The many faces of treatment-refractory spondyloarthritis.

Williams, J.C.; Harrison, S.R.; Freeston, J.; Barr, A.; Vandevelde, C.; Marzo-Ortega, H.

The many faces of treatment-refractory spondyloarthritis.

All Authors

Williams, J.C.

Harrison, S.R.

Freeston, J.

Barr, A.

Vandevelde, C.

Marzo-Ortega, H.

LTHT Author

Williams, Jacob Corum
Harrison, Stephanie
Freeston, Jane
Barr, Andrew
Vandevelde, Claire
Marzo-Ortega, Helena

LTHT Department

NIHR Leeds Biomedical Research Centre
Rheumatology

Publication Date

2025

Item Type

Conference Abstract

Abstract

Introduction: Spondyloarthritis is a group of inflammatory diseases sharing diverse genetic and clinical features, chiefly inflammation of peripheral or axial joints and entheses. Tissue involvement outside the musculoskeletal systems is typically located in the skin, bowel and anterior uvea in the eye. The term encompasses axial spondyloarthritis, psoriatic arthritis, reactive arthritis, enteropathic arthritis and undifferentiated spondyloarthritis. There can be significant overlap in these conditions, and they may be hard to distinguish clinically. Below, we describe an evolving case of spondyloarthritis over two decades spanning multiple disease phenotypes and several treatment modalities. Case description: A 23-year-old man presented in 2002 with a swollen left knee and purulent penile discharge. He was otherwise well, though his father had axial spondyloarthritis. Investigations showed HLA-B27 positivity and a positive Chlamydia trachomatis screen. A diagnosis of reactive arthritis was made, and he was treated with doxycycline, NSAIDs and intra-articular corticosteroids. Due to ongoing symptoms, sulfasalazine and methotrexate were added, with full resolution. In 2006, he developed psoriasis while on methotrexate and sulfasalazine, prompting reclassification to psoriatic arthritis (PsA) and successful treatment with topical therapies. In 2008, after travelling to South Asia, he presented with polyarthritis, dactylitis, and inflammatory back pain. His CRP was very high (335 mg/L), Campylobacter was cultured, and MRI confirmed sacroiliitis. His diagnosis was revised to axial and peripheral PsA, and therapy was escalated to etanercept alongside methotrexate. He discontinued both drugs while abroad in Australia in 2011. Upon return to the UK in 2012, he relapsed with a TJC of 10, a swollen left knee and BASDAI 8.2. Etanercept was restarted without response, prompting a switch to adalimumab. Methotrexate was stopped due to family planning. By 2015, he had recurrent left-sided knee effusions requiring aspiration every 2-3 months. Adalimumab was paused perioperatively for a synovectomy, leading to secondary non-response. Following this, he rapidly cycled through therapies including infliximab 3 mg/kg (2017), infliximab 5 mg/kg (2017-2018) and certolizumab pegol (2018-2019). His left knee monoarthritis worsened, and an MRI scan in 2019 showed secondary osteoarthritis by age 40. Left ankle swelling and a fluctuating CRP were ongoing. Between 2019 and 2021, he trialled empirical antibiotics, tocilizumab, and apremilast without a lasting response. Tofacitinib and methotrexate finally led to good disease control for 3 years, though complicated by recurrent uveitis in year one and infections in year two of therapy. He is currently stable on this regimen. Discussion(s): This case illustrates a complex, evolving form of spondyloarthritis with overlapping features of reactive arthritis, PsA, and axial spondyloarthritis. The clinical phenotype progressed over time, with musculoskeletal involvement expanding from monoarthritis to oligoarthritis, polyarthritis, and eventually axial disease. Extra-musculoskeletal manifestations'including psoriasis and anterior uveitis'also emerged. Another key feature of this case was accumulated inflammatory damage, culminating in secondary osteoarthritis of the left knee, his most severely affected joint for many years. This presentation emphasises the heterogeneity of spondyloarthritis and the need for clinicians to remain vigilant to evolving disease patterns. Reclassification is crucial, which may open new therapeutic avenues. It is equally important to consider non-inflammatory causes, such as secondary osteoarthritis'as seen here'or other confounders like obesity and fibromyalgia. The patient's experience highlights the substantial personal burden of disease progression, including impacts on mental health, function, and relationships. A holistic approach that considers these alongside inflammatory burden and cumulative damage is essential to delivering effective, patient-centred care. A recurring theme was treatment-refractory disease. Although reactive arthritis rarely requires long-term DMARDs, our patient required early escalation to sulfasalazine and methotrexate. Over time, he cycled through four TNF inhibitors, off-label therapies (tocilizumab), and underwent surgery before achieving sustained remission with tofacitinib. Notably, most episodes of treatment failure occurred following infection or treatment interruption. Recognising this, subsequent infections during tofacitinib therapy were managed with minimal or no cessation to retain clinical response. However, the eventual loss of response to different treatment options, together with markers of ongoing inflammation (CRP and MRI findings), led the clinical team to consider different treatment strategies, including off-label indications, in an attempt to suppress disease activity. This case highlights the need to understand the underlying endotypic signatures underpinning evolving phenotypes, which are likely to be heterogeneous, in order to personalise treatment. Key learning points: 1. Spondyloarthritis is a heterogenous disease with an evolving clinical phenotype. 2. The extra-musculoskeletal manifestations of spondyloarthritis may accumulate as the disease progresses. 3. Disease reclassification and identification of ongoing inflammation are important to allow for accurate targeting of pharmacological interventions (for example, from reactive arthritis to PsA) and non-pharmacological interventions (for example, secondary osteoarthritis and fibromyalgia). 4. Severe, refractory disease has a significant impact on mental health and personal relationships. 5. Infections and treatment cessation may trigger secondary non-response to therapy; in patients prone to secondary non-response, every effort should be made to minimise treatment breaks as much as possible. Disclosures: * JCW has received honoraria/speaker fees from Novartis. * SRH has received speaker fees for non-promotional education talks from Janssen and Novartis. * CV has received speaker fees from UCB and Janssen. * HM-O has received research grants from Janssen, Novartis, Pfizer, and UCB; and has received honoraria/speaker fees from AbbVie, Amgen, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda, and UCB.