Immunomodulatory Enzyme Therapy and Conventional Therapy to Boost Therapeutic Outcomes in Chronic Refractory Gout

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 


How were leucopenia and elevated liver enzymes managed in the MIRROR study?
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By lowering the dose of methotrexate.

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.

References

  1. Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the national health and nutrition examination survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999. doi:10.1002/art.40807
  2. Ragab G, Elshahaly M, Bardin T. Gout: an old disease in a new perspective – a reviewJ Adv Res. 2017;8(5):495-511. doi:10.1016/j.jare.2017.04.008
  3. Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment optionsBMC Med. 2017;15(1):123. doi:10.1186/s12916-017-0890-9
  4. Singh JA, Gaffo A. Gout epidemiology and comorbiditiesSemin Arthritis Rheum. 2020;50(3S):S11-S16. doi:10.1016/j.semarthrit.2020.04.008
  5. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of goutArthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  6. de Lautour H, Dalbeth N, Taylor WJ. Outcome measures for gout clinical trials: a summary of progress. Curr Treat Options in Rheum. 2015;1(2):156-166. doi:10.1007/s40674-015-0014-7
  7. Schlesinger N, Lipsky PE. Pegloticase treatment of chronic refractory gout: update on efficacy and safety. Semin Arthritis Rheum. 2020;50(3S):S31-S38. doi:10.1016/j.semarthrit.2020.04.011
  8. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of goutAnn Rheum Dis. 2017;76(1):29-42.  doi:10.1136/annrheumdis-2016-209707
  9. Schlesinger N, Padnick-Silver L, LaMoreaux B. Enhancing the response rate to recombinant uricases in patients with gout. BioDrugs. 2022;36(2):95-103.  doi:10.1007/s40259-022-00517-x
  10. Sundy JS, Baraf HSB, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-720. doi:10.1001/jama.2011.1169
  11. Araujo EG, Bayat S, Petsch C, et al. Tophus resolution with pegloticase: a prospective dual-energy CT studyRMD Open. 2015;1(1):e000075. doi:10.1136/rmdopen-2015-000075
  12. Becker MA, Baraf HSB, Yood RA, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatmentAnn Rheum Dis. 2013;72(9):1469-1474.  doi:10.1136/annrheumdis-2012-201795
  13. Lipsky PE, Calabrese LH, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic goutArthritis Res Ther. 2014;16(2):R60. doi:10.1186/ar4497
  14. Keenan RT, Baraf HSB, LaMoreaux B. Use of pre-infusion serum uric acid levels as a biomarker for infusion reaction risk in patients on pegloticaseRheumatol Ther. 2019;6(2):299-304.  doi:10.1007/s40744-019-0151-9
  15. KRYTEXXA. Prescribing information. Savient Pharmaceuticals, Inc.; 2012. Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125293s034lbl.pdf
  16. Botson, JK. Changing the standard of care: the case for combining pegloticase with immunomodulatory agents in gout. Rheumatology Advisor. April 1, 2022. Accessed May 18, 2022. https://www.rheumatologyadvisor.com/home/topics/gout/changing-the-standard-of-care-the-case-for-combining-pegloticase-with-immunomodulatory-agents-in-gout/
  17. 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 responseCurr Rheumatol Rep. 2022;24(1):12-19. doi:10.1007/s11926-022-01055-9
