Julien Paccou

Dosage Adjustment of Anti-Tumor Necrosis Factor-α Inhibitor in Ankylosing Spondylitis Is Effective in Maintaining Remission in Clinical Practice

Objective. While remission is possible in patients with ankylosing spondylitis (AS), it is often unclear what attitude should be adopted once remission has occurred. We investigated whether dosage adjustment is an effective means of maintaining remission. Methods. This was a retrospective study drawn from clinical situations. Remission was defined using clinical measures [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≤ 20/100 and no peripheral joint disease] and biological measures [C-reactive protein (CRP) levels ≤ normal value]. The tumor necrosis factor-α (TNF-α) inhibitors used were infliximab, adalimumab, and etanercept. Response predictors of remission were evaluated by logistic regression (age, CRP, HLA-B27 positivity, sex, duration of disease, and anti-TNF-α naivety). CRP and BASDAI were evaluated before and after dosage adjustment at about 6, 12, 24, and 36 months. Results. One hundred eighty-nine patients with AS were included in the study, with a mean followup of 43.5 (± 17.9) months after the introduction of the first anti-TNF-α inhibitor. Mean age was 45.6 (± 12.5) years. Remission had occurred in 65 patients (35%). Significant response predictors of remission were male sex (p = 0.003) and anti-TNF-α naivety (p < 0.001). Dosage adjustment was observed 49 times, and progressively reducing treatment frequency was effective to maintain remission in a large number of patients for 36 months. The cumulative probability of continuing anti-TNF-α after dosage adjustment was 79.0% at 12 months, 70.5% at 24 months, and 58.8% at 36 months. Conclusion. Remission had occurred in 35% of the patients with AS under anti-TNF-α inhibitor therapy. Dosage adjustment and progressively reducing treatment frequency was effective in maintaining remission.

Efficacy in current practice of switching between anti-tumour necrosis factor-α agents in spondyloarthropathies

OBJECTIVE Anti-TNF-α agents are remarkably effective in the treatment of SpAs. However, 30% of patients withdraw from anti-TNF-α agents yearly because of inadequate efficacy or side effects. The objective of this study was to assess in current practice the response to a second and a third anti-TNF-α. METHODS Retrospectively, all records of patients who had received at least two anti-TNF-α agents have been studied. For axial forms, treatment was considered effective if 3 months after switching the patient had a favourable expert opinion or showed an improvement in BASDAI of at least 2 on a scale of 0-10 or an improvement of 50% (BASDAI 50). For peripheral forms, the treatment was considered effective if the patient had a favourable expert opinion or if a clinical improvement of >30% of the swollen and tender joint counts was established. The reasons for switching were: (i) primary non-responder; (ii) loss of efficacy; and (iii) occurrence of side effects. To identify response predictor factors bivariate analysis was performed. RESULTS Three hundred and seventy-seven patients under anti-TNF-α agents were treated and 99 patients had received at least two anti-TNF-α agents. Twenty-eight of these 99 patients had been treated with three anti-TNF-α agents. Following the failure of a first anti-TNF-α, the response to a second agent was satisfactory in 80.8%. Patients who had received a third anti-TNF-α following failure of the first two also showed a satisfactory response in 82.1%. The reason for switching from the first or second agent was not predictive of the response. CONCLUSION In the event of failure or intolerance to anti-TNF-α in the treatment of SpAs, performing a first or second switch produces a satisfactory therapeutic response.

Treatment response, drug survival and safety of anti-tumour necrosis factor α therapy in 193 patients with psoriatic arthritis: A twelve-year “real life” experience

OBJECTIVE To evaluate the performance of anti-TNFα therapy in psoriatic arthritis (PsA) in a routine care setting. METHODS Inclusion criteria were patients with PsA who initiated anti-TNFα therapy between April 2001 and April 2013 with a follow-up of at least 6 months. For peripheral forms, treatment was considered to be effective for patients with a favourable expert opinion or>30% clinical improvement of swollen and tender joint counts. For axial forms, efficacy criteria were: improvement of BASDAI by at least 2 points on a scale from 0 to 10 or 50% improvement (BASDAI 50) or expert opinion. Drug survival of first anti-TNFα therapy was also investigated. RESULTS The study included 193 patients (107/86M/F, mean age: 46.8 years, mean disease duration: 6.7 years, 171/22 peripheral/axial forms). Only 48 (25%) patients received concomitant DMARD therapy (65% were treated with methotrexate). The majority of patients started with first-line etanercept (n=102), followed by adalimumab (n=46), infliximab (n=44) and golimumab (n=1). At 3 months, 90% of patients had obtained an adequate response, 7% had discontinued due to lack of efficacy and 3% due to adverse events. Median drug survival was 2 years. One-year and 2-year drug survival rates were 77% and 67%, respectively. Seventy-nine (41%) patients switched to a second anti-TNFα and 29 to a third anti-TNFα; 82% of switchers responded to second-line therapy and 83% responded to third-line therapy. CONCLUSION High drug survival and high response rates were observed in these patients with PsA receiving their first anti-TNFα therapy in routine clinical practice.

