Ilfita Sahbudin

B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis

The clinical efficacy of B cell targeting therapies highlights the pathogenic potential of B cells in inflammatory diseases. Expression of Fc Receptor like 4 (FcRL4) identifies a memory B cell subset, which is enriched in the joints of patients with rheumatoid arthritis (RA) and in mucosa-associated lymphoid tissue. The high level of RANKL production by this B cell subset indicates a unique pathogenic role. In addition, recent work has identified a role for FcRL4 as an IgA receptor, suggesting a potential function in mucosal immunity. Here, the contribution of FcRL4+ B cells to the specific autoimmune response in the joints of patients with RA was investigated. Single FcRL4+ and FcRL4- B cells were sorted from synovial fluid and tissue from RA patients and their immunoglobulin genes characterized. Levels of hypermutation in the variable regions in both populations were largely consistent with memory B cells selected by an antigen- and T cell-dependent process. Recombinant antibodies were generated based on the IgH and IgL variable region sequences and investigated for antigen specificity. A significantly larger proportion of the recombinant antibodies generated from individual synovial FcRL4+ B cells showed reactivity towards citrullinated autoantigens. Furthermore, both in analyses based on heavy chain sequences and flow cytometric detection, FcRL4+ B cells have significantly increased usage of the IgA isotype. Their low level of expression of immunoglobulin and plasma cell differentiation genes does not suggest current antibody secretion. We conclude that these activated B cells are a component of the local autoimmune response, and through their RANKL expression, can contribute to joint destruction. Furthermore, their expression of FcRL4 and their enrichment in the IgA isotype points towards a potential role for these cells in the link between mucosal and joint inflammation.

Initial validation and results of the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: a EULAR project

Objectives To describe the development and assess the psychometric properties of the novel ‘Symptoms in Persons At Risk of Rheumatoid Arthritis’ (SPARRA) questionnaire in individuals at risk of rheumatoid arthritis (RA) and to quantify their symptoms. Methods The questionnaire items were derived from a qualitative study in patients with seropositive arthralgia. The questionnaire was administered to 219 individuals at risk of RA on the basis of symptoms or autoantibody positivity: 74% rheumatoid factor and/or anticitrullinated protein antibodies positive, 26% seronegative. Validity, reliability and responsiveness were assessed. Eighteen first degree relatives (FDR) of patients with RA were used for comparison. Results Face and content validity were high. The test-retest showed good agreement and reliability (1 week and 6 months). Overall, construct validity was low to moderate, with higher values for concurrent validity, suggesting that some questions reflect symptom content not captured with regular Visual Analogue Scale pain/well-being. Responsiveness was low (small subgroup). Finally, the burden of symptoms in both seronegative and seropositive at risk individuals was high, with pain, stiffness and fatigue being the most common ones with a major impact on daily functioning. The FDR cohort (mostly healthy individuals) showed a lower burden of symptoms; however, the distribution of symptoms was similar. Conclusions The SPARRA questionnaire has good psychometric properties and can add information to currently available clinical measures in individuals at risk of RA. The studied group had a high burden and impact of symptoms. Future studies should evaluate whether SPARRA data can improve the prediction of RA in at risk individuals.

Nocturnal seizure and simultaneous bilateral shoulder fracture-dislocation.

An otherwise fit and well 27-year-old man presented with acute onset unexplained bilateral shoulder pain, and was found to have bilateral shoulder fractures and dislocations on imaging. Although features were atypical, a nocturnal seizure causing the bilateral shoulder fractures was suspected and EEG showed features compatible with epilepsy.

