Primary aim was to evaluate whether presence of osteoarthritis (OA), as assessed by ordinal grading on whole-body computed tomography (CT), is associated with 68 Ga fibroblast activation protein inhibitor (FAPI) positron emission tomography (PET) tracer uptake as a measure of fibroblastic activation. Secondary aim was to evaluate whether OA disease severity is positively correlated with increased tracer uptake and to evaluate reliability. In a retrospective study design, patients who had undergone 68 Ga-FAPI PET-CT for a spectrum of clinical reasons were included. Whole-body CT was assessed for OA using the OsteoArthritis Computed Tomography‐Score in multiple joints and the spine. Maximum standard uptake value (SUVmax) was determined correspondingly. Logistic regression and correlation analyses were used to describe associations between structural OA and 68 Ga-FAPI PET activity. Fifty-four patients were included. Presence of OA in the acromioclavicular joints (ACJ) was associated with odds of SUVmax being in the highest tertile. Increased odds were seen for one location of the cervical spine (OR 5.7, 95

Objectives T-cell engagers (TCEs) are well-established treatments in haematology; strategies in autoimmune diseases are evolving. As an alternative to high-dose protocols optimising depletion, lower-dose protocols might optimise safety. Methods We assessed safety and efficacy of low-dose blinatumomab in a named patient use case series of 15 patients (median age 55) with multidrug-resistant rheumatoid arthritis (MDR-RA) (28-joint disease activity score C-reactive protein 5.0; clinical disease activity index [CDAI] 28). We monitored safety (cytokine release syndrome [CRS]; immune effector cell-related neurotoxicity syndrome [ICANS]), clinical scores, and tissue inflammation via ultrasound and fibroblast activation protein inhibitor (FAPI)-positron emission tomography/computed tomography (PET/CT). B-cell depletion was quantified in blood, synovium, and lymph nodes. Results CRS (grade 1) occurred in 3 of 15 patients. No ICANS occurred. One patient developed hypogammaglobulinaemia. One fatal cardiovascular event occurred after 1 year; it was adjudicated as unrelated by treating investigators but not independently reviewed. By week 12, disease activity decreased; 9 of 15 patients achieved CDAI low disease activity, and 3 of 15 patients achieved CDAI remission. Synovial B cells were depleted (4 of 5 biopsies) but not in lymph nodes. FAPI PET/CT showed reduced tracer uptake in the involved joints after blinatumomab. Although 14 of 15 patients flared, disease activity remained lower, and responsiveness lasting >3 months to previously failed drugs (Janus kinase inhibitors, abatacept, tumour necrosis factor inhibitors) was observed in 7 of 15 patients. Conclusions Short-term control of RA disease activity, depleted synovial B cells, and reduced fibroblast activation on FAPI-PET were observed 3 months after blinatumomab. Flares after blinatumomab responded to previously ineffective disease-modifying antirheumatic drugs in some patients. Low-dose TCE therapy may offer an accessible path to disease control in MDR-RA, although causal inference and generalisability require validation in controlled trials.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrotic remodeling of the skin and internal organs. Fibrotic tissue changes are considered hardly reversible with current therapies, suggesting that new strategies are required to modulate the disease-associated molecular and cellular phenotype to enable regeneration of affected tissues. Here, analyzing skin biopsy samples from patients with SSc who had received CD19-CAR T cell therapy as part of the CASTLE study or named patient use, we demonstrate structural regeneration of SSc skin structure, as evidenced by recovery of skin papillae. Consistent with these histological changes, cyclic in situ hybridization and imaging mass cytometry analyses suggested that fibroblast populations shifted towards a physiological state, both in terms of composition and function. Moreover, we describe signs of vascular repair and changes in epidermal cell function. These results suggest that B cell depletion using CD19-CAR T cell therapy may lead to skin tissue remodeling in SSc and highlight its potential for tissue regeneration in fibrotic diseases.

