Vascular synovial phenotype indicates poor response to JAK inhibitors in rheumatoid arthritis patients: a pilot study (2024)

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disorder primarily affecting the joints, characterized by synovitis and joint damage (Lee & Weinblatt, 2001). The implementation of the treat-to-target strategy in RA has demonstrated improved clinical outcomes, including enhanced symptom control, preservation of joint function, and a reduction in radiographic joint damage (Zink & Albrecht, 2017; Quinn & Emery, 2003). Treatment options encompass nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), and biologics (Alivernini, Firestein & McInnes, 2022). Recently, Janus kinase inhibitors (JAKi) have emerged as a widely used therapy for RA. When traditional DMARDs like methotrexate are ineffective or poorly tolerated in RA patients, JAKi therapy is recommended due to its significant efficacy in reducing inflammation and slowing down joint damage (Fraenkel et al., 2021).

JAKi, targeting the Janus kinase enzymes involved in the inflammatory process, have played a crucial role in the treat-to-target strategy for RA (Aletaha & Smolen, 2018). Clinical trials and real-world studies consistently indicate that JAKi, whether used as monotherapy or in combination with traditional DMARDs like methotrexate, can significantly reduce disease activity and improve patient outcomes (Taylor et al., 2017). Compared to biologics, JAKi offer the advantages of oral administration and lower cost, thus gaining wider application in RA patients with poor response to methotrexate (Liu et al., 2022). However, not all patients achieve the expected results, with approximately 30% of RA patients exhibiting an inadequate response to JAKi (Fleischmann et al., 2012).

Early prediction of response to JAKi treatment not only aids in minimizing unnecessary healthcare costs but also enables more precise treatment planning, thereby alleviating patient suffering and enhancing prognosis. However, forecasting the response to JAKi therapy remains a complex and evolving endeavor, with no single predictor or method ensuring accuracy for all cases (Zhang et al., 2014; Zeng et al., 2021). Despite ongoing research endeavors and the exploration of potential biomarkers, attaining precise prediction of treatment outcomes with JAKi continues to pose a challenge in the medical domain.

The central pathology of RA is synovitis, characterized by significant alterations in the synovium, such as synovial lining hyperplasia, neovascularization, stromal activation, and immune cell infiltration. However, the extent and nature of these changes vary among individuals. Previous research utilizing a combination of global gene expression, histologic, and cellular analyses has identified four distinct synovial phenotypes in RA patients: lymphoid, myeloid, low inflammatory, and fibroid, each displaying unique underlying gene expression patterns (Kay & Upchurch, 2012). These studies suggest that different synovial phenotypes may respond differently to treatment. However, there is currently limited information available regarding synovial phenotypes associated with response to JAKi.

We initiated a study in January 2023 involving 27 active RA patients who had received at least 3 months of JAK inhibitor therapy. The study aims to identify synovial predictors associated with the response to JAK inhibitor therapy in RA patients.

Patients and methods

Results

Discussion

RA is a progressive and erosive joint disorder characterized by distinct synovitis, which serves as the primary driver of joint damage in RA. Positioned amidst joints, tendons, and bursae, the synovium plays a pivotal role in maintaining joint health and function. Consisting of two primary layers—the lining layer and the sublining layer, with a mere 5 mm thickness—the synovium undergoes significant structural changes in response to inflammation in RA.

Upon the onset of inflammation, an influx of inflammatory cells infiltrates the sublining layer of the synovium, leading to thickening of the lining layer. Persistent inflammation exacerbates synovial lining hyperplasia, thereby fostering neovascularization within the sublining layer. These newly formed blood vessels serve to supply oxygen and nutrients to the proliferating synovial cells, thereby perpetuating synovial proliferation and exacerbating joint damage. This process of neovascularization assumes a critical role in sustaining the inflammatory cascade and driving joint destruction in RA (McInnes & Schett, 2011; Marrelli et al., 2011).

The mechanism underlying synovial neovascularization in RA is intricate, governed by a plethora of mediators and cytokines (Brandao et al., 2023; Szekanecz & Koch, 2007). Among the principal regulatory factors implicated in this process are HIF-a (hypoxia-inducible factor-alpha) and VEGF (vascular endothelial growth factor) (McInnes & Schett, 2011; Leblond, Allanore & Avouac, 2017). Despite several studies demonstrating the inhibitory effect of JAKi on synovial neovascularization in RA (Szekanecz et al., 2009), it is important to note that synovial vascularization represents a chronic and protracted process, often marking the transition from the acute to chronic phase of RA (Quinonez-Flores, Gonzalez-Chavez & Pacheco-Tena, 2016). Consequently, targeting this process therapeutically poses considerable challenges.