Observing real-time images during ultrasound-guided procedures improves patients’ experience

SIR, US-guided intra-articular and soft tissue steroid injections are common procedures in rheumatology and are taking the place of fluoroscopic and CT-guided injections. Little is known about patients’ views about US-guided steroid injections despite several efficacy studies comparing blind to US-guided injections [1 4]. In the obstetric and gynaecological specialties, patients’ views related to sonography examinations are well documented [5,6]. We conducted a survey to quantitatively capture data relating to patients’ views of US-guided procedures. Ethical approval was not required from the National Health Service (NHS) because this work was considered to be a service evaluation in the NHS Trust in which it took place. Fifty questionnaires that included balanced Likert scale questions were distributed to rheumatology patients who underwent a US-guided procedure between January 2011 and January 2012. Survey receipt was concluded in April 2012 relating to a post-injection period ranging from 4 to 16 months. Of the 50 questionnaires distributed, 30 (60%) were returned and 26 (50%) were completed and included for data analysis (for the full questionnaire, see Supplementary data, available at Rheumatology Online). A rheumatology consultant with US experience (A.F.) performed all the procedures. During the procedure the sonographer explained to the patient the anatomical features of the diseased target site, power Doppler activity and dynamic needle progression through the superficial tissues into the target site. A total of 34 joints/tendon regions were injected in 26 patients (hand, n = 12; wrist, n = 9; elbow, n = 2; knee, n = 3; ankle, n = 3; feet, n = 5). All procedures were part of the patients’ normal care pathways. All patients felt that seeing the US images was very helpful or helpful in understanding the procedure (Fig. 1A). Eighty-eight per cent of the patients felt that their levels of worry or anxiety were better or much better as a result of being able to see a US image of the

The role of ultrasound-defined tenosynovitis and synovitis in the prediction of rheumatoid arthritis development.

Abstract Objectives Tenosynovitis (TS) is common in early arthritis. However, the value of US-defined TS in predicting RA development is unclear. We assessed the predictive utility of US-defined TS alongside US-defined synovitis and clinical and serological variables in a prospective cohort of early arthritis patients. Methods One hundred and seven patients with clinically apparent synovitis of one or more joint and symptom duration ⩽3 months underwent baseline clinical, laboratory and US assessment of 19 bilateral joint sites and 16 bilateral tendon compartments. Diagnostic outcome was determined after 18 months, applying the 2010 ACR/EULAR classification criteria for RA. The predictive values of US-defined TS for persistent RA were compared with those of US-defined synovitis, clinical and serological variables. Results A total of 4066 US joint sites and 3424 US tendon compartments were included in the analysis. Forty-six patients developed persistent RA, 17 patients developed non-RA persistent disease and 44 patients had resolving disease at follow-up. US-defined TS in at least one tendon compartment at baseline was common in all groups (RA 85%, non-RA persistent disease 71% and resolving 70%). On multi-variate analysis, US-defined digit flexor TS provided independent predictive data over and above the presence of ACPA and US-defined joint synovitis. Conclusion US-defined digit flexor TS provided independent predictive data for persistent RA development in patients with early arthritis. The predictive utility of this tendon site should be further assessed in a larger cohort; investigators designing imaging-based predictive algorithms for RA development should include this tendon component as a candidate variable.

New headaches with normal inflammatory markers: an early atypical presentation of giant cell arteritis

An 80-year-old man presented repeatedly to his general practitioner with 3 months of unexplained persistent frontal headaches. CT head revealed no diagnosis. His dentist diagnosed his co-existing jaw pain as bruxism. Three months later, the patient happened to attend a routine ophthalmology follow-up appointment. During this routine appointment, features of giant cell arteritis (GCA) including worrying visual complications were first noted. His inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) were not significantly raised—contrary to the norm. A temporal artery ultrasound and biopsy were performed, in light of the history. This confirmed GCA. He was commenced on high-dose oral prednisolone and was managed by ophthalmology and rheumatology. At 4 weeks, symptoms resolved with no permanent visual loss despite a prolonged initial symptomatic period. Multiple symptomatic presentations to different specialties should therefore alert clinicians to a unifying diagnosis, for example, vasculitis. Serious illnesses may present with severe symptoms despite normal screening investigations.

