[Show abstract][Hide abstract] ABSTRACT: Despite their limited licensed indications, anti-interleukin-1 (anti-IL-1) agents are often used in clinical practice for an increasing number of auto-inflammatory diseases. We conducted a national cross-sectional observational study from January 2011 to January 2013 to record the off-label use of such agents in France. We aimed to estimate the off-label use of anti-IL-1 treatments in France, assess their efficacy in rare diseases, and increase the reporting of their possible side effects.
Physicians answered a questionnaire that covered patient and disease data, anti-IL-1 agent use, efficacy and adverse events. The study involved adult or paediatric patient who had received an anti-IL-1 agent after January 2005 in France.
In total, 189 patients from 38 centres were included. The main diseases were adult-onset Still's disease (AOSD) (35), gout (28), systemic juvenile idiopathic arthritis (27), cryopyrin-associated periodic syndrome (CAPS) (21), familial Mediterranean fever (14) and mevalonate kinase deficiency (12). The main off-label used agent was anakinra, used at least once for 185 patients, with canakinumab used for 25. Anakinra was effective in most patients (90%), with higher complete clinical response rates for Schnitzler's syndrome, gout, CAPS and AOSD. Overall, 58% of patients showed at least one adverse event, mainly minor injection-site reactions. The main reported serious adverse event was severe infection. Injection-site reactions and liver toxicity were significantly more frequent in children than adults. The main non-cutaneous adverse event was liver toxicity, significantly associated with treatment duration. Weight gain was reported in about 10% of patients and was associated with treatment duration and CAPS. Canakinumab was rarely used and showed better cutaneous tolerance than anakinra but similar rates of non-cutaneous and severe adverse events.
Anakinra was well tolerated and effective in most patients with various inflammatory diseases. The main adverse events were mild injection-site reactions, especially in children. The survey allowed for collecting limited information on the off-label use of canakinumab.
[Show abstract][Hide abstract] ABSTRACT: To estimate annual direct costs of early RA by resource component in an inception cohort, with reference to four distinct treatment strategies: no disease modifying antirheumatic drugs (DMARDs), synthetic DMARDs only, biologic DMARDs in the first year ('first-year biologic', FYB), and biologic DMARDs from the second year after inclusion ('later-year biologic', LYB); to determine predictors of total and non-DMARD related costs.
The ESPOIR cohort is a French multicentric, prospective study of 813 patients with early arthritis. Data assessing RA-related resource utilisation and disease characteristics were collected at baseline, biannually during the first two years and annually thereafter. Costs predictors were determined by generalised linear mixed analyses.
Over the 4-year follow-up, mean annual direct total costs per treatment strategy group were €3,612 for all patients and €998, €1,922, €14,791, €8,477 respectively for no DMARDs, synthetic DMARDs only, FYB and LYB users. The main predictors of higher costs were biologic use and higher Health Assessment Questionnaire (HAQ) scores at baseline. Being a biologic user led to a higher total cost (FYB Rate Ratio (RR) 7.22, [95% CI 5.59-9.31]; LYB RR 4.39, [95% CI 3.58-5.39]) compared to non-biologic users. Only LYB increased non-DMARD related costs compared to all other patients by 60%.
FYB users incurred the highest levels of total costs, while their non-DMARD related costs remained similar to non-biologic users, possibly reflecting better RA control.
PLoS ONE 05/2014; 9(5):e97077. DOI:10.1371/journal.pone.0097077 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of the Outcome Measures in Rheumatology (OMERACT) Worker Productivity working group is to identify worker productivity outcome measures that meet the requirements of the OMERACT filter. At the OMERACT 11 Workshop, we focused on the at-work limitations/productivity component of worker productivity (i.e., presenteeism) - an area with diverse conceptualization and instrumentation approaches. Various approaches to quantify at-work limitations/productivity (e.g., single-item global and multi-item measures) were examined, and available evidence pertaining to OMERACT truth, discrimination, and feasibility were presented to conference participants. Four candidate global measures of presenteeism were put forth for a plenary vote to determine whether current evidence meets the OMERACT filter requirements. Presenteeism globals from the Work Productivity and Activity Impairment Questionnaire (72% support) and Rheumatoid Arthritis-specific Work Productivity Survey (71% support) were endorsed by conference participants; however, neither the presenteeism global item from the Health and Work Performance Questionnaire nor the Quantity and Quality method achieved the level of support required for endorsement at the present time. The plenary was also asked whether the central item from the Work Ability Index should also be considered as a candidate measure for potential endorsement in the future. Of participants at the plenary, 70% supported this presenteeism global measure. Progress was also made in other areas through discussions at individual breakout sessions. Topics examined include the merits of various multi-item measures of at-work limitations/productivity, methodological issues related to interpretability of outcome scores, and approaches to appraise and classify contextual factors of worker productivity. Feedback gathered from conference participants will inform the future research agenda of the working group.
