The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis.

OBJECTIVES: Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. METHODS: Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. RESULTS: None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P = 0.001), whereas CCR6 and TNIP1 expression increased (P < 0.001 and P = 0.002, respectively) over a 2 year period. Expression levels in ACPA-positive and ACPA-negative CSA patients who developed IA were similar. CONCLUSION: Whole-blood gene expression of assessed cytokines, chemokines and related receptors did not change significantly from CSA to IA development. This suggests that changes in expression of these molecules may not be related to the final process of developing chronicity and may have occurred preceding CSA onset. Changes in gene expression in CSA patients without IA development may provide clues for processes related to resolution.

Work participation is reduced during the development of RA, months before clinical arthritis manifests.

OBJECTIVES: We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis were used as a reference. METHODS: Three groups of patients were studied: arthralgia patients converting to RA (n = 114), arthralgia patients with spontaneous symptom resolution (n = 57), and early RA patients (n = 617). Both presenteeism (i.e. working while sick, scale 0-10) and absenteeism (i.e. sick leave) were taken into account. Work ability 1 year prior to clinical arthritis was estimated (in absolute numbers). The course of work restriction over time was studied using linear mixed models (ß coefficient; delta per month) within each patient group. RESULTS: One-year prior to the development of clinical arthritis, mean presenteeism was 7.0 (95% CI 5.8, 8.1) in patients with arthralgia, indicating 30% loss, and further worsened to 6.1 (95% CI 5.3, 6.6) at RA diagnosis, thus indicating 39% loss. In early RA patients, presenteeism improved over time after DMARD initiation (ß 0.052 per month 95% CI 0.042, 0.061, P < 0.0001). Presenteeism also improved in arthralgia patients who achieved spontaneous symptom resolution (ß 0.063 per month, 95% CI 0.024, 0.10, P = 0.002). Absenteeism did not change significantly in arthralgia patients, but did improve in RA after DMARD-start. ACPA stratification revealed similar results. CONCLUSION: In the months preceding RA, presenteeism was already apparent, and it worsened further during progression to clinical arthritis and diagnosis. This underlines the relevance of the symptomatic pre-RA phase for patients. The observed reversibility in arthralgia patients with symptom resolution may suggest that intervention in pre-RA could improve work participation.

An ultrasound negative for subclinical synovitis in arthralgia patients: is it helpful in identifying those not developing arthritis?

OBJECTIVE: To investigate the negative predictive value (NPV) of musculoskeletal US (MSUS) in arthralgia patients at risk for developing inflammatory arthritis. METHODS: An MSUS examination of hands and feet was performed in arthralgia patients at risk for inflammatory arthritis in four independent cohorts. Patients were followed for one-year on the development of inflammatory arthritis. Subclinical synovitis was defined as greyscale ≥2 and/or power Doppler ≥1. NPVs were determined and compared with the prior risks of not developing inflammatory arthritis. Outcomes were pooled using meta-analyses and meta-regression analyses. In sensitivity analyses, MSUS imaging of tender joints only (rather than the full US protocol) was analysed and ACPA stratification applied. RESULTS: After 1 year 78, 82, 77 and 72% of patients in the four cohorts did not develop inflammatory arthritis. The NPV of a negative US was 86, 85, 82 and 90%, respectively. The meta-analysis showed a pooled non-inflammatory arthritis prevalence of 79% (95% CI 75%, 83%) and a pooled NPV of 86% (95% CI 81, 89%). Imaging tender joints only (as generally done in clinical practice) and ACPA stratification showed similar results. CONCLUSION: A negative US result in arthralgia has a high NPV for not developing inflammatory arthritis, which is mainly due to the high a priori risk of not developing inflammatory arthritis. The added value of a negative US (<10% increase) was limited.

Subclinical synovitis in arthralgia: how often does it result in clinical arthritis? Reflecting on starting points for disease-modifying anti-rheumatic drug treatment.

OBJECTIVES: According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. 'false positives'). METHODS: Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. RESULTS: Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. CONCLUSION: Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44-89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.

Long-term outcomes of bilateral direct-to-implant breast reconstruction in women at high breast cancer risk.

INTRODUCTION: Challenges of direct-to-implant breast reconstruction (BR) are to achieve sufficient implant coverage and lower pole projection. We assessed reoperation rates, long-term patient satisfaction and aesthetic outcome after direct-to-implant BR without acellular dermal matrix (ADM) in women with high breast cancer risk. METHODS: Women who underwent bilateral skin or nipple-sparing mastectomy and immediate direct-to-implant BR between 1994 and 2006 completed a survey on reoperations and the Breast-Q Reconstruction questionnaire. Photographs taken during follow-up were rated for long-term aesthetic outcome (scale 1-10) by five plastic surgeons. Outcomes were compared between women who never underwent unanticipated reoperations after immediate BR and women who underwent one or more reoperations, adjusted for potential confounders using multivariable linear regression. RESULTS: Of 143 women, 70 (49%) were never reoperated and 73 (51%) had undergone reoperations. Median follow-up was 12 years in both groups (range 7-17 and 6-19 years, respectively). Baseline characteristics were comparable except for history of prophylactic oophorectomy with 81% in the no-reoperations group versus 66% in the reoperated group (p = .03). Breast-Q scores were 59.7 ± 17.3 versus 58.0 ± 17.8 (p = .67) for 'satisfaction with breasts' and 71.1 ± 20.3 versus 68.1 ± 22.9 (p = .47) for 'satisfaction with outcome' in the no-reoperation versus reoperation group, respectively. Aesthetic outcome was scored 5.8 ± 1.1 in the no-reoperation group versus 5.3 ± 1.3 in the reoperation group (p = .01). CONCLUSIONS: The single-stage intent did not prevent unanticipated surgical reinterventions in 51% of the patients. Long-term patient satisfaction was reasonable and not affected by reoperations. Aesthetic outcome, however, was only poor to reasonable and scores were significantly lower in the reoperated group.