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Resume Objectifs Etablir sous l’egide de la Societe francaise de rhumatologie (SFR) des recommandations sur les traitements pharmacologiques de la gonarthrose. Methodes Le groupe de bibliographie a realise une analyse de la litterature sur l’efficacite et la tolerance de chaque traitement. Ce groupe a rejoint un groupe de travail pluridisciplinaire pour elaborer les recommandations par vote et recueil du niveau d’accord. Chaque recommandation a fait l’objet d’une force de recommandation et d’un niveau d’evidence. Un groupe de lecture a donne son niveau d’agrement. Resultats Cinq principes generaux ont ete emis sur : (1) la necessite de combiner traitements pharmacologiques et non pharmacologiques, (2) la personnalisation de la prise en charge, (3) l’objectif symptomatique et/ou fonctionnel des traitements pharmacologiques, (4) la necessite d’une reevaluation medicale reguliere des traitements et (5) la discussion d’une arthroplastie en cas d’echec du traitement medical. Six recommandations ont concerne les traitements oraux : (1) le paracetamol qui ne doit pas necessairement etre prescrit de maniere systematique et/ou continue, (2) les AINS, eventuellement en 1re intention, (3) les opioides faibles, (4) les opioides forts et (5) les anti-arthrosiques symptomatiques d’action lente et, (6) hors AMM, la duloxetine. Deux recommandations ont concerne les topiques (AINS et capsaicine Conclusion Il s’agit des 1res recommandations de la SFR sur la prise en charge pharmacologique de la gonarthrose.

Resume Objectifs Les inhibiteurs de l’interleukine (IL)-1β, efficaces dans les crises de goutte, sont recommandes en cas de contre-indications a la prise en charge standard, notamment insuffisance renale chronique (IRC) de stade 4 ou 5. Or, il existe peu de donnees disponibles sur l’efficacite et la securite de ces agents dans cette population de patients. Nous avons souhaite explorer l’efficacite et la securite de l’anakinra utilise pour traiter les crises de goutte chez des patients presentant une IRC de stade 4 ou 5 ou ayant subi une transplantation renale. Methodes Cette etude retrospective menee dans trois centres universitaires a inclus des patients consecutifs presentant une IRC de stade 4 ou 5 ou ayant subi une transplantation renale qui prenaient de l’anakinra en traitement d’une arthrite goutteuse aigue et avaient effectue au moins une visite de suivi. L’efficacite, la survenue d’infections et les variations de la fonction renale ont ete consignees. Resultats Sur les 31 patients inclus (24 hommes, âge moyen 72 ± 11 ans), 25 n’avaient pas subi de transplantation et presentaient une IRC de stade 4 ou 5 (estimation du debit de filtration glomerulaire moyen [eDFG] selon la formule MDRD 22,7 ± 6,5 mL/min/1,73 m2) et 6 avaient subi une transplantation renale (eDFG moyen 41,5 ± 22,8 mL/min/1,73 m2). La duree mediane de la goutte etait de 3,5 ans et le taux moyen d’uricemie de 8,7 mg/dL. Vingt-et-un patients (68 %) presentaient des tophi et 21, une arthropathie goutteuse. L’anakinra a ete efficace chez tous les patients (EVA final 10 et CRP finale 10 mg/L). Dix patients (32 %) etaient dependants de l’anakinra (c.-a-d. qu’un traitement prolonge d’anakinra etait necessaire). Une infection grave a ete enregistree chez une seule patiente, trois mois apres l’instauration de l’anakinra. Aucune variation significative de la fonction renale n’a ete observee. Conclusion L’anakinra peut constituer une option therapeutique sure chez les patients goutteux presentant une IRC a un stade avance. Des etudes comparatives randomisees supplementaires sont necessaires pour confirmer nos resultats.

To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France.On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement.Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections.These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

Objectives Interleukin (IL)-1β blocking is effective for the treatment of gout flares and is recommended in patients with contraindications to the standard of care, such as stage 4–5 chronic kidney disease (CKD) patients. However, efficacy and safety data regarding these agents are lacking in this population. We aimed to investigate the efficacy and safety of anakinra for the treatment of gout flares in patients with stage 4–5 CKD or renal transplantation. Methods This retrospective study encompassing 3 academic centres included consecutive patients with stage 4–5 CKD or kidney transplantation who received anakinra for the treatment of acute gouty arthritis and completed at least one follow-up visit. Efficacy, occurrence of infection, and renal function variations were recorded. Results Of the 31 included patients (24 men, mean age 72 ± 11 years), 25 were non-transplant subjects with stage 4–5 CKD (mean estimated glomerular filtration rate, MDRD formula (eGFR) 22.7 ± 6.5 mL/min/1.73 m 2 ), and six had undergone kidney transplantation (mean eGFR 41.5 ± 22.8 mL/min/1.73 m 2 ). Median gout duration was 3.5 years, and the mean serum urate (SUA) level was 8.7 mg/dL. Twenty-one (68%) patients had tophi, and 21 had gout arthropathy. Anakinra was efficacious in all patients (final VAS 10 and CRP level 10 mg/L). Ten patients (32%) were anakinra dependent (i.e., required prolonged treatment with anakinra). A serious infection was recorded in only one patient, occurring 3 months after starting anakinra. No significant variation in renal function was observed. Conclusion Anakinra may be a safe therapeutic option for gout patients with advanced CKD. Further randomized controlled studies are required to confirm our results.

Objective To explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases. Methods Patients with stable rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) under OI were proposed to switch to CT-P13 at the same regimen. A prospective cohort of infliximab-naive patients beginning CT-P13 and a retrospective cohort of patients treated with OI were used as controls. The primary outcome was to evaluate the retention rate of CT-P13. Secondary outcomes were the switch acceptance rate, reasons of failure and safety. Results Switch was proposed to 100 patients and accepted by 89 of them (63 AS, 12 PsA and 14 RA). After a median follow-up of 33 weeks, 72% of patients were still treated with CT-P13. This retention rate was significantly lower than the one found in our retrospective and prospective control cohorts: 88% and 90% respectively (P-value = 0.0002). Within patients who asked to be reswitched to OI, 13/25 (52%) presented clinical disease activity, one developed serum sickness and 11 (44%) presented no objective activity. A subanalysis excluding these 11 patients abrogated difference in retention rates between the 3 cohorts (P-value = 0.453). After reswitching to OI, patients without objective disease activity claimed to recover original efficacy. Conclusions Retention rate was lower after switching from OI to CT-P13 compared to our control cohorts. However, this difference faded after excluding patients without objective clinical activity, suggesting a reluctance of patients to the switch and a negative perception of the biosimilar.