The Journal of Rheumatology 10/2013; 41(1). DOI:10.3899/jrheum.130815 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: We investigated access to biologic and synthetic disease modifying drugs (bDMARDs and sDMARDs) in patients with rheumatoid arthritis (RA) across Europe. METHODS: A cross-sectional study at national level was performed in 49 European countries. A questionnaire was sent to one expert, addressing the number of approved and reimbursed bDMARDs and sDMARDs, prices and co-payments, as well as acceptability of bDMARDs (barriers). Data on socio-economic welfare (gross domestic product per capita (GDP), health expenditure, income) were retrieved from web-based sources. Data on health status of RA patients were retrieved from an observational study. Dimensions of access (availability, affordability and acceptability) were correlated with the country's welfare and RA health status. RESULTS: In total, 46 countries (94%) participated. Six countries did not reimburse any of the five sDMARDs surveyed, and in ten countries no bDMARDs were reimbursed. While the price of annual treatment with an average sDMARD was never higher than GPD, the price of one year treatment with a bDMARD exceeded GPD in 26 countries. Perceived barriers for access to bDMARDs were mainly found among financial and administrative restrictions. All dimensions of access were positively correlated with the country's economic welfare (coefficients 0.69 to 0.86 for overall access scores). CONCLUSIONS: Patients with RA in lower income European countries have less access to bDMARDs and sDMARDs, with particularly striking unaffordability of bDMARDs in some of these countries. When accepting that sDMARDs and bDMARDs are equally needed across countries to treat RA, our data point to inequities in access to pharmacological treatment for RA in Europe.
Annals of the rheumatic diseases 03/2013; 73(1). DOI:10.1136/annrheumdis-2012-202603 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Purpose: Blocking TNF alpha (TNFα) with monoclonal antibodies (mAbs) has been successful in the treatment of rheumatoid arthritis. However secondary resistances are frequent and impose treatment changes. Active immunization with a TNF-Kinoid that safely induces self polyclonal anti-TNFα antibodies (Abs) could be an alternative to anti-TNFα mAbs. We evaluated the immunogenicity and safety of TNF-K in patients with rheumatoid arthritis and secondary resistance to TNF blockers.
Methods: TNFα-Kinoid (TNF-K, Neovacs SA, Paris, France) is an immunotherapeutic composed of recombinant human TNFα conjugated to KLH, inactivated and adjuvanted with ISA-51 emulsion. 40 patients with active rheumatoid arthritis (DAS28≥3.2) with history of positive clinical response to at least one TNF-blocker followed by secondary failure (35% IFX, 30 % ADA, 42.5% ETA) were enrolled in a double-blind, placebo-controlled, phase 2 study to evaluate three different intramuscular doses of TNF-K (90, 180, 360 mcg) and two immunization schedules (D0 and 28 or D0, 7 and 28). Humoral immune responses were evaluated through titration of anti-TNFα and anti-KLH Abs and neutralization assay. The T cell response was assessed by lymphoproliferative assay with tritiated thymidine incorporation. Clinical response was evaluated by the ACR and EULAR core set response.