  18. Guttmann A, Krasnokutsky S, Pillinger MH, Berhanu A. Pegloticase in gout treatment – safety issues, latest evidence and clinical considerations. Ther Adv Drug Saf. 2017;8(12):379-388. doi:10.1177/2042098617727714
  19. Keenan RT, Botson JK, Masri KR, et al. The effect of immunomodulators on the efficacy and tolerability of pegloticase: a systematic reviewSemin Arthritis Rheum. 2021;51(2):347-352. doi:10.1016/j.semarthrit.2021.01.005
  20. Botson JK, Tesser JRP, 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
  21. 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
  22. Bessen MY, Bessen SY, Yung CM. Concomitant immunosuppressant use with pegloticase in patients with tophaceous gout – a case series. Int J Clin Rheum. 2019;14(6):238. doi:10.37532/1758-4272.2019.14(6).238-245
  23. Botson JK, Peterson J. Pretreatment and coadministration with methotrexate improved durability of pegloticase response: an observational, proof-of-concept case series. J Clin Rheumatol. 2022;28(1):e129-e134. doi:10.1097/RHU.0000000000001639
  24. Khanna PP, Khanna D, Cutter G, et al. Reducing immunogenicity of pegloticase with concomitant use of mycophenolate mofetil in patients with refractory gout: a phase II, randomized, double-blind, placebo-controlled trialArthritis Rheumatol. 2021;73(8):1523-1532. doi:10.1002/art.41731
  25. Baraf H, Rainey H, Lipsky P, Lipsky P. The impact of azathioprine on the frequency of persistent responsiveness to pegloticase in patients with chronic refractory gout. Arthritis Rheumatol. 2020;72(suppl 10).
  26. Masri KR, Padnick-Silver L, Winterling K, LaMoreaux B. Effect of leflunomide on pegloticase response rate in patients with uncontrolled gout: a retrospective study. Rheumatol Ther. 2022;9(2):555-563. doi:10.1007/s40744-021-00421-w
  27. Dalbeth N, Becce F, Botson JK, Zhao L, Kumar A. Dual-energy CT assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapyRheumatology (Oxford). 2022;keac173. doi:10.1093/rheumatology/keac173
  28. Horizon therapeutics plc submits supplemental biologics license for the concomitant use of KRYSTEXXA® (pegloticase injection) plus methotrexate for people living with uncontrolled gout. News release. Horizon Therapeutics plc. January 10, 2022. Accessed May 18, 2022. https://ir.horizontherapeutics.com/node/19886/pdf
  29. Bedoui Y, Guillot X, Sélambarom J, et al. Methotrexate an old drug with new tricks. Int J Mol Sci. 2019;20(20):5023. doi:10.3390/ijms20205023
  30. Khanna PP, Khanna D, Cutter G, et al. Reducing immunogenicity of pegloticase with concomitant use of mycophenolate mofetil in patients with refractory gout: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2021;73(8):1523-1532. doi: 10.1002/art.41731
  31. Methotrexate. Prescribing information. DAVA Pharmaceuticals, Inc.; 2016. Accessed May 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008085s066lbl.pdf
  32. CellCept. Prescribing information. Roche Laboratories, Inc.. Accessed May 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf
  33. Imuran. Prescribing information. Prometheus Laboratories, Inc; 2011.  Accessed May 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf
  34. Arava. Prescribing information. Sanofi-Aventis US LLC; 2011. Accessed May 24, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020905s022lbl.pdf
  35. Sandimune. Prescribing information. Novartis Pharmaceuticals Corporation; Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050573s039,050574s047,050625s053lbl.pdf

