Is JAK inhibitor the option to prevent difficult-to-manage axial spondyloarthritis?

In this journal, a case report on the use of Upadacitinib in a patient with concurrent refractory axial spondyloarthritis (axSpA) and inflammatory bowel disease (IBD) was published.¹ Recently, there have been significant therapeutic advances in axSpA with the advent of TNF inhibitors and IL17 inhibitors. However, not all cases have benefited, especially in axSpA patients with coexisting IBD. This editorial aimed to share the current situation of difficult-to-manage axSpA, including treatment options for axSpA patients with IBD, providing useful knowledge for daily practice. Furthermore, this editorial will discuss insights from approaches used in rheumatoid arthritis (RA) for managing difficult-to-treat groups, which may also be relevant to SpA.

In RA, the European Alliance of Associations for Rheumatology (EULAR) task force defined the concept of “difficult-to-treat (D2T) RA.”² Among its criteria, the concept includes the ineffectiveness of two or more biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) (with different mechanisms of action) with certain refractory disease status. A patient population corresponding to D2T RA may exist in spondyloarthritis (SpA), and whether such a group can be found in axSpA, or psoriatic arthritis (PsA) has been discussed.^{3, 4} In patients with SpA, reasons for treatment failure may be related to the disease itself but may also be associated with comorbidities other than the ineffectiveness of the medications. For example, it has been reported in radiographic axial SpA (r-axSpA; AS) that 42% of patients always have extra-articular symptoms,⁵ and certain drugs are difficult to use depending on their coexisting diseases.^{6, 7} Some reports suggest that high comorbidities are associated with difficult-to-treat axSpA,⁸ especially in axSpA patients with IBD.⁹ Based on these findings, the ASAS group is currently working on a project to identify “difficult-to-manage axSpA,” and the term “manage” here includes a sense of comorbidities and concurrent related conditions.¹⁰

The refractory axSpA patient reported here had coexisting IBD. IBD is reported to occur in 5–10% of SpA patients,¹¹ and SpA is reported to occur in 1–46% of IBD patients.¹² A study we reported on IBD coexistence in Asia found that 1.6–7.8% of axSpA patients and 1.5–4.8% of peripheral SpA patients had IBD.¹³ Treatment for SpA and IBD is summarized in Table 1. Although there are many treatment options for patients with peripheral SpA and IBD, the only b/tsDMARDs that are effective for both axSpA and IBD are TNF inhibitors or JAK inhibitors. JAK inhibitors may be an option to prevent the development of “difficult-to-manage” axSpA.

For JAK inhibitors, safety concerns should be mentioned. In an international multicenter clinical study involving tofacitinib versus TNF inhibitors in RA patients aged ≥50 years with cardiovascular risk, it was revealed that the incidence rates of major adverse cardiovascular events (MACE) and malignancies (excluding non-melanoma skin cancer) were higher in the tofacitinib group compared with the TNF inhibitor group.¹⁴ Although other JAK inhibitors, including upadacitinib, have not been evaluated in comparable trials, they may have similar risks due to their shared mechanisms of action. A sub-analysis of the aforementioned study suggested that the incidence of MACE and malignancy tended to be lower in patients from outside North America than those from North America. To draw robust conclusions about their safety, further studies, including those involving populations outside of North America and, furthermore, those involving other diseases such as SpA, are necessary.

As mentioned above for RA, a group of patients has been defined as D2T RA, and the focus is on the treatment of this patient group. A report from the R4RA trial,¹⁵ a biopsy-based randomized clinical trial of precision medicine in RA reported that treatment resistance was associated with a genetic profile of fibroblasts in the synovium before treatment initiation.¹⁶ Cellular phenotypes identified in other studies have also shown that the fibroblast type category was associated with the treatment-resistant group in the R4RA trial, firmly suggesting this association.¹⁷ JAK inhibitor has been reported to show a predominant improvement against D2T RA,¹⁸ and this result is convincing because STAT4 is involved in the transcriptional regulation of fibroblast-mediated inflammation, which may suggest JAK inhibitor may be beneficial to treat synovial fibroblast predominant D2T RA.^{19, 20} In RA, attempts have been made to provide appropriate treatment to this difficult-to-treat group, and it is hoped that a comparable effort will be made in SpA in the future.

Keisuke Ono drafted the manuscript, and Mitsumasa Kishimoto reviewed and revised it.

Keisuke Ono has nothing to declare. Mitsumasa Kishimoto is an editorial board member of the International Journal of Rheumatic Diseases and a coauthor of this article. To minimize bias, they were excluded from all editorial decision-making related to the acceptance of this article for publication. Mitsumasa Kishimoto received consulting fees and/or speaker fees from AbbVie, Amgen-Astellas BioPharma, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, Teijin Pharma, and UCB Pharma.

None.