Results: No related serious adverse event has been reported. Few minor transient local and systemic reactions have been recorded following immunization. Anti-TNFα Abs were induced in 50%, 75% and 91% of patients at 90 mcg, 180 mcg and 360 mcg, respectively. 100% of patients with three injections of 180 or 360 mcg had immunogenic response against TNF versus 67% in the groups receiving two injections. The anti-TNF antibody geometric mean titres were higher in patients who received 3 injections of 360 mcg. No lymphoproliferative response could be measured after stimulation with native TNF. Among the 21 patients who developed anti-TNF Abs, 48% present a moderate to good response according to EULAR score as opposed to only 31% of the 16 patients without Abs. A mean decrease of -14% of the C reactive protein level is measured in patients with Abs while in patients without Abs, the mean CRP level increased by 5%.
Conclusion: Active immunization with TNFα kinoid to induce a polyclonal, self-anti-TNFα antibody response is safe and immunogenic. A clear dose-response was observed for the dose of kinoid as well as for the number of administrations. Association of anti-TNF Abs induced by the kinoid with clinical and biological responses were observed in patients included in this preliminary phase 2 study. Further studies are needed to confirm this new approach in RA.
[Show abstract][Hide abstract] ABSTRACT: The total cost of RA is substantial, particularly in patients with high levels of disability. There are considerable differences in cost between countries, driven in part by differences in the use of biologic therapies. Economic evaluations are needed to assess the extra cost of using these treatments and the benefits obtained, to ensure appropriate allocation of limited health care resources. The BeSt trial, evaluating four treatment strategies, found comparable medium-term efficacy but substantially higher costs with early biologic therapy. A systematic review of such cost-effectiveness analyses concluded that biologic therapy should be used after therapy has failed with less costly alternatives such as synthetic DMARDs and glucocorticoids. Optimizing such relatively low-cost therapy to improve outcomes may delay the need for biologic therapy, thereby saving costs. A simple model has confirmed the value of this approach. The addition of modified-release prednisone 5 mg/day to existing synthetic DMARD therapy in patients with active disease resulted in improvement in DAS-28 to below the threshold level for initiation of reimbursed biologic therapy in 28-34% of patients. On a conservative estimate (i.e. assuming no further benefits beyond the 12 weeks of the study and a 12-week wait-and-see approach to starting biologic therapy), cost savings amounted to nearly € 400 per patient. While treatment decisions should never be based only on cost considerations, prolonging disease control by optimizing the use of non-biologic treatments may bring benefits to patients and also economic benefits by delaying the need for biologic treatments.
[Show abstract][Hide abstract] ABSTRACT: Interleukin 1β (IL-1β) is emerging as a master mediator of adult onset Still's disease (AOSD) pathogenesis. This pleiotropic cytokine, whose expression is under the control of the inflammasome pathway, has a wide type of effects. As a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations. The study of proinflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity. These experimental evidences and the analogy with other autoinflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1β as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases. Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFα failed to control symptoms. While a growing number of evidences supports the utilisation of anakinra in AOSD, a new generation of anti-IL1β antagonists is developing. Canakinumab and rilonacept, thanks to their higher affinity and longer half-life, could improve the management of this invalidating disease.
[Show abstract][Hide abstract] ABSTRACT: In 2010, new classification criteria for rheumatoid arthritis (RA) were developed.
To assess agreement between 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria and the potential source of discordance, based on ESPOIR cohort data.
813 early arthritis patients were included in ESPOIR between 2002 and 2005. Between-criteria agreement was based on the κ coefficient. Discordance was explored by logistic regression.
Data for 811 patients were available, with their main characteristics as follows: women 77%, swollen joint count 7.2, tender joint count 8.4, disease activity score in 28 joints 5.2, rheumatoid factor 46%, anticitrullinated protein antibody (ACPA) 39%, structural damage 22%. At baseline, 579 (71.4%) patients met the 1987 ACR criteria and 641 (79.0%) the 2010 criteria. Agreement at baseline was discordant for 168 patients: 115 satisfied the 2010 criteria and 53 the 1987 criteria. Concordance between the two sets was fair, with a κ coefficient of 0.45 and 0.42 at baseline and year 2, respectively. The main sources of discordance were the number and symmetry of joint involvement, as well as ACPA status.
2010 ACR/EULAR criteria identified more patients with RA than did 1987 criteria. The 2010 criteria failed to identify RA patients with symmetrical seronegative arthritis and limited joint involvement.