ObjectivesTo evaluate the prevalence and type of rheumatic immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), as well as the correlation with tumour response.MethodsThis was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs and tumour response was assessed on a regular basis. Patients who experienced musculoskeletal symptoms were referred to the department of rheumatology for clinical evaluation and management.ResultsFrom September 2015 to May 2017, 524 patients received ICIs and 35 were referred to the department of rheumatology (6.6%). All but one of the rheumatic irAEs occurred with anti-programmed cell death protein 1(PD-1)/PD-1 ligand 1(PD-L1) antibodies, with a median exposure time of 70 days. There were two distinct clinical presentations: (1) inflammatory arthritis (3.8%) mimicking either rheumatoid arthritis (n=7), polymyalgia rheumatica (n=11) or psoriatic arthritis (n=2) and (2) non-inflammatory musculoskeletal conditions (2.8%; n=15). One patient with rheumatoid arthritis was anti-cyclic citrullinated peptide (anti-CCP) positive. Nineteen patients required glucocorticoids, and methotrexate was started in two patients. Non-inflammatory disorders were managed with non-steroidal anti-inflammatory drugs, analgesics and/or physiotherapy. ICI treatment was pursued in all but one patient. Patients with rheumatic irAEs had a higher tumour response rate compared with patients without irAEs (85.7% vs 35.3%; PConclusionSince ICIs are used with increasing frequency, knowledge of rheumatic irAEs and their management is of major interest. All patients were responsive either to low-to-moderate doses of prednisone or symptomatic therapies and did not require ICI discontinuation. Furthermore, tumour response was significantly higher in patients who experienced rheumatic irAEs.

although the outcome for patients with rheumatoid arthritis (ra) has improved in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. new drugs with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of baricitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. Expert opinion: Baricitinib is an oral targeted synthetic (ts) disease-modifying antirheumatic drug (DMARD) that mainly inhibits JAK1 and JAK2. Baricitinib monotherapy, or in combination with conventional synthetic (cs) DMARDs, has demonstrated its efficacy while having an acceptable safety profile in early active RA naive to DMARDs, and active RA with an inadequate response to csDMARDs and/or biologic (b)DMARDs. The future place of baricitinib in the management of RA patients will depend on several factors. However, baricitinib offer few advantages: oral administration, rapidity of action, efficacy in monotherapy and over adalimumab in one study and non-immunization. However, pending further safety data, current practice would be to start a bDMARD when the treatment target is not achieved with csDMARDs. Availability of additional long-term safety data may influence prescribing decisions.

Although there is an unmet need for pain medications that are both effective and safe, virtually no novel analgesics have been approved over the past two decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the clinical development of humanised anti-nerve growth factor monoclonal antibodies (anti-NGF mAbs) aroused particular interest. However, the US Food and Drug Administration (FDA) placed a clinical hold on anti-NGF mAb clinical studies in late 2010, first because of reports of serious joint-related adverse events, and afterwards because of sympathetic nervous system safety concerns. The development programmes of tanezumab and fasinumab resumed after the FDA lifted its hold in March 2015, whereas other anti-NGF mAbs were dropped by their sponsors. This article provides an updated review on the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies and public information from websites, and discusses the possible future role of these agents in managing chronic pain. The efficacy of anti-NGF mAbs was highly variable depending on the chronic pain condition studied. The most consistent and convincing results were obtained in patients with symptomatic osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain and peripheral neuropathic pain generated mixed results. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in cancer pain and urological chronic pelvic pain syndromes. Treatment-emergent adverse events were similar across anti-NGF mAbs, thus being suggestive of 'class-specific effects'. Although most patients tolerated anti-NGF agents well, neurosensory symptoms occurred frequently, and some patients developed new or worsened peripheral neuropathies. However, the most problematic safety issue was rapidly destructive arthropathies, leading to joint replacement surgery. To date, the aetiologies of joint-related side effects and their pathophysiology have not been clearly elucidated. However, some risk factors have been identified, such as higher doses of anti-NGF mAbs and longer drug exposure, concurrent nonsteroidal anti-inflammatory drug use and pre-existing subchondral insufficiency fractures. Taken together, the present data suggest that low-dose anti-NGF mABs may exhibit a favourable risk-benefit ratio in selected patients with certain chronic pain conditions, especially symptomatic osteoarthritis.

Background: Dietary long-chain polyunsaturated fatty acids (PUFAs) of the n3 and n6 families are involved in immune homeostasis and can contribute to modulate inflammatory processes. Dietary intake of n3PUFA (by either supplementation or fish consumption) has been inversely associated with RA incidence in different populations. Some evidence suggests that, in subject at high risk of developing rheumatoid arthritis (RA), high erythrocyte membrane content in long-chain n3-PUFA is associated with lower ACPA prevalence and progression to RA. While long-chain n6PUFA are considered mainly proinflammatory, some, like gamma-linolenic acid (GLA), are endowed with anti-inflammatory activity, and the erythrocyte content in n6 linoleic acid was inversely associated with the development of RA in a nested-case control study. No study hitherto evaluated the longitudinal association between individual PUFA profile and disease activity in early RA. Objectives: To characterize serum profiles of PUFA and to determine their association with baseline variables and with 6-month disease activity in a cohort of patients with early RA. Methods: Serum PUFAs were quantified by gas chromatography-mass spectrometry (GC/MS) in 594 patients with early RA at the time of recruitment in the French Etude et Suivi des POlyarthrites Indifferenciees Recentes (ESPOIR) cohort. Principal component analysis on 19 serum fatty acids with 14 to 22 carbon atoms allowed to determine 3 orthogonal patterns of baseline serum PUFA. Pattern 1 included high proportions of short-chain fatty acids, pattern 2 was high in n3 long-chain PUFA (EPA et DHA), pattern 3 was rich in n6 long-chain fatty acids (among which, GLA had the highest concentration). Patients were stratified in tertiles according to how much the fitted into each pattern, with tertile 1 meaning lowest and tertile 3 highest fitting into the pattern. The association of PUFA patterns with baseline variables was tested in univariate analysis. The association with 6-month disease activity (with high disease activity defined as DAS28>5.1) was tested in multivariable analysis after adjustment on baseline CRP, corticosteroid and/or NSAIDs use, socioeconomic status, ACPA and RF positivity, traditional and biologic DMARDs treatment between 0 and 6 months after inclusion. Results: In baseline univariate analysis, pattern 1 was associated with high BMI, active smoking and with non-Caucasian origin. Profile 2 was associated with higher socioeconomic status and inversely associated with DAS28 and CRP. Profile 3 was associated with ACPA positivity and higher baseline CRP. In multivariate analysis, fitting into pattern 2 and 3 was associated with lower odds of having active disease after 6 months (OR for tertile 3 vs. tertile 1: 0.49 (95% CI 0.25 to 0.97, p Conclusion: In a cohort of early RA patients, we could identify a high serum long-chain n3PUFA profile associated with low disease activity between 0 and 6 months of follow-up in the cohort. This is consistent with a presumed immunomodulatory action of n3PUFA. Despite the baseline association with disease severity features, like ACPA positivity and high CRP, a high serum long-chain n6PUFA profile is also associated with 6-month lower disease activity, possibly due to the presence of high concentrations of GLA in this profile. Disclosure of Interests: Johanna Sigaux Speakers bureau: celgene, Camille de Brauer Buscail: None declared, Chantal Julia: None declared, Rene Marc Flipo: None declared, Alain Cantagrel: None declared, Bernard Bannwarth: None declared, Francois Laporte: None declared, marie-Christophe Boissier Grant/research support from: Pfizer MSD, Speakers bureau: Pfizer Lilly Biogen, Luca Semerano Grant/research support from: pfizer, Speakers bureau: pfizer, roche, msd.

