sign in sign up
<<
Home , Methotrexate, TNF inhibitor

Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218019 on 11 June 2020. Downloaded from opportunities and collaborative research Smart battles: efforts, in new directions and with new part- ners—rheumatologists working with infec- versus immunomodulation in the tious disease physicians, pulmonologists and intensivists as we join forces to fight inflammatory RMDs COVID-19. Indeed, it is critical that rheu- matologists are present at the COVID-19 1 2 table, providing insights into the risk:ben- John D Isaacs ‍ ‍ , Gerd R Burmester ‍ ‍ efit ratio of using cytokine blockade, based on more than two decades of experience. During such discussions, we must not forget The past two decades have witnessed the >90%, using drugs such as , normal physiology, for example, that type I revolution of targeted therapies for mycophenolate and sometimes glucocorti- is essential for viral defence and immune-mediated­ inflammatory diseases, coids.7 However, this success comes at the GM-­CSF for surfactant production by alve- largely pioneered for rheumatological indi- cost of a significantly heightened risk of olar myeloid cells, stressing the potential cations. These include tumour necrosis serious infections and .8 9 Rheumatol- importance of timing when using targeted factor (TNF) blockade, interleukin (IL)-6 ogists are cognisant of similar risks when we interventions. We should be appropriately blockade, IL-1 blockade, IL-17 use glucocorticoids, , cautious when advocating trials of these blockade, IL-12/23 blockade, B-cell­ deple- and mycophenolate, particu- potent therapies, as we are every day in our tion and costimulation blockade. Other larly in combination. clinics, reflecting common sense principles as well as formal guidance. targets, such as type I and gran- The way we describe our tools and our The important message, when contrasting ulocyte macrophage-­colony stimulating actions has a profound effect on the under- targeted therapies and immunosuppres- factor (GM-C­ SF) remain under investiga- standing of our patients and other health- 1 sants, is that the is a highly tion. Most recently, (JAK) care professionals. The choice between the sophisticated organ, which adopts a ‘belt inhibition has provided a small molecule terms immunosuppressants and immuno- and braces’ approach when protecting our route to targeted interventions. These ther- modulators to describe the drugs that we body from foreign invaders. Consequently, apies have been revolutionary, largely use to treat inflammatory rheumatic and when an allograft is detected, multiple because they have provided previously musculoskeletal diseases (RMDs) provides a immune effector mechanisms are mobil- unprecedented efficacy with relative safety. topical and important example. For patients, ised synchronously, to rapidly eliminate Thus, the risk of a serious infection with a the difference between their immune the ‘invader’; therefore reversal of allograft TNF inhibitor is slightly higher than with a system being suppressed, with the implicit rejection requires broadly acting immuno- conventional synthetic disease-modifying­ susceptibility to infection, and modulation suppressive drugs to disable multiple mecha- drug such as but significantly to become more normal, can affect their nisms, unavoidably enhancing infection risk less than with higher doses of glucocorti- behaviours in terms of work and social 2 3 in parallel. In contrast, immune-mediated­ coids for example. Similarly, multiple activities. In their COVID-19 guidance, the studies have failed to demonstrate an inflammatory diseases (IMIDs) are complex American College of (ACR) disorders in which multiple, subtle, inher- enhanced risk of solid or repeatedly distinguishes immunosuppres- with biological and targeted synthetic ited defects in immune regulatory pathways, sants (eg, tacrolimus, cyclosporin A (CSA), combined with environmental triggers, http://ard.bmj.com/ disease-­modifying anti-­rheumatic drugs mycophenolate mofetil (MMF), azathio- (DMARDs).4 Notably, also treatment with result in the gradual onset of autoreactivity prine [AZA]), biologics and/or JAK inhibi- and a chronic inflammatory state. While methotrexate