Fostamatinib for warm antibody autoimmune hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled, global study (FORWARD).

Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period. Ninety patients were randomized, 45 to each arm. Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398). A post hoc analysis revealed a large placebo response in Eastern European patients. Significantly more patients on fostamatinib from North America, Australia and Western Europe exhibited a durable Hgb response compared to placebo (36% vs. 10.7%, p = .030). After censoring for Hgb values impacted by steroid rescue received during screening and excluding 2 placebo patients found to likely not have wAIHA, a reanalysis demonstrated a difference in durable Hgb response between fostamatinib and placebo (15/45 [33.3%] vs. 6/43 [14.0%], p = .0395). At least 1 AE was reported in 42 (93.3%) and 40 (88.9%) patients receiving fostamatinib and placebo, respectively. The most common AEs in the fostamatinib group were diarrhea (26.7%), hypertension (24.4%), and fatigue (15.6%). In this study, fostamatinib demonstrated a clinically meaningful benefit for patients in Western regions, and no new safety signals were identified.

Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.

Histone deacetylase inhibitors are under investigation in the clinic as a new class of anti-cancer therapeutics. While recent studies have also suggested their potential as inhibitors of a wide spectrum of inflammatory reactions, the anti-inflammatory mechanism of action of these compounds is not fully defined. We show here that the histone deacetylase inhibitors MS-275 and SAHA induce the generation of regulatory T cells (Tregs) from anti-CD3/anti-CD28-stimulated human CD4(+)CD25(-) T cells. These Tregs express the regulatory T cell-associated transcription factor Foxp3 and display suppressive activity against CD4(+)CD25(-) T cell proliferation. Topical treatment with histone deacetylase inhibitors also induces Foxp3 expression in the draining lymph nodes and the skin in the context of a murine contact hypersensitivity model. These findings suggest that Treg generation may serve as a novel mechanism by which histone deacetylase inhibitors regulate the immune response, and provide an additional rationale for the use of histone deacetylase inhibitors in the treatment of inflammation.

5th annual conference on cytokines and inflammation 29-30 January 2007, Breckenridge, Colorado, USA.

The concept of anticytokine therapies for the treatment of inflammatory diseases has been proven with the successful launch of therapeutics targeting TNF and IL-1, and with numerous additional anticytokine strategies in development. The 5th annual conference on Cytokines and Inflammation provided a timely update on this topic with sections devoted to cytokine biology, chemokines, new technologies for cytokine-based therapy and small-molecule agonists and antagonists. This brief review summarizes key findings from the conference.

Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis.

Since the discovery of cytokines as key mediators in inflammation, targeting the cytokine network has represented a promising therapeutic approach. Psoriasis and atopic dermatitis, as T cell-mediated diseases with a strong cytokine component and a high unmet medical need, have moved into the focus of experimental therapies. Whereas pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha are overexpressed in both diseases, a type 1 cytokine pattern predominates in psoriasis and a type 2 cytokine pattern is of pathophysiological importance at least in the initial stages of atopic dermatitis. Strategies for intervention into the cytokine network have included antagonism of pro-inflammatory cytokines (e.g. TNFalpha, interleukin [IL]-1, IL-8, IL-12, IL-18, IL-23) with neutralizing antibodies and soluble receptors, application of recombinant cytokines (e.g. IL-4, IL-10, IL-11, interferon [IFN]-gamma) to shift the cytokine balance, and administration of small molecules to modulate cytokine expression or signaling. Results from the clinic have led to novel therapeutic options as well as a better understanding of the pathophysiology of inflammatory skin diseases. This review highlights the various therapeutic strategies, results from the clinic (that are in some cases preliminary), and insights that can be drawn from the more advanced clinical studies and the use of approved cytokine-directed therapies.

Cytokines as potential therapeutic targets for inflammatory skin diseases.

A network of pro-inflammatory cytokines is a central feature in the pathophysiology of cutaneous inflammatory diseases. Thus, the delineation of precise roles for particular cytokines and the development of cytokine-directed therapeutics have become areas of intense investigation. While anti-TNF therapeutics have proven to be effective for the treatment of psoriasis, clinical investigations have now begun with other cytokine-directed therapies, such as those targeting IFN-g, IL-12p40, and IL-18. In addition to therapeutics that target cytokines directly, strategies that target cytokine signaling pathways are in development too. In this short review, we summarize key findings from a recent workshop on cytokines as potential therapeutic targets for inflammatory skin diseases.