Coronary and abdominal aorta calcification in rheumatoid arthritis: relationships with traditional cardiovascular risk factors, disease characteristics, and concomitant treatments.

Objective. To assess the influence of traditional cardiovascular (CV) risk factors, disease characteristics, and concomitant treatments in patients with rheumatoid arthritis (RA) on coronary artery calcification (CAC) and abdominal aorta calcification (AAC). Methods. In our cross-sectional study, 75 patients with RA were compared with 75 age-matched and sex-matched control participants. The CAC and AAC scores were measured by computed tomography in patients with no clinical evidence of coronary artery disease. The relationships between the presence or absence of CAC and AAC and traditional CV risk factors, disease characteristics, and concomitant treatments in patients with RA were assessed in a multiple logistic regression analysis. Results. The RA and control groups did not differ significantly in terms of age, sex composition, or the prevalence of traditional CV risk factors. AAC and CAC were more prevalent and severe in patients with RA than in controls. Older age (OR = 1.15, p < 0.01) and hypertension (OR = 3.77, p = 0.04) were found to be independently associated with CAC, whereas current use of methotrexate (MTX; OR = 0.12, p = 0.01) was found to be associated with the absence of CAC. Older age (OR per yr = 1.17, p < 0.001) and erosive arthritis (OR = 3.78, p = 0.03) were found to be independently associated with AAC. Conclusion. Our study demonstrates that in patients with RA, (1) CAC and AAC are more prevalent and more severe compared with age-matched and sex-matched control participants, (2) current use of MTX is a major determinant of the absence of CAC, and (3) erosive arthritis is a major determinant of AAC.

Bone Samples Extracted from Embalmed Subjects Are Not Appropriate for the Assessment of Bone Quality at the Molecular Level Using Raman Spectroscopy.

Bone samples extracted from embalmed cadavers are commonly used as controls in the study of bone. The effects of embalmment on the molecular composition of bone are unknown. The objective of this study was to determine the effect of embalmment on the molecular composition and structure of bone, as evaluated by Raman spectroscopy. Bone samples of femoral heads from five embalmed donors and five fresh-frozen donors were compared using Raman microspectroscopy with DuoScan technology. Physicochemical parameters simultaneously describing the organic and mineral phases of bone were compared using the Mann-Whitney U test. Partial least squares discriminant analysis (PLS-DA) was used to determine specific Raman spectral features of each group. Study of the mineral phase showed a 15% reduction of the mineral-to-matrix ratio (p < 0.001), an 8% decrease of type B carbonate substitution (p < 0.001), and a 2% increase in crystallinity (p < 0.001) in the embalmed donors group compared to those of the fresh donors group. Regarding the organic phase of bone, the hydroxyproline-to-proline ratio was increased by 18% in the embalmed group (p < 0.001), with no variation in both the relative proteoglycan content (GAG/CH3) (p = 0.08) and collagen maturity (p = 0.57). PLS-DA showed that the embalmed group was characterized mainly by peaks assigned to hydroxyproline, lipids, and collagen. Embalmment induces significant modifications of the molecular composition of bone. Bone samples from embalmed subjects should be avoided as controls for Raman spectroscopy studies. Preservation procedures performed prior to bone sampling should be reported in studies using human cadaver samples.

Tumor Necrosis Factor-α Inhibition in Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis: Treatment Response, Drug Survival, and Patient Outcome

Objective. The purpose of this study was to (1) evaluate baseline characteristics of nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) treated with tumor necrosis factor-α inhibitors (TNFi), (2) assess the response to first TNFi treatment, and (3) compare drug-survival duration and rates. Methods. Inclusion criteria were patients with axSpA who initiated first TNFi treatment between April 2001 and July 2014 and were followed up for at least 3 months. Efficacy criteria were an improvement of at least 2 points (on a 0–10 scale) or a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Baseline characteristics, responses at 12 months, and drug survival were compared between AS and nr-axSpA. Results. A total of 361 patients were included in the study (AS, n = 263 and nr-axSpA, n = 98). Patients with AS were more often men (65.02% vs 45.92%, p = 0.001) and had longer symptom duration (11.71 ± 9.52 vs 7.34 ± 9.30 yrs, p < 0.001). Median levels of acute-phase reactants (C-reactive protein and erythrocyte sedimentation rate) were significantly higher in patients with AS (p < 0.001 for both). Median BASDAI scores at first TNFi initiation were not higher in patients with nr-axSpA than in patients with AS (59, 49–70 vs 60, 50–70, p = 0.73). BASDAI 20 and BASDAI 50 response rates at 12 months were not statistically different between patients with AS and patients with nr-axSpA (74.58% vs 64.58%, p = 0.19 and 61.02% vs 50.00%, p = 0.19, respectively). No statistically significant difference in terms of survival was observed between patients with AS and nr-axSpA (p = 1.00). Conclusion. Treatment response and drug survival were similar in patients with AS and nr-axSpA after first TNFi initiation.

