Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis.

OBJECTIVES: Psoriatic arthritis (PsA) and psoriasis are immune-mediated inflammatory diseases sharing common immunological mechanisms. Regulatory B cells (Breg cells) producing IL-10 (B10 cells), a critical anti-inflammatory B-cell subset, were found to be decreased in both PsA and psoriasis. Apremilast, a phosphodiesterase-4(PDE4) inhibitor, increases IL-10 and therefore, we examined the effect of apremilast on Breg cells. METHODS: Fifty patients, including 20 with PsA and 30 with psoriasis, were included in the study. The effect of apremilast on Breg cells at 3, 6 and 12 months post-treatment, was examined by flow cytometry in ODN2006 (TLR9)-stimulated peripheral blood mononuclear cells and magnetically-isolated cells. Th1 cells, Th17 cells and NKT were also measured. RESULTS: Ex vivo stimulated cell analysis identified that post-apremilast (IL-10+CD19+) B10 cells were increased in all PsA and psoriasis patients and correlated with psoriatic skin and joint clinical improvement. Apremilast decreased IFNγ(+) T and NKT cells and IL-17(+)NKT cells. B10 cells also inversely correlated with Th1 cells, and IFNγ(+)NKT cells. CONCLUSION: These results suggest that Breg cells are a major target of apremilast in PsA and psoriasis and that apremilast-induced increase of Breg cells is associated with a decrease of Th1 cells, IFNγ-producing NKT cells and IL-17-producing NKT cells.

IL-10 producing Bregs are impaired in psoriatic arthritis and psoriasis and inversely correlate with IL-17- and IFNγ-producing T cells.

Our aim was to study CD19(+)CD27(+)CD24(high) memory and CD19(+)CD24(high)CD38(high) transitional and IL-10+Breg cells, known to inhibit Th1 and Th17 cells in experimental arthritis, in psoriatic arthritis (PsA) and psoriasis (Ps). Peripheral blood Breg cells from 60 patients with PsA, 50 patients with Ps and 23 healthy controls were analyzed by flow cytometry. IL-17A-producing CD3(+) T cells and IFNγ-producing CD3(+) T cells and activation of p38 MAPK and STAT3 were also studied. CD19(+)CD27(+)CD24(high) and CD19(+)CD24(high)CD38(high) Breg cells were decreased in PsA and Ps. In Ps patients, CD19(+)CD27(+)CD24(high) Breg cells inversely correlated with PASI score. IL-10+Bcells were also decreased and inversely correlated with IL-17A+CD3+ and IFN-γ+CD3+ T cells. B cells from patients exhibited impaired activation of p38 MAPK and STAT3. In conclusion, IL-10+Breg cells are decreased PsA and Ps and inversely correlated with the severity of psoriasis and IL-17A+ and IFNγ+ T cells.

Effectiveness of Autologous Whole-Blood Injections in Patients with Refractory Chronic Spontaneous Urticaria.

BACKGROUND: Nonsedating antihistamines are the treatment of choice for chronic spontaneous urticaria (CSU), while omalizumab and immunosuppressants have also been approved as an add-on treatment. Autologous whole-blood injection (AWBI) has been used in previous studies with ambiguous results. The aim of our study was to evaluate changes in the Urticaria Activity Score (UAS7), Dermatology Life Quality Index (DLQI), and Chronic Urticaria Quality of Life (CU-Q2oL) score, and also the association of serologic markers with disease severity measures after AWBI. METHODS: In this observational study, AWBIs were performed (8 courses on a weekly basis) in adults with refractory CSU, who refused an add-on treatment with either omalizumab or immunosuppressants. UAS7, DLQI, and CU-Q2oL questionnaires and serum concentrations of total IgE, C-reactive protein (CRP), and D-dimer were evaluated before and after the intervention. RESULTS: Nineteen patients (12 females; mean age 54 ± 20.8 years) completed the protocol. Following AWBI, significant improvements in the UAS7 (34.26 ± 8.04 vs. 12.52 ± 10.83, p < 0.001), DLQI (11.63 ± 5.51 vs. 3.47 ± 2.85, p < 0.001), and CU-Q2oL score (32.97 ± 18.71 vs. 10.94 ± 7.71, p < 0.001) were recorded. A negative correlation between the baseline D-dimer levels and UAS7 and DLQI variations (p = 0.002 and p = 0.001, respectively) was noted. D-dimer levels ≥292 ng/mL have been associated with poor responsiveness (sensitivity 75%; specificity 83.3%). No correlation with either total immunoglobulin E or CRP levels was observed. CONCLUSION: AWBI appears to be a safe, alternative, add-on therapeutic option in refractory CSU, particularly in patients with low plasma levels of D-dimer.

Delphinidin diminishes in vitro interferon-γ and interleukin-17 producing cells in patients with psoriatic disease.

The anthocyanidin delphinidin reduces psoriasiform lesions and inflammatory mediators in human cell culture systems. Its role in psoriatic disease has not yet been investigated. We assessed delphinidin's in vitro immunomodulatory effect on ex vivo stimulated peripheral blood mononuclear cells (PBMCs) from 50 individuals [26 with psoriasis, 10 with psoriatic arthritis (PsA) and 14 healthy controls (HCs)]. Cells were either left untreated or stimulated with PMA plus ionomycin in the presence or absence of delphinidin. Intracellular production of interferon-γ (IFNγ), interleukin-17A (IL-17A), and interleukin-10 (IL-10) was measured flow cytometrically. Delphinidin dose-dependently reduced IFNγ+ T cells from patients and HCs. The mean IFNγ decrease in CD4+ T subpopulations was 42.5 ± 28% for psoriasis patients, 51.8 ± 21.5% for PsA patients and 49 ± 17% for HCs (p < 0.001 for all). Similarly, IFNγ reduction in CD8+ T cells was 34 ± 21.6% for psoriasis patients, 47.1 ± 22.8% for PsA and 44.8 ± 14.3% for HCs (P < 0.001 for all). An inhibitory effect of delphinidin was also noted in IFNγ producing NKs and NKTs from psoriasis individuals. Delphinidin also significantly decreased IL-17+ CD4+ T cells in all tested subjects, with marginal effect on the increase of IL-10-producing T regulatory subsets. In conclusion, delphinidin exerts a profound in vitro anti-inflammatory effect in psoriasis and psoriatic arthritis by inhibiting IFNγ+ innate and adaptive cells and T helper (Th) 17 cells. If this effect is also exerted in vivo, delphinidin may be regarded as a nutraceutical with immunosuppressive potential.

