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psoriasis and injection site reactions , have been reported . 6 , 7
In post-marketing surveillance an increased risk of TB was seen following anti-TNF use . 3 Hence , the European Alliance of Associations for Rheumatology ( EULAR ) guidelines suggest patients should be routinely screened and treated ( if positive ) for latent TB , hepatitis B and C and HIV prior to commencing treatment .
A slight increase in non-melanoma skin cancer has been seen with anti-TNF agents , so regular skin checks are also recommended .
Interleukin-6 inhibitors ( IL-6i ) The monoclonal antibody tocilizumab is directed against IL-6 , an important cytokine in the pathogenesis of RA . 8 The side effect profile remains broadly similar to TNFi . In addition , a slight increase in lower intestinal perforations was reported in the clinical trial program . 8 Clarification of any existing risk factors for perforation , such as history of diverticulitis , is important prior to initiation of IL-6i , although such history is not an absolute contraindication .
The recommendations for monitoring tocilizumab include regular FBC and LFTs prior to initiation and every 4-8 weeks for the first six months of treatment . A reduction in neutrophils may be seen but has not been shown to translate into an increased risk of infection . 8 , 9
CD20 depleting antibodies Rituximab leads to B-cell depletion by binding to the CD20 molecule on B lymphocytes , which results in reduced disease activity , particularly in seropositive RA . 10 Rituximab has a favourable dosing schedule , being given by a six-monthly IV infusion .
This agent is well tolerated with only a slight increase in infection risk . Following
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multiple courses immunoglobulin levels may fall necessitating co-administration of IV gamma globulin . 11
T-cell co-stimulation inhibitors Abatacept binds to CD80 and CD86 on antigen presenting cells and selectively inhibits T-cell activation in addition to having an effect on other pro-inflammatory mediators . Abatacept has demonstrated equivalent efficacy when compared to TNFi thus adding a further option for those whose disease remains active . 12 Similar to all bDMARDs a slight increase in infection is seen particularly those of the upper respiratory tract . 13
Biosimilars Given the costs of bDMARDs , biosimilars have been developed as analogous agents with equivalent efficacy and safety to
the originator products at a lower cost . 14 Biosimilars do not deviate from their reference products , which means the approach to management of patients on these drugs remains the same .
How are the side effects of bDMARDs combated ?
Despite fundamentally altering the
immune system , these agents are well tolerated overall both in the short and long term . While the rate of infection and possibly non-melanoma skin cancer have been shown to be increased with bDMARDs , reassuringly there is no increased risk of solid organ tumours or recurrence of previous cancer . 15 In
addition , there is no increased risk of poorer cardiovascular outcomes .
Other factors need to be considered in relation to infection risk , including the nature of the disease with immune dysregulation , concomitant glucocorticoid use and comorbidities . 16 Reactivation of latent TB and lower intestinal perforations have been of greatest concern with TNFi and IL-6i respectively although the risk has been mitigated with screening strategies . Akin to the EULAR guidelines , the British Society for Rheumatology recommends prebiologic screening to include TB , hepatitis B and C and HIV serology , with treatment of these conditions prior to starting bDMARDs although this may occur concurrently . 17
National vaccination schedules should be continued ( influenza , pneumococcal and COVID-19 vaccines ), with avoidance of
Patients should be advised of the importance of skin surveillance and exercise appropriate sun protection measures .
live attenuated vaccines such as live herpes zoster , MMR and yellow fever vaccines . All patients should undergo regular national cancer screening programs such as bowel , breast and cervical screening . While evidence of an increased risk of non-melanoma skin cancers remains uncertain , patients should be advised of the importance of skin surveillance and exercise appropriate sun protection measures .
Regular LFTs and FBCs should be performed in the early phases of treatment with bDMARDs but this is generally undertaken for methotrexate monitoring . Although recent data have been reassuring , caution is advised when treating patients with New York Heart Association
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Class III or IV heart failure or interstitial lung disease . 1
COVID-19
In relation to COVID-19 , bDMARDs are generally considered to be safe , with similar hospitalisation rates and risk of death seen for patients taking bDMARDs compared to controls . As IL-6i have been used for severe COVID-19 there may be a therapeutic advantage in continuing treatment . TNFi and IL-6 antagonists have been deemed safe to continue during COVID-19 and during vaccination , whereas timing of COVID-19 vaccination is important for patients who are on rituximab and abatacept . 19 A tailored approach in conjunction with the treating rheumatology team is recommended for patients receiving these agents , who may require CD19 B-cell monitoring , planned timing of vaccine prior to treatment dosing , and / or additional vaccine doses . 20
Pregnancy
Anti-TNF agents particularly certolizumab may be safely continued during pregnancy and breastfeeding , however specialist input is recommended . 5
Conclusion
Biologics have revolutionised the treatment of RA and their side effect profile remains favourable in the context of the therapeutic benefit in lowering disease activity . The role of primary care is critical however in monitoring for adverse events . The risks can be mitigated with pre-therapy infection screening and maintaining national cancer screening and vaccination schedules . In special circumstances , such as serious infections , pregnancy and intercurrent illness , specialist advice should be sought .
References on request from kate . kelso @ adg . com . au
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Rheumatoid arthritis has significant potential impacts on quality of life and function . |