Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases

Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed

Evaluating the association of central centrifugal cicatricial alopecia (CCCA) and fibroproliferative disorders

Background: In central centrifugal cicatricial alopecia (CCCA), a lymphocytic scarring alopecia that primarily affects black women, it has been postulated that there is a "pro-fibrotic" tendency and increased risk for systemic fibroproliferative disorders. Objective: To determine whether women with biopsy-proven CCCA have a greater likelihood of systemic fibroproliferative disorders (FPDs) of the lungs (interstitial lung disease), arteries (atherosclerosis of the aorta), liver (non-alcoholic steatohepatitis), kidney (end stage renal disease), or uterus (uterine leiomyoma). Methods: We conducted a retrospective matched cohort study evaluating 427 cases with biopsy-proven CCCA and 1281 age- and sex-matched controls. Results: Black women with biopsy-proven CCCA, were not more likely to have interstitial lung disease (ILD), atherosclerosis of the aorta, non-alcoholic steatohepatitis (NASH), end stage renal disease (ESRD), or uterine leiomyoma. Central centrifugal cicatricial alopecia was associated with a history of never smoking and higher body mass index. Conclusion: In this large cohort of biopsy-proven women with CCCA, there was no association with specific fibroproliferative disorders when compared with age and sex matched controls. Future longitudinal studies may help confirm these results

A randomized controlled trial of an emollient with ceramide and filaggrin-associated amino acids for the primary prevention of atopic dermatitis in high-risk infants

Background: Skin barrier dysfunction may precede infantile development of clinical atopic dermatitis (AD). Early-life emollient therapy to enhance barrier function may prevent or modify AD development in high-risk infants. Objectives: (a) To determine whether daily full-body application of an emollient with ceramide and amino acids (study emollient) can reduce the cumulative AD incidence compared to standard skin care at 1 year of age. (b) To evaluate the study emollient's effect on skin barrier function, natural moisturizing factor and the microbiome using non-invasive biophysical and biochemical techniques. Methods: We performed a single-centre, investigator-blinded, randomized controlled trial enrolling infants at high risk for AD development determined by family history. The intervention was full-body once-daily application of the study emollient. The control arm was asked to not apply full-body emollient regularly and only use an emollient of their choice for dry skin. The primary outcome was the cumulative incidence of AD diagnosed at 12 months by a blinded investigator. Results: Less than half the target sample size was enrolled (n = 100, goal sample was 208) with 28% lost to follow-up. Across all clinical end points, a numerical trend was observed in favour of the intervention, although not statistically significant likely due to lack of power from under-enrolment. AD was diagnosed in 13.2% vs. 25.0% at 12 months (P = 0.204) and 19.4% vs. 31.0% at 2 years (P = 0.296) in intervention vs. control groups, respectively. There were no significant differences between groups in skin barrier or microbiome assessments. While there were no serious adverse events, there were more cases of reported contact dermatitis in the intervention vs. control arms, 9.3% vs. 4.3%, respectively; however, these events were not related to the study emollient and most mild in severity. Conclusion: The observed trends suggest a protective effect of daily study emollient therapy compared to control