Background Immune checkpoint inhibitors (ICIs) are revolutionizing the treatment of some advanced cancers. Gut microbiota has emerged as an important component of anti-tumoral response and can also be related to the occurrence of immune-related adverse events (irAEs). It has recently been shown that antibiotic treatment given at the initiation of ICI therapy had a dramatic impact on microbiota that compromised the anti-tumoral effect of ICIs (1). Objectives To evaluate whether co-medications known to have a potential impact on gut microbiota may alter ICI efficacy and/or irAE occurrence when given at ICI onset. Methods This was a retrospective cohort study including all cancer patients who received ICIs at our institution from May 2015 to September 2017. Co-medications given to the patients within one month before or one month after the first administration of ICI were extracted from medical records on the basis of a predefined list of medications known to impact gut microbiota. The tumour response, occurrence of irAEs and patient outcomes were assessed on a regular basis. Overall survival (OS) has been considered from the start of ICI therapy. Results 635 patients (70% male, mean age 64.5 years) were included, of whom 293 had melanoma, 150 had advanced non-small cell lung cancer and 83 had renal carcinoma. A previous autoimmune disorder was present in 8% of patients, mainly rheumatic and endocrine diseases. Psychotropic drugs (41.1%), proton pump inhibitors (PPIs) (37.3%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARBs) (32%), glucocorticoids (GC) (24.2%), antibiotics (21.4%), statins (20.8%) and morphine (20.6%) were the most co-prescribed medications. Baseline GC use, when ≥ 10mg of prednisone equivalent, was associated with a significant decrease in OS (median 4.5 months versus 24.3 months; p Conclusion As many of these treatments are used by rheumatologists, one should be aware of their potential detrimental effect when used at ICI initiation, that sometimes could have been avoided. Reference [1] Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97. Disclosure of Interests None declared

Resume Objectifs Etudier l’acceptabilite et le taux de maintien de l’infliximab biosimilaire CT-P13 (Inflectra©) apres switch a partir de l’infliximab original (IO) chez des patients atteints de rhumatismes inflammatoires. Methodes Il a ete propose a des patients atteints de polyarthrite rhumatoide (PR), de spondylarthrite ankylosante (SA) ou de rhumatisme psoriasique (RhPso) controles sous IO, un switch pour le CT-P13 en poursuivant le meme schema therapeutique. Une cohorte prospective de patients naifs d’infliximab debutant le CT-P13 et une cohorte historique de patients traites par IO ont ete utilisees comme groupes temoins. L’objectif principal etait d’etudier le taux de maintien du CT-P13. Les objectifs secondaires etaient l’etude de l’acceptabilite, des raisons d’echec du switch et de la tolerance. Resultats Le switch a ete propose a 100 patients et accepte par 89 d’entre eux (63 SA, 12 RhPso et 14 PR). Apres un suivi median de 33 semaines, 72 % des patients etaient toujours traites par CT-P13. Ce taux de maintien etait significativement plus faible que celui retrouve dans les cohortes temoins historique et prospective : 88 % et 90 % respectivement (p = 0,0002). Parmi les patients demandant un retour a l’IO, 13/25 (52 %) presentaient une activite clinique de leur maladie, un patient a presente une maladie serique et 11 (44 %) ne presentaient pas d’activite objective. Une analyse excluant ces 11 patients faisait disparaitre la difference de taux de maintien entre les 3 cohortes (p = 0,453). Apres retour a l’IO, les patients sans activite clinique objective retrouvaient tous leur etat anterieur. Conclusion Le taux de maintien etait significativement plus faible apres le switch de l’IO vers le CT-P13 par rapport aux cohortes temoins. Cependant, cette difference disparaissait apres exclusion des patients sans activite clinique objective, suggerant une reticence des patients pour le switch et une perception negative du biosimilaire.

