The value of ultrasound-defined tenosynovitis and synovitis in the prediction of persistent arthritis.

OBJECTIVES: The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis. METHODS: One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months' follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables. RESULTS: At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis [odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002] provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis. CONCLUSION: US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development.

Estimation of the burden of shielding among a cross-section of patients attending rheumatology clinics with SLE-data from the BSR audit of systemic lupus erythematosus.

OBJECTIVES: We aimed to estimate what proportion of people with SLE attending UK rheumatology clinics would be categorized as being at high risk from coronavirus disease 2019 (COVID-19) and therefore asked to shield, and explore what implications this has for rheumatology clinical practice. METHODS: We used data from the British Society for Rheumatology multicentre audit of SLE, which included a large, representative cross-sectional sample of patients attending UK Rheumatology clinics with SLE. We calculated who would receive shielding advice using the British Society for Rheumatology's risk stratification guidance and accompanying scoring grid, and assessed whether ethnicity and history of nephritis were over-represented in the shielding group. RESULTS: The audit included 1003 patients from 51 centres across all 4 nations of the UK. Overall 344 (34.3%) patients had a shielding score ≥3 and would have been advised to shield. People with previous or current LN were 2.6 (1.9-3.4) times more likely to be in the shielding group than people with no previous LN (P < 0.001). Ethnicity was not evenly distributed between the groups (chi-squared P < 0.001). Compared with White people, people of Black ethnicity were 1.9 (1.3-2.8) and Asian 1.9 (1.3-2.7) times more likely to be in the shielding group. Increased risk persisted after controlling for LN. CONCLUSION: Our study demonstrates the large number of people with SLE who are likely to be shielding. Implications for clinical practice include considering communication across language and cultural differences, and ways to conduct renal assessment including urinalysis, during telephone and video consultations for patients who are shielding.

BSR guideline on the management of adults with systemic lupus erythematosus (SLE) 2018: baseline multi-centre audit in the UK.

OBJECTIVES: To assess the baseline care provided to patients with SLE attending UK Rheumatology units, audited against standards derived from the recently published BSR guideline for the management of adults with SLE, the NICE technology appraisal for belimumab, and NHS England's clinical commissioning policy for rituximab. METHODS: SLE cases attending outpatient clinics during any 4-week period between February and June 2018 were retrospectively audited to assess care at the preceding visit. The effect of clinical environment (general vs dedicated CTD/vasculitis clinic and specialized vs non-specialized centre) were tested. Bonferroni's correction was applied to the significance level. RESULTS: Fifty-one units participated. We audited 1021 episodes of care in 1003 patients (median age 48 years, 74% diagnosed >5 years ago). Despite this disease duration, 286 (28.5%) patients had active disease. Overall in 497 (49%) clinic visits, it was recorded that the patient was receiving prednisolone, including in 28.5% of visits where disease was assessed as inactive. Low documented compliance (<60% clinic visits) was identified for audit standards relating to formal disease-activity assessment, reduction of drug-related toxicity and protection against comorbidities and damage. Compared with general clinics, dedicated clinics had higher compliance with standards for appropriate urine protein quantification (85.1% vs 78.1%, P ≤ 0.001). Specialized centres had higher compliance with BILAG Biologics Register recruitment (89.4% vs 44.4%, P ≤ 0.001) and blood pressure recording (95.3% vs 84.1%). CONCLUSIONS: This audit highlights significant unmet need for better disease control and reduction in corticosteroid toxicity and is an opportunity to improve compliance with national guidelines. Higher performance with nephritis screening in dedicated clinics supports wider adoption of this service-delivery model.

Translocator Protein as an Imaging Marker of Macrophage and Stromal Activation in Rheumatoid Arthritis Pannus.

