Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases

Abstract

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn’s disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.

Inflammatory Bowel Disease: Emerging Therapies and Future Treatment Strategies

“…PDE4 indirectly enhances the activation of NF-κB, promotes the production of proinflammatory mediators such as tumor necrosis factor-a (TNF-a), IL-23, IL-17, and interferon-gamma (IFN-γ), and decreases the expression of anti-inflammatory cytokines such as IL-10. Thus, PD4 inhibitors may represent a therapeutic target in IBD by acting at multiple levels [ 54 ].…”

Different biologics for biological-naïve patients with psoriatic arthritis: a systematic review and network meta-analysis

“…In terms of safety, PDE4i had the lowest probability to cause adverse events among the 5 kinds of biologics despite no significant difference observed among IL-17Ai, TNFi, JAKi, IL-12/23i and PDE4i biologics. PDE4i including apremilast blocks PDE4 enzyme and elevates the levels of intracellular cyclic adenosine monophosphate (cAMP), leading to downregulated inflammatory reactions through suppressing IL-17, interferon-γ, TNF, and so forth ( Nassim et al, 2020 ; Picchianti-Diamanti et al, 2021 ), which may explain the potential adventage of PDE4i over other biologics. To be noted, merely apremilast was evaluated as a representative of PDE4i, the information of which was provided by one qualified study in the current network meta-analysis.…”

Protective effects of 4‐geranyloxy‐2,6‐dihydroxybenzophenonel on DSS‐induced ulcerative colitis in mice via regulation of cAMP/PKA/CREB and NF‐κB signaling pathways

“…In addition, PDE4 inhibitors are considered to suppress NF‐κB. High intracellular levels of cAMP and PKA activation also contribute to NF‐κB inhibition (Picchianti‐Diamanti et al, 2021). It is important to note that PKA activation can negatively regulate phosphorylated ERK (Mizuno et al, 2014), resulting in decreased expression of specific pro‐inflammatory cytokines and chemokines (Zou et al, 2017).…”

“…PDE4 is a key enzyme in regulating cellular homeostasis and inflammation, and its inhibition plays a crucial role in diseases such as UC and psoriasis. PDE4 inhibitors, which activate the cAMP/PKA/CREB pathway, have been used in the treatment of UC (Picchianti‐Diamanti et al, 2021). Briefly, inhibition of PDE4 leads to accumulation of cAMP, which further activates PKA and CREB phosphorylation and decreases the expression of pro‐inflammatory cytokines and chemokines.…”