Background Immune checkpoint inhibitors (ICI) represent a new standard of care for the treatment of selected advanced cancers and are still being investigated in many other tumour types. By enhancing the T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs), including various well-described rheumatic manifestations. Data regarding the association between irAEs and patient outcomes are conflicting. Objectives To evaluate the incidence and characteristics of irAEs in patients receiving ICI, as well as the correlation with tumour response and patient survival. Methods This was a single-centre prospective observational study including all cancer patients receiving ICIs. The occurrence of irAEs, tumour response and patient outcomes were assessed on a regular basis. Overall survival has been considered from the start of ICI. Results From May 2015 to September 2017, 636 patients (70% male, mean age 64 years) have been included in this cohort while receiving anti PD-1 (n=435), anti PD-L1 (n=66) or anti CTLA-4 (n=3) as single agent or as sequential (n=100) or combined (n=32) therapies. Cancer types were mainly melanoma (n=293), non-small cell lung cancer (n=150) and renal carcinoma (n=83). Overall, 274/633 patients (43%) experienced irAEs, either 1 irAE (n=162), 2 irAEs (n=78) or ≥3 irAEs (n=34), with a median exposure time of 52 days30–91 for the first irAE. Dermatological irAEs were by far the most frequent (n=160), followed by digestive (n=80), endocrine irAEs (n=67), rheumatic (n=49) and pulmonary irAEs (n=17). So far, evaluation of tumour response was available for 551 patients, including 190 responders (complete response n=36 and partial response n=154), 192 patients with stable disease and 169 with progressive disease. 122/189 responders (65%) and 107/192 with stable disease (56%) experienced at least one irAE while reported only in 40/169 non responders (24%). Patients experiencing at least one irAE had an increased overall survival (median of 1169 days versus 224 days, p Conclusions Although irAE occurrence is not required for treatment benefit, it strongly associates with overall survival. Optimal multidisciplinary management of irAEs, including rheumatologists when needed, is worthwhile to maintain beneficial responses. Disclosure of Interest None declared

Resume Les notables progres realises au cours des dernieres decennies dans la connaissance des mediateurs et des circuits impliques dans la genese et le controle de la douleur n’ont pas debouche a ce jour sur la decouverte de medicaments innovants. Or nous manquons d’antalgiques performants et surs, d’ou les espoirs suscites par les anticorps monoclonaux ciblant le nerve growth factor (NGF) apres que des travaux experimentaux eurent revele le role cle de cette neurotrophine dans le declenchement et l’entretien d’un large eventail de syndromes algiques. Le tanezumab est la molecule pionniere dans le domaine et la plus avancee dans le developpement clinique. Les donnees disponibles attestent l’efficacite des anti-NGF dans l’arthrose symptomatique ; des resultats plus contrastes ont toutefois ete rapportes dans la lombalgie chronique commune, les douleurs neuropathiques et un modele de douleurs dysfonctionnelles (syndromes pelviperineaux chroniques). Mais la survenue d’arthropathies destructrices chez des patients traites decida l’Agence etasunienne, The Food and Drug Administration (FDA), a suspendre les essais des anti-NGF dans les affections non cancereuses en 2010. Sur proposition d’une commission consultative (Arthritis Advisory Committee) qui avait procede a l’analyse approfondie du rapport benefice/risques des anti-NGF, la FDA autorisa la reprise, sous conditions, des essais therapeutiques en aout 2012. Des etudes complementaires ayant etabli la neurotoxicite des anti-NGF chez l’animal, la FDA prononca un second interdit en decembre de la meme annee. Bien que les negociations entre la FDA et les firmes concernees aient finalement permis de definir les indications et le cadre dans lesquels les futurs essais pourront etre conduits, l’avenir des anti-NGF reste incertain.

Background Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) axis have been a major advance in cancer immunotherapy. By enhancing T cell activity, unprecedented long-lasting tumour responses are observed in selected cancers but some patients experience immune related adverse events (irAE). Objectives To evaluate the prevalence and type of rheumatic and musculoskeletal disorders in patients receiving ICI at a single institution (University Hospital of Bordeaux, France). Methods All cancer patients with musculoskeletal disorders while receiving ICI were referred to our rheumatology department. For each referred patient, an experienced rheumatologist performed a comprehensive clinical evaluation. Blood tests (inflammatory markers, serum creatine kinase, autoantibodies) and imaging (X-rays, ultrasound) were obtained according to clinical findings. HLA-DR phenotyping was also performed for some patients to search for shared epitope. Results From September 2015 to December 2016, 329 patients received ICI (anti CTLA-4: n=38; anti PD-1: n=251; anti PD-L1: n=29; combination anti CTLA-4/anti PD-1: n=11) and 21 patients were referred to our rheumatology department (6.4%). Mean age was 65 years and cancer types included melanoma (n=10), non small cell lung cancer (n=9), Merkel carcinoma (n=1) and renal carcinoma (n=1). All musculoskeletal disorders occurred in patients receiving anti PD-1 (nivolumab: n=12; pembrolizumab: n=6) or anti PD-L1 (avelumab: n=2; atezolizumab: n=1), with a median exposure time of 90 days (range: 1–650 days). There were two distinct clinical presentations: 1) inflammatory arthritis (IA) mimicking either rheumatoid arthritis (n=5) or polymyalgia rheumatica (n=8) and, 2) non-inflammatory musculoskeletal conditions (n=8). Of note, one patient was anti-CCP positive but negative for RF. Shared epitope HLA-DRB1 *01:01 was present in 4 patients. Eleven patients required corticosteroid therapy with a median dose of 15mg/day (range: 7–30 mg/day). Non-inflammatory disorders were easily managed with NSAIDs, analgesics and/or physiotherapy. ICI treatment was temporarily discontinued in one patient only, in line with the clinical trial protocol. To date, there was a partial or complete tumour response to ICI in 10 patients whereas 3 had stable disease and 7 had progressive disease. Tumour response or stable disease was observed in 11 of 12 patients with IA but only in 2 of 8 patients with non-inflammatory conditions. Conclusions In our series, patients with immune-related IA mimicking rheumatoid arthritis and polymyalgia rheumatica were responsive to low-to-moderate dose of prednisone and did not require ICI discontinuation. Furthermore, tumour response was frequently observed in such patients. Disclosure of Interest None declared

Apart from non-steroidal anti-inflammatory drugs (NSAIDs), there are only two categories of systemic analgesics, namely paracetamol (acetaminophen) and opioids, that are currently available worldwide for clinical use. Paracetamol is poorly effective in relieving pain and improving function in patients with symptomatic osteoarthritis (OA). Furthermore, its safety profile is less favourable than classically thought. In fact, there is evidence paracetamol acts as a weak inhibitor of the cyclooxygenase enzymes. Given that paracetamol poses a lower risk of severe adverse events than NSAIDs while being better tolerated than opioids, it is usually considered as the first-line systemic analgesic for OA. Commonly prescribed opioids are primarily agonists of the mu receptors, thereby producing similar desirable (analgesia) and untoward effects. Meta-analyses of short-term clinical trials showed that, on average, the modest clinical benefits of opioids did not outweigh the side effects in patients with knee or hip OA. Accordingly, most current guidelines support the use of opioids for selected OA patients only (e.g. patients who have not had an adequate response to other treatment modalities and are not candidates for total joint arthroplasty). In view of the limited efficacy and/or potential harms of available analgesics, particular attention was paid to novel painkillers, especially nerve growth factor (NGF) antagonists. Although these agents provided clinically meaningful improvements in pain and physical function in patients with hip or knee OA, they lead to severe side effects, including rapidly destructive arthropathies and neuropathies. Thus, if approved for marketing, NGF antagonists would be reserved for selected and well-defined patients with OA.