Immunoglobulin characteristics and RNAseq data of FcRL4+ B cells sorted from synovial fluid and tissue of patients with rheumatoid arthritis

This manuscript is a companion paper to Amara et al. [1]. Data shown here include detailed clinical characteristics from anonymized patients, the Ig subclass data generated from B cells sorted from four individual patients, tables detailing variable gene region sequences from sorted cells linked to the patient information and the sequence yields from individual patients. Furthermore a URL link to the RNAseq datasets submitted to GEO is included.

ULTRASOUND-DEFINED TENOSYNOVITIS PREDICTS RA IN PATIENTS WITH RECENT-ONSET INFLAMMATORY ARTHRITIS

Background and objective Tenosynovitis is common in early arthritis and the OMERACT Ultrasound Task Force recommended that US is a reproducible tool for evaluating tenosynovitis (TS) in RA. However, the value of US-defined tenosynovitis (TS) in the prediction of RA development is unclear. We assessed the ability of US-defined TS to predict the development of persistent RA in a prospective cohort of patients with early arthritis. Methods 107 patients with clinically apparent synovitis of at least one joint and symptom duration ≤3 months underwent baseline clinical, laboratory and tendon US assessments and the presence of grey scale and Power Doppler TS at 16 bilateral tendon compartments was determined [bilateral fingers (flexor compartments), wrists (extensor and flexor compartments), shoulders (biceps tendon), ankles (anterior extensors, peroneals, posterior tibialis)]. Outcome was determined after 18 months, applying the 2010 ACR/EULAR classification criteria for RA. The predictive values of US-defined TS for persistent RA were compared with clinical and serological variables. Results A total of 3424 tendon compartments were included in the analysis. 43 patients developed persistent RA (RA), 20 patients developed non-RA persistent disease (NRAP) and 44 patients had resolving disease at follow-up. All groups had evidence of TS in at least one tendon compartment at baseline (RA 85%, NRAP 71%, and Resolving 71%). In multivariate logistic regression, extensor carpi ulnaris (ECU) and digit flexor tendon involvement were predictive of persistent RA and provided additional predictive data over and above the presence of high levels of autoantibodies and clinical involvement of more than 10 joints [ECU or digit flexor TS (OR = 5.25, p = 0.001), >10 clinically tender or swollen joints (OR = 7.96, p < 0.001), RF or ACPA high-positivity (OR = 7.31, p = 0.001); AUC = 0.86, Nagelkerke’s R2 = 0.499]. Conclusion This is the first study to illustrate that US-detected TS is predictive of persistent RA in patients with early arthritis. ECU and digit flexor tendon scanning provides optimal predictive data over and above clinical and serological variables.

