Tocilizumab induces corticosteroid sparing in rheumatoid arthritis patients in clinical practice.

OBJECTIVE: . The aim of this study was to evaluate the impact of introducing tocilizumab (TCZ) as co-therapy with CS in patients with RA. METHODS: This study was an open, observational, retrospective multicentre study. RA patients treated with oral CS for >3 months who started treatment with TCZ between December 2009 and June 2011 in five centres were included. Variables included demographic data, disease history, co-treatments, disease activity and dose of CS at inclusion and at weeks 4, 8, 12 and 24. The evolution of disease activity and of the dose of CS (analysis of variance with repeated measures) were analysed, searching for factors correlated with changes in the dose of CS. RESULTS: Inclusion of 130 patients [women 80.8%, mean age 56.7 years (s.d. 14.0), RA duration 16.3 years (s.d. 10.4), mean baseline 28-joint DAS (DAS28) 5.1 (s.d. 1.4), mean baseline dose of CS 10.0 mg/day (s.d. 8.2) prednisone equivalent. Decreases in the mean daily dose of CS and in the DAS28 were observed during follow-up [respectively 6.5 mg (s.d. 4.8) at week 24 (P < 0.0001) and 3.0 mg (s.d. 1.4) at week 24 (P < 0.0001)]. The only variable that correlated with the decrease in the dose of CS was the initial dose of the drug (r = 0.82, P < 0.001). CONCLUSION: The introduction of TCZ led to rapid and long-lasting CS sparing that did not correlate with the reduction in disease activity. It is possible that in patients treated with high-dose CS, the main objective of the clinician is to reduce dosage of CS rather than RA activity.

Predictors of response and remission in a large cohort of rheumatoid arthritis patients treated with tocilizumab in clinical practice.

OBJECTIVE: The objective of this study was to identify predictors of response and remission to tocilizumab (TCZ) in RA patients seen in daily routine clinical practice. METHODS: The efficacy of TCZ was evaluated after 12 and 24 weeks of treatment by the European League Against Rheumatism (EULAR) response criteria. Regression analysis was performed to study the association between remission or EULAR response and the following characteristics: gender, age, current smokers, prior cardiovascular disease (CVD), 28-joint disease activity score (DAS28), CRP, RF or ACPA positivity, combination therapy with DMARDs and TCZ as the first biological therapy or after failure of at least one biological therapy. RESULTS: In total, 204 patients were included with a mean DAS28 score of 5.14. EULAR response and remission were obtained in 86.1% and 40% of patients, respectively, at week 24. In multiple regression analysis, a high baseline CRP level [odds ratio (OR) 4.454 (95% CI 1.446, 13.726)] was significantly associated with EULAR response at week 24 and, inversely, age >55 years [OR 0.285 (95% CI 0.086, 0.950)] and prior CVD [OR 0.305 (95% CI 0.113, 0.825)] were significantly associated with lower EULAR response at week 24. Older age was also associated with less remission at week 24 [OR 0.948 (95% CI 0.920, 0.978)]. No additional effectiveness was found when TCZ was used in combination with a DMARD or when patients were naive to biological agents. CONCLUSION: In daily practice we identified three predictors of a better response for TCZ therapy in RA: a younger age, a high baseline CRP level and no history of CVD.

Ultrasonographic evaluation of the anterior chest wall in spondyloarthritis: a prospective and controlled study.

