Potential of phosphodiesterase type of IV inhibitors in the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a crippling autoimmune disease which afflicts over 1% of the population. Non-steroidal anti-inflammatory drugs are widely used palliatives, but these disease-modifying drugs are of variable and limited efficacy, and are frequently associated with side-effects which restrict their use. Agents that elevate cAMP, including cAMP-specific phosphodiesterase (PDE) inhibitors, possess a profile of anti-inflammatory activities which suggest potential benefit in RA. In several rodent RA models, PDE IV inhibitors reduce the incidence and severity of disease symptoms and histological analysis reveals a significant, beneficial effect on joint pathology. Several potential mechanisms may underpin the anti-arthritic actions of PDE IV inhibitors. These include inhibition of tumor necrosis factor (TNF)-alpha release, increase of interleukin (IL)-10 release, and suppression of T-lymphocyte function, as well as direct, protective effects on cartilage and bone. Although stimulation of the hypothalamic-pituitary-adrenal axis in rodents has previously been suggested as a possible mechanism by which PDE IV inhibitors exert their anti-arthritic effects, recent data question its importance. For example, RP-73401 ameliorates disease severity in Streptococcal cell wall-induced arthritis in Lewis rats, a strain whose susceptibility to this disease has been attributed to a defective HPA response, without affecting either ACTH or corticosterone levels. In a small clinical study, RA patients treated with low doses of RP-73401, showed a positive (non-significant) trend in respect of serum concentrations of IL-6 and CRP. Although levels of TNFalpha and IL-1beta were unaffected, patients reported some symptomatic relief. The administration of higher doses was prohibited due to side-effects and compounds with an improved therapeutic window will have to be identified to further explore the potential of PDE IV inhibitors in the treatment of RA.