[⁶⁸ Ga]Ga-FAPI-04 PET/CT may be a predictor for early treatment response in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder that primarily involves synovial joints. Early use of disease-modifying antirheumatic drugs (DMARDs) and efforts toward tight control with a treat-to-target strategy are essential to the good control of synovitis and prevention of joint injury [1]. The expanding array of drugs available for treating RA is creating challenges in drug selection for the individual patient. Some of the patients do not have good response to these drugs, for example, the remission rate of methotrexate ranges between 30 and 50% [2], while 30 to 40% of patients have unsatisfactory control of disease symptoms with biological DMARDs [3]. The efficacy also varies over time in individual patients [4]. Apart from this, the potential side effects of these agents, such as hepatotoxicity from methotrexate [5], infusion reactions and risk of infection [6], as well as their cost and accessibility should also be considered when making treatment plan [7]. Thus the identification of biomarkers that would predict the treatment response prior to drug exposure is therefore a current priority. Antibodies to citrullinated peptides, rheumatoid factor, and the interferon signature are the most robust validated biomarkers identified to date [4]. However, the complexity of the treatment response in a given patient and substantial variability across patients suggest that biomarkers may be more helpful in combination than singly.

The imaging techniques for assessing RA, including musculoskeletal ultrasound, MRI and positron emission tomography/computed tomography (PET/CT), may be more sensitive and specific than clinical exam to reveal subclinical inflammation. As to disease pathogenesis of RA, an increasing role is attributed to fibroblast-like synoviocyte, which contribute to the pannus formation and destruction of articular cartilage and bones [8]. Recently, fibroblast-like synoviocyte targeted treatment showed promising results for RA therapy in preclinical animal models and early phase trials of RA patients [9‐13]. Fibroblast activation protein (FAP), a type II cell surface serine protease, was demonstrated to be overexpressed in activated synovial fibroblasts [14, 15]. Preclinical studies of immuno-PET and immuno-SPECT with radiolabeled anti-FAP antibody also showed high tracer accumulation in the arthritic joints in murine experimental RA [16‐18]. Recently we have conducted a prospective cohort study to verify the use of FAP-targeted PET/CT imaging in patients with RA. We imaged the arthritic joints in RA patients with [⁶⁸ Ga]Ga-fibroblast activation protein inhibitor-04 ([⁶⁸ Ga]Ga-FAPI-04), a recently introduced FAP-targeted PET agent, and found markedly increased uptake of [⁶⁸ Ga]Ga-FAPI-04 in the arthritic joints of patients with RA. The positive joint count detected in [⁶⁸ Ga]Ga-FAPI-04 PET/CT was found to be positively correlated with clinical disease activity variables [19]. Further in this study, we wonder whether [⁶⁸ Ga]Ga-FAPI-04 PET/CT can be used as a predictor of treatment response in RA.

The rationale for treatment response prediction lies in the pathophysiological, clinical, and therapeutic heterogeneity of RA. In the current study, we found PJC, TSU and MSV of the synovitis detected in [⁶⁸ Ga]Ga-FAPI-04 PET/CT before treatment had significant difference between responders and non-responders according to CDAI and SDAI response criteria at 3-months after initiation of tight control treatment. However, none of the clinical variables for assessing disease activity except CRP levels showed significant difference between responders and non-responders. Furthermore, we found those indices of [⁶⁸ Ga]Ga-FAPI-04 PET/CT > cutoff values successfully predicted early responders in ROC curve analysis. [⁶⁸ Ga]Ga-FAPI-04 PET/CT identified these differences in patients with different response status at baseline which preliminarily qualified it as a treatment response predictor.

Our results showed that the early responders had more involved joints shown in [⁶⁸ Ga]Ga-FAPI-04 PET/CT and significantly higher TSU_FAPI and MSV_FAPI of the synovitis, although the responders and non-responders had similar clinical disease activity indexes and comparable counts of tender or swollen joints. The parameters derived from [¹⁸F]FDG PET/CT showed similar results to [⁶⁸ Ga]Ga-FAPI-04 between the responders and non-responders, however [¹⁸F]FDG had a lower number of affected joints and uptake values compared with [⁶⁸ Ga]Ga-FAPI-04. It is known that [¹⁸F]FDG uptake depends on the high glycolytic activity of inflammatory cells of synovitis. Meanwhile [⁶⁸ Ga]Ga-FAPI-04 is a tracer targeting at FAP of the fibroblast-like synoviocytes [23], which play a key role in the development of RA through displaying an aggressive phenotype and pro-inflammatory effects by producing cytokines that activate B and T cells [24‐26]. DMARDs, a class of anti-inflammatory and immunomodulatory agents, prevent and relieve RA aggression through suppressing the key inflammatory cells and synovial fibroblasts, proteins and inflammatory cytokines [27, 28]. Therefore we think higher uptake of [⁶⁸ Ga]Ga-FAPI-04 and [¹⁸F]FDG before treatment suggested more activated inflammation of synovitis, thus indicated better reaction to systemic mediators against inflammation and better clinical response [29]. This speculation was also supported by our result that early responders had significantly higher level of CRP than non-responders, which was in accordance with previous studies [30, 31], and that TSU and MSV in [⁶⁸ Ga]Ga-FAPI-04 and [¹⁸F]FDG PET/CT were positively correlated with CRP level.