OBJECTIVE: To determine the prevalence and type of ultrasonographic (US) lesions of the anterior chest wall (ACW) in cases of spondyloarthritis (SpA). METHODS: This monocentric, prospective, and controlled study included patients consulting for SpA (Assessment of Spondyloarthritis International Society criteria) and control subjects. Clinical (pain and swelling) and US assessments (synovitis, joint effusion, erosion, ankylosis, margin narrowing, or Doppler signal) were performed on the sternoclavicular (SCJ) and the manubriosternal (MSJ) joints. The main characteristics of SpA were recorded [disease duration, biologic features, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), radiographic and extraarticular involvement]. RESULTS: The study included 131 patients with SpA and 49 control subjects (same age and sex ratio). Clinical and US involvement of ACW were found in, respectively, 39% and 35.5% of SpA and in 12% and 14.3% of controls (p < 0.01). US highlighted erosions (34 vs 0), margin narrowing (12 vs 0), power Doppler activity (18 vs 2; p < 0.05), and ankylosis of the MSJ (24 vs 3). US involvement was associated with disease duration (14.9 vs 11.1 years; p = 0.04), age (45 vs 41 years; p = 0.004), radiographic change of sacroiliac joint (p = 0.05), and presence of inflammatory bowel disease (IBD; p = 0.03). No associations were found with HLA-B27, psoriasis, enthesitis, uveitis, or clinical involvement of ACW. Clinical involvement is associated with a higher BASDAI (47 vs 32; p = 0.0009) and ASDAS (2.9 vs 2.2; p = 0.006). CONCLUSION: US involvement of ACW is frequent in SpA (36.5%), mainly with erosion of SCJ and ankylosis of MSJ. It is associated with disease duration, radiographic sacroiliitis, and IBD.

Flare in spondyloarthritis: Thresholds of disease activity variations.

UNLABELLED: There is no definition of flare in spondyloarthritis (SpA). The aim of this study was to evaluate thresholds of disease activity variations using validated composite indexes. METHODS: SpA patients (ASAS criteria) prospectively followed with at least two visits, were evaluated. Patients and physician answered at each visit the question: "do you consider your SpA/patient in a state of flare?". Variations of BASDAI and ASDAS between visits were assessed and associated to the change of perception of a flare (yes/no). ROC curves were built to assess thresholds of variation in BASDAI and ASDAS associated with the change flare between visits. RESULTS: The patients were issued from a prospective series of 250 SpA. Ninety-nine cases with at least 2 visits were analysed. They were: 67% men, mean age 45±12 years; disease duration: 16±10 years; 84% HLA-B27 positive; purely axial SpA: 81%; PASS at baseline: 56%; mean CRP: 8.6±13.5mg/l. Mean BASDAI and ASDAS-CRP at baseline were 4.3±2.2 and 2.5±1.1, respectively. The kappa coefficient of agreement between patient and physician for considering a flare was 0.68. The main results of the ROC curves are: a variation ≥2.1 units in BASDAI (sensitivity 59%, specificity 83%), 0.8 units in ASDAS-ESR (sen 56%, spe 91%) or 1.3 units in ASDAS-CRP (sen 47%, spe 100%) is associated to a flare. CONCLUSION: We propose thresholds of variations of BASDAI, ASDAS-ESR, and ASDAS-CRP associated to (and that may define) a flare, as considered by the patient and the physician.

Dysregulated serum IL-23 and SIRT1 activity in peripheral blood mononuclear cells of patients with rheumatoid arthritis.

Sirtuin 1 (Sirt1) is a class III histone deacetylase (HDAC) that modulates gene expression and is involved in the regulation of proinflammatory cytokines. Interleukin-23 (IL-23) is produced by activated macrophages and dendritic cells and could fuel the progression of rheumatoid arthritis (RA). The goal of our study was to evaluate serum IL-23 levels and both Sirt1 activity and expression in peripheral blood mononuclear cells (PBMCs) in patients with RA compared to healthy controls (HC) and to determine the relationship between Sirt1 activity/expression and IL-23 levels. We assessed apoptosis in PBMCs of RA patients and its association with Sirt1 expression and serum IL-23. Serum IL-23 levels were increased in RA patients in comparison with controls. We found a positive correlation between the levels of serum IL-23 and serum IL-6 in RA patients. Decreased cytoplasmic Sirt1 activity was observed in RA patients with severe disease compared to HC. The expression of Sirt1 protein was significantly decreased in PBMCs of RA patients compared to HC using western blotting. Serum IL-23 levels correlated positively with the cytoplasmic Sirt1 activity in RA patients. Apoptosis rate of PBMCs isolated from RA patients was increased compared to HC and correlated negatively with the expression of Sirt1 protein and serum IL-23 levels. Levels of serum IL-23 and Sirt1 activity and expression were disturbed in RA parallel to increased PBMC apoptosis. Our findings might provide the rationale for the development of new therapeutic approaches in RA.

Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis.

OBJECTIVE: To assess the safety and efficacy of tocilizumab (TCZ) in elderly (≥65 years) rheumatoid arthritis (RA) patients treated in daily practice. METHODS: We conducted a retrospective study of TCZ use in RA patients in five French university hospitals between 2009 and 2012. We considered two age groups, under 65 years (<65) and over 65 years (≥65). TCZ efficacy was evaluated at 24 weeks by the European League Against Rheumatism (EULAR) response and remission score. We also evaluated drug maintenance and safety, relative to adverse events discontinuation. A multivariate cumulative logit model for ordinal categories was performed to assess the relationship between age class and EULAR response (none, moderate and good) adjusted on possible confounders. TCZ retention (drug survival) over time was estimated with the Kaplan-Meier method. Treatment retention curves were compared according to age group with the log-rank test. RESULTS: Among 222 RA patients treated with TCZ, 61 (27.5%) were≥65 years at the initiation of treatment. After 6 months, this elderly patient group less often reached remission (27.8% versus 45.6%; P=0.02) or good EULAR response (40.7% versus 61.0%; P<0.01) compared to the younger patient group (<65). Multivariate analysis adjusted on baseline C-reactive protein and disease duration confirmed that elderly patients were more likely to have a lower EULAR response (none vs moderate-good or none-moderate vs good) (OR: 3.63; 95% CI [1.86-7.06], P<0.001) compared to younger patients. Drug maintenance for TCZ and adverse events discontinuation rates were similar between the two age groups. CONCLUSION: In daily practice, TCZ seems to be well tolerated in RA patients but is less efficient in elderly patients. A broader field of analysis to include an international register will be required to confirm these results.

Response to tocilizumab in rheumatoid arthritis is not influenced by the body mass index of the patient.

OBJECTIVE: To assess the relationship between the body mass index (BMI) and the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). METHODS: We conducted a retrospective study in 222 patients with RA followed by 5 centers. The European League Against Rheumatism response was evaluated at 6 months. Univariate and multivariate logistic regressions were performed. RESULTS: No significant association between the BMI and the response to TCZ at 6 months was found after adjustment for potential confounding factors (adjusted OR 0.45, 95% CI 0.16-1.24, p = 0.13 and OR 1.19, 95% CI 0.31-4.48, p = 0.78 for BMI 25-30 kg/m(2) and BMI > 30 kg/m(2), respectively, compared to BMI < 25 kg/m(2)). CONCLUSION: Response to TCZ in patients with RA is not influenced by the baseline BMI, in contrast to anti-tumor necrosis factor drugs.

Endothelial dysfunction in joint disease.

Inflammatory joint diseases and autoimmune diseases with joint manifestations are associated with premature and accelerated atherogenesis. Patients with rheumatoid arthritis (RA) have a 5- to 10-year decrease in life expectancy compared to the general population, and those exhibiting extraarticular manifestations have the greatest excess mortality. RA is now established as an independent cardiovascular risk factor. Complex interactions linking conventional cardiovascular risk factors, systemic inflammation, and vascular function may explain the increased cardiovascular risk among RA patients. Endothelial dysfunction is now recognized as both the key step in early atherogenesis and a contributor to atheroma plaque progression at later stages. Endothelial dysfunction is defined as impaired endothelium-dependent blood-vessel dilation in response to a stimulus. The underlying mechanisms remain speculative. Over the last decade, a role for endothelial dysfunction in the cardiovascular complications of inflammatory joint disease has been hypothesized and several maintenance drugs targeting this phenomenon have been tested, with promising results.

