Biological Therapies for Rheumatoid Arthritis: An Overview for the Clinician

Figures & data

Table 1 Summary of Biological DMARDs Used in Rheumatoid Arthritis

Drug Class	Efficacy (ACR70*)	Adverse Effects	Contraindications^^
TNF-α inhibitor
Adalimumab 40mg SC fortnightly	20–21% (MTX inadequate responders)^Citation6,Citation8,Citation9 12% (TNFi inadequate responders)^Citation12	Infections, TB reactivation, injection site reactions, hypersensitivity reactions, LFT derangements, psoriasis, drug-induced lupus, blood dyscrasias, malignancy (non-melanomatous skin cancers, lymphoma), exacerbation demyelinating disease, exacerbation of heart failure	Serious or untreated infections including TB, current malignancy, multiple sclerosis, severe heart failure, hypersensitivity
Certolizumab pegol 200mg SC fortnightly
Etanercept 50mg SC weekly or 25mg twice weekly
Golimumab 50–100mg SC monthly
Infliximab 3–10mg/kg IV 4–8 weekly
IL-6 inhibitor
Tocilizumab 162mg SC weekly or 8mg/kg IV monthly	22% (MTX inadequate responders)^Citation24 12% (TNFi inadequate responders)^Citation21	Infections, injection site reactions, hypersensitivity reactions, LFT derangements, hyperlipidaemia, neutropenia, diverticulitis and GI perforation	Serious or untreated infections, hypersensitivity, diverticulitis
Sarilumab 150–200mg SC fortnightly
CD20 depleting antibody
Rituximab IV 2 course dose 500–1000mg, repeat after >6 months	20% (MTX inadequate responders)^Citation67 12% (TNFi inadequate responders)^Citation68	Infections, hypersensitivity reactions, cytopaenias, hepatitis B reactivation, progressive multifocal leukoencephalopathy	Serious or untreated infections including hepatitis B, hypersensitivity
CD80/86 costimulation inhibitor
Abatacept 125mg SC weekly or IV infusion	21% (MTX inadequate responders)^Citation18 10% (TNFi inadequate responders)^Citation19	Infections, hypersensitivity reactions, infusion reactions, leukopenia, bronchitis	Serious or untreated infections, current malignancy, hypersensitivity
IL-1 inhibitor
Anakinra 100mg SC daily	7% (either MTX naïve or MTX inadequate responders)^Citation27	Infections, injection site reactions	Serious or untreated infections, hypersensitivity

Notes: Drug dosing, adverse effect profile and contraindications were adapted from the Australian Medicine Handbook⁶⁹. The adverse effects listed are a selective and far from an exhaustive list. *ACR70 is a composite measure defined as an improvement of at least 70% in the number of tender and number of swollen joints, and at least a 70% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein. ACR70% response rates correspond with a state of either remission or low disease activity and are used as surrogates of low disease activity. ^{^}Absolute or relative.

Table 2 Summary of EULAR and ACR RA Treatment Guidelines

	EULAR	ACR
First-line (Immediately at diagnosis)	Start csDMARD (MTX preferred, if intolerant or contraindicated use another csDMARD)	Start csDMARD (MTX preferred in moderate-to-high disease activity, hydroxychloroquine then sulfasalazine preferred in low disease activity)
Second line (At three months if no significant improvement, or at six months if complete remission not attained)	If no poor prognostic factors*: add second csDMARD or If poor prognostic factors*: add bDMARD or tsDMARD or If poor prognostic factors* and unable to tolerate csDMARDs: preference IL-6i or tsDMARD monotherapy.	Add any bDMARD or tsDMARD to csDMARD or If previous serious infection in the previous 12 months or history of NTMB lung disease: add second csDMARD or If history of heart failure: add non-TNFi bDMARD or tsDMARD to csDMARD or If history of lymphoproliferative disorder: add rituximab to csDMARD
Third line and beyond (At nine months if no significant improvement, or at twelve months if complete remission not attained)	Add bDMARD or tsDMARD to current csDMARD regimen. or Change to another bDMARD or tsDMARD in combination with continued csDMARD or If failure of TNFi bDMARD: switch to another TNFi bDMARD, or non-TNFi bDMARD or tsDMARD	If failure of bDMARD or tsDMARD, change to a bDMARD or tsDMARD of a different class, in combination with continued csDMARD
Remission (After six months of complete remission)	Consider tapering bDMARD or tsDMARD first, continue csDMARD. If 6 months remission on csDMARD, consider tapering csDMARD but beware of relapse risk.	Continuation of all DMARDs is recommended, even if remission is achieved (and if this is not an option tapering is recommended over discontinuation)
Additional information	Short-term glucocorticoids should be considered when initiating or changing csDMARDs, but taper as quickly as possible	Initiation of csDMARDs without short-term glucocorticoids is recommended over doing so with glucocorticoids

