Page 46 - IDF Journal 2023

IDF – Webinar Series IDF News – Spring 2023
Advanced Therapies for Rheumatoid Arthritis
Dr Elisa Astorri
How RA stratification
based on synovial histology might lead to a stratified personalised targeted treatment approach with biologic response-modifying drugs.
Rheumatoid Arthritis (RA) is a chronic, inflammatory, autoimmune disease affecting diarthrodial joints and extra- articular tissues. In the absence of an effective treatment, it is characterised
by persistent symmetrical and erosive synovitis, which leads to structural joint damage and lifelong disability. Several autoantibodies have been associated with RA such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). B cells have been shown to play a crucial role in the pathogenesis of RA by both producing autoantibodies and promoting synovial inflammation through antigen presentation, T cell activation, and cytokine production. Although biologic agents
have notably improved disease outcome and patients’ quality of life, so far around 30-40% of subjects do not respond to treatment and the mechanisms leading
to resistance are still not known. For this reason, new prognostic biomarkers and predictors of response are needed and development in this context may come from pre-therapy patients’ stratification according to the histo-pathological pattern of disease and from the many new treatments currently in trials.
To date, Tumor Necrosis Factor (TNF) α has been shown to be one of the master elements of inflammation. However, even though therapies aimed at blocking this cytokine have emerged as a major tool
in the treatment of RA, several patients
do not achieve a good clinical response but instead are exposed to side-effects without any benefit. The same limitation can be addressed in the use of second- line treatments. The revised classification criteria published by the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) have clearly highlighted the critical importance
of the early diagnosis of RA.
According to the recently updated EULAR recommendations for the management
of RA, patients newly diagnosed with active RA should be initially treated with synthetic disease-modifying anti-rheumatic drugs (sDMARDs), favouring methotrexate (MTX), unless contraindicated or not tolerated. If this is the case, leflunomide and sulfasalazine have been demonstrated to be the best alternative treatment. Addition of low doses of glucocorticoids to conventional sDMARDs has been proven to be beneficial in the first phases of the disease, while the combination of more than one sDMARDs from the beginning is still controversial. Alternatively, in patients who failed biological treatment, the new approved Janus Kinase (JAK) inhibitor tofacitinib could be considered. Only after failing these DMARSs patients can try biologic drugs but only on a trial-and-error approach.
A customised stratification of RA patients according to B-cell grade of infiltration
at tissue level may advise the early identification of the expected non- responders to Rituximab, who may instead benefit from a different targeted therapy (i.e. Tocilizumab, the interleukin -IL- 6 receptor monoclonal blocking antibody).
Overall, defining RA synovial histo- pathology could be used as a potential prognostic biomarker to stratify patient response to specific biologic therapy and to evaluate the efficacy during follow-up. This approach would allow a personalised targeted drug approach and would eventually guide the most adequate change in therapy when not effective enough.
Since the overall efficacy of the available biologic agents has been proven in all the stages of the disease, the current real challenging topic is the pre-therapy identification of those subsets of patients who have the greater chances to achieve the clinical response with a specific treatment instead of wasting time on ineffective DMARDs.
In conclusion, even if standard algorithms of treatment have been proposed, and biologics have definitely transformed the outcome of RA, the clinical response
at individual patient level remains very heterogeneous with a variable disease course and major differences in joint damage scores. As cited above, the
current use of biologics has serious issues, mainly due to a lack of prognostic predictors.
To summarise:
1) 30-40% of patients do not respond
at all or become unresponsive during treatment and the ideal target of treatment is achieved in only 20-25% of patients.
2) The mechanisms of “non-response” remain largely unknown.
3) Biologic agents are still used on a “trial and error” sequential basis rather than on a rational pathobiological stratification.
4) Patients may develop treatment- related adverse effects such as infections, tuberculosis reactivation and demyelinating diseases with TNF inhibitors agents, and alteration of the lipoprotein profile with increased risk of lower gastrointestinal perforation in concomitance with tocilizumab.
5) Unnecessary delays can occur in targeting the “therapeutic window of opportunity” and therefore in preventing erosions and long-term disability.
6) The spreading attitude of using TNF inhibitors as first line biologics is based mainly on historical discovery and licensing.
In conclusion, this parallel development of synovial biomarkers and novel diagnostic modalities, has the potential to categorise and partition patients into different prognostic and therapeutic response categories. Such approach would not only maximise the efficacy of existing biologic therapies with target specificity, like TNF, IL-6 or B cells, but also would help identify new targets and new drugs.
Dr Elisa Astorri MD PhD
Consultant Rheumatologist
Rheumatology Harley Street Practice Founder
25 Harley Street, London, UK
E: astorri@ rheumatologyharleystreet.com
W: www.rheumatologyharleystreet. com
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