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Rheumatology Advisor had no role in this content’s preparation.

                                                                                                            Reviewed June 2022

IL-17A Inhibition: A Treatment Option for Psoriatic Arthritis With Axial Involvement

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 symptoms8,9—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


Secukinumab adverse effects
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Secukinumab adverse effects commonly reported include nasopharyngitis, diarrhea, and upper respiratory tract infection.

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


Ixekizumab adverse effects
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Ixekizumab adverse effects commonly reported include injection site reactions, upper respiratory tract infection, nausea, and tinea infections.

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


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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.

References

  1. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019;80(4):1073-1113. doi:10.1016/j.jaad.2018.11.058
  2. National Psoriasis Foundation. About psoriasis. Updated January 14, 2021. Accessed May 4, 2021. www.psoriasis.org/about-psoriasis/
  3. Johns Hopkins Arthritis Center. Psoriatic arthritis. Updated February 5, 2020. Accessed May 4, 2021. www.hopkinsarthritis.org/arthritis-info/psoriatic-arthritis/
  4. Eder L, Cohen AD, Feldhamer I, Greenberg-Dotan S, Batat E, Zisman D. The epidemiology of psoriatic arthritis in Israel – a population-based study. Arthritis Res Ther. 2018;20(1):3. doi:10.1186/s13075-017-1497-4
  5. Gottlieb AB, Merola JF. Axial psoriatic arthritis: an update for dermatologists. J Am Acad Dermatol. 2021;84(1):92-101. doi:10.1016/j.jaad.2020.05.089
  6. Spondylitis Association of America. In psoriatic arthritis, axial involvement is associated with more severe psoriasis.  August 2018. Accessed May 4, 2021. https://spondylitis.org/research-new/in-psoriatic-arthritis-axial-involvement-is-associated-with-more-severe-psoriasis/
  7. Kampylafka E, Simon D, d’Oliveira I, et al. Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation—data from the prospective IVEPSA study. Arthritis Res Ther. 2019;21(1):178. doi:10.1186/s13075-019-1957-0
  8. Sieper J, Poddubnyy D, Miossec P. The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat Rev Rheumatol. 2019;15(12):747-757. doi:10.1038/s41584-019-0294-7
  9. McGonagle DG, McInnes IB, Kirkham BW, Sherlock J, Moots R. The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann Rheum Dis. 2019;78(9):1167-1178. doi:10.1136/annrheumdis-2019-215356
  10. Tsukazaki H, Kaito T. The role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int J Mol Sci. 2020;21(17):6401. doi:10.3390/ijms21176401
  11. Frieder J, Kivelevitch D, Menter A. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9(1):5-21. doi:10.1177/2040622317738910
  12. Croxford AL, Karbach S, Kurschus FC, et al. IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions. J Invest Dermatol. 2014;134(3):728-735. doi:10.1038/jid.2013.404
  13. Langley RG, Elewski BE, Lebwohl M, et al; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371(4):326-338. doi:10.1056/NEJMoa1314258
  14. Mease P, van der Heijde D, Landewé R, et al. Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis. 2018;77(6):890-897. doi:10.1136/annrheumdis-2017-212687
  15. Mease PJ, McInnes IB, Kirkham B, et al; FUTURE 1 Study Group. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015;373(14):1329-1339. doi:10.1056/NEJMoa1412679
  16. Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1 Study Group; UNCOVER-2 Study Group; UNCOVER-3 Study Group. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. doi:10.1056/NEJMoa1512711
  17. Chandran V, van der Heijde D, Fleischmann RM, et al. Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). Rheumatology (Oxford). 2020;59(10):2774-2784. doi:10.1093/rheumatology/kez684
  18. Ono T, Okamoto K, Nakashima T, et al. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun. 2016;7:10928. doi:10.1038/ncomms10928
  19. Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5):1060-71. doi:10.1002/art.39573
  20. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499-510. doi:10.1136/annrheumdis-2015-208337
  21. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2016;68(2):282-298. doi:10.1002/art.39298
  22. Schreiber S, Colombel J-F, Feagan BG, et al. Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials. Ann Rheum Dis. 2019;78(4):473-479. doi:10.1136/annrheumdis-2018-214273
  23. Cosentyx. Prescribing information. Novartis; 2018. Updated June 2020. Accessed May 4, 2021. www.novartis.us/sites/www.novartis.us/files/cosentyx.pdf
  24. Taltz. Prescribing information. Eli Lilly and Company; 2020. Updated March 2021. Accessed May 4, 2021. https://uspl.lilly.com/taltz/taltz.html#pi
  25. Deodhar A, Mease PJ, McInnes IB, et al. Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res Ther. 2019;21(1):111. doi:10.1186/s13075-019-1882-2
  26. Leonardi C, Reich K, Foley P, et al. Efficacy and safety of ixekizumab through 5 years in moderate-to-severe psoriasis: long-term results from the UNCOVER-1 and UNCOVER-2 phase-3 randomized controlled trials. Dermatol Ther (Heidelb). 2020;10(3):431-447. doi:10.1007/s13555-020-00367-x

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Rheumatology Advisor had no role in this content’s preparation.

Reviewed August 2021

Treating Rheumatic and Musculoskeletal Diseases During the COVID-19 Pandemic

Treating Rheumatic and Musculoskeletal Diseases During the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic has significantly changed the face of healthcare practice. Healthcare providers across the spectrum of medical practice have initiated emergency measures that have affected in-person patient consultation and new guidelines to provide a road map for chronic disease management. Patients with rheumatic and musculoskeletal diseases and healthcare practitioners who treat those diseases are no exception. As physicians and patients come to terms with the new normal, several questions emerge related to the delivery of care across the patient population.



The impact of SARS-CoV-2, the coronavirus responsible for COVID-19, has been global. As of September 18, 2020, almost 30 million coronavirus cases have been reported globally with approximately 943,000 deaths.3 Statistics for the United States alone reflect almost 7 million cases and more than 200,000 deaths.4 Furthermore, COVID-19 hospitalization and death rate ratios have been increasing staggeringly in every age group older than the 18- to 29-year-old age group.

The focus of this review is not a discussion of the reasons why, currently, the United States has the highest cumulative number of COVID-19 cases and deaths,5 with a projection to continue to increase into 2021.6 Rather, these statistics provide a window into the significant impact the pandemic is having and will continue to have on health care. These statistics also challenge the need to rethink the delivery of patient care — from consultation to disease management — in the short, medium, and long term, given what is unknown about getting the pandemic under control and the uncertainty over the time frame for COVID-19 vaccine development and approval.