Objectives: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. Methods: The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. Results: 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. Conclusion: The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Background Retention rate, efficacy, and safety of abatacept (ABA) was compared between patients with rheumatoid arthritis receiving ABA as monotherapy to those in combination ABA + conventional synthetic DMARD (csDMARD). Methods The patients were obtained from the ORA registry. The retention rate was analysed in two ways: (1) therapeutic strategy retention, in which the addition of a csDMARD was considered to indicate failure of the monotherapy strategy; and (2) ABA retention, which was assessed by the discontinuation of ABA regardless of other treatment modifications. Efficacy and safety were compared between ABA initiated alone and ABA used in combination with a csDMARD. Results The retention rate at month 6 (M6) was evaluated in 569 patients. A significant difference was identified in the retention rate between the ABA monotherapy strategy and the ABA + csDMARD strategy (58.5 % [110/188] vs. 68 % [258/381], respectively, p = 0.031). No significant difference was identified in the ABA retention rate initiated either as a monotherapy or in combination with csDMARDs (75 % [142/188] vs. 76 % [291/381], respectively, p = 0.824). Data regarding ABA efficacy were available for 444 patients. There was no significant difference in the responder proportion after 6 months of treatment between ABA monotherapy and ABA + csDMARD treatment (60.2 % [88/146] vs. 60 % [179/298], respectively, p = 0.967). Conclusions This “real-life” analysis, which is relevant for bedside practice, emphasised the satisfactory efficacy and safety of ABA used in monotherapy, which provides an acceptable alternative when csDMARDs are undesirable.

During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox® was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin. While acknowledging that no one formulation can be expected to deter all types of opioid-abusive behaviours and no product is likely to be abuse proof in the hands of clear and determined abusers, the reductions in abuse these new products would provide may be an incremental step towards safer prescription opioids.

The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure-activity relationship (QSAR) study. After intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (fb) was determined using ultracentrifugation. The total (CT) and free (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the compounds was expressed as their polycratic capacity factors (log k'w) measured in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%. The compounds with an intermediate lipophilicity value (3logk'w3.6) easily entered the CSF (RAUC1). A parabolic relationship was found between log k'w and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion into CSF. Considering the fb value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilicity.

Resume L’inflammation d’origine rhumatismale procede de mecanismes physiopathologiques polymorphes et, partant, elle n’admet pas de solution therapeutique univoque. Ainsi, les arthrites aigues microcristallines se distinguent par leur reponse quasi specifique a la colchicine. Quant a la spondylarthrite ankylosante, elle est surtout sensible aux anti-inflammatoires non steroidiens (AINS) ou, a defaut, aux anti-TNF alors que les corticoides oraux n’y ont guere de place. Ceux-ci forment en revanche la pierre angulaire du traitement de la pseudo-polyarthrite rhizomelique, et ils surclassent les AINS dans la polyarthrite rhumatoide (PR). Mais le but etant de mettre la maladie en remission, ce sont les medicaments de fond synthetiques, dont le methotrexate, et/ou biologiques, tels que les anti-TNF, qui jouent le role majeur dans la prise en charge de la PR. L’elucidation progressive des mecanismes moleculaires sous-tendant les affections inflammatoires orienteront a l’avenir nos choix therapeutiques qui, pour l’heure, sont essentiellement probabilistes.

Resume De nombreux medicaments ont ete testes dans la lombalgie commune. Si l’on s’en tient aux formes chroniques, il n’est finalement que les anti-inflammatoires non steroidiens (AINS), l’association paracetamol-tramadol, les antidepresseurs non selectifs de la recapture de la serotonine et des injections rachidiennes de corticoides ou d’anesthesiques locaux qui ont peu ou prou demontre leur superiorite antalgique par rapport au placebo. Encore cette efficacite est-elle modeste et limitee a la douleur, les AINS semblant seuls capables d’ameliorer l’incapacite fonctionnelle. Il apparait neanmoins que l’evolution de la lombalgie est generalement favorable, quelle que soit la therapeutique mise en œuvre, y compris un placebo. Par ailleurs, le benefice du traitement est eminemment variable d’un essai a l’autre. Cela s’explique, au moins en partie, par l’heterogeneite des malades inclus dans les essais, et pose la question d’une selection plus rigoureuse des patients qui prenne notamment en compte les diverses composantes, nociceptives, dysfonctionnelles, voire neuropathiques, du syndrome algique.

Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab.This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions.The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia.Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.

Objective A survey was performed in 5 European countries (France, Germany, Italy, Portugal, and Spain) to estimate the prevalence of fibromyalgia (FM) in the general population. Methods In each country, the London Fibromyalgia Epidemiological Study Screening Questionnaire (LFESSQ) was administered by telephone to a representative sample of the community over 15 years of age. A positive screen was defined as the following: (1) meeting the 4-pain criteria alone (LFESSQ-4), or (2) meeting both the 4-pain and the 2-fatigue criteria (LFESSQ-6). The questionnaire was also submitted to all outpatients referred to the 8 participating rheumatology clinics for 1 month. These patients were examined by a rheumatologist to confirm or exclude the FM diagnosis according to the 1990 American College of Rheumatology classification criteria. The prevalence of FM in the general population was estimated by applying the positive-predictive values to eligible community subjects (ie, positive screens). Results Among rheumatology outpatients, 46% screened positive for chronic widespread pain (LFESSQ-4), 32% for pain and fatigue (LFESSQ-6), and 14% were confirmed FM cases. In the whole general population, 13 and 6.7% screened positive for LFESSQ-4 and LFESSQ-6, respectively. 3The estimated overall prevalence of FM was 4.7% (95% CI: 4.0 to 5.3) and 2.9% (95% CI: 2.4 to 3.4), respectively, in the general population. The prevalence of FM was age- and sex-related and varied among countries. Conclusion FM appears to be a common condition in these 5 European countries, even if data derived from the most specific criteria set (LFESSQ-6) are considered.

Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.