which is still the cornerstone tors.10 In contrast, the National Institutes of of treatment in (RA), multiple immuno-inflammatory­ pathways Health (NIH) highlights ‘the broad immu- may be upregulated in tissues, the success of does not have profound immunosuppres- 11 nosuppressive effect of JAK inhibitors’ sive effects, since in the Cardiovascular targeted therapies suggest that these operate and the EULAR COVID-19 guidance in series with one or a few dominating. Reduction Trial (CIRT) with on October 1, 2021 by guest. Protected copyright. refers to ‘immunosuppressive treatments, non-­RA patients the hazard rate for infec- Therefore, targeting TNF in RA, or IL-17 including synthetic DMARDs and biologic tions was low (1.15 (CI: 1.01 to 1.30)) in , may restore homeostasis and DMARDs'. 12 Thus, there appears to be despite significant comorbidities in the health, without a major impact on infection some uncertainty around how we should population studied.5 6 These data sit in risk. Furthermore, unlike allograft rejec- describe the drugs that we, as rheumatolo- contrast to immunosuppressive drugs used tion, efficacy does not necessitate targeting gists, use daily. Indeed, there was animated for indications such as transplantation— of underlying autoreactivity. discussion among the EULAR COVID-19 which were also revolutionary in their time. The immune system is often likened to Task Force around the most appropriate Renal allografts have a 1-year­ survival of an army, the different arms of the immune adjective to use, some members preferring response, and distinct cell subsets, viewed

1 the term ‘immunomodulatory’, which is as regiments, with coordinating roles Translational and Clinical Research Institute and Musculoskeletal Unit, Newcastle University and also not used in the ACR guidance. for ‘generals’ such as dendritic cells, and Newcastle upon Tyne Hospitals NHS Foundation Trust, The COVID-19 pandemic has thrust communicating roles for molecules such as Newcastle upon Tyne, UK several targeted therapies into the spotlight cytokines. Redundancy is a critical virtue 2 Department of Rheumatology and Clinical due to the perception that some serious of the immune system and of armies—if Immunology, Charité University Hospital, Berlin, Germany complications of Severe Acute Respiratory one element is destroyed, or neutralised, Syndrome-­Coronavirus-2 (SARS-­CoV-2) another can often take over. During Correspondence to Professor John D Isaacs, infection reflect excess cytokine production conflicts of the 20th century, however, Newcastle University Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle upon locally in the lungs and, potentially, system- relatively untargeted fighting and attacks Tyne NE2 4HH, UK; john.​ ​isaacs@newcastle.​ ​ac.uk​ ically. This has stimulated tremendous were used in an attempt to overcome this

Isaacs JD, Burmester GR. Ann Rheum Dis Month 2020 Vol 0 No 0 1 Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218019 on 11 June 2020. Downloaded from

Table 1 Immunosuppressant versus immunomodulatory drugs and their actions. Immunomodulatory drugs are usually biological therapeutics with specific, extracellular effects on a particular pathway/cell type. Immunosuppressive drugs are small molecule therapeutics with selective effects on intracellular pathways. We have placed JAK inhibitors (and methotrexate) as immunomodulatory drugs because, to date, their risk:benefit profile aligns more precisely with this category Immunosuppressant—broad effects Immunomodulators—specific effects/anti-­inflammatory Drug Effect Drug Effect Azathioprine Multiple—antiproliferative TNF inhibition Specific cytokine blockade Mycophenolate biosynthesis—antiproliferative, especially lymphocytes IL-6 receptor blockade Specific cytokine blockade Cyclophosphamide Alkylating agent—antiproliferative B-cell­ depletion inhibitor—inhibition of lymphocyte signalling Costimulation blockade (T-­cell modulator) Tacrolimus Calcineurin inhibitor—inhibition of lymphocyte signalling Specific cytokine blockade (IL-1) Glucocorticoids Multiple genomic effects on immune and inflammatory pathways IL-17 inhibition Specific cytokine blockade Inhibits mTOR—inhibits lymphocyte signalling and activation