Sirtuin 1 activity in peripheral blood mononuclear cells of patients with osteoporosis.

BACKGROUND: Sirtuin 1 (SIRT1) is a class III histone deacetylase that may play a critical role in several biological functions, including lifespan, stress, and inflammation. Our main objective was to evaluate SIRT1 activity in peripheral blood mononuclear cells (PBMCs) in patients with osteoporosis and to analyze the relationship between the SIRT 1 activity and markers of inflammation and bone remodelling. MATERIAL AND METHODS: We performed a prospective monocentric study of patients with osteoporosis and measured the nuclear and cytoplasmic activities of SIRT1 in PBMCs. Levels of proinflammatory cytokines were assessed in culture supernatants of PBMCs isolated from the osteoporosis patients. The level of serum C-terminal cross-linking telopeptide of type I collagen (CTX), a marker of bone resorption, was measured in the serum of osteoporosis patients. RESULTS: Sixteen women with osteoporosis were included. A statistically significant correlation between the cytoplasmic and nuclear SIRT 1 activities was found in PBMCs of patients with osteoporosis. Although non-significant, we observed a negative trend between nuclear SIRT 1 activity and the rate of serum CTX and a positive trend between IL-6 and CTX levels in patients with osteoporosis. CONCLUSIONS: This study shows that the cytoplasmic and nuclear SIRT 1 activities are measurable in circulating PBMCs of patients with osteoporosis and that these 2 activities are correlated. The potential role of inflammation in bone resorption in patients with osteoporosis was also studied.

Evaluation of spondylarthritis activity by patients and physicians: ASDAS, BASDAI, PASS, and flares in 200 patients.

OBJECTIVES: In patients with spondyloarthritis, to determine Ankylosing Spondylitis Disease Activity Score (ASDAS) cutoffs matching the patient-acceptable symptom state (PASS) and patient-reported levels of disease activity, to assess associations between disease activity levels and presence of depression, and to identify ASDAS and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) cutoffs indicating a flare and indicating a remission. METHODS: Prospective single-center study of patients meeting ASAS criteria for spondyloarthritis receiving follow-up at the Besançon teaching hospital, France, between February 2011 and February 2012. In each patient, the BASDAI, ASDAS, Bath Ankylosing Spondylitis Functional Index (BASFI), patient-acceptable symptom state (PASS) and signs of depression were assessed. Receiver-operating characteristic (ROC) curves were drawn to identify the ASDAS cutoffs separating different levels of disease activity. The kappa coefficient was computed to evaluate agreement between patients and physicians regarding the presence of flares. RESULTS: Two hundred patients with a mean age of 44.4 ± 12.5 years and mean disease duration of 12.9 ± 10.5 years were included. Mean BASDAI was 4.1 ± 2.2, mean ASDAS-C-reactive protein (CRP) was 2.4 ± 1, mean BASFI was 3.3 ± 2.7, and 58.9% of patients reported being in the PASS. The PASS was associated with BASDAI values inferior or equal to 4.1 and ASDAS-CRP values inferior or equal to 2.3. Mild patient-reported disease activity was associated with BASDAI values inferior or equal to 3.8 and ASDAS-CRP values inferior or equal to 2.3; corresponding values for high patient-reported disease activity were superior to 5.2 and superior to 3.1. Among patients reporting high disease activity, 64.5% had Beck Depression Inventory scores consistent with severe depression. At the time of the visit, 36.9% of the patients and 28.3% of the physicians felt there was a flare. Cutoffs indicating a flare were superior or equal to 5.2 for the BASDAI and superior or equal to 2.3 for the ASDAS-CRP. Agreement between patients and physicians regarding flares was good (Kappa, 0.61). An evaluation in 43 patients indicated that an ASDAS-CRP cutoff inferior or equal to 2.2 separated the 25.6% of patients who reported being in remission from the other patients. CONCLUSION: Our results show a significant association between disease activity and depression severity, as well as good agreement between BASDAI and ASDAS. The ASDAS cutoffs for the various levels of patient-reported disease activity differed from the cutoffs suggested by ASAS; a 2.3 cutoff was found for both patient-reported absence of disease activity and PASS, indicating that achieving PASS should be included among our treatment objectives.