Virtual Patient Consultation: Is Telehealth for Every Patient?

The need for ongoing routine care during a deadly global disease has brought new challenges to clinical practice and the need for virtual patient care via telehealth. This includes assessing clinical symptoms; evaluating the results of routine blood tests; making adjustments to medications; managing treatment side effects; and providing psychological support, patient education, and advice.

To accommodate the recommendations for social distancing and the avoidance of in-person medical consultations, the US Centers for Medicare & Medicaid Services expanded access to and relaxed the regulations for use of telehealth for medical consultations.8 While telehealth has enabled some continuum of patient care, it has also been associated with questions and uncertainties related to the approved platforms for telehealth services, state licensure requirements, commercial payer policies, and coding and billing. The American College of Rheumatology (ACR) has developed a comprehensive resource on telehealth as a guide to help physicians navigate virtual consultancy for ongoing patient care.9

Telehealth is not a new concept and has been a critical component of medical care in some parts of the world, particularly in the rural areas of low- and middle-income countries. The successful use of telemedicine for the treatment of patients with rheumatologic and musculoskeletal diseases was demonstrated in a study of more than 4800 patients in Iran who were managed remotely for longer than 5 years by a rheumatologist based in the United States.10 The most common disorders managed were osteoarthritis (23.6%), rheumatoid arthritis (13.4%), axial spondyloarthropathies (13.3%), lumbar spinal stenosis (8.8%), meniscal tear of the knee (6.7%), psoriatic arthritis (4.5%), fibromyalgia (3.5%), and lupus (0.4%).10 Disease management included diagnostic tests (serologic tests, plain radiographs, magnetic resonance imaging, bone densitometry, and electromyography and nerve conduction studies) and prescription medicines (nonsteroidal anti-inflammatory drugs, methotrexate, pregabalin, duloxetine, sulfasalazine, etanercept, tofacitinib, adalimumab, and infliximab).10

Given the trajectory of the COVID-19 pandemic, as well as the uncertainty over its duration, the latter study suggests that telehealth can be used to successfully manage patients with rheumatologic and musculoskeletal diseases on a long-term basis.11 However, a cautious note comes from Syed Atiqul Haq, MD, MBBS, FRCP, FCPS, professor of rheumatology, president of the Asia Pacific League of Associations for Rheumatology (APLAR), and vice president of the Lupus Foundation of Bangladesh. “Telehealth is appropriate for the majority [of patients but], not for all,” said Dr Haq. So, when is telehealth not appropriate? “In case of emergencies,” Dr Haq clarified, “for example, systemic lupus erythematosus (SLE) with acute breathlessness, when the need for palpation, auscultation, etc cannot be obviated by supplementary history, inspection, and investigations.” The European League Against Rheumatism (EULAR) guidelines recommend postponement of nonessential rheumatology appointments if these can be safely delayed; for essential appointments, virtual consultations should be considered. Despite the uncertainties and the evolving understanding of COVID-19, telehealth has become an essential medium for communicating accurate information and providing education and support to patients. The current advice to patients is to observe the guidelines for social distancing, masking, and regular hand washing, especially if the patients are receiving immunosuppressive therapy or have lung fibrosis.

Rules of Engagement: Treating Rheumatic and Musculoskeletal Diseases During the COVID-19 Pandemic

Immunosuppressive agents are central to the treatment of many rheumatic and musculoskeletal diseases, especially those that are driven by the uncontrolled response of the immune system that manifests as a tissue-damaging inflammatory cascade. Appropriately and optimally treating rheumatic and musculoskeletal diseases is challenged by the atypical manifestations of COVID-19 that can mimic the symptoms of rheumatic and musculoskeletal diseases and complicated by side effects from the various antiviral agents that have been used to treat COVID-19 infection.12,13 In fact, the proinflammatory cytokines induced in COVID-19 — interleukin (IK)-6, IL-1β, tumor necrosis factor (TNF), and the Janus kinase (JAK) pathway — have similarities to those targeted in the treatment of rheumatoid arthritis.14 However, the impact of the COVID-19-induced proinflammatory cytokines on rheumatic and musculoskeletal diseases is currently unknown.

