Markus Friedrich

German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version)

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1–S126, 2006; or http://www.psoriasis-leitlinie.de).

Is there an interaction between interleukin-10 and interleukin-22?

Interleukin(IL)-10 and IL-22 are structurally related cytokines. Their heterodimeric receptors consist of the cytokine-specific chains IL-10R1 and IL-22R1, respectively, and the common chain IL-10R2. This study focused on the question of whether IL-10 modulates IL-22 effects and vice versa. This question is important because IL-10 and IL-22 exert anti- and proinflammatory effects, respectively, and, as we show here, are simultaneously present in both systemic and local inflammation. The revealed lacking concomitance of IL-10R1 and IL-22R1 on identical cells excluded any possible interaction between IL-10 and IL-22 apart from the competition for IL-10R2. To study this competition, monocytes and hepatocytes were chosen. The dependence of the cytokine action on IL-10R2 was verified. Interestingly, no influence of IL-22 on IL-10 effects was observed. The same was true when IL-22 was used in complex with IL-22-binding protein. Similarly, no influence of IL-10 was found on IL-22 action. This missing competition seemed to be due to a lack of binding between IL-10R2 and the native cytokines in the absence of their corresponding R1 chain. However, IL-10R2 interacted with defined IL-10- and IL-22-derived peptides supporting the hypothesis that cytokine binding to its corresponding R1 chain creates a binding site on this cytokine for IL-10R2.

Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy.

Interleukin‐10 (IL‐10), originally identified as an inhibitor of pro‐inflammatory cytokine production, exerts multiple immunomodulatory functions. Its ability to inhibit a Th1 response has been used in clinical trials for the treatment of inflammatory diseases including psoriasis. However, little is known about the molecular mechanisms of IL‐10 functions. We aimed at identifying possiblemediators of in vitro IL‐10 treatment in monocytes by gene chip technology using Hu95a Affymetrix mRNA arrays with 12,000 genes. To prove relevance of the identified genes for the clinicalsituation we compared these in vitro results with genes being regulated by IL‐10 in peripheral blood mononuclear cells from psoriatic patients undergoing IL‐10 therapy. A high proportion of the 1,600 genes up‐regulated and 1,300 genes down‐regulated in vitro was found to be similarly regulated in vivo. Some genes, which were previously unknown to be regulated by IL‐10, can be assigned to known IL‐10 functions like e.g. the increase of pathogen clearance. Other new potentially immunomodulating genes have been identified to be regulated by IL‐10, but their impact needs to be experimentally evaluated. We could confirm a recently reported up‐regulation of heme oxygenase‐1 (HO‐1). However, we demonstrate that the anti‐inflammatory mechanisms of IL‐10 remain functional even when HO‐1 is irreversibly inhibited.

Pan-selectin antagonism improves psoriasis manifestation in mice and man

The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients. In vitro bimosiamose proved to be inhibitory to E- or P-selectin dependent lymphocyte adhesion under flow conditions. Using xenogeneic transplantation models, bimosiamose reduced disease severity as well as development of psoriatic plaques in symptomless psoriatic skin. The administration of bimosiamose in patients suffering from psoriasis resulted in a reduction of epidermal thickness and lymphocyte infiltration. The clinical improvement was statistically significant (P=0.02) as analyzed by comparison of psoriasis area and severity index before and after treatment. Assessment of safety parameters showed no abnormal findings. These data suggest that pan-selectin antagonism may be a promising strategy for the treatment of psoriasis and other inflammatory diseases.

Interleukin-10: An Important Immunoregulatory Cytokine With Major Impact on Psoriasis

Interleukin (IL)-10 is a pluripotent cytokine with effects on numerous cell populations, in particular circulating and resident immune cells as well as epithelial cells. With its potent immunoregulatory capacities its main biological function seems to be the limitation and termination of inflammatory responses. Thus its low level expression found in psoriasis may have pathophysiological relevance for this immune disease. Remarkably, induction of IL-10 expression was found by conventional antipsoriatic therapies, supporting the hypothesis that IL-10 may be a key cytokine in psoriasis and that application of this cytokine itself may have therapeutic effects. In first clinical trials in patients with established psoriasis IL-10 showed moderate antipsoriatic effects and was well tolerated. Moreover, long term application in psoriatic patients remission showed that IL-10 therapy decreases the incidence of relapse and prolongs the disease free interval. The immunological effects observed during these clinical studies together with in vitro observations suggests that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen presenting cells and T-cells (lasting type 1/ type 2 cytokine balance shift), but not through direct effects on keratinocytes. In conclusion IL-10 seems to have major importance in psoriasis. Further investigations, in particular multicenter, placebo-controlled, double blind trials are required to fully determine whether IL-10 application will become a successful antipsoriatic therapy.