When gout involves the spine: five patients including two inaugural cases.

UNLABELLED: Spinal involvement is uncommon during gout and may raise diagnostic challenges. We describe five cases seen at a single center. METHODS: We retrospectively reviewed the medical charts of the five patients with spinal gout seen over a 3-year period. RESULTS: There were four men and one woman with an age range of 52 to 87 years. One patient presented with acute neck pain and visualization by imaging studies of a discovertebral tophus, another had febrile arthritis of a lumbar facet joint, and a third presented with a synovial cyst in a lumbar facet joint. The remaining two patients had acute febrile discitis confirmed by magnetic resonance imaging, at the cervical spine and lumbar spine, respectively. Laboratory tests showed systemic inflammation in four patients and marked serum uric acid elevation in two patients. Only three patients reported a previous history of peripheral acute gout attacks. Specimens of the spinal lesions were obtained in three patients and consistently showed monosodium urate crystals with tissue inflammation or a tophus. The outcome was rapidly favorable, either with colchicine therapy alone in four patients or after surgical resection of a facet joint cyst (during surgery to stabilize the lumbar spine) in the remaining patient. The patient with neck pain due to a tophus experienced nerve root pain at the acute phase. No other neurological manifestations were recorded. CONCLUSION: These case reports illustrate the diagnostic challenges raised by spinal involvement due to gout. The spinal lesions can be inaugural, as seen in two of our five patients.

Resveratrol, a sirtuin 1 activator, increases IL-6 production by peripheral blood mononuclear cells of patients with knee osteoarthritis.

BACKGROUND: Sirtuin 1 (Sirt1) is a nuclear enzyme from the class III histone deacetylases that modulates gene expression and is involved in bone and cartilage remodeling. The goal of our study was to evaluate Sirt1 activity in peripheral blood mononuclear cells in patients with osteoarthritis in comparison with control patients, and to determine the relationship between Sirt1 activity and production of TNFα, IL-6 and IL-8 by peripheral blood mononuclear cells after ex vivo treatment with resveratrol, a Sirt1 activator. RESULTS: A prospective study was performed to compare the activity of Sirt1 in patients with primary osteoarthritis of the knee (American College of Rheumatology criteria) with its activity in controls. Peripheral blood mononuclear cells were isolated from peripheral blood, and Sirt1 activity evaluated from cytoplasmic and nuclear compartments using a fluorometric assay. Culture supernatant levels of TNFα, IL-6, and IL-8 were quantified before and after resveratrol ex vivo treatment. Nineteen patients with symptomatic knee osteoarthritis (age 64 ±9 years) and 18 controls (age 54 ±13 years) were included. No differences were found in cytoplasmic or nuclear Sirt1 activity between patients and controls. After resveratrol treatment, no changes in TNFα or IL-8 levels were found, but a significant dose-dependent increase in IL-6 levels was demonstrated in patients with osteoarthritis, but not controls. Sirt1 activity did not correlate with clinical activity (Lequesne's index) or inflammation (erythrocyte sedimentation rate, C-reactive protein). CONCLUSION: Sirt1 activity (cytoplasmic and nuclear) from peripheral blood mononuclear cells did not differ between patients with osteoarthritis and controls. Ex vivo treatment of peripheral blood mononuclear cells with resveratrol was associated with a dose-dependent increase in IL-6 levels only in patients with osteoarthritis.