ULTRASOUND-DETECTED SYNOVITIS AND TENOSYNOVITIS PREDICT RA IN EARLY DISEASE

Background Ultrasound-detected synovitis improves the prediction of RA in early disease. Although ultrasound-detected tenosynovitis in common in early RA, its relative utility in the prediction of RA alongside ultrasound-detected synovitis and conventional serological and clinical variables is unclear. Objectives To identify a minimal core set of ultrasound, clinical and serological variables predicting RA in a cohort of patients with early arthritis using a data-driven approach. Methods 107 patients [female n=60, median age 51] with ≥1 joint with clinically apparent synovitis and a symptom duration ≤3 months underwent clinical, laboratory and ultrasound assessments. Final diagnoses were determined at 18 month follow-up. Ultrasound assessment determined the presence of synovitis at 28 joints (bilateral MCPs 1–5, PIPs 1–5, wrists, and MTPs 2–5) and tenosynovitis at four tendon sites (bilateral finger flexor and extensor carpi ulnaris tendon). First, principal component analysis (PCA) was performed on 1) clinical and serological variables (age, gender, symptom duration, ESR, CRP, RF, ACPA, duration of early morning stiffness, tender joint and swollen joint count), and 2) joint and tendon ultrasound variables. Then the variable with the highest loading factor from each component was extracted and made available in a forward step-wise multivariate logistic regression analysis. Results 46 patients developed RA, 17 developed non-RA persistent inflammatory arthritis and 44 patients had resolving disease. Seven components were identified on clinical and serological PCA and four components were identified within ultrasound synovitis and tenosynovitis variables (Table 1). The final multivariate logistic regression model included ACPA positivity (OR=12.61, CI: 3.50–45.52, p<0.001), digit flexor ultrasound tenosynovitis (OR=4.58, CI: 1.67–12.56, p=0.003) and MCP 1 ultrasound synovitis positivity (OR=4.75, CI: 1.78–12.64, p=0.002).Table 1. PCA analysis of clinical, serological, joint and tendon ultrasound variables Component Clinical and serological variables 1 Swollen joints >6* , tender joints >6 2 Age ≥60* 3 Early morning stiffness ≥60 min* 4 Swollen joint = 1*, Tender joint = 1 5 ACPA positivity* 6 Abnormal CRP*, abnormal ESR 7 Gender* Component Joint and tendon ultrasound variables 1 MCP 1*, MCP 4, MCP 5, PIP 1, PIP 4 2 Digit flexor tendon*, MCP 2, MCP 3, extensor carpi ulnaris tendon, wrist joint 3 PIP 2*, PIP 3, PIP 5 4 MTP 2*, MTP 3, MTP 4 *Variables with the highest loading factor within each component. Conclusions Both ultrasound-detected synovitis and tenosynovitis provide independent data in addition to clinical and serological variables in the prediction of RA in early disease. MCP 1 and digit flexor scanning provide the optimal predictive data in this cohort. Disclosure of Interest None declared

PREDICTION OF PERSISTENT INFLAMMATORY ARTHRITIS WITH ULTRASOUND: A DATA-DRIVEN METHOD

Background Prediction of disease persistence in early inflammatory arthritis is important to enable timely initiation of appropriate therapy. Currently available predictive algorithms for persistent arthritis do not include US variables. We used a data-driven method to identify the minimal core set of US, clinical and serological variables predicting persistent inflammatory arthritis in a cohort of patients with early arthritis. Methods 107 patients [female n = 60, median age 51] with ≥1 clinically apparent synovitis and symptom duration ≤3 months underwent clinical, laboratory and US assessments. Final diagnosis was determined at 18-months follow-up. US assessment determined the presence of Grey scale (GS) and Power Doppler (PD) synovitis at 38 joints (bilateral MCPs 1–5, PIPs 1–5, wrists, shoulders, elbows, ankles and MTPs 2–5). First, univariate analysis was performed to identify clinical, serological and US variables significantly associated with persistent disease at 18-months. Second, principal component analysis (PCA) was performed on 1) clinical and serological variables (age, gender, symptom duration, ESR, CRP, RF, ACPA, duration of early morning stiffness, tender joint and swollen joint count), 2) US GS variables and 3) US PD variables to identify variables that reflected similar themes. Finally, one variable from each component was extracted and made available in a forward step-wise multivariate logistic regression analysis. Results 63 patients developed persistent inflammatory arthritis and 44 patients had resolving disease. On PCA, three components were identified within the clinical and serological variables, four components were identified within the GS US variables and four components within the PD US variables. The final multivariate logistic regression model included RF positivity (OR = 5.83, p = 0.01), MCP2 PD positivity (OR = 4.33, p = 0.002) and MTP2 PD positivity (OR = 10.72, p = 0.030). In seronegative patients, the final multivariate logistic regression included early morning stiffness >60mins (OR=3.62, p = 0.017) and PIP 2 PD (OR = 8.44, p = 0.003). Conclusion This is the first study using a data-driven method to show that US provides independent data beyond clinical and serological variables in the prediction of persistent arthritis, even in RF and ACPA-negative patients. Bilateral MCP2 and MTP2 is the minimal joint sub-set that provides independent predictive data in this cohort.