Notes: *Poor prognostic factors = high number of swollen joints, high level of acute phase reactants, presence of early erosions, rheumatoid factor or anti-cyclic-citrullinated peptide positivity, persistently high disease activity on csDMARD. Data from these studies.^14,50

Abbreviations: csDMARD, conventional synthetic disease modifying anti-rheumatic drug; MTX, methotrexate; bDMARD, biological disease modifying anti-rheumatic drug; tsDMARD, targeted synthetic disease modifying anti-rheumatic drug; NTMB, non-tuberculous mycobacterial lung disease; IL6i, interleukin 6 inhibitor; TNFi, tumour necrosis factor inhibitor.

Keystone E, Genovese M, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO‐FORWARD Study. Ann Rheum Dis. 2009;68(6):789–796. doi:10.1136/ard.2008.099010

 PubMed Web of Science ®Google Scholar

Keystone E, Kavanaugh A, Sharp J, et al. Radiographic, clinical, and functional outcomes of treatment with Adalimumab (a human anti‐tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy. A randomized, placebo‐controlled, 52‐week trial. Arthritis Rheum. 2004;50(5):1400–1411. doi:10.1002/art.20217

 PubMed Web of Science ®Google Scholar

Keystone E, van der Heijde D, Mason D, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two–week, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319–3329. doi:10.1002/art.23964

 PubMed Web of Science ®Google Scholar

Smolen JS, Kay J, Doyle MK, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO‐AFTER study): a multicentre, randomised, double‐blind, placebo‐controlled, phase III trial. Lancet. 2009;374(9685):210–221. doi:10.1016/S0140-6736(09)60506-7

 PubMed Web of Science ®Google Scholar

Vershueren P, Emery P, van Hoogstraten H, et al. Efficacy of sarilumab in patients with rheumatoid arthritis with and without previous response to tocilizumab. Ann Rheum Dis. 2018;77(supp 2):327–328. doi:10.1136/annrheumdis-2018-eular.1376

 Web of Science ®Google Scholar

Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–1523. doi:10.1136/ard.2008.09293

 PubMed Web of Science ®Google Scholar

Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54(5):1390–1400. doi:10.1002/art.21778

 PubMed Web of Science ®Google Scholar

Cohen S, Emery P, Greenwald M, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793–2806. doi:10.1002/art.22025

 PubMed Web of Science ®Google Scholar

Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096–1103. doi:10.1136/ard.2007.080002

 PubMed Web of Science ®Google Scholar

Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353(11):1114–1123. doi:10.1056/NEJMoa050524

 PubMed Web of Science ®Google Scholar

Merten M, Singh J. Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev. 2009. doi:10.1002/14651858.CD005121.pub3

 Web of Science ®Google Scholar

Gary M.H. Misan. Australian Medicines Handbook 2020. Adelaide: Australian Medicines Handbook Pty Ltd; July, 2020. Available from https://amhonline.amh.net.au/. Accessed August 3, 2021.

 Google Scholar

Fraenkel L, Bathon J, England B, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021;73(7):924–939. doi:10.1002/acr.24596

 PubMed Web of Science ®Google Scholar

Smolen JS, Landewe RB, Bijlsma JW, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2019;79(6):685–699. doi:10.1136/annrheumdis-2019-216655

 Web of Science ®Google Scholar