Methotrexate Folic acid antagonist—precise mode of action in IMIDs uncertain   JAK inhibition Selective inhibition of lymphocyte signalling IL, interleukin; mTOR, mammalian target of rapamycin. inherent redundancy, with great loss of Ultimately, the EULAR Task Force on Provenance and peer review Commissioned; life and destruction of infrastructure. The COVID-19 decided to use the term ‘immu- internally peer reviewed. ravages of these conflicts have in part cata- nosuppressive’, ‘since it is the fear for and This article is made freely available for use in lysed the modern concept of technology-­ perception of inappropriate suppression accordance with BMJ’s website terms and conditions enabled ‘smart warfare’, for example, using of the immune system that leads to the for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download drones to target critical installations, such discontinuation of these drugs in the case and print the article for any lawful, non-­commercial as communications systems, incapacitating of COVID-19’. Nonetheless, this approach purpose (including text and data mining) provided capabilities while minimising loss of mili- could reinforce rather than allay concerns, that all copyright notices and trade marks are tary and civilian life and infrastructure. conjuring up the risks of calcineurin retained. Using this analogy, traditional immu- inhibitors, cyclophosphamide and gluco- © Author(s) (or their employer(s)) 2020. No commercial nosuppression is akin to traditional corticoids. Equally importantly, immuno- re-­use. See rights and permissions. Published by BMJ. conflicts—disabling multiple immune modulatory does not equal safety. Used elements simultaneously, often using drug with knowledge, experience, skill, confi- combinations. This relatively broad attack dence and common sense, however, we can on the immune system contrasts with To cite Isaacs JD, Burmester GR. Ann Rheum Dis study the potential benefits of modern day, Epub ahead of print: [please include Day Month Year]. modern targeted therapies, which interrupt immunomodulatory targeted therapies in doi:10.1136/annrheumdis-2020-218019 communications using cytokine blockade, the fight against COVID-19, while mini- or disable just a particular type of lympho- mising the potential for serious adverse Received 16 May 2020 cyte, or regiment, with rituximab, leaving Revised 30 May 2020 events. In this way we, as rheumatologists, Accepted 30 May 2020 the remaining immune army unscathed. can help to find effective treatments for the Of course, targeted therapies still carry Ann Rheum Dis 2020;0:1–3. http://ard.bmj.com/ devastating complications of SARS-CoV­ -2 doi:10.1136/annrheumdis-2020-218019 risks, particularly if not used with care— infection (table 1). combining such treatments leads to more ORCID iDs 13 adverse events ; and, when used long-­ Handling editor Josef S Smolen John D Isaacs http://orcid.​ ​org/0000-​ ​0002-6103-​ ​7056 term, drugs such as rituximab can eventu- Gerd R Burmester http://orcid.​ ​org/0000-​ ​0001-7518-​ ​ Twitter John D Isaacs @ProfJohnIsaacs ally weaken immune defences, and reduced 1131 IgG levels may presage an increased risk Contributors Both authors contributed to the writing References on October 1, 2021 by guest. Protected copyright. 14 of the manuscript. of severe infection. Similarly, there are 1 Baker KF, Isaacs JD. Novel therapies for immune-­ circumstances where even a targeted inter- Funding Work in JDI’s laboratory is supported by mediated inflammatory diseases: what can we the National Institute for Health Research Newcastle learn from their use in rheumatoid arthritis, vention leads to a specific complication due Biomedical Research Centre based at Newcastle upon to lack of redundancy—TNF blockade and spondyloarthritis, systemic erythematosus, Tyne Hospitals NHS Foundation Trust and Newcastle psoriasis, Crohn’s disease and ? Ann (TB) reactivation providing University; and the Research into Inflammatory Arthritis Rheum Dis 2018;77:175–87. a classic example. Perhaps the strongest Centre Versus Arthritis. Work in GRB’s laboratory is 2 Kang EH, Jin Y, Tong AY, et al. Risk of serious infection supported by the German Science Foundation (DFG) endorsement of the potency but relative among initiators of TNF inhibitors plus methotrexate and the German Ministry of Education and Science. safety of these drugs is our willingness to versus triple therapy for rheumatoid arthritis: a cohort study them in populations at risk for RA, in Disclaimer The views expressed are those of the study. Arthritis Care Res 2019. doi:10.1002/acr.24038. authors and not necessarily those of the NHS, the NIHR an attempt to prevent disease onset.15 [Epub ahead of print: 03 Aug 2019]. or the Department of Health. 