Annals of the rheumatic diseases 03/2012; 71(3):386-9. DOI:10.1136/annrheumdis-2011-200259 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many outcomes have been proposed in the assessment of psoriatic arthritis (PsA). The Outcome Measures in Rheumatology (OMERACT) core set for PsA evaluation comprises 6 domains: joints, skin, function, pain, patient's global assessment, and quality of life. The objective of this work was to assess reporting of outcomes in PsA, including patient-reported outcomes (PROs) in recent publications.
A systematic literature search of clinical trials related to PsA and reporting at least 1 clinical outcome between 2006 and 2010 was performed in PubMed, i.e., just before to just after publication of the OMERACT core set. All clinical outcomes were noted and subdivided into domains of health. Data analysis was descriptive.
Fifty-eight articles (12,405 patients) were included in the analysis: 17 (29%) were randomized clinical trials; the patients' mean ± SD age was 48.2 ± 5.4 years and the mean ± SD disease duration was 9.0 ± 3.1 years. Eighty-four different outcomes were reported, with a mean ± SD of 6.9 ± 4.3 per study. Patients were mainly assessed using the 6 core set domains, reported in 37.9% (quality of life) to 55.2% (skin) of articles; however, the core set was rarely completely reported since only 10.3% of the studies reported all 6 core domains. PROs were heterogeneous and in particular there was no consensus regarding the number of joints to assess and instruments for dactylitis and enthesitis. PROs were assessed in more than 75% of publications using 28 different instruments.
There is great heterogeneity in PsA assessment, even since publication of the OMERACT core set. Better consensus on instruments to assess each domain of health and better insight into which outcomes are important for patients is needed.
[Show abstract][Hide abstract] ABSTRACT: Musculoskeletal manifestations are common in the course of type I or type II diabetes mellitus. All are directly or indirectly related to the consequences of chronic hyperglycaemia which explains that they are prevalent in patients with poor glycaemia control and/or other diabetic complications. Several entities can be distinguished: (1) limited joint mobility syndromes which are due to the “brownisation” of articular and periarticular collagen. Their treatment is largely based on physiotherapy and rehabilitation since steroid injections, although efficacious on pain, are associated with a risk of glycaemic instability as well as infections; (2) neurogenic osteoarthropathy or Charcot's foot, due to the sensitive and dysautonomic neuropathy. They require unloading of the involved foot and may benefit from bisphosphonates infusions to rapidly block the pathogenic process originating bone and joint destruction; (3) an increased risk of osteoporotic fractures, which reflects partly the interactions between insulin, IGF1 and bone mineralization, but mainly a substantial increase of the risk of falls related to vitamin D deficiency (especially in the context of renal failure), to neuropathy-induced balance disorders ant to partial vision loss in relation with diabetic retinopathy; (4) bone and joint infections since bacterial development and proliferation is facilitated by chronic hyperglycaemia; (5) finally, the rare but quite classical risk of muscle infarction in patients with long-term unbalanced diabetes.
Revue du Rhumatisme Monographies 09/2011; 78(4):239-245. DOI:10.1016/j.monrhu.2011.07.001
[Show abstract][Hide abstract] ABSTRACT: To identify the predictive factors of MRI-determined structural progression in patients with rheumatoid arthritis (RA) in remission or with low disease activity (LDA).
In this 1-year longitudinal study, patients with RA in clinical remission (disease activity score (DAS) 44≤1.6) or with LDA (1.6<DAS 44≤2.4) underwent low-field MRI of the dominant hand at baseline and at 6 and 12 months. MRI images were scored by the rheumatoid arthritis MRI system (RAMRIS) by rheumatologists blind to clinical and biological data. Structural progression was defined as a change in the RAMRIS(erosion) score between baseline and 1 year greater than the smallest detectable difference. Predictive factors of structural disease progression were analysed by logistic and linear regression.