The antipsoriatic activity of IL-10 is rather caused by effects on peripheral blood cells than by a direct effect on human keratinocytes

Abstract IL-10 is a promising candidate for the treatment of cutaneous disorders. Antipsoriatic efficacy of systemic IL-10 treatment has been already demonstrated. This includes histomorphological changes in the epidermis, suggesting effects on keratinocytes. However, less is known about direct effects of IL-10 on this cell population, although effects are likely since IL-10 receptor expression on keratinocytes has been demonstrated recently. Therefore we analysed the effects of IL-10 on keratinocytes in vitro, using concentrations of human recombinant IL-10 corresponding to those detectable in plasma during therapy. Proliferation, cytokine formation (IL-6, IL-8, IL-1ra), and expression of surface molecules (MHC class I and II, costimulatory molecules CD80 and CD86, CD29, CD54, CD95) were measured in stimulated and unstimulated cells. Although stimulation influenced the expression levels of certain surface markers, no or only slight effects of IL-10 were found. In contrast considerable inhibitory effects of IL-10 on surface molecule expression and cytokine secretion by peripheral blood human monocytes were observed. Our results suggest that the antipsoriatic activity of IL-10 is rather caused by modulatory effects on circulating immune cells, which subsequently might infiltrate the skin, than by direct effects on human keratinocytes. Considering the remarkable antipsoriatic activity of IL-10 and the observation that IL-10 seem to act on peripheral blood mononuclear cells but not on keratinocytes provide further evidence that circulating immune cells play a key role in the pathology of psoriasis. Finally, our results argue against the value of IL-10 therapy in dermatoses strictly limited to keratinocyte involvement.

Addition of pentoxifylline could reduce the side effects of fumaric acid esters in the treatment of psoriasis.

Sir, then gradually decreased to normal levels as the disease activity decreased. We report on a possible association between epidermolysis This appears to be the ® rst reported case of EBA in which bullosa acquisita (EBA) and elevated levels of circulating IgE. IgE has been evaluated. Although the potential pathophysioA 23-year-old man with a 3-month history of intensely itchy logical relevance of our ® ndings is not clear as yet, we suggest blisters ful® lled the diagnostic criteria for EBA (subepidermal that it may be useful to evaluate total immunoglobulin levels blisters, linear IgG deposits in basement membrane zone, in new patients with EBA and possibly also in other blistering circulating IgG antibodies to dermal part of the basement diseases (3, 4). membranezone in split skin test, circulatingantibodies reacting with a 290 kD component in dermal extracts by immunoblotting) (1, 2). The patient was successfully treated with a REFERENCES combination of betamethasone and dapsone. After 10 months 1. Woodley DT, Briggaman RA, O’Keefe EJ, Inman AO, Queen LL, of treatment, direct immuno uorescence had become negative, Gammon WR. Identi® cation of the skin basement-membrane and circulating antibodies to basement membrane zone comautoantigen in epidermolysis bullosa acquisita. N Engl J Med 1984; ponents could no longer be detected. Treatment was discon310: 1007± 1013. tinued after 15 months, and the patient has been in remission 2. Shimizu H, McDonald JN, Gunner DB, Black MM, Bhogal B, Leigh IM, et al. Epidermolysis bullosa acquisita antigen and the during the 2 months that have elapsed since the treatment carboxy terminus of type VII collagen have a common immunowas stopped. localization to anchoring ® brils and lamina densa of basement Interestingly, the patient had elevated serum levels of IgE membrane. Br J Dermatol 1990; 122: 577± 585. (3,480 IU/ml vs. normally <250IU/ml) at the ® rst visit. 3. Maekawa N, Hosokawa H, Soh H, Kasahara M, Izumi H, Radio-allergosorbent tests showed polyclonal IgE against a Yodoi J, et al. Serum levels of soluble CD23 in patients with wide variety of common environmental allergens such as dustbullous pemphigoid. J Dermatol 1995; 22: 310± 315. and house mites, and Candida albicans. The serum IgE levels 4. Soh H, Hosokawa H, Asada Y. IgE and its related phenomena in bullous pemphigoid. Br J Dermatol 1993; 128: 371± 377. remained high as long as the patient had skin symptoms, but

Expression of Tolerance Associated Gene-1, a Mitochondrial Protein Inhibiting T Cell Activation, Can Be Used to Predict Response to Immune Modulating Therapies

Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137+ cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.

Comprehensive biomarker monitoring in cytokine therapy: heterogeneous, time