Peer Reviewed
Rheumatology clinic

New targeted therapies for rheumatoid arthritis

Emily Martin, David Liew

Better understanding of the pathophysiology of rheumatoid arthritis has led to the development of targeted biologic and small molecule (synthetic) disease-modifying antirheumatic drugs (DMARDs), including the janus kinase inhibitors.

Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis, affecting around 1.9% of Australians.1 RA is characterised by polyarthritis, causing pain, irreversible joint damage and disability if left untreated. Treatment aims not just to improve symptoms but to induce remission or control inflammation to prevent joint injury and disability.

The aetiology of RA is unknown; however, tumour necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) appear to be the most abundant cytokines involved. This knowledge has led to the development of targeted therapies that have revolutionised the management of RA.

The early use of disease-modifying antirheumatic drugs (DMARDs) results in better outcomes and a lower risk of refractory disease.2-6 The mainstay of treatment continues to be the conventional synthetic DMARDs (csDMARDs), which include methotrexate, leflunomide and sulfasalazine. However, since the late 1990s, the addition of targeted biological agents, such as the TNF inhibitors, to csDMARDs has provided treatment options for patients with demonstrated inadequate disease control. More recently, targeted small molecule (synthetic) agents, the janus kinase (JAK) inhibitors, have provided further benefit for the up to 30% of patients who continue to have inadequate disease control with targeted biological agents.7 All these agents have also been found useful in patients with other inflammatory diseases, including different inflammatory arthritides.

Targeted therapies require specialist provision, but it is important that all clinicians have some understanding of their increasing role in the management of patients with RA. Here we summarise the role of targeted biologic and small molecule (synthetic) DMARDs in RA.

When is targeted therapy considered? 

Targeted DMARD therapy needs to be considered if a patient with RA fails to achieve disease control or remission within three to six months of treatment with csDMARDs. All targeted therapy has greater efficacy when combined with csDMARDs, and treatment guidelines therefore recommend combination therapy.8-11 Methotrexate is often used as the ‘anchor’ drug, following trials demonstrating a faster onset of action, comparable or greater efficacy, better long-term tolerance and improved survival compared with other conventional DMARDs.12,13 Methotrexate also inhibits the development of antibodies directed at biologic agents that reduce their efficacy, thereby strengthening the case for methotrexate to be used in combination with targeted DMARDs. 

Nonpharmacological management is also important in reducing disease activity and optimising function and quality of life in patients with RA, including those receiving DMARDs. A multidisciplinary approach focusing on patient education, psychosocial interventions, physical activity, nutrition and occupational therapy is recommended (Box).14-24 

Biologic DMARDs

Biologic DMARDs are antibodies that target inflammatory pathways involved in the pathophysiology of RA. Eight biologic DMARDs are currently subsidised by the PBS for the treatment of RA (Table).25 They target TNF, IL-1, IL-6, B-lymphocyte CD20 receptors and T cells. All biologics are injectables, administered either subcutaneously or by infusion.


In 2015-16, the cost of RA to the Australian healthcare system was about $1.2 billion, representing 1% of total disease expenditure.26 Targeted DMARDs have contributed to a large proportion of this cost. Now with patents expiring, biosimilars are emerging and have the potential to reduce treatment costs significantly. Unlike small synthetic agents, biologic agents are large complex molecules and cannot be copied identically to create generics. A biosimilar is a biologic that is highly similar, but not identical, to a reference biologic drug. Despite a theoretical risk of increased immunogenicity, the overall consensus is that biosimilars are sufficiently equivalent in efficacy and safety to their reference biologic as to allow for a single switch from the reference biologic to a biosimilar, although the safety of multiple switches is less certain.27 PBS-funded biosimilars are currently available in Australia for several TNF inhibitors and for rituximab. 

Targeted synthetic DMARDs

The most recent advance in RA treatment has been the development of the JAK inhibitors. The first of these agents, tofacitinib, was listed on the PBS in 2015. Since then, two other JAK inhibitors, baricitinib and upadacitinib, have become available (Table).25 Others are in the later stages of development. 

JAK inhibitors are small synthetic agents that block intracellular signalling of inflammatory cytokines, activation of lymphocytes, and ultimately inflammatory pathways that normally result in joint destruction. In contrast to biologic agents, JAK inhibitors are administered orally and lack the potential to generate antidrug antibodies.