OBJECTIVES:To assess the clinical and imaging characteristics associated with fibroblast activation detected by 68Gallium-labelled fibroblast activation protein inhibitor positron emission tomography/CT (68Ga-FAPI-PET/CT) in patients with psoriasis and whether 68Ga-FAPI uptake correlates with the risk of progression to psoriatic arthritis (PsA). METHODS:Psoriasis patients with arthralgia underwent 68Ga-FAPI-PET/CT and were followed up prospectively. 68Ga-FAPI uptake was assessed at 71 articular sites and patients with ≥1 joint with 68Ga-FAPI uptake and PET/CT Joint Index≥2 were considered FAPI positive. The associations between FAPI uptake and clinical and ultrasound (US) findings were investigated. Survival analyses were conducted to assess the association between 68Ga-FAPI uptake and progression to PsA. RESULTS:45 patients with psoriasis were enrolled, 37 of whom (82%) were FAPI positive. FAPI-positive psoriasis patients had significantly higher body mass index (BMI) (p=0.036) and Disease Activity Score 28-C reactive protein (p=0.033) compared with FAPI-negative patients. 68Ga-FAPI uptake was most frequent in large joints and mechanically stressed sites and was more likely in the presence of low-grade synovial hyperplasia (OR: 1.77, 95% CI 1.08 to 2.89), entheseal Power Doppler (OR: 3.80, 95% CI 1.66 to 8.72) and concomitant osteoarthritis (OA). FAPI-positive patients showed a higher risk of progression to PsA compared with FAPI-negative patients (HR 7.1, 95% CI 0.9 to 53.6) (log-rank p=0.028). Only 1/8 patients with psoriasis (12.5%) without 68Ga-FAPI uptake developed PsA, as opposed to 18/37 (49%) of FAPI-positive patients. CONCLUSIONS:In psoriasis patients with arthralgia, 68Ga-FAPI uptake, indicating fibroblast activation, is associated with higher BMI, more pain, subclinical US changes and concomitant OA. Pathological 68Ga-FAPI uptake at articular sites was indicative of higher risk of progression to PsA in our cohort, suggesting fibroblast activation as a crucial step to develop PsA.

PET/CT imaging with radiolabeled fibroblast activation protein inhibitors (FAPI), as an emerging modality for imaging fibroinflammatory diseases, targets activated fibroblasts involved in active tissue remodeling and fibrogenesis. Although initially introduced for oncologic indications, FAPI PET imaging provides a distinctive molecular insight into various fibroinflammatory conditions, including rheumatologic disorders, interstitial lung disease, inflammatory bowel disease, thyroid inflammation, and multiorgan immune‑mediated diseases. Unlike 18F-FDG PET/CT, which reveals the metabolic demand of inflammatory cells, FAPI PET imaging enables non-invasive distinction between active cellular inflammation and permanent fibrotic changes. Several studies demonstrate its exceptional diagnostic performance and the potential to monitor therapeutic response to anti-fibrotic and immunomodulatory medications. Despite these encouraging results, the transition of FAPI PET into routine clinical practice requires large-scale, multi-center prospective trials to standardize imaging protocols and establish validated diagnostic thresholds and interpretation criteria. Ultimately, FAPI imaging and theranostics have significant potential to revolutionize precision medicine for inflammatory and fibrotic disorders.

CD19 chimeric antigen receptor (CD19 CAR) T cell therapy has been shown to induce stable drug-free remission in patients with refractory autoimmune disease. The management of potential relapses is currently unclear. Here we report on a 45-year-old woman with treatment-refractory Jo-1-associated anti-synthetase syndrome, who initially achieved disease remission after CD19 CAR T cell therapy but then experienced disease relapse after 9 months. After reinfusion of the same product, CAR T cells failed to expand and T cells targeting the CD19 CAR were detected. Despite full-dose lymphodepletion, no clinical response was observed. After bridging with anti-CD38 antibody daratumumab, which was efficacious with limited durability, plasma-cell-targeting B-cell maturation antigen (BCMA) CAR T cell therapy was performed. BCMA CAR T cells expanded, cleared plasma cells in lymphoid tissue, reduced autoantibody levels and re-induced stable drug-free remission. This case highlights the challenges in CAR T cell reinfusion, the potential of alternative targets and products, and suggests that the depletion of plasma cells may enhance therapeutic outcomes in patients who become treatment-refractory.