Resume Objectif Etudier les caracteristiques des effets indesirables medicamenteux (EIM) ayant motive l’entree des sujets âges dans des Services d’Accueil des Urgences (SAU) francais. Methodes Les donnees de deux etudes prospectives menees en 1999 et 2003 selon un protocole identique ont ete regroupees. La part des EIM dans les motifs d’admission, leur gravite et leur degre d’evitabilite ont ete evalues chez les patients ≥ 70 ans (groupe A) et compares a ceux observes chez des patients Resultats Sur les 2907 patients inclus, 1158 (39,8 %) avaient ≥ 70 ans. Dans ce groupe, l’incidence des EIM atteignait 17,1 % vs . 13,2 % dans le groupe B (p = 0,004). Les EIM apparaissaient plus severes dans le groupe A que dans le groupe B. La proportion d’EIM evitables ne differait pas significativement entre le groupe A (48,9 %) et le groupe B (43,7 %). Conclusion Les EIM sont une cause frequente – souvent evitable – d’admission aux SAU, en particulier dans la population âgee.

Background A 42-year-old man with a 10-year history of HLA-B27-positive ankylosing spondylitis presented with upper abdominal pain and nausea after receiving oral ketoprofen 200 mg/day. His gastrointestinal symptoms did not improve with the addition of ranitidine 150 mg twice daily. He had previously responded well to conventional nonsteroidal anti-inflammatory drugs. Investigations Physical examination, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, radiography, laboratory tests, upper gastrointestinal endoscopy, histopathologic examination and culture of biopsy specimens. Diagnosis Helicobacter pylori-positive duodenal ulcer. Treatment For eradication of H. pylori: omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily for 1 week. For ankylosing spondylitis: diclofenac 150 mg/day in combination with omeprazole 20 mg/day for 2 months.

Purpose In clinical guidelines for acute and subacute low-back pain, pharmacological treatment is recommended for short-term symptomatic relief. The objective was to study the effect of the guidelines' advise to remain active, alone and with the addition of the drug adenosine tri-phosphate (ATP), in patients with subacute low-back pain. Methods A drug-guidelines effectiveness trial was undertaken simultaneously to an experimental drug efficacy placebo controlled trial in subacute (4–12 weeks) non-specific low-back pain patients. The 132 participating primary care physicians across France were randomised to participate to either trial. In the drug-guidelines trial, all physicians received a quick consultation card containing the key elements of the clinical guidelines and a brochure that gave their patients practical tips to remain active. Patients were then randomised to receive Atepadene®, containing 90 mg of ATP by mouth daily for 30 days (guidelines plus ATP group), or nothing beside the rescue drug that was made available to all patients (guidelines alone group). The principal outcome was functional improvement on the Roland–Morris Disability Questionnaire (RDQ) at 90 days. Results In the drug-guidelines effectiveness trial, 157 patients were randomised. The rate of improvement in the RDQ over the 90 days of follow-up was superior in the group guidelines plus ATP (8.3 points, 95% confidence interval (CI): 7.3–9.3) than in the group guidelines alone (6.5 points, 95%CI: 5.3–7.7) (p = 0.02). In terms of probability of improving between two to five points on the RDQ at 90 days this difference translated in a 2 to 13 times higher probability compared to the group guidelines alone (odds ratios ranging from 2.1, 95%CI: 0.9–5.0 to 12.9, 95%CI: 1.6–103.4). Patients in the group guidelines plus ATP were also three times less likely to report a condition that had worsened or remained unimproved at 90 days (p = 0.02). Conclusion This drug-guidelines effectiveness trial showed a modest advantage of combined specific pharmacologic and non-pharmacological treatments on absolute improvement on the RDQ. A threefold reduction in the risk of chronicity was observed, an important goal in low-back pain guidelines. Copyright © 2005 John Wiley & Sons, Ltd.

Paracetamol is classically considered as a very safe analgesic/antipyretic compound and, more specifically, as being virtually devoid of any gastrointestinal (GI) ulcerogenic potential. Accordingly, it is widely stated that paracetamol is particularly suitable for patients at high risk of developing GI ulcers or bleeds. This view has been challenged by recent epidemiological studies using computerised prescription data, which indicated that paracetamol exhibits dose-dependent GI toxicity. However, the results of these studies are most likely incorrect for reasons of inherent biases and confounding. Furthermore, their findings conflict with those of clinical trials and case-control studies in which information about drug exposure was obtained by direct questioning of both cases and controls. Finally, paracetamol, especially at high doses, may induce upper GI symptoms such as abdominal pain/discomfort, heartburn, nausea or vomiting. Conversely, the risk for ulcers and ulcer complications due to paracetamol is not supported by available data.

Resume Chez des sujets indemnes de lesion muqueuse prealable, l’incidence des ulceres gastro-duodenaux deceles par des examens endoscopiques systematiques ne differe pas significativement entre les coxibs, anti-inflammatoires non steroidiens (AINS) inhibiteurs selectifs de la cyclooxygenase-2 et un placebo. Mais la pertinence clinique de cette donnee est sujette a caution. Le celecoxib et le rofecoxib, qui furent le mieux evalues, reduisent de moitie environ la probabilite de developper un ulcere symptomatique, simple ou complique (perforation, obstruction pylorique, saignement) par rapport aux AINS classiques administres a leur posologie maximale. Les coxibs conservent neanmoins une gastrotoxicite residuelle, chez les malades a risque digestif surtout. C’est le cas notamment lors d’une co-prescription d’aspirine a visee antithrombotique, l’avantage des coxibs sur les AINS classiques etant alors controverse. Quant aux manifestations fonctionnelles a type de dyspepsie, gastralgies ou nausees, elles restent la premiere cause d’arret premature des coxibs, meme si elles sont moins frequentes qu’avec les AINS classiques.

