StemCell Therapy

The treatment of Rheumatoid Arthritis has been transformed in the last two decades by the introduction of biologic agents. Dr Sharon Cowley looks at how management and treatment of RA has changed

Rheumatoid Arthritis (RA) is a common condition, estimated to affect 1% of the caucasian population and over 45,000 people in Ireland.1 It results from a complex interaction between genes and environment, leading to a breakdown of immune tolerance and synovial inflammation in a characteristic symmetric pattern.

Each year in Ireland 2,000 new cases are diagnosed, and 3 out of 4 are in patients of working age. There have been many recent advances in the treatment of RA and new treatment strategies have substantially changed the course of RA. Many patients can achieve remission if the disease is recognised early, and it is treated promptly and continuously.

In 2019 the European Alliance of Associations for Rheumatology (EULAR) updated its treatment guidelines and the American College of Rheumatology (ACR) is preparing to release updated 2021 guidelines later this year. These guidelines aim to reflect newly licenced drugs, data on long-term efficacy and safety of previously approved drugs, comparative effectiveness studies, and considerations of the cost involved.

Conventional Synthetic Disease Modifying Anti-Rheumatic Agent (csDMARD)Methotrexate (MTX) is the anchor drug in RA and is the preferred first-line treatment agent.2,3

Not only is it efficacious by itself, but it is also the basis for combination therapies, either with glucocorticoids or with other csDMARDs, biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs).3

The efficacy of biological and other targeted therapies are enhanced when administered in combination with MTX.4 Safety screening for MTX includes full blood count, liver and renal function tests, hepatitis B and C serology, assessment of underlying lung and liver disease, determination of alcohol use and potential future pregnancy, although the risks are low.

MTX is commenced at a dose of 10-15mg weekly with folic acid and can be up-titrated to 25mg weekly. It is important to note that its onset of effect can take up to 12 weeks so patients may require additional cover with non-steroidal anti-inflammatories or corticosteroids during this period. Response is monitored in a treat to target fashion with up-titration of MTX dose to achieve clinical response. If a patient has a contraindication to methotrexate, other first line csDMARDs include salazopyrin, hydroxychloroquine can be added.

BiologicsBiologicals are large molecules (80,000-150,000 dalton molecular weight) and produced in living cells using recombinant DNA technology. The biologic era started in the late nineties, with the tumour necrosis factor inhibitors (TNFi) infliximab and etanercept. In the succeeding years, other TNFi and several other biologic molecules with varying targeted mechanisms of action have emerged. Rheumatology was one of the earliest specialties to commence biologic therapy following their availability in the late 1990s.

Pre-biologic screening to ensure safe administration includes full blood count, liver and renal function tests, hepatitis B and C serology, TB screening and an accurate history concerning congestive heart failure, nervous system disorders, malignancies, allergies, vaccination status and plans for future pregnancy.

Despite initial concerns about biologic-associated potential side effects in major areas such as malignancy, pregnancy and in the risk of infection, a growing body of real world data is now available and confirms their agents to high very good benefits/side-effects ratios.

At present bDMARDs are second line treatments in both the EULAR and ACR guidelines. They are typically commenced if a patient has less than optimal response to csDMARDs. Recent head-to-head data comparing various biological medications including the RED SEA trial comparing adalimumab and etanercept,5 the AMPLE study6 comparing abatacept and adalimumab and the ADACTA study comparing tocilizumab and adalimumab,7 have shown comparable outcomes between the treatment arms in all of these studies.

Generally the choice of first biologic is physician-dependant. If one TNFi has failed, patients generally receive an agent with a different mode of action rather than a second TNFi.

BiosimilarsThe end of patents of the original biological agents (originators) has resulted in the availability of cheaper biosimilar agents. These must have identical amino acid sequence with the originator biological agent, and have very similar affinity for the target protein (e.g. TNF or IL-6). Potential differences in glycosylation between originator and biosimilar agents could affect pharmacokinetics, pharmacodynamics or immunogenicity of these agents.

To date however there have been no clinically significant issues found in rheumatic patients treated with biosimilars. Common examples are Inflectra, a biosimilar of Infliximab; Benepali, an Etanercept biosimilar; and Amgevita, a biosimilar of Adalimumab. Data from several studies switching patients with RA from an original biologic to a biosimilar drug showed no changes in efficacy, safety, trough serum drug concentration, or immunogenicity between the biosimilars and their reference product.8

Despite the European Medicines Agency granting market authorisation for 28 biosimilars, introduction was initially slow in Ireland; however the list of biosimilars reimbursable by the State is gradually increasing. Once a biosimilar medicine is available, the price of the originator product must be reduced by 30 per cent, following an agreement reached between the Irish Pharmaceutical Healthcare Association and the State. As a result of lower unit prices of the drug, both biosimilar and reference medicine, the drug can be provided to patients for a substantially lower cost.

Janus Kinase InhibitorsJanus Kinase Inhibitors (JAKi) are the newest players in the treatment of rheumatoid arthritis. They are small molecules, rather than biologicals, and target a key pro-inflammatory intracellular signalling pathway. They compare favourably to existing bDMARDs and have been shown to slow radiographic progression in RA.

The EULAR 2019 guidelines have revised the preference of bDMARDs over targeted synthetic DMARDs because of new evidence regarding the successful long-term efficacy and safety of JAK inhibitors and now both JAK inhibitors and bDMARDs are equally recommended as a second line option.2

Tofacitinib, baricitinib and upadacitinib are the first three JAK inhibitors to become commercially available in Ireland. Similar to bDMARDS the most frequently reported side-effects of JAK inhibitors are increased rate of infection. In contrast to the bDMARDS there are signals for slightly increased incidence of thrombosis, shingles and gastrointestinal perforations, so careful history-taking is important before initiation, and some patients may benefit from shingles vaccination before administration.

Future treatmentsThere are a number of potential future treatments for RA to add to the ever expanding armamentarium.

Sariluzumab is an interleukin 6 inhibitor (IL-6i) approved by the European Medicines Agency but not yet used in Ireland. Olokizumab is another IL-6i in phase III trials and has shown benefit versus placebo in clinical response however concerns are present over the high incidence of treatment-related adverse events.9

Extended studies will be needed to prove safety. Otilimab is another new agent that works by inhibiting granulocyte-macrophage colony-stimulating factor (GM-CSF). Current phase III trials are evaluating both long-term safety and efficacy in patients with active RA who have an inadequate response to DMARDs or JAK inhibitors.10

Targeting of non-immune cells such as RA synovial fibroblasts is an emerging area11 this cell type drives both inflammation and tissue destruction in joints.12

Non pharmacological treatmentIn conjunction with drug-based treatment, non-pharmacological interventions such as dynamic exercises and occupational therapy should be considered as adjuncts to drug treatment. Smoking cessation, dental care, weight control, assessment of vaccination status, and management of comorbidities, especially cardiovascular risk, should be included in overall patient care.

The treatment of rheumatoid arthritis has undoubtedly been transformed in the past two decades with the introduction of targeted biologic agents. Although biologic agents are more costly in the short term than synthetic DMARDs, drug-specific costs may be offset by significant improvements symptoms, slowed disease progression, and improved quality of life for patients.

References

Continue reading here:
A changing landscape in the treatment of Rheumatoid Arthritis - Irish Medical Times

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