Andrew K. Brown

Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study

Objectives The treatment target for patients with rheumatoid arthritis (RA) is remission. Imaging techniques and remission criteria may identify patients at risk of flare and associated consequences. This study aimed to determine the clinical, functional and imaging associations of disease flare in patients with RA in remission and any effect on long-term outcomes. Methods RA patients in clinical remission as determined by their treating rheumatologist were assessed using clinical, remission criteria, imaging, functional and quality of life measures over 12 months. Flare was defined as any increase in disease activity requiring a change in therapy. Results 26% of patients (24/93) in remission experienced a flare within 1 year. Fulfilment of remission criteria was not associated with a reduced likelihood of flare. Increased baseline ultrasound power Doppler (PD) activity (unadjusted OR (95% CI) 4.08 (1.26 to 13.19), p=0.014) and functional disability (Health Assessment Questionnaire Disability Index (HAQ-DI) per 0.1 unit1.27 (1.07 to 1.52), p=0.006) were independently associated with risk of flare. Patients who had a flare had significantly worse long-term clinical (Disease Activity Score 28; mean (95% CI) 2.90 (2.55 to 3.24) vs 2.26 (2.06 to 2.46), p=0.002) and functional outcomes (HAQ-DI; 0.412 (0.344 to 0.481) vs 0.322 (0.282 to 0.362), p=0.029) at 12 months compared with patients in sustained remission. Conclusion The presence of PD activity was the most accurate determinant of flare in RA patients in remission. Flare was associated with worse clinical and functional outcomes. These results suggest ultrasound could form an important part of remission assessment in RA.

Synovitis and osteitis are very frequent in rheumatoid arthritis clinical remission: results from an MRI study of 294 patients in clinical remission or low disease activity state.

Objective. In rheumatoid arthritis (RA), radiographic progression may occur despite clinical remission. This may be explained by subclinical inflammation. Magnetic resonance imaging (MRI) provides a greater sensitivity than clinical examination and radiography for assessing disease activity. Our objective was to determine the MRI characteristics of RA patients in clinical remission or low disease activity (LDA) state. Methods. Databases from 6 cohorts were collected from 5 international centers. RA patients in clinical remission according to Disease Activity Score28-C-reactive protein (DAS28-CRP < 2.6; n = 213) or LDA-state (2.6 ≤ DAS28-CRP < 3.2; n = 81) with available MRI data were included. MRI were assessed according to the OMERACT RA MRI scoring system (RAMRIS). Results. Patient characteristics: 70% women, median age 55 (interquartile range, IQR 43–63) years, disease duration 2.3 (IQR 0.7–5.1) years, DAS28-CRP 2.2 (IQR 1.8–2.6), Simplified Disease Activity Index, SDAI, 3.9 (IQR 1.9–6.5), Clinical Disease Activity Index, CDAI, 3.1 (IQR 1.5– 5.8), rheumatoid factor/anti-cyclic citrullinated peptide positivity 57%/54%, presence of radiographic erosions: 66%. Wrist and metacarpophalangeal MRI (MCP-MRI) data were available for 287 and 241 patients, respectively. MRI inflammatory activity in wrist and/or MCP joints was observed in the majority [synovitis: 95%, bone edema (osteitis): 35%] of patients. The median (IQR) RAMRIS score was 6 (3–9) for synovitis and 0 (0–2) for osteitis. Synovitis and osteitis were not less frequent in DAS28 clinical remission (synovitis/osteitis 96%/35%) than LDA (91/36). A trend towards lower frequencies of osteitis in patients in SDAI and CDAI remission was observed. Conclusion. Subclinical inflammation was identified by MRI in the majority of RA patients in clinical remission or LDA state. This may explain structural progression in such patients. Further work is required to understand the place of modern imaging in future remission criteria.

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse

Objectives: An abnormal CD4+ T cell subset related to inflammation exposure (inflammation-related cells, IRC) has been identified in rheumatoid arthritis (RA). Patients with inflammatory and non-inflammatory diseases were used to examine the relationship between inflammation and this T cell subset in vivo. Methods: Blood was collected from healthy controls and patients with RA (active disease or in clinical remission), Crohn’s disease and osteoarthritis. IRC and chemokine receptors were quantified by flow cytometry. Thymic activity and apoptotic factors were measured by real-time polymerase chain reaction. Circulating cytokines were measured by enzyme-linked immunosorbent assay. CXCR4 and SDF1 in synovial biopsies were measured using immunohistochemistry. Results: IRC were identified in patients with RA (p<0.0001) and Crohn’s disease (p = 0.005), but not in those with osteoarthritis. In RA in remission, IRC persisted (p<0.001). In remission, hyperproliferation of IRC was lost, chemokine receptor expression was significantly lowered (p<0.007), Bax expression dropped significantly (p<0.001) and was inversely correlated with IRC (rho = −0.755, p = 0.03). High IRC frequency in remission was associated with relapse within 18 months (OR = 6.4, p<0.001) and a regression model predicted 72% of relapse. Conclusions: These results suggest a model in which, despite the lack of systemic inflammation, IRC persist in remission, indicating that IRC are an acquired feature of RA. They have, however, lost their hyper-responsiveness, acquired a potential for survival, and no longer express chemokine receptors. IRC persistence in remission confirms their important role in chronic inflammation as circulating precursors of pathogenic cells. This was further demonstrated by much higher incidence of relapse in patients with high IRC frequency in remission.

Relationship between early bone mineral density changes and long‐term function and radiographic progression in rheumatoid arthritis

To ascertain whether bone mineral density loss during the first year of treatment for early rheumatoid arthritis (RA) as assessed by dual x‐ray absorptiometry (DXA) is associated with long‐term function, quality of life, and radiographic progression.

Response to Intramuscular Methyl Prednisolone in inflammatory hand pain: Evidence for a targeted clinical, ultrasonographic and therapeutic approach.

Background: Hand pain with stiffness is a common clinical presentation to early arthritis clinics, with outcome varying from resolution to the development of rheumatoid arthritis. Objective: To assess the response and predictors of response to intramuscular methylprednisolone (MP) and hydroxychloroquine (HCQ) using a standardised treatment protocol. Methods: Patients with inflammatory hand pain (IHP), defined as predominantly hand pain and morning stiffness of at least 30 min duration, received a standardised assessment prior to receiving intramuscular MP. Response (primary outcome) at 4 weeks was a 50% improvement in symptoms as perceived by the patient; responders who relapsed received repeat intramuscular MP and HCQ. Results: 102 patients were recruited, of which 21% were rheumatoid factor (RF) positive, 23% had clinical synovitis, 25% had raised C-reactive protein level and 55% had ultrasound-detected synovitis. 73% responded, with associated significant reductions in morning stiffness, Health Assessment Questionnaire, painful and tender joint counts, and visual analogue scores (p⩽0.006 for all). Ultrasound-detected synovitis (p<0.001) and RF (p = 0.04), but not clinical synovitis (p = 0.74), were significantly associated with response to intramuscular MP. 86% who remained on HCQ long term reported a benefit. Conclusions: Patients with IHP have significant improvement in symptoms and function following intramuscular MP. Further placebo-controlled trials are required to assess the role of intramuscular MP and ultrasonography in managing this patient group.