OBJECTIVES:Activated synovial fibroblasts play a key role in rheumatoid arthritis (RA). Positron emission tomography-CT (PET-CT) using 68gallium-labelled fibroblast activation protein inhibitor (FAPI) allows the detection of FAP-expressing activated fibroblasts in humans in vivo. Herein, this study aimed to investigate whether fibroblast activation already occurs in the pre-clinical phase of RA and whether it is associated with the development of clinical disease. METHODS:68Ga-FAPI-46 PET-CT was performed in individuals positive for anti-citrullinated protein antibodies (ACPAs) with clinically suspect arthralgia without present or past signs of joint swelling or present or past anti-rheumatic therapy. All participants underwent structured clinical and laboratory evaluations and were followed for the development of RA. Synovial FAPI uptake was quantified and related to demographic characteristics, joint tenderness, ACPA levels and RA development. FINDINGS:Eighteen RA-at-risk individuals (male/female: 7/11; mean age, 47 (SD 14) years) underwent 68Ga-FAPI-46 PET-CT and were followed for a median of 42 weeks. Five participants (28%) developed RA with a median of 12 weeks (IQR, 11-20), whereas 13 remained disease-free. Total lesion FAPI-uptake (TL-FAPI) was a significant predictor of RA development (HR 4.58, 95% CI 1.38 to 15.22, p=0.013). Increasing TL-FAPI at the joint level was also associated with tenderness (isk ratio 1.14, 95% CI 1.08 to 1.22, p=0.001). CONCLUSIONS:The findings in this small RA-at-risk cohort suggest that synovial fibroblast activation occurs early in the disease process of RA and is associated with an increased risk for clinical RA onset. These results warrant further research on FAPI-PET-CT to improve risk assessment for clinical RA onset.

We sought to assess the diagnostic value of 68Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT for obtaining information on organ involvement in the process of inflammation and fibrosis in patients with juvenile systemic sclerosis (jSSc). Methods: In this retrospective study, 4 children with a diagnosis of jSSc underwent 68Ga-FAPI-46 PET/CT imaging, 3 immediately after the diagnosis and before implementing immunmodulatory drugs and 1 a few years after active disease. Results: In this case series, 68Ga-FAPI-46 PET/CT detected all clinically known organ manifestations of jSSc. Additionally, this diagnostic tool provided previously unknown information about cardiac and muscular involvement in jSSc. Conclusion: 68Ga-FAPI-46 PET/CT provides valuable information to better assess disease activity and detect organ involvement. Further studies using 68Ga-FAPI-46 PET/CT in patients with jSSc are encouraged.

Psoriatic arthritis (PsA) is a complex heterogeneous inflammatory disease that affects about one-third of patients with psoriasis. PsA leads to significant physical impairment and reduced quality of life. Therefore, early diagnosis and intervention are critical for improving long-term outcomes. The purpose of this review is to highlight the advantages of unconventional imaging methods in the diagnosis and management of PsA and to discuss recent advancements in imaging technology. Conventional imaging methods, such as radiography, musculoskeletal ultrasound, and magnetic resonance imaging, have been instrumental in detecting structural joint damage and inflammation. However, these imaging modalities have several limitations, resulting in their inability to detect early disease changes. Recent advancements in imaging technology have led to the development of novel imaging modalities capable of characterizing not only early structural but also molecular aspects of disease activity. These cutting-edge approaches have been lately applied to both psoriasis and PsA patients, offering new insights into disease progression, the transition from psoriasis to PsA, and treatment responses. By providing more detailed and individualized assessments, unconventional imaging modalities may bring us closer to realizing the potential of personalized medicine in the management of PsA.

It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively.Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation.Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.

Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200-CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.