Management after first-line antiresorptive treatment for postmenopausal osteoporosis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 16 mars 2016

Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk. Response to comments by Bredemeier

Dear Editor, We thank Dr. Bredemeier for his interest and for his comments [1] about our article entitled “Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk” [2], in which we demonstrated that the risk of new clinical fractures was 40% higher in women who had taken a BP “drug holiday” in a cohort of 166 postmenopausal osteoporosis. Dr. Bredemeier argues that if the duration of follow-up in both groups is similar, the hazard ratio (HR) should provide values similar to those observed using relative risk (RR). As indicated in the paper and as is usual, we used Cox proportional hazards models to investigate the relationships between continuation or discontinuation of osteoporosis medication and the risk of new clinical fractures, controlling for confounding factors. There is a distinction between rate and proportion. The incidence (hazard) rate is the number of new cases of disease (clinical fractures in our study) per population at risk per unit time, whereas the cumulative incidence is the proportion of new cases that develop in a given time period. We calculated the incidence (hazard) rate, whereas Dr. Bredemeier calculated the relative risk using the cumulative incidence. Using the Cox regression allowed us to gain power/ precision, and this is the most commonly used multivariable survival method, as we previously indicated. Survival without any new clinical fractures was also analyzed by means of Kaplan-Meier curves and log-rank tests. Kaplan-Meier curves are another way to estimate survival but cannot evaluate covariates like Cox model. We acknowledge that incomplete observations would have been censored. When fracture-free survival curves were compared between the two groups (censoring incomplete observations), no statistical significant difference was found (log-rank p = 0.4035). The table below illustrates the complete and incomplete observations.

Bone disorders associated with diabetes mellitus and its treatments

Both type 1 and type 2 diabetes mellitus are associated with bone disorders, albeit via different mechanisms. Early studies in patients with type 1 diabetes suggested a 10-fold increase in the hip fracture risk compared to non-diabetic controls. Meta-analyses published more recently indicate a somewhat smaller risk increase, with odds ratios of 6 to 7. Diminished bone mineral density is among the contributors to the increased fracture risk. Both types of diabetes are associated with decreased bone strength related to low bone turnover. The multiple and interconnected pathophysiological mechanisms underlying the bone disorders seen in type 1 diabetes include insulin deficiency, accumulation of advanced glycation end products, bone microarchitecture alterations, changes in bone marrow fat content, low-grade inflammation, and osteocyte dysfunction. The bone alterations are less severe in type 2 diabetes. Odds ratios for hip fractures have ranged across studies from 1.2 to 1.7, and bone mineral density is higher than in non-diabetic controls. The odds ratio is about 1.2 for all bone fragility fractures combined. The pathophysiological mechanisms are complex, particularly as obesity is very common in patients with type 2 diabetes and is itself associated with an increased risk of fractures at specific sites (humerus, tibia, and ankle). The main mechanisms underlying the bone fragility are an increase in the risk of falls, sarcopenia, disorders of carbohydrate metabolism, vitamin D deficiency, and alterations in cortical bone microarchitecture and bone matrix. The medications used to treat both types of diabetes do not seem to play a major role. Nevertheless, thiazolidinediones and, to a lesser extent, sodium-glucose cotransporter inhibitors may have adverse effects on bone, whereas metformin may have beneficial effects. For the most part, the standard management of bone fragility applies to patients with diabetes. However, emphasis should be placed on preventing falls, which are particularly common in this population. Finally, there is some evidence to suggest that anti-fracture treatments are similarly effective in patients with and without diabetes.

An appraisal of golimumab in the treatment of severe, active nonradiographic axial spondyloarthritis

Golimumab (Simponi®) is a fully human tumor necrosis factor α inhibitor (TNFi) antibody administered subcutaneously. In the European Union, golimumab is indicated for the treatment of adults with severe, active axial spondyloarthritis (axSpA), which includes both ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA). In the US, it is indicated for the treatment of adults with active AS only. This article reviews the efficacy and tolerability of golimumab in nr-axSpA patients compared to other TNFi agents (adalimumab, infliximab, etanercept, and certolizumab pegol). In one ongoing, well-designed controlled study (GO-AHEAD), data at 16 weeks showed that treatment with golimumab (50 mg every 4 weeks) was effective in improving the clinical signs and symptoms of disease in nr-axSpA patients. In addition, 16 weeks of treatment with golimumab reduced inflammation in the sacroiliac joints and spine in patients with nr-axSpA. Moreover, objective evidence of active inflammation at baseline, such as a positive magnetic resonance imaging scan and/or an elevated CRP level, was a good predictor of treatment response to golimumab. Golimumab was generally well tolerated in this study, with a tolerability profile consistent with that seen in previous clinical trials for other indications. Although additional long-term data are needed, current evidence indicates that golimumab is an effective option for the treatment of nr-axSpA. However, in the absence of comparative head-to-head trials, there is no recommended hierarchy for the first prescription of a TNFi agent for the treatment of either nr-axSpA or AS.