Recommendations of the French Society of Rheumatology on pharmacological treatment of knee osteoarthritis.

OBJECTIVES: To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France. METHODS: 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. RESULTS: 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 capsaicin<1%). 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. CONCLUSION: These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

Effectiveness and safety of anakinra in gout patients with stage 4-5 chronic kidney disease or kidney transplantation: A multicentre, retrospective study.

OBJECTIVES: Interleukin (IL)-1ß 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±6.5mL/min/1.73m2), and six had undergone kidney transplantation (mean eGFR 41.5±22.8mL/min/1.73m2). Median gout duration was 3.5 years, and the mean serum urate (SUA) level was 8.7mg/dL. Twenty-one (68%) patients had tophi, and 21 had gout arthropathy. Anakinra was efficacious in all patients (final VAS 10 and CRP level 10mg/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.

Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance.

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-naïve 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.

Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study.

OBJECTIVES: To 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. METHODS: This 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. RESULTS: From 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%; P<0.0001). CONCLUSION: Since 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.

Efficacy of baricitinib in the treatment of rheumatoid arthritis.

INTRODUCTION: 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.

Nerve Growth Factor Antagonists: Is the Future of Monoclonal Antibodies Becoming Clearer?

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.

Abatacept monotherapy compared with abatacept plus disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients: data from the ORA registry.

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.

Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice.

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.

Atacicept as an investigated therapy for rheumatoid arthritis.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Targeting nerve growth factor (NGF) for pain management: what does the future hold for NGF antagonists?

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.

A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis.

INTRODUCTION: 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, driven largely by the advent of biological disease-modifying antirheumatic drugs (DMARDs) and updated management strategies, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, DMARDs, with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Tofacitinib is a novel synthetic DMARD that selectively inhibits Janus kinases (JAKs), particularly JAK1 and JAK3. AREAS COVERED: This review describes the pharmacokinetics of tofacitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. The authors furthermore assess data derived from the FDA's RA development program. EXPERT OPINION: Tofacitinib is an oral synthetic DMARD displaying linear pharmacokinetics. Metabolism, primarily mediated by CYP3A4, accounts for 70% of the total clearance of the drug; the remaining 30% are renally excreted. Tofacitinib monotherapy, or in combination with traditional DMARDs, has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs, including TNF antagonists. In view of its undetermined benefit to risk ratio, in the real-world population, tofacitinib should, for now, only be prescribed to selected patients.

Will abuse-deterrent formulations of opioid analgesics be successful in achieving their purpose?

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.

Nonspecific low back pain: assessment of available medications.

Many medications have been evaluated for the treatment of nonspecific low back pain. The only medications proven to be more effective than a placebo in chronic low back pain are nonsteroidal antiinflammatory drugs (NSAIDs), the acetaminophen-tramadol combination, antidepressants other than selective serotonin reuptake inhibitors, and some types of spinal applications of glucocorticoids or local anesthetics. However, the efficacy of these drugs in inducing pain relief is limited, and NSAIDs are the only drugs that also improve function. Nevertheless, the outcome of nonspecific low back pain is favorable in most cases, even in placebo-treated patients. In addition, treatment effects vary dramatically across studies. One factor in this variability is the heterogeneity of patient populations. To improve the uniformity of patient populations enrolled in therapeutic trials, the selection criteria should take into account the nociceptive, dysfunctional, and possible neuropathic components of the pain syndrome.

[Pharmacological management of inflammatory rheumatic conditions]. / Prise en charge thérapeutique de l'inflammation d'origine rhumatismale.

Inflammatory rheumatic disorders are related to different pathophysiological mechanisms and, hence, their therapeutic management varies according to the underlying disease. Crystal-induced arthritis is characterized by its almost specific responsiveness to colchicine. Regarding ankylosing spondylitis, non steroidal anti-inflammatory drugs (NSAIDs) and TNF blockers are the cornerstones of pharmacological intervention whereas oral corticosteroids at conventional doses are of little value, if any. Conversely, corticosteroids are the drug of choice to treat polymyalgia rheumatica. Furthermore, low-dose corticosteroids were shown to be more effective than NSAIDs in patients with rheumatoid arthritis (RA). However, the main goal being to achieve remission, disease-modifying antirheumatic drugs, either synthetic, especially methotrexate, and/or biologic, such as TNF inhibitors, have a major role in the management of RA. Finally, enhanced understanding of molecular pathogenesis of inflammatory disorders may help to find out how to best target available drugs to right individuals in the future.