an inadequate response or were intolerant of methotrexate.
 
Post hoc analyses of the MOBILITY and MONARCH studies reported that patients with elevated IL-6 levels at baseline had greater clinical response to sarilumab compared with patients with normal IL-6 levels.⁵ Hence, higher levels of IL-6 at baseline may predict better response to sarilumab treatment and identify potential candidates for IL-6 receptor antagonist therapy.
 
In addition to the impact of tocilizumab and sarilumab on joint symptoms and structural damage, both medications may improve extra-articular symptoms including fatigue, morning stiffness, and anemia, and improve glucose metabolism.⁵

Warnings and Precautions

Tocilizumab and sarilumab have a boxed warning about the risk for developing serious infections that may lead to hospitalization or death. Reported infections included active tuberculosis; invasive fungal infections; and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. The recommendation is to monitor patients and interrupt treatment with the IL-6 receptor antagonist if a serious infection develops until the infection is controlled.^9,10  Prior to initiating tocilizumab or sarilumab, it is recommended to complete testing for latent tuberculosis and consider treatment if results are positive.^9,10
 
Tocilizumab and sarilumab initiation is not recommend in patients with absolute neutrophil count <2000/mm³, platelet count <150,000/mm³, or liver transaminases >1.5 times the upper limit of normal.^9,10

Tocilizumab and sarilumab are both contraindicated in patients with known hypersensitivity to the medication. The medications should be used with caution in patients at risk for gastrointestinal perforation. Laboratory monitoring is recommended due to potential changes in neutrophils, platelets, lipids, and liver function tests.^9,10  
 
Refer to the full Prescribing Information for additional details about Actemra^® and Kevzara^®.

References

1. Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014;73(7):1316-1322. doi:10.1136/annrheumdis-2013-204627
2. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576-1582. doi:10.1002/art.27425
3. Lo, J, Chan L, Flynn S. A systematic review of the incidence, prevalence, costs, and activity and work limitations of amputation, osteoarthritis, rheumatoid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: a 2019 update. Arch Phys Med Rehabil. 2020; S0003-9993(20)30216-1. doi:10.1016/j.apmr.2020.04.001
4. Institute for Health Metrics and Evaluation. GBD Results Tool. http://ghdx.healthdata.org/gbd-results-tool. Accessed September 9, 2020.
5. Yip RML, Yim CW. Role of interleukin 6 inhibitors in the management of rheumatoid arthritis. JCR J Clin Rheumatol. Published online December 24, 2019. doi:10.1097/rhu.0000000000001293
6. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):1-16. doi:10.1101/cshperspect.a016295
7. Straub RH, Muller-Ladner U, Lichtinger T, Scholmerich J, Menninger H, Lang B. Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. Br J Rheumatology. 1997;36(12):1298-1303. doi:10.1093/rheumatology/36.12.1298
8. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):S685-S699. doi:10.1136/annrheumdis-2019-216655
9. Actemra. Prescribing information. Genentech, Inc. May 2020. Accessed August 31, 2020. https://www.gene.com/download/pdf/actemra_prescribing.pdf.
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