This study observed that patients exhibiting a poor response to JAKi displayed significantly heightened synovial neovascularization compared to the responder group. Following multivariate analysis, synovial neovascularization persisted as a risk factor for inadequate response to JAKi. This suggests that a synovial vascular phenotype could serve as a predictive indicator for non-response to JAKi.

RA is characterized by its complexity and high heterogeneity, traits that are evident in RA synovial tissue both histologically and molecularly. Recent research has proposed four major phenotypes of RA synovium: lymphoid (dominated by B cells and plasmablasts), myeloid (characterized by macrophages and NF-κB processes), fibroid (comprising hyperplastic but pauci-immune tissues), and low inflammatory (Dennis et al., 2014). These synovial phenotypes have been shown to correlate with responses to biologic therapeutics. For instance, RA patients with the myeloid phenotype tend to exhibit the most robust response to anti-TNFα therapy. Additionally, studies have observed an association between the pretreatment expression of genes related to angiogenesis and the clinical response to anti-TNFα, suggesting that the presence of synovial neoangiogenesis may contribute to a favorable outcome following TNFα blockade (Rivellese et al., 2020).

Our study compared several histological manifestations of synovial pathology, such as synovial lining hyperplasia, stromal activity, inflammatory infiltration, and neovascularization. We found that RA patients with poor response to JAKi exhibited significantly pronounced vascular lesions in the synovium. Therefore, it is plausible that when prominent neovascularization is observed in the synovium, TNF inhibitors may be a more suitable treatment option.

Our study further validated that disease duration acts as a predictive marker for a diminished response to JAKi. However, employing disease duration to forecast the efficacy of JAKi in the context of early diagnosis and targeted treatment of RA is not practical. The goal of achieving early disease control in RA necessitates indicators that can guide treatment decisions more effectively from the onset. In this regard, our findings suggest that synovial neovascularization could serve as a valuable early predictive marker for guiding clinical treatment decisions. This marker offers a more immediate reflection of disease activity and therapeutic response potential, thus providing a practical approach for optimizing early treatment strategies in RA.

Interestingly, the levels of observed immune cells (CD20, CD3, CD138) tended to be lower in the non-responder group, though most did not reach statistical significance except for CD20. This is consistent with previous research suggesting that RA patients with a low-inflammatory synovial subset tend to exhibit poor clinical responses to therapy (Dennis et al., 2014). However, despite the lower level of synovial immune cell infiltration in the non-responder group, their clinical disease activity score (DAS28-CRP) was not lower.

Research has classified synovial tissue into two phenotypes based on the abundance of synovial B cells: B cell-rich and B cell-poor, with differences in clinical characteristics and treatment responses between the two (Rivellese et al., 2020). Our findings demonstrated that RA patients who responded to JAKi therapy had higher levels of synovial CD20+ B cells (P = 0.044), suggesting that the B cell-rich phenotype may be associated with a more favorable response to JAKi.

Previous studies have shown that JAK inhibitors exert their anti-inflammatory effects by suppressing the JAK-STAT pathway, thereby inhibiting the signaling of various cytokines. Among these cytokines, IL-4, IL-6, and others have been shown to influence B cell differentiation. Consequently, for RA patients exhibiting a synovial phenotype characterized by B cell-rich infiltration, JAKi therapy may yield particularly promising outcomes.

Our findings underscore the substantial influence of synovial pathophysiological diversity on the clinical response to JAK inhibitor therapy in RA patients. Particularly noteworthy is the observation that patients with a synovial phenotype characterized by neovascularization with low inflammtory infiltration are less responsive to JAK inhibitor treatment. These insights highlight the potential utility of synovial biomarkers in predicting responses to targeted therapies in RA, offering a promising avenue for personalized treatment strategies in this complex autoimmune disease.

Due to the small sample size in this study and the fact that the samples were primarily drawn from a single center, the findings may not be broadly generalizable to other regions or the wider population. Additionally, while the vast majority of patients in this study used Tofacitinib, we included three patients who used Baricitinib in order to adhere to the original study design, which aimed to include all patients using JAK inhibitors. An additional analysis excluding these three patients yielded consistent statistical results, and thus we retained them in accordance with the original registered protocol. Future research with a larger sample size and focused analyses on specific JAK inhibitors is recommended to enhance the generalizability and specificity of the results.

Conclusions

In summary, our study revealed that RA patients with poor response to JAKi exhibit significantly increased synovial neovascularization (OR = 16.157, P = 0.039) and longer disease duration (OR = 1.015, P = 0.033). Increased synovial neovascularization, along with low inflammation, serves as a potentially valuable early predictive indicator for guiding clinical treatment decisions.

Supplemental Information