In this new normal, rheumatologist and other healthcare providers treating rheumatic and musculoskeletal diseases must make critical decisions for disease management that include patient eligibility for treatment, selection of appropriate treatment, and dose management, as well as disease monitoring and treatment side effect mitigation. Healthcare providers must also consider when it is appropriate to temporarily halt treatment or discontinue therapy, particularly nonbiologic and biologic DMARDs that may be associated with increased infection risk.

The potential for an increased risk for SARS-CoV-2 infection is a serious concern for both physicians and patients. The at-risk population has been widely recognized as older people with a pre-existing condition. Severe cases of SARS-CoV-2 infection have been determined to involve potentially fatal respiratory dysfunction; therefore, SARS-CoV-2 infection is a major concern for patients with systemic sclerosis who are vulnerable to interstitial lung disease.15 Consequently, patients with rheumatic and musculoskeletal diseases, who generally fall into the “at-risk population,” are likely to be anxious about an increased risk for SARS-CoV-2 infection. Although there are currently no robust data that have assessed the risks of SARS-CoV-2 infection in specific rheumatic and musculoskeletal diseases, small-scale single-center studies suggest higher infection rates in this population.

A study of 1641 Italian patients with autoimmune systemic disease found a higher prevalence of COVID-19 disease compared with the general Italian population; prevalence among patients with connective tissue diseases (including systemic sclerosis, lupus, undifferentiated connective tissue disease, polymyositis/dermatomyositis, and Sjögren syndrome) was significantly higher compared with patients with inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis). A higher frequency of COVID-19 was also seen in patients who were not receiving ongoing treatment with hydroxychloroquine and methotrexate.16 Similar findings were observed in a study of hospitalized COVID-19 patients with chronic inflammatory rheumatic diseases.17 In this study, patients with connective tissue disease (but not those with inflammatory disease or those previously treated with immunosuppressive therapies) had more severe COVID-19 presentation.17 These findings suggest that hydroxychloroquine and methotrexate may have a protective role against COVID-19.

It has been generally thought that a robust immune system is essential for recovery from a SARS-CoV-2 infection. Key questions that arise are whether SARS-CoV-2 infection presents a serious challenge for immunocompromised patients with inflammatory autoimmune systemic disease and whether treatment regimens, particularly immunosuppressive medications, should be modified in dosage or temporarily discontinued. These are questions that can be answered with some degree of confidence only as studies are conducted and data emerge. However, early small-scale studies conducted in areas with a high rate of cases of COVID-19 suggested that among patients with rheumatic diseases, poor outcome and mortality were more closely associated with older age and comorbidities than with the degree of pharmacologic immunosuppression.18 Another study suggests that the incidence and severity of SARS-CoV-2 infection in patients with rheumatic diseases treated with targeted synthetic or biologic DMARDs were not significantly different from those of the general population.19

The confusion in the early days of the COVID-19 pandemic was reflected in patients’ perceived increased risk to SARS-CoV-2 infection and poor outcomes from immunosuppressive therapy. These perceptions resulted in suboptimal disease management, either from patients changing or stopping their medication schedule without consultation with their healthcare provider or from disruption to their medication due to shortages in supply, such as that seen with hydroxychloroquine.20

Guidance for the Treatment of Rheumatic and Musculoskeletal Diseases

The uncertainty over the appropriate and optimal treatment of rheumatic and musculoskeletal diseases in the setting of SARS-CoV-2 infection prompts a concerted effort for evidence-based guidance. The following guidelines have been published since April 2020 to provide a guide for the management of patients with rheumatic and musculoskeletal diseases in the setting of COVID-19:

• American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic: Version 221
• EULAR Provisional Recommendations for the Management of Rheumatic and Musculoskeletal Diseases in the Context of SARS-CoV-211
• Care for Patients With Rheumatic Diseases During COVID-19 Pandemic: A Position Statement From APLAR22
• Managing Patients With Rheumatic Diseases During the COVID-19 Pandemic: The French Society of Rheumatology Answers to Most Frequently Asked Questions Up to May 202023
• British Society of Rheumatology COVID-19 Guidance24
 
The guidelines acknowledge the organic nature of the recommendations and the need for updates as new knowledge emerges. A case in point is the guidance published by the ACR in April 202025 that was updated in July 202019 to reflect the latest evidence; future updates are anticipated. Robert B.M. Landewé, MD, PhD, professor of rheumatology at the Amsterdam Rheumatology & Clinical Immunology Center, the Netherlands, and lead author on the EULAR provisional recommendations, commented that currently much is not known regarding the treatment of patients with rheumatic and musculoskeletal diseases, including recommendations for delaying or stopping routine vaccinations. “A good question. [The] answer [is] still unknown [and] should be figured out first,” said Dr Landewé.