Similarly to biologic DMARDs, contraindications to JAK inhibitors include severe infections, active tuberculosis, neutropenia (neutrophil count less than 1.0 x 109 cells/L) and severe liver impairment. The safety of the targeted synthetic DMARDs during pregnancy is unclear, and thus patients who are pregnant or planning pregnancy need ongoing specialist input.

Which targeted therapy?

With the rapid evolution of treatment options for RA, choosing the ‘correct’ agent to optimise treatment success has become more challenging. Research has failed to identify clinical or biological markers that would enable individual responsiveness to a particular targeted therapy to be predicted. There is some evidence that the JAK inhibitors may be effective as monotherapy, although they have higher efficacy when prescribed in combination with methotrexate.28,29 There is even some suggestion that they have potential superior efficacy over biologics in some contexts.30-32

Therapy choice depends mostly on PBS criteria, specialist experience and acceptability of the route of administration to the individual patient. However, some disease characteristics and comorbidities help direct treatment choice. 

  • Rituximab and abatacept may be more efficacious in patients who are seropositive (i.e. with antibodies to rheumatoid factor and/or anticyclic citrullinated peptides [anti-CCP]).33-35 
  • For patients who show an inadequate initial response to anti-TNF therapy, meta-analyses suggest that agents with alternative mechanisms of action are more likely to be efficacious, although other anti-TNF agents may still lead to benefit.36 
  • Comorbid interstitial lung disease and chronic obstructive lung disease are not uncommon. TNF inhibitors have been reported to have possible pulmonary complications, and may best be avoided in the first instance in patients with severe lung disease.37 
  • Rituximab, also previously avoided in patients with severe lung disease, has now been shown to stabilise symptoms and lung function in patients with interstitial lung disease.38 

Despite these differences, the likelihood of efficacy is largely indistinguishable between targeted agents. Individual biologic and targeted synthetic DMARDs remain of equal standing in treatment guidelines as options in patients with inadequate disease control on conventional DMARDs.

Pretreatment evaluation

Before initiating therapy, all patients should have baseline blood tests, including a full blood examination and measurement of serum creatinine and liver enzyme levels. Patients should also be screened for latent or chronic infections such as hepatitis B, hepatitis C, HIV infection and tuberculosis. Pregnancy, lactation, malignancy and other medical comorbidities are further important considerations before the initiation of therapy. Notably, certolizumab has been shown to lack placental transfer, and biologic DMARDs are not effectively absorbed by breastfeeding children, although targeted synthetic DMARDs may be absorbed.39,40

Adverse effects and management concerns 


Cytokines involved in inflammation play an important role in protecting against infection. All targeted therapies increase the risk of infection. Symptoms and signs are often absent, emphasising the need for medical practitioners to remain alert to the possibility of both common and opportunistic infections in patients receiving targeted therapies. 

Rates of serious infection are comparable between biologic and targeted synthetic DMARDs, with the exception of herpes zoster, which occurs more often with targeted synthetic DMARDS.4,5 The rates of serious infection are increased in patients with lymphopenia, emphasising the importance of monitoring lymphocyte counts.41

Rates of reactivation of latent tuberculosis and other opportunistic infections appear higher in patients receiving targeted therapies compared with the general population.41 The risk of tuberculosis reactivation appears greatest with monoclonal antibody TNF inhibitors (e.g. infliximab and adalimumab, but not etanercept).42-45 It remains unclear whether the JAK inhibitors carry a similar risk.


Patients with RA are recommended to have annual influenza vaccination, as they are at increased risk of complications, and to be up to date with pneumococcal vaccination. Although live vaccines such as the zoster, measles, mumps and rubella, and yellow fever vaccines are strictly contraindicated in patients receiving biologic or targeted synthetic DMARDs, inadvertent dosing has not shown any infective complications.46,47


Patients with RA are at increased risk of lung and lymphoma malignancies compared with the general population.48 Aside from an increased risk of nonmelanoma skin cancers, particularly with TNF inhibitors, biologic and targeted synthetic DMARDs do not appear to increase the risk of malignancy.49 Regular six to 12-monthly skin checks and age-appropriate malignancy screening are recommended. Ongoing longer term data are required to further evaluate malignancy risk.