85 patients with RA in remission (n=47) or with LDA (n=38) were included. Their mean age was 50 ± 13 years, 81% were female, mean disease duration was 35 ± 20 months, rheumatoid factor (RF)/anti-CCP positivity was 63%/64% and 77% had radiographic erosion. At baseline most patients showed inflammatory activity on MRI: 87% had at least one synovitis and 23% at least one location of bone marrow oedema (BME). BME at baseline was predictive of change in RAMRIS(erosion) (OR 1.25, 95% CI 1.09 to 1.43, p=0.0013, area under the curve=0.78).
BME is a predictive factor of MRI-determined structural progression in patients with RA in clinical remission or with LDA.
Annals of the rheumatic diseases 08/2011; 70(12):2159-62. DOI:10.1136/ard.2010.149377 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) epidemiologic data are scarce in Europe. To estimate the prevalence of symptomatic knee and hip OA in a multiregional sample in France.
A two-phase population-based survey was conducted in six regions in 2007-2009. On initial phone contact using random-digit dialing, subjects 40-75 years old were screened with a validated questionnaire. Subjects screened positive were invited for ascertainment: physical examination and hip and/or knee radiography (Kellgren-Lawrence grade≥2). Multiple imputation for data missing not-at-random was used to account for refusals.
Of 63,232 homes contacted, 27,632 were eligible, 9621 subjects screened positive, 3707 participated fully in the ascertainment phase, and 1010 had symptomatic OA: 317 hip, 756 knee. Hip OA prevalence according to age class ranged from 0.9% to 3.9% for men and 0.7-5.1% for women. Knee OA ranged from 2.1% to 10.1% for men and 1.6-14.9% for women. Both differed by geographical region. The hip and knee standardized prevalence was 1.9% and 4.7% for men and 2.5% and 6.6% for women, respectively.
This confirmed the feasibility of using a screening questionnaire for eliciting population-based estimates of OA. In France, it increases with age and is greater among women above the age of 50. The geographical disparity of hip and knee OA parallels the distribution of obesity. Study registration ID number 906297 at http://www.clinicaltrials.gov/.
Osteoarthritis and Cartilage 08/2011; 19(11):1314-22. DOI:10.1016/j.joca.2011.08.004 · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort).
After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26±0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ). Disease duration was longer in GUEPARD patients (5.6±4.6 vs 3.5±2.0 months, p<0.001). After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045). However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses. More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005). Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group. The mean SHS progression was similar in the two groups as was the percentage of patients without progression.
In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression.
Annals of the rheumatic diseases 03/2011; 70(4):611-5. DOI:10.1136/ard.2010.137695 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs).
To describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors.
A 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case-control study was performed with three controls treated with anti-TNF agents per case, matched for gender and underlying inflammatory disease.
45 cases were collected of non-TB OIs in 43 patients receiving infliximab (n=29), adalimumab (n=10) or etanercept (n=4) for rheumatoid arthritis (n=26), spondyloarthritides (n=3), inflammatory colitis (n=8), psoriasis (n=1) or other conditions (n=5). One-third (33%) of OIs were bacterial (4 listeriosis, 4 nocardiosis, 4 atypical mycobacteriosis, 3 non-typhoid salmonellosis), 40% were viral (8 severe herpes zoster, 3 varicella, 3 extensive herpes simplex, 4 disseminated cytomegalovirus infections), 22% were fungal (5 pneumocystosis, 3 invasive aspergillosis, 2 cryptococcosis) and 4% were parasitic (2 leishmaniasis). Ten patients (23%) required admission to the intensive care unit, and four patients (9%) died. Risk factors for OIs were treatment with infliximab (OR=17.6 (95% CI 4.3 - 72.9); p<0.0001)or adalimumab (OR=10.0 (2.3 to 44.4); p=0.002) versus etanercept, and oral steroid use >10 mg/day or intravenous boluses during the previous year (OR=6.3 (2.0 to 20.0); p=0.002).
Various and severe OIs, especially those with intracellular micro-organisms, may develop in patients receiving anti-TNF treatment. Monoclonal anti-TNF antibody rather than soluble TNF receptor therapy and steroid use >10 mg/day are independently associated with OI.
Annals of the rheumatic diseases 12/2010; 70(4):616-23. DOI:10.1136/ard.2010.137422 · 10.38 Impact Factor