When we further analyzed the PET positive joints and tender or swollen joint in physical examination, we found that the non-responders had significantly higher rate of joints that were tender or swollen but were PET negative (non-responders vs. responders, 44.0% vs. 12.4% in CDAI response, P < 0.0001; 43.7% vs. 13.7% in SDAI response, P < 0.0001). It may indicate that the non-responders have more secondary damage in the joints rather than active inflammation of synovitis, and their inflammatory activity was actually lower than it was revealed by physical examination. This overestimation of disease activity may lead to unsatisfactory response to anti-inflammation therapy. On the other side, we found that the responders had significantly higher rate of PET positive joints that were not tender or swollen in physical examination (responders vs. non-responders, 25.9% vs. 12.8% in CDAI response, P = 0.0081; 26.2% vs. 11.7% in SDAI response, P = 0.0037). It may suggest that some subclinical inflammation can only be detected by PET imaging rather than by physical examination. Early initiation of treatment is an essential strategy in treating RA, because joint damage, which may ultimately result in disability, begins early in the course of disease, and that the longer disease activity persists, the less likely the patient is to respond to therapy [32]. Thus physical examination, a less sensitive method to detect subclinical inflammation may not be an optimal method to evaluate disease activity.

Some studies showed that poor clinical response at 3-months’ time point makes achievement of low disease activity at 1 year unlikely [33], and good response at 6-months’ time point independently predicts significantly better 5-year clinical and radiographic outcome [34]. In our study, PET-derived parameters failed to predict 6-months’ response. As one patient was excluded from 6-months’ response analysis due to self-withdrawal of the drugs, and the treatment regimens were adjusted in some patients, further clinical trials are needed to find out whether [⁶⁸ Ga]Ga-FAPI-04 PET/CT could predict late response, clinical remission after tight control treatment, clinical relapse, and radiographic progression.

As to the clinical markers for predicting treatment response, some studies found that rheumatoid factor and anti-cyclic peptide containing citrulline antibodies were closely associated with treatment response. The presence of rheumatoid factor or anti-cyclic peptide containing citrulline antibodies were reported to be associated with a good response to rituximab at 24 weeks, and were associated with better effectiveness of abatacept therapy, which may reflect a more specific autoimmune B cell and T cell reactivity allowing better efficacy of biologic DMARDs [35‐37]. In our study, we did not find any association of rheumatoid factor and anti-cyclic peptide containing citrulline antibodies with treatment response (not shown in the results). It may because of the small cohort number as well as the fact that nearly all recruited patients in the current study having positive rheumatoid factor and anti-cyclic peptide containing citrulline antibodies.

To avoid some of the systemic immune suppressive effects of current therapies of RA, there has been renewed interest in the synovium-targeted therapy [38]. Recently, cyclin-dependent kinases inhibitors, that directly suppresses proliferation of fibroblast-like synoviocyte have demonstrated good efficacy and potency in preclinical models of arthritis, and the corresponding clinical trial in RA patients is ongoing [9‐13]. There are also other candidate drugs that directly target fibroblast-like synoviocyte currently being studied [39, 40]. Another preclinical study showed the feasibility of depleting activated synovial fibroblasts through photodynamic therapy targeting fibroblast activation protein for locoregional therapy of RA [41]. Thus, there is increasingly need to establish a direct method to image fibroblast-like synoviocyte in RA patients. We think [⁶⁸ Ga]Ga-FAPI-04 may have a greater role in patients treated with synoviocyte-targeted therapy.

Our study had several limitations. First, the cohort had a relatively small number of patients with a short-term follow-up. Second, the treatment included a spectrum of conventional, biological and targeted synthetic DMARDs. Prospective studies with specific therapeutic regimen should be conducted to further investigate the role of [⁶⁸ Ga]Ga-FAPI-04 PET in the prediction and response evaluation. Third, because of the limited number of patients in our study, we did not further perform a multivariate logistic regression model to validate the potential predictors.

[⁶⁸ Ga]Ga-FAPI-04 demonstrated a greater number of affected joints and higher tracer uptake in RA compared with [¹⁸F]FDG. The PJC, TSU and MSV in [⁶⁸ Ga]Ga-FAPI-04 PET/CT at baseline were significantly higher in early responders than those in non-responders based on CDAI and SDAI response criteria. The result suggested that [⁶⁸ Ga]Ga-FAPI-04 PET/CT may predict the treatment response in RA patients.