Thrombotic complications

Patients with RA have an increased background risk of thromboembolic complications. JAK inhibitors may contribute to a small increase in this risk, but further confirmation and quantification are required.50,51

The future of targeted therapy

The future role of targeted therapies, especially JAK inhibitors, in Australia as initial or monotherapy in RA is unclear. With longer term data, greater clinical experience, the availability of biosimilar drugs and the development of precision medicine, this will likely change. Nevertheless, around 20% of patients with RA continue to have refractory disease despite targeted therapies, and further therapeutic developments are needed.52,53


RA is a chronic, inflammatory disease capable of causing joint destruction, pain and disability. Early diagnosis and treatment are essential to avoid complications. Optimal management involves a multidisciplinary approach, with nonpharmacological as well as pharmacological therapies. Over the past three decades, better understanding of the pathophysiology of RA has led to improved targeted therapies, including biologic DMARDs and, more recently, the JAK inhibitors. Knowledge of their relative benefits will facilitate their best use.     MT

COMPETING INTERESTS: Dr Liew was formerly a member of an Advisory Board unrelated to rheumatoid arthritis for Bristol Myers Squibb, for which he received no remuneration. Dr Martin: None.   



1.    Australian Institute of Health and Welfare (AIHW). Rheumatoid arthritis. Canberra: AIHW; 2020. Available online at: (accessed March 2021).
2.    Bécède M, Alasti F, Gessl I, et al. Risk profiling for a refractory course of rheumatoid arthritis. Semin Arthritis Rheum 2019; 49: 211-217.
3.    Benjamin O, Bansal P, Goyal A, Lappin SL. Disease modifying anti-rheumatic drugs (DMARD). StatPearls; 2020. Available online at: (accessed March 2021).
4.    Demoruelle MK, Deane KD. Treatment strategies in early rheumatoid arthritis and prevention of rheumatoid arthritis. Curr Rheumatol Rep 2012; 14: 472.
5.    Emery P, Duquenne L. It’s never too soon to treat rheumatoid arthritis: finally, some supportive evidence. Lancet Rheumatol 2020; 2: e311-e313.
6.    Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000; 43: 22-29.
7.    Mewar D, Wilson AG. Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors. Br J Pharmacol 2011; 162: 785-791.
8.    Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis 2016; 75: 1081-1091.
9.    Emery P, Burmester GR, Bykerk VP, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis 2015; 74: 19-26.
10.    Kaneko Y, Atsumi T, Tanaka Y, et al. Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study). Ann Rheum Dis 2016; 75: 1917-1923.
11.    Fleischmann R, Mysler E, Hall S, et al; ORAL Strategy investigators. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017; 390: 457-468. 
12.    Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359: 1173-1177. 
13.    Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 2000; 39: 975-981. 
14.    Roelsgaard IK, Ikdahl E, Rollefstad S, et al. Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients. Rheumatology (Oxford) 2020; 59: 1997-2004.
15.    Saevarsdottir S, Wedrén S, Seddighzadeh M, et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum 2011; 63: 26-36.
16.    Warsi A, LaValley MP, Wang PS, Avorn J, Solomon DH. Arthritis self-management education programs: a meta-analysis of the effect on pain and disability. Arthritis Rheum 2003; 48: 2207-2213.
17.    Cramp F, Hewlett S, Almeida C, et al. Non-pharmacological interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev 2013; (8): CD008322.
18.    Bradley LA, Young LD, Anderson KO, et al. Effects of psychological therapy on pain behavior of rheumatoid arthritis patients. Treatment outcome and six-month follow up. Arthritis Rheum 1987; 30: 1105-1114.
19.    Stavropoulos-Kalinoglou A, Metsios GS, Veldhuijzen van Zanten JJJCS, Nightingale P, Kitas GD, Koutedakis Y. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann Rheum Dis 2013; 72: 1819-1825.
20.    Katz P, Andonian BJ, Huffman KM. Benefits and promotion of physical activity in rheumatoid arthritis. Curr Opin Rheumatol 2020; 32: 307-314.
21.    Rausch Osthoff A-K, Juhl CB, Knittle K, et al. Effects of exercise and physical activity promotion: meta-analysis informing the 2018 EULAR recommendations for physical activity in people with rheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis. RMD Open 2018; 4: e000713.
