No abstract

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.

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.

Low-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile. Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable. A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process. Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxymethotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors. Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy. Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may redu...