3 Sepriano A, Kerschbaumer A, Smolen JS, et al. Having worked with targeted therapies Safety of synthetic and biological DMARDs: a for two decades, rheumatologists now have Competing interests JDI: grant from Pfizer, fees for lectures and consulting: AbbVie, Amgen, Eli Lilly, Gilead, systematic literature review Informing the 2019 a unique opportunity to educate colleagues Merck & Co, Roche, UCB. GRB: honoraria for lectures update of the EULAR recommendations for the in other specialities about these inter- and consulting: AbbVie, Amgen, BMS, Gilead, Janssen, management of rheumatoid arthritis. Ann Rheum Dis ventions, which have become our daily Lilly, Novartis, Pfizer, Sanofi-­Aventis, Roche, UCB. 2020;79:annrheumdis-2019-216653. bread. Critically, we should take care when 4 Mercer LK, Regierer AC, Mariette X, et al. Spectrum Patient and public involvement Patients and/or of lymphomas across different drug treatment describing their effects, to avoid inap- the public were not involved in the design, or conduct, groups in rheumatoid arthritis: a European propriate assumptions as to their poten- or reporting, or dissemination plans of this research. registries collaborative project. Ann Rheum Dis tial complications and adverse effects. Patient consent for publication Not required. 2017;76:2025–30.

2 Isaacs JD, Burmester GR. Ann Rheum Dis Month 2020 Vol 0 No 0 Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218019 on 11 June 2020. Downloaded from

5 Ridker PM, Everett BM, Pradhan A, et al. Low-­Dose during the COVID-19 pandemic. Arthritis Rheumatol arthritis who have been treated unsuccessfully with methotrexate for the prevention of atherosclerotic 2020. doi:10.1002/art.41301. [Epub ahead of print: methotrexate. Arthritis Rheum events. N Engl J Med 2019;380:752–62. 29 Apr 2020]. 2004;50:1412–9. 6 Solomon DH, Glynn RJ, Karlson EW, et al. Adverse 11 National Institutes of Health (NIH). Coronavirus 14 van Vollenhoven RF, Emery P, Bingham CO, et al. Long-­ effects of low-dose­ methotrexate: a randomized trial. disease 2019 (COVID-19) treatment guidelines, 2020. Term safety of rituximab in rheumatoid arthritis: 9.5-­ Ann Intern Med 2020;172:369–80. Available: https://​files.covi​ ​d19treat​ ​mentguid​ ​elines.​ 7 Jardine AG, Hartmann A, Holdaas H. Long-­Term nih.gov/​ ​guidelines/covi​ ​d19treat​ ​mentguid​ ​elines.​ year follow-­up of the global programme renal allograft survival: a quiet revolution. Kidney Int pdf.[Accessed 10th June 2020]. with a focus on adverse events of interest in RA 2018;94:853–5. 12 Landewé RB, Machado PM, Kroon F, et al. EULAR patients. Ann Rheum Dis 8 Fishman JA. Infection in organ transplantation. Am J provisional recommendations for the management of 2013;72:1496–502. Transplant 2017;17:856–79. rheumatic and musculoskeletal diseases in the context 15 Al-­Laith M, Jasenecova M, Abraham S, et al. Arthritis 9 Singavi AK, Harrington AM, Fenske TS. Post-­Transplant of SARS-­CoV-2. Ann Rheum Dis 2020. doi:10.1136/ prevention in the pre-­clinical phase of RA with lymphoproliferative disorders.. Cancer Treat Res annrheumdis-2020-217877. [Epub ahead of print: 05 abatacept (the APIPPRA study): a multi-­centre, 2015;165:305–27. Jun 2020]. 10 Mikuls TR, Johnson SR, Fraenkel L, et al. American 13 Genovese MC, Cohen S, Moreland L, et al. randomised, double-blind,­ parallel-­group, placebo-­ College of rheumatology guidance for the Combination therapy with and anakinra controlled clinical trial protocol. Trials management of adult patients with rheumatic disease in the treatment of patients with rheumatoid 2019;20:429. http://ard.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Isaacs JD, Burmester GR. Ann Rheum Dis Month 2020 Vol 0 No 0 3