Challenging definitive recommendations is the lack of data, explained Jose L Pablos, MD, PhD, professor at the Universidad Complutense de Madrid (UCM), Spain. “There is no evidence of a deleterious effect of maintaining previous therapy, but most rheumatologists stop the therapy when COVID-19 is suspected or diagnosed, and therefore there is not much information on the outcomes in patients maintaining immunosuppressants.” Overall, however, the guidelines are consistent in their recommendations for the treatment of patients with rheumatic and musculoskeletal diseases. In the setting of active SARS-CoV-2 infection, treatment should be individualized to the patients’ specific needs. Patients should not stop or reduce their medication, including recommended vaccinations, unless considered necessary by the physician. Indeed, the EULAR provisional recommendations specifically caution that stopping immunosuppressant drugs could lead to a flare-up of rheumatic conditions, although evidence is still emerging about the effects of immunosuppressant drugs on COVID-19.11 On vaccination, Dr Haq agrees: “The recommended vaccines must be given to the rheumatic patients as per schedule; vaccination should not be deferred.” Dr Haq added, “Vaccinations may be deferred when a patient is infected with SARS-CoV-2 until recovery, as we are not sure about the probability of virus-mediated allergy and other consequences.”

The current general guidance is for the continuation of glucocorticoids and antimalarial (hydroxychloroquine/chloroquine) with consideration for dose reduction. According to Dr Pablos, “Glucocorticoids should not be stopped and have shown efficacy to treat COVID-19 at intermediate or high doses.” Treatment with agents including sulfasalazine, methotrexate, leflunomide, immunosuppressants, and biological agents other than IL-6 receptor inhibitors and JAK inhibitors should be stopped or withheld during active COVID-19. Treatment should resume when the patient is free of COVID-19 symptoms and at least 2 weeks after documentation of COVID-19.13,26

Although the various guidelines are consistent in their recommendations, the details and focus of each guideline vary. The most comprehensive is the guidance provided by the ACR as summarized in Table 1; the focus of the other guidelines is summarized in Table 2. The provisional guideline recommendations from EULAR specifically state that currently there are no data to support that patients with rheumatic and musculoskeletal diseases or patients treated with DMARDs have increased susceptibility to SARS-CoV-2 or have a worse prognosis if infected.11 Furthermore, although patients with systemic inflammatory rheumatic and musculoskeletal diseases are reported to be at increased risk for viral infections, there is currently no evidence that this risk is also associated with COVID-19.27

Table 1. American College of Rheumatology Guidance for the Management of Rheumatic Disease in Adult Patients During the COVID-19 Pandemic, Version 2
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Table 2. Additional Guidance on the Management of Rheumatic and Musculoskeletal Disorders During the COVID-19 Pandemic
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Given the evolving nature in the understanding of COVID-19, a few practice pearls were provided by Drs Haq, Pablos, and Landewé that may serve as a guide to practitioners:

Dr Haq:

• Heighten professional attitude, including empathy, and maintain appropriate demeanor, including paying full attention and maintaining eye-to-eye contact during teleconsultations;
• Practice evidence-based medicine strictly, and exercise due caution in prescribing immunosuppressive medicines, with particular emphasis on exclusion of infections;
• Give due emphasis on evidence-based nonpharmacologic treatment options.

Dr Pablos:

• It is important to maintain contact with patients who are receiving treatment and reassure them that it is not advisable to withdraw [treatment] preventively;
• In the case of suspected or diagnosed COVID-19, provide patients with instructions on what to do with the usual treatment;
• There does not seem to be a greater risk of severe COVID-19 in patients with chronic arthritis, whereas the risk doubles in patients with systemic autoimmune diseases and, therefore, this group should take extreme protective measures.

Dr Landewé:

• Advise patients not to stop their antirheumatic treatment, to practice social distancing, and to consult their rheumatologist.