Autoantibodies against specific nuclear antigens are present in psoriatic disease and are diminished by secukinumab.

Anti-nuclear antibodies (ANA) are frequently detected in patients with psoriasis (Ps) and psoriatic arthritis (PsA), but their target autoantigens remain unknown. We assessed antibody (ab) reactivity against 23 known nuclear antigens in patients with Ps and PsA and assess the effects of secukinumab (anti-IL17A) treatment on ANA levels. A total of 201 patients, 101 with Ps and 100 with PsA, and 50 ANA-negative healthy controls (HCs) were tested for ANAs by a line immunoassay testing reactivity to 23 nuclear antigens. Ab reactivity to at least 1 antigen was found in 20.4% psoriatic disease patients (25.7% Ps and 15% PsA) compared to 8% HCs (p = ns), the most frequent being against dense fine speckled 70 (DFS70) (6.5%). In Ps and PsA patients with secukinumab-induced remission, anti-DFS70 and other antigen-specific autoantibodies were diminished over time. No decline was noted for IgG abs against antigens from pathogens such as cytomegalovirus, Epstein-Barr virus and Helicobacter pylori. Autoantibody decrease was associated with significant reduction of plasmablasts, follicular B and follicular T cells. In conclusion, one third of antigen-specific ANA patients with psoriatic disease recognize DFS70. Secukinumab decreases nuclear antigen autoreactivity, plasmablasts, follicular B and follicular T cells, highlighting a new mechanism of its action.

Increased HIF-1 alpha immunostaining in psoriasis compared to psoriasiform dermatitides.

BACKGROUND: Expression of hypoxia inducible factor 1 (HIF-1) alpha can be linked to inflammation through reciprocal interactions with several cytokines. This finding is in accordance with the previously noted HIF-1 alpha overexpression in psoriatic lesional keratinocytes. METHODS: In this study we have employed a carefully selected panel of antibodies and quantitative morphometric analysis to compare HIF-1 alpha immunoreactivity in psoriatic biopsy samples vs. that in samples obtained from psoriasiform dermatitides. RESULTS: We found statistically significant HIF-1 alpha overexpression in psoriasis. Furthermore, we observed a previously unreported preferential localization of immunoreactive keratinocytes in the immediate vicinity of inflamed and elongated papillae. This pattern of immunoreactivity may partially account for the observed increase of HIF-1 alpha immunostaining in psoriasis. CONCLUSIONS: Overall, our findings imply that possible novel therapeutic intervention(s) on the HIF-1 alpha pathway may offer another approach in controlling the inflammatory activity of psoriatic lesions.

The effect of Apremilast on signal transduction and IL-10 production in CD39high regulatory B cells in patients with psoriatic arthritis.

BACKGROUND: IL-10-producing regulatory B cells (Bregs) are of great importance in autoimmunity, as they inhibit proinflammatory T cells. We have shown that IL-10-producing Bregs in psoriatic arthritis(PsA) were decreased and inversely correlated with IFNγ+T cells (TH1 cells) and IL-17+ T cells (TH17 cells). B cells with overexpression of CD39 have also inhibitory effects on proinflammatory T cells. PRELIMINARY RESULTS: Our preliminary data showed that Apremilast, a phosphodiesterase-4(PDE-4) inhibitor, used in the treatment of PsA and psoriasis (Ps) increased IL-10-producing Bregs and reduced IFNγ+CD3+ T cells and IL-17+CD3+ T cells. We also found reduced activation of p38MAP kinase and the transcription factor STAT3, two important signaling pathways of IL-10 production, in PsA. SPECIFIC AIMS: The aim of this research proposal is to study for the first time the immunomodulatory effect of Apremilast on signaling pathways in peripheral blood mononuclear cells (PBMCs) and CD39high B cells in PsA and Ps. METHODS: We will study CD39 expression in B cells from patients with PsA and Ps before and after Apremilast treatment and their relation to IFNγ+ and IL-17+ T cells. Activation of CREB (cAMP response element-binding protein), STAT3, and p38MAPK in PBMCs and CD39high B cells from patients with PsA and Ps before and after Apremilast. The effect of CD39high B cells on T cell IFNγ and IL-17 production will also be studied. SIGNIFICANCE: This study will elucidate the molecular pathways of Apremilast and better define Bregs in PsA and Ps.

Multidisciplinary lymphedema treatment program.

Lymphedema is an underrecognized and undertreated condition that requires a multidisciplinary approach in an individualized program that will address the special needs of each patient. In an ideal setting of an outpatient management program the team should be composed of a vascular surgeon, a dermatologist, a physiotherapist, a dietician, a psychologist, a social worker, and an office employee, working together in the assessment and management of all aspects of lymphedema. All treatment strategies and actions taken should ultimately focus on the improvement of the quality of life of patients suffering from lymphedema and on the prevention of lymphedema in high-risk patients.