Background: Diary recording of pain and disabling activities in osteoarthritis (OA) is widely recommended, but, to our knowledge, its impact on symptoms has not been investigated. Exercise programmes have been shown to be effective when patients are closely supervised by nurses or physiotherapists; however, data are lacking on the efficacy of an unsupervised home based exercise regimen in patients with OA. Objectives: To evaluate the clinical efficacy of patient administered assessment tools and an unsupervised home based exercise programme alone or in combination in patients with OA. Methods: The study was a 24 week, open cluster randomised controlled trial with a factorial design. Rheumatologists (n = 867) were assigned to four groups according to the treatment given: standardised tools (ST; n = 220), exercises (EX; n = 213), both tools and exercises (ST+EX; n = 213), or usual care (n = 221). Each rheumatologist was to enrol four patients who met the American College of Rheumatology criteria for OA (three with knee OA, one with hip OA). "Tools" consisted of weekly recording of pain and disabling activities in a diary. A home based exercise programme was performed daily at least four times per week with the aid of videotape and booklet. In addition to exercise and asessment, all patients received 12.5 mg or 25 mg of the non-steroidal anti-inflammatory drug rofecoxib once daily. Outcome variables were: pain (measured on a visual analogue scale, 0–100); Western Ontario and McMaster Universities Osteoarthritis Index, function subscale (0–100); and patient assessment of the quality of care (0–100). Results: Overall, 2957 patients with OA (2216 knee, 741 hip) were included. After 24 weeks, both pain and function improved in the ST, EX, ST+EX, and usual care groups (mean (SD) −17 (27), −20 (29), −15 (27), −19 (29); and −11 (19), −12 (19), −10 (19), −11 (20), respectively), without significant differences between groups. However, patients in the EX and ST+EX groups were more likely to agree that their rheumatologist had done his best to preserve their functional and physical activities. Conclusion: Although patients’ assessments favoured the exercise programme, results from this study failed to demonstrate a short term symptomatic effect of the two non-pharmacological treatments (weekly recording of condition and exercise) in patients with OA concurrently receiving nonsteroidal anti-inflammatory drugs.

Various studies have shown that adverse drug events (ADE) are a substantial cause of hospital admissions. However, little is known about the incidence and severity of ADE resulting in hospital visits. To address this issue, we conducted a prospective survey in 10 primary care and emergency departments of French public hospitals. This study was performed over two periods of one week, one in June 1999 and one in December 1999, in primary care and emergency departments of five university hospitals and five general hospitals throughout France. Out of a total of 1,937 patients consulting, 1,562 were taking at least one drug during the previous week and were included for analysis according to the protocol. Altogether, 328 (21%; 95% confidence interval 19% to 23%) of these patients receiving at least one drug consulted because of an ADE. The sex ratio (M/F) was the same in both groups with or without ADE (1.04 vs 1.02, respectively, P = 0.83). Patients with ADE were older than those without (63.5 vs 54.8 years, P < 0.0001). Furthermore, ADR patients were more likely to have a higher severity score than no-ADE group (P = 0.019). The outcome seemed to be worse in patients with an ADE. The percentage of patients treated with 2 or more drugs and the number of drug exposures were significantly higher in patients with ADE than in those without (90.9% vs 75.0%, P < 0.0001, and 5.17 vs 3.82, P < 0.0001, respectively). The most frequent causes of visits for ADE-patients were digestive (n = 53, 16.2%), neurological (n = 52, 15.9%), cardiovascular (n = 49, 14.9%) and malaise (n = 49, 14.9%) events. In total, 410 drugs were incriminated in the occurrence of 328 ADE. The most frequently incriminated drug classes were (1) psychotropic agents, including anxiolytics and/or hypnotics, antidepressants and antipsychotics (n = 84, 20.5%), (2) diuretics (n = 48, 11.7%), (3) anticoagulants (n = 38, 9.3%), (4) other cardiovascular drugs (n = 63, 15.4%), and (5) analgesics, including non steroidal antiinflammatory agents (n = 57, 13.9%). The avoidability of ADE could be estimated by an external expert panel in 280 of the 328 cases. In 106 cases (37.9%), ADE was considered to be preventable because a contra-indication or a warning about drug use had not been respected.

Objective: To evaluate the safety profile of rofecoxib, a selective cyclo-oxygenase-2 inhibitor, in patients with osteoarthritis who are receiving care in non-hospital practice settings. Design: All patients participating in a large 24-week, open-label, non-pharmacological intervention trial were given rofecoxib for painful osteoarthritis of the knee or hip. They started at a dose of 12.5mg once daily for the first month, with the option of increasing to 25mg daily thereafter, if needed for efficacy. Adverse events were closely monitored. We considered all adverse events that occurred during treatment and within 14 days of discontinuation of rofecoxib. Patient Group Studied: 2896 patients (861 males and 2035 females) were involved in the safety analysis. Their mean (SD) age was 66.8 (9.9) years, and 631 patients (21.8%) were aged ≥75 years. There were 913 patients (31.5%) with hypertension and 151 (5.2%) with diabetes mellitus at the start of the study; 78 patients (2.7%) had a prior medical history of angina and/or myocardial infarction. The mean (SD) duration of rofecoxib treatment was 139 (62) days. Results: A total of 519 patients (17.9%) discontinued rofecoxib. The main reasons for discontinuation were dyspepsia (4.4%), nausea (2.4%) and dizziness (2.1%). The annualised incidence rates (95% CI) of complicated and uncomplicated upper gastrointestinal ulcers, myocardial infarction, and stroke were 1.36 (0.76–2.23), 0.09 (0–0.50) and 0.45 (0.16–1.05), respectively. Conclusion: This study conducted in conditions close to daily practice confirms that the use of rofecoxib is associated with a low rate of serious adverse events in patients with osteoarthritis.

The advantage of paracetamol (acetaminophen) is that it can be administered via the oral, intravenous or rectal routes. The last mentioned differs from the oral route in the slow and irregular absorption of the active substance. At therapeutic concentrations, the pharmacokinetics of paracetamol are

Background: Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR standing committee for clinical trials met in 1998 to determine the methodological and logistical approach required for the development of evidence-based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available therapies for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. Methods: The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and key words. All European language publications in the form of systematic reviews, meta-analyses, randomized-controlled trials, controlled trials and observational studies were included. During stage three all of the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and where practical the numbers needed to treat (NNT) and the effect size (ES) for each therapy was calculated. The fourth stage involved determination of key clinical propositions by expert consensus employing a Delphi approach. The final stage involved ranking of these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. Results: Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. Conclusions: These are the first clinical guidelines on knee OA to combine an evidence-based approach and a consensus approach across a wide range of treatment modalities. It is apparent that only certain clinical propositions are supported by substantial research-based evidence, while others are not. There is thus an urgent need for future well designed trials to address key clinical questions. (Less)

To the Editor: I read with interest the article by Wiland, et al 1 reporting on patients with early moderate to severe rheumatoid arthritis who achieved remission while receiving etanercept (ETN) 50 mg once weekly (QW) plus methotrexate (MTX). They experienced significant worsening in patient-reported outcome (PRO) measures when switched to placebo or …