References

1. United States COVID-19 cases and deaths by state. Centers for Disease Control and Prevention website. https://covid.cdc.gov/covid-data-tracker/#cases_totaldeaths. Updated September 24, 2020. Accessed September 24, 2020.
2. COVID-19 hospitalization and death by age. Centers for Disease Control and Prevention website. https://www.cdc.gov/coronavirus/2019-ncov/downloads/covid-data/hospitalization-death-by-age.pdf. Updated September 24, 2020. Accessed September 24, 2020.
3. Worldometer. COVID-19 Coronavirus Pandemic. https://www.worldometers.info/coronavirus/. Updated September 17, 2020. Accessed September 17, 2020.
4. Worldometer. COVID-19 Coronavirus Pandemic. Reported Cases and Deaths by Country, Territory, or Conveyance. https://www.worldometers.info/coronavirus/#countries. Updated September 24, 2020. Accessed September 24, 2020.
5. Worldometer. COVID-19 Coronavirus Pandemic. Coronavirus Worldwide Graphs. https://www.worldometers.info/coronavirus/worldwide-graphs/. Updated September 17, 2020. Accessed September 17, 2020.
6. IHME. COVID-19 Projections, United States. https://covid19.healthdata.org/united-states-of-america/?view=total-deaths&tab=trend. Updated September 11, 2020. Accessed September 17, 2020.
7. IHME. COVID-19 Projections, Global. https://covid19.healthdata.org/global?view=total-deaths&tab=trend. Updated September 11, 2020. Accessed September 17, 2020. 
8. Medicare Telemedicine Health Care Provider Fact Sheet. CMS.gov. https://www.cms.gov/newsroom/fact-sheets/medicare-telemedicine-health-care-provider-fact-sheet. Accessed September 17, 2020.
9. COVID-19 Practice and Advocacy Resources. American College of Rheumatology. https://www.rheumatology.org/Announcements/COVID-19-Practice-and-Advocacy. Updated September 11, 2020. Accessed September 17, 2020.
10. Rezaian MM, Brent LH, Roshani S, et al. Rheumatology care using telemedicine. Telemed J E Health. 2020;26(3):335-340. doi:10.1089/tmj.2018.0256
11. Landewé RB, Machado PM, Kroon F, et al. EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2. Ann Rheum Dis. 2020;79(7):851-858. doi:10.1136/annrheumdis-2020-217877
12. Shah S, Danda D, Kavadichanda C, Das S, Adarsh MB, Negi VS. Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment. Rheumatol Int. 2020;40(10):1539-1554. doi:10.1007/s00296-020-04639-9
13. Misra DP, Agarwal V, Gasparyan AY, Zimba O. Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clin Rheumatol. 2020;39(7):2055-2062. doi:10.1007/s10067-020-05073-9
14. Schett G, Manger B, Simon D, Caporali R. COVID-19 revisiting inflammatory pathways of arthritis. Nat Rev Rheumatol. 2020;16(8):465-470. doi:10.1038/s41584-020-0451-z
15. Orlandi M, Lepri G, Bruni C, et al. The systemic sclerosis patient in the COVID-19 era: the challenging crossroad between immunosuppression, differential diagnosis and long-term psychological distress. Clin Rheumatol. 2020;39(7):2043-2047. doi:10.1007/s10067-020-05193-2
16. Ferri C, Giuggioli D, Raimondo V, et al. COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series. Clin Rheumatol. Published online Aug 27, 2020. doi:10.1007/s10067-020-05334-7
17. Pablos JL, Galindo M, Carmona L, et al. Clinical outcomes of hospitalised patients with COVID-19 and chronic inflammatory and autoimmune rheumatic diseases: a multicentric matched cohort studyAnn Rheum Dis. Published online Aug 12, 2020. doi:10.1136/annrheumdis-2020-218296
18. Fredi M, Cavazzana I, Moschetti L, Andreoli L, Franceschini F; Brescia Rheumatology COVID-19 Study Group. COVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case-control study. Lancet Rheumatol. 2020;2(9):e549-e556. doi:10.1016/S2665-9913(20)30169-7
19. Favalli EG, Monti S, Ingegnoli F, Balduzzi S, Caporali R, Montecucco C. Incidence of COVID-19 in patients with rheumatic diseases treated with targeted immunosuppressive drugs: what can we learn from observational data? Arthritis Rheumatol. Published online June 7, 2020. doi:10.1002/art.41388
20. Michaud K, Wipfler K, Shaw Y, et al. Experiences of patients with rheumatic diseases in the United States during early days of the COVID-19 pandemic. ACR Open Rheumatol. 2020;2(6):335-343. doi:10.1002/acr2.11148
21. Mikuls TR, Johnson SR, Fraenkel L, et al. American College of Rheumatology guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic: version 2. Arthritis Rheumatol. Published online July 30, 2020. doi:10.1002/art.41437
22. Tam LS, Tanaka Y, Handa R, et al. Care for patients with rheumatic diseases during COVID-19 pandemic: a position statement from APLAR. Int J Rheum Dis. 2020;23(6):717-722. doi:10.1111/1756-185X.13863
23. Richez C, Flipo RM, Berenbaum F, et al. Managing patients with rheumatic diseases during the COVID-19 pandemic: the French Society of Rheumatology answers to most frequently asked questions up to May 2020. Joint Bone Spine. Published online May 27, 2020. doi:10.1016/j.jbspin.2020.05.006
24. COVID-19 guidance. British Society of Rheumatology. https://www.rheumatology.org.uk/practice-quality/covid-19-guidance. Updated July 29, 2020. Accessed September 17, 2020.
25. Mikuls TR, Johnson SR, Fraenkel L, et al. American College of Rheumatology guidance for the management of rheumatic disease in adult patients during the COVID-19 pandemic: version 1. Arthritis Rheumatol. Published online Apr 29, 2020. doi:10.1002/art.41301
26. Kow CS, Hasan SS. Pharmacotherapeutic considerations for systemic rheumatic diseases amid the COVID-19 pandemic: more questions than answers. Drugs Ther Perspect. Published online Aug 16, 2020. doi:10.1007/s40267-020-00767-1
27. Romão VC, Cordeiro I, Macieira C, et al. Rheumatology practice amidst the COVID-19 pandemic: a pragmatic view. RMD Open. 2020;6(2):e001314. doi:10.1136/rmdopen-2020-001314
 