PET radioligands targeted to translocator protein (TSPO) offer a highly sensitive and specific means of imaging joint inflammation in rheumatoid arthritis (RA). Through high expression of TSPO on activated macrophages, TSPO PET has been widely reported in several studies of RA as a means of imaging synovial macrophages in vivo. However, this premise does not take into account the ubiquitous expression of TSPO. This study aimed to investigate TSPO expression in major cellular constituents of RA pannus-monocytes, macrophages, fibroblastlike synoviocytes (FLS cells), and CD4-positive (CD4+) T lymphocytes (T cells)-to more accurately interpret TSPO PET signal from RA synovium. Methods: Three RA patients and 3 healthy volunteers underwent PET of both knees using the TSPO radioligand 11C-PBR28. Through 3H-PBR28 autoradiography and immunostaining of synovial tissue in 6 RA patients and 6 healthy volunteers, cellular expression of TSPO in synovial tissue was evaluated. TSPO messenger RNA expression and 3H-PBR28 radioligand binding was assessed using in vitro monocytes, macrophages, FLS cells, and CD4+ T cells. Results:11C-PBR28 PET signal was significantly higher in RA joints than in healthy joints (average SUV, 0.82 ± 0.12 vs. 0.03 ± 0.004; P < 0.01). Further, 3H-PBR28-specific binding in synovial tissue was approximately 10-fold higher in RA patients than in healthy controls. Immunofluorescence revealed TSPO expression on macrophages, FLS cells, and CD4+ T cells. The in vitro study demonstrated the highest TSPO messenger RNA expression and 3H-PBR28-specific binding in activated FLS cells, nonactivated M0 macrophages, and activated M2 reparative macrophages, with the least TSPO expression being in activated and nonactivated CD4+ T cells. Conclusion: To our knowledge, this study was the first evaluation of cellular TSPO expression in synovium, with the highest TSPO expression and PBR28 binding being found on activated synovial FLS cells and M2 macrophages. TSPO-targeted PET may therefore have a unique sensitivity in detecting FLS cells and macrophage-predominant inflammation in RA, with potential utility for assessing treatment response in trials using novel FLS-cell-targeted therapies.

The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory 'M1' human macrophages.

The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-ß1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.

Pro-inflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans.

The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with 3H-PBR28 in primary human macrophages. As observed previously, we found that TSPO expression increases (∼9-fold) in rodent-derived macrophages and microglia upon pro-inflammatory stimulation. However, TSPO expression does not increase with classical pro-inflammatory activation in primary human microglia (fold change 0.85 [95% CI 0.58-1.12], p = 0.47). In contrast, pro-inflammatory activation of human monocyte-derived macrophages is associated with a reduction of both TSPO gene expression (fold change 0.60 [95% CI 0.45-0.74], p = 0.02) and TSPO binding site abundance (fold change 0.61 [95% CI 0.49-0.73], p < 0.0001). These findings have important implications for understanding the biology of TSPO in activated macrophages and microglia in humans. They are also clinically relevant for the interpretation of PET studies using TSPO targeting radioligands, as they suggest changes in TSPO expression may reflect microglial and macrophage density rather than activation phenotype.

Advances in positron emission tomography for the imaging of rheumatoid arthritis.

Imaging techniques, such as US, are well recognized as important tools to aid early diagnosis and assess response to treatment in RA. PET offers a means of imaging the inflammatory processes of RA at a cellular level and thus may be a highly sensitive method of assessing synovitis. In this review we discuss the advantages of PET as an imaging modality for RA and summarize the existing clinical studies of PET in RA. We also highlight potentially important preclinical studies of PET in arthritis and discuss current limitations of PET as well as ongoing developments in PET technology likely to be of benefit for arthritis imaging.

Sulfasalazine induced immune thrombocytopenia in a patient with rheumatoid arthritis.

Sulfasalazine has long been used for the treatment of rheumatoid arthritis and is often chosen as a first-line treatment. Here, we report a case of sulfasalazine-induced autoimmune thrombocytopenia and review the mechanisms behind drug-induced immune thrombocytopenia (DITP) and the approach to its diagnosis and management.