New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast.

Psoriasis is a chronic inflammatory skin disease, most commonly resulting in the occurrence of red and silver scaly plaques. About 30% of psoriasis sufferers develop psoriatic arthritis (PsA), a disorder that presents with additional joint inflammation and other clinical features. At present, the most effective treatment for moderate and severe psoriasis and PsA are biologics such as antitumor necrosis factor alpha therapy. Biologics are costly and typically require repeated injections; hence, the development of novel, orally available, small molecular inhibitors that are less expensive to produce is highly desirable. The phosphodiesterase 4 inhibitor apremilast is a small molecular inhibitor that acts by increasing cyclic adenosine monophosphate levels, ultimately suppressing tumor necrosis alpha production. Apremilast has been tested in a number of psoriasis and PsA pilot and Phase II trials to evaluate its efficacy and safety. More recently, three larger double-blinded, and randomized multicenter studies demonstrate that apremilast is efficacious in the treatment of psoriasis and PsA, with significantly higher numbers of apremilast-treated patients achieving endpoints of a 75% reduction compared to baseline in Psoriasis Area and Severity Index (PASI-75) or American College of Rheumatology-20 scores, relative to placebo. This encouraging data, along with a tolerable incidence of mild to moderate adverse events, has led to the initiation of several large Phase III trials that aim to further validate apremilast as a treatment for psoriasis and PsA. Here, we provide an overview of the current treatments for psoriasis and PsA, and summarize the findings from multiple Phase II clinical trials where the effects of apremilast in the treatment of psoriasis and PsA patients have been investigated.

IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration.

Interleukin-17 (IL-17) and tumour necrosis factor-α (TNF) are critical in the pathogenesis of arthritis but their relationship during inflammatory pain has received limited attention. We aimed to establish whether IL-17 can induce hyperalgesia in acute conditions, and investigated the role of TNF in mediating the pain response. Hyperalgesia was elicited in C57BL/6 mice by injection of recombinant IL-17, TNF or vehicle into the plantar tissue. Elevated pain was measured by the Hargreaves test for thermal hyperalgesia and Linton incapacitance tester for weight-bearing change. Cellular infiltration during hyperalgesia was determined by histological analysis and myeloperoxidase assay. IL-17 was found to induce hyperalgesia, but this was dependent on neutrophil migration and TNF binding to TNF receptor 1 (TNFR1). Because TNF-induced hyperalgesia was also dependent on neutrophil migration, the relationship between the resident fibroblasts, the cytokines and the migrating neutrophils was further investigated. By means of an air pouch model of cell migration, it was established that IL-17-induced neutrophil infiltration was dependent of TNF/TNFR1 as this interaction was required for the induction of the chemokine keratinocyte chemoattractant. These findings suggest that IL-17 causes acute hyperalgesia indirectly by inducing TNF from resident cells. The subsequent production of keratinocyte chemoattractant then triggers neutrophil chemotaxis to the plantar tissue, releasing algesic mediators locally to sensitise the nerve.

Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain.

The origin of pain in osteoarthritis is poorly understood, but it is generally thought to arise from inflammation within the innervated structures of the joint, such as the synovium, capsule and bone. We investigated the role of nerve growth factor (NGF) in pain development in murine OA, and the analgesic efficacy of the soluble NGF receptor, TrkAD5. OA was induced in mice by destabilisation of the medial meniscus and pain was assessed by measuring hind-limb weight distribution. RNA was extracted from joints, and NGF and TNF expressions were quantified. The effect of tumour necrosis factor (TNF) and neutrophil blockade on NGF expression and pain were also assessed. NGF was induced in the joints during both post-operative (day 3) and OA (16weeks) pain, but not in the non-painful stage of disease (8weeks post-surgery). TrkAd5 was highly effective at suppressing pain in both phases. Induction of NGF in the post-operative phase of pain was TNF-dependent as anti-TNF reduced NGF expression in the joint and abrogated pain. However, TNF was not regulated in the late OA joints, and pain was not affected by anti-TNF therapy. Fucoidan, by suppressing cellular infiltration into the joint, was able to suppress post-operative, but not late OA pain. These results indicate that NGF is an important mediator of OA pain and that TrkAd5 represents a potent novel analgesic in this condition. They also suggest that, unlike post-operative pain, induction of pain in OA may not necessarily be driven by classical inflammatory processes.

Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells.

IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55(-/-) but not p75(-/-) mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55(-/-) mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells.

Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system.

OBJECTIVE: OA is the most common joint disease, affecting 10-15% of people over 60 years of age. However, up to 40% of individuals with radiologic damage are asymptomatic. The purpose of this study was to assess the role of the endogenous opioid system in delaying the onset of pain in a murine model of osteoarthritis (OA). METHODS: Osteoarthritis was induced by transection of the medial meniscotibial ligament. Pain was assessed by monitoring weight distribution and activity. At various times postsurgery, the opioid receptor antagonists naloxone or peripherally restricted naloxone methiodide were administered, and pain was assessed. Levels of the micro-opioid receptor were assessed in the nerves innervating the joint by real-time reverse transcription-polymerase chain reaction analysis. RESULTS: As in human disease, significant joint damage occurred in mice before the onset of pain. To assess whether delayed pain was partly the result of increased endogenous opioid function, naloxone or naloxone methiodide was administered. Both opioid receptor antagonists led to pain onset 4 weeks earlier than in vehicle-treated mice, indicating a role of the peripheral opioid system in masking OA pain. The expression of the micro-opioid receptor in the peripheral nerves supplying the joint was transiently increased in naloxone-responsive mice. CONCLUSION: These findings indicate that a temporal induction of micro-opioid receptors in the early stages of OA delays the onset of pain. This is of clinical relevance and may contribute to the assessment of patients presenting with pain late in the disease. Furthermore, it may point to a mechanism by which the body blocks pain perception in moderate states of tissue damage, allowing an increased chance of survival.