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Rheumatology Advisor had no role in this content’s preparation.

Reviewed October 2020

Interleukin-6 Receptor Inhibitors for the Treatment of Rheumatoid Arthritis

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

Click Here for PDF

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
Flip
Side Effects
Side effects most commonly reported include injection side redness, upper respiratory tract infection, urinary tract infection, headache, high blood pressure, high cholesterol, and the common cold.
Sarilumab
Flip
Side Effects
Side effects most commonly reported include injection site redness, upper respiratory tract infection, urinary tract infection, nasal congestion, sore throat, and runny nose.

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

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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.
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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.
10. Kevzara. Prescribing information. Sanofi and Regeneron Pharmaceuticals, Inc. April 2018. Accessed August 31, 2020. http://products.sanofi.us/Kevzara/Kevzara.pdf
11. AAC (Arthritis Advisory Committee, FDA). Summary Minutes of the Arthritis Advisory Committee Meeting August 2. Silver Spring, MD: Food and Drug Administration; 2017. August 2017. Accessed August 31, 2020.  https://www.fda.gov/media/107409/download.
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15. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88-96. doi:10.1136/ard.2008.105197
16. Yamamoto K, Kawai S, Takeuchi T, Murata N, Van Der Heijde D, Kishimoto T. Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162-1167. doi:10.1136/ard.2006.068064
17. Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition. Mod Rheumatol. 2009;19:12-19. doi:10.1007/s10165-008-0125-1
18. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43-50. doi: 10.1136/annrheumdis-2011-201282
19. Burmester GR, Rigby WF, Vollenhoven RF Van, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081-1091. doi:10.1136/annrheumdis-2015-207628
20. Heurkens AHM, Teitsma XM, Tekstra J, Marijnissen ACA, Lafeber FPJ, Jacobs JWG. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-355. doi:10.1016/S0140-6736(16)30363-4
21. Gabay C, Emery P, Van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. doi:10.1016/S0140-6736(13)60250-0
22. Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: Results from the double‐blind treatment phase of a randomized placebo‐controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63(3):609-621. doi:10.1002/art.30158
23. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987-997. doi:10.1016/S0140-6736(08)60453-5
24. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012;71(2):198-205. doi:10.1136/ard.2010.148700
25. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968-2980. doi:10.1002/art.23940
26. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2004;50(6):1761-1769. doi:10.1002/art.20303
27. Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology. 2012;51(10):1860-1869. doi:10.1093/rheumatology/kes131
28. Ogata A, Kato Y, Higa S, Yoshizaki K. IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review. Mod Rheumatol. 2019;29(2):258-267. doi:10.1080/14397595.2018.1546357
29. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate. Arthritis Rheumatol. 2015;67(6):1424-1437. doi:10.1002/art.39093
30. Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2018;69(2):277-290. doi:10.1002/art.39944

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Reviewed September 2020

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