22.    Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones J, Van den Ende ECHM. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database Syst Rev 2009; (4): CD006853.
23.    Forsyth C, Kouvari M, D’Cunha NM, et al. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int 2018; 38: 737-747.
24.    Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017; 76: 17-28.
25. Ng B, Wong PKK. Established rheumatoid arthritis: achieving remission. Med Today 2020; 21(5): 29-34. 26.    Australian Institute of Health and Welfare (AIHW). Arthritis. Impact of arthritis. Canberra: AIHW; 2020. Available online at: (accessed March 2021).
27.    Kay J, Schoels MM, Dörner T, et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann Rheum Dis 2018; 77: 165-174.
28.    Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014; 370: 2377-2386.
29.    Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367: 495-507.
30.    Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 2017; 69: 506-517.
31.    Genovese MC, Kremer JM, Kartman CE, et al. Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis. Rheumatology (Oxford) 2018; 57: 900-908.
32.    Rubbert-Roth A, Enejosa J, Pangan A, et al. Efficacy and safety of upadacitinib versus abatacept in patients with active rheumatoid arthritis and prior inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (Select-Choice): a double-blind, randomized controlled phase 3 trial [abstract]. Ann Rheum Dis 2020; 79(Suppl 1): 1015-1016.
33.    Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis 2011; 70: 1575-1580.
34.    Mariette X, Kivitz A, Isaacs J, et al. Effectiveness of rituximab (RTX)+ methotrexate (MTX) in patients (pts) with early active rheumatoid arthritis (RA) and disease characteristics associated with poor outcomes. Arthritis Rheum 2009; 60(Suppl): 1687.
35.    Porter D, van Melckebeke J, Dale J, et al. Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet 2016; 388: 239-247.
36.    Gottenberg JE, Morel J, Perrodeau E, et al; French Society of Rheumatology and the investigators participating in AIR, ORA, and REGATE registries. Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study. BMJ 2019; 364: l67. 
37.    Kang EH, Jin Y, Desai RJ, Liu J, Sparks JA, Kim SC. Risk of exacerbation of pulmonary comorbidities in patients with rheumatoid arthritis after initiation of abatacept versus TNF inhibitors: A cohort study. Semin Arthritis Rheum 2020; 50: 401-408.
38.    Md Yusof MY, Kabia A, Darby M, et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology (Oxford) 2017; 56: 1348-1357.
39.    Clowse ME, Förger F, Hwang C, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis 2017; 76: 1890-1896.
40.    Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis 2018; 77: 228-233.
41.    Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open 2020; 6: e001395.
42.    Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis 2015; 74: 2107-2116.
43.    Ai J-W, Zhang S, Ruan Q-L, et al. The risk of tuberculosis in patients with rheumatoid arthritis treated with tumor necrosis factor-α antagonist: a metaanalysis of both randomized controlled trials and registry/cohort studies. J Rheumatology (Oxford) 2015; 42: 2229-2237.
44.    Minozzi S, Bonovas S, Lytras T, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis. Expert Opin Drug Saf 2016; 15(Suppl 1): 11-34.
45.    Godfrey MS, Friedman LN. Tuberculosis and biologic therapies: anti-tumor necrosis factor-α and beyond. Clin Chest Med 2019; 40: 721-739.
46.    Zhang J, Xie F, Delzell E, et al. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA 2012; 308: 43-49.
47.    Friedman MA, Winthrop KL. Vaccines and disease-modifying antirheumatic drugs: practical implications for the rheumatologist. Rheum Dis Clin North Am.2017; 43: 1-13.
48.    Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther 2015; 17: 212.
49.    Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 2019; 46: 7-18.
50.    Köhler BM, Günther J, Kaudewitz D, Lorenz H-M. Current therapeutic options in the treatment of rheumatoid arthritis. J Clin Med 2019; 8: 938. 
51.    Scott IC, Hider SL, Scott DL. Thromboembolism with janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk? Drug Saf 2018; 41: 645-653.
52.    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: 685-699. 
53.    Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA 2018; 320: 1360-1372.
To continue reading unlock this article
Already a subscriber?