Anti-drug antibodies (ADAbs) develop in up to a third of patients treated with biologic agents, with such immunogenicity being one of the main reasons for the loss of efficacy observed in an important proportion of patients treated with such agents. The appearance of ADAbs has consequences in terms of efficacy and tolerance of the biodrug: the development of ADAbs is associated with a poorer clinical response and with an increased risk of adverse effects. Formation of ADAbs has been observed with all biologic DMARDs, but anti-TNF agent mAbs appear to be the largest contributors, independent of humanization of the antibody. ADAb identification is technically difficult and not standardized, partly explaining important variations between published studies. A variety of factors can influence the risk of ADAb appearance, some of which are linked to the treatment strategy, such as the combination with synthetic DMARDs or the rhythm of administration of the biodrug, whereas other factors are dependent on the patient, such as the level of inflammation at onset or body weight. The detection of these antibodies and/or the dosage of the biologic agent itself could have consequences for the bedside practice of clinicians and should be well understood. This review of the literature proposes an overview of the data published on the subject to help clinicians manage the biodrugs according to these new concepts.

Rheumatoid arthritis (RA) is a chronic, painful and debilitating autoimmune disease. Although the outcome for patients with RA has improved markedly in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, new drugs with a novel mechanism of action may represent a valuable addition to the current armamentarium.This review focuses on the pharmacodynamics and pharmacokinetics of atacicept . Furthermore, the article both summarises and comments on the drug's efficacy and safety profile in RA patients.Atacicept is designed to neutralise B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand, two cytokines involving B-cell function and survival. Two recent Phase II studies have demonstrated that atacicept was not effective in RA patients with an inadequate response to methotrexate or TNF antagonists. However, atacicept displayed significant biological activity, including reduction of Ig and rheumatoid factor levels. Adverse events were slightly more frequent among patients treated with atacicept compared with placebo. In contrast to patients with systemic lupus erythematosus, RA patients receiving atacicept did not show an increased susceptibility to infections. In view of its important impact on immunoglobulin-secreting cells, this drug might be a rational therapy for hematological diseases.

It is unanimously accepted that there is an unmet need for pain medications that are both effective and safe. Unfortunately, no really novel analgesics have been approved over the past three decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, drug discovery efforts focusing on the development of anti-NGF agents have aroused particular interest. Several humanized anti-NGF monoclonal antibodies (mAbs) have entered clinical trials as potential analgesics. In this respect, tanezumab is at an advanced stage of clinical development while fulranumab, fasinumab and ABT-110, previously known as PG110, are in early phases of clinical development. This Current Opinion article aims at describing the rationale for targeting NGF for pain, reviewing the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies, conference abstracts, and the US Food and Drug Administration (FDA) website, and discussing the possible future of these agents in managing chronic pain. Anti-NGF mAbs produced significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain generated mixed results; overall, this condition appeared to be less responsive to anti-NGF agents than osteoarthritis. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in some types of chronic visceral or neuropathic pain. Furthermore, these studies raised safety concerns about anti-NGF mAbs. As a class, these drugs may cause or worsen peripheral neuropathies. But the most problematic issue—which prompted the FDA to place studies of these compounds on clinical hold in 2010—was rapid joint destruction leading to joint replacement surgery. The aetiologies of these side effects have been much debated and their pathophysiology is poorly understood. After an Arthritis Advisory Committee meeting held in March 2012, pharmaceutical companies negotiated with the FDA on the conditions for restarting clinical studies. Although the FDA lifted its clinical hold, there remain many unresolved issues about the long-term efficacy and safety of anti-NGF mAbs. While acknowledging that the future of these drugs is unforeseeable, it appears that they may not be the safe and effective painkillers that have been awaited for decades.

Molecular lipophilicity can be expressed by log Pow or, more conveniently, by log kw, i.e., determined by the traditional shake-flask technique, or by reversed-phase high performance liquid chromatography (RP-HPLC). Moreover, the unionized form of solutes is usually taken as the reference state for the measurement of lipophilicity. This can be problematic for the RP-HPLC determination of lipophilicity of acidic compounds due to the limited pH operating range of silica bonded phases. The measured dissociation constant values (pKa) of the twelve arylpropionic non steroidal antiinflammatory drugs (NSAIDs) are comprised between 3.80 and 5.70; consequently, the lipophilicities of the unionized forms must be measured at pH below 2. Accordingly, their capacity factors (log kw) were determined on a column packed with a hydrophilic polymethacrylate gel having octadecyl groups. This RP-column allows separations at low pH values of the mobile phase. In practice, the values of log kw are obtained by a series of isocr...

Resume Un groupe de travail du Comite directeur des essais therapeutiques de l’EULAR a determine, a partir des donnees etablies, des directives pour le traitement de la gonarthrose. Methodes. La premiere etape selectionnait les modalites therapeutiques a prendre en consideration. La deuxieme etape etait une recherche bibliographique concernant toutes les publications en langues europeennes. La qualite de chaque etude a ete notee. Lorsque cela etait possible, il a ete calcule pour chaque traitement etudie le nombre de patients a traiter pour en ameliorer un et l’importance de l’effet therapeutique. La troisieme etape a defini des recommandations de base ; ces definitions ont ete etablies par consensus d’experts, par votes successifs (approche Delphi ). L’etape finale a consiste a classer ces propositions selon les donnees scientifiques disponibles. Le groupe d’experts a egalement developpe une deuxieme serie de propositions relatives aux axes de recherche futurs. Resultats. Sept cent quarante-quatre etudes concernaient les traitements de la gonarthrose. L’analyse quantitative de l’effet therapeutique n’a ete possible que dans 61 etudes. Neanmoins, des recommandations pour la prise en charge de la gonarthrose reposant sur les donnees actuellement disponibles et l’avis des experts ont pu etre etablies, de meme que des propositions relatives aux axes de recherche futurs. Conclusion. Ces directives cliniques sur le traitement de la gonarthrose sont les premieres a combiner une approche fondee sur des donnees scientifiques et une approche consensuelle fondee sur l’avis d’experts, pour evaluer differentes modalites therapeutiques. Il apparait que seules certaines propositions sont corroborees par des donnees scientifiques etablies. Ce constat souligne le besoin urgent de conduire des essais bien concus afin d’obtenir des reponses a des questions cliniques majeures.