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Clinically suspect arthralgias: justified or artefact?

Some subjects in rheumatology seem to create contention the more they get explored, and one of those areas is a traditional crowd favourite for discussion at EULAR - clinically suspect arthralgias. At EULAR 2023 in Milan, the perfect platform was provided for an airing of grievances, in a debate entitled ‘Clinically suspect arthralgias: fact or myth’.

Traditionally, rheumatologists have been very cautious about treating any inflammatory arthritis in the absence of clinical synovitis on examination. As the physicians responsible for safeguarding methotrexate safety, it was incumbent on us to ensure that such patients were not inappropriately started on therapies which required safety monitoring. Apart from direct harm from this, both biological and financial, it can be the start of a prescribing cascade - where non-response leads to more and more intensive immunomodulatory therapy. If such therapy is being used for an arthropathy not primarily inflammatory, then not only is a patient encumbered with an unjustified and potentially harmful burden, it can be a burden that in practice can be extremely difficult to subsequently unwind.

Subsequent investigation, however, opened the possibility that there might be something to be gained from treating patients without overt synovitis. It became apparent that, as part of the evolution of early rheumatoid arthritis, a stage might exist where overt synovitis was not apparent but was nevertheless in development. Further than that, this might be the ideal opportunity to suppress the aberrant inflammatory response, and avoid its persistence. 

While this might not be apparent on clinical examination, imaging - and specifically, ultrasound and MRI - might detect subclinical inflammation in and around joints. When the features that were seen in patients with overt RA became apparent on patients without synovitis, but who would go on to develop RA - the possibility of detection a pre-RA state became far more conceivable than before. Despite this, it subsequently became apparent that not all changes on imaging are specific to inflammatory arthritis, and biomechanical strain might trigger some of these. Similarly, autoantibodies may sometimes herald new RA, but also might not. These tenets of modern rheumatology might underpin the inherent scepticism behind clinically suspect arthralgias (CSA).

Annette van der Helm-van Mil, who leads the Leiden Early Arthritis Clinic and who was the project leader on the EULAR taskforce which created the definition of CSA, naturally made a strong case as to why definitions matter, with the aim of countering such scepticism. CSA, as she said, does not represent every ache and pain - it represents a defined entity that captures patients who rheumatologists would be concerned would be at high risk of progressing to RA, as 22% of them will.

She made it clear that this is something patients feel in a very real way, that functionally impairs them with morning stiffness, pain, and fatigue, correlates to the underlying identified pathology on imaging, and leads to a socioeconomic burden on society. In this context, the greatest success from recent studies - in particular TREAT EARLIER examining methotrexate in CSA - has come about from benefits in pain, functional impairment, and presenteeism, sustained at least 12 months after methotrexate ceased.

Filip Van Den Bosch, who has led in early axial spondyloarthritis, set out to capture the clinical rheumatologist’s concern, with added follow-up burden and disease labelling in mind. TREAT EARLIER failed to prevent RA development, and such futility raises questions about the necessity of this approach. He made the case that perhaps neither definitions not imaging were not large gains over clinician suspicion, that escalation of therapy in such patients might invoke a cascade of escalating unnecessary treatment, and that an incorrect label has life-long implications but is hard to remove.

Fundamentally, this genial debate captured the internal conflict that rheumatologists grapple with with CSA. The concern about labelling CSA as a disease is unlikely to be about belittling the real problems that such patients face, but is likely borne out of genuine concerns for patients. The right stratification could facilitate the right therapy - and the APPIPRA study (OP0130), presented at this meeting, showed one year of abatacept not only led to functional benefits while it was being taken, but a substantive benefit for patients with multiple autoantibodies present including IgG ACPA, IgA ACPA, ACarP, AAPA, and RF. Indeed, the right CSA label is important if therapies truly are to be licensed in this area.

The debate ended congenially, but rheumatologists will continue to be torn until consistent stratification can truly identify patients who will get outsized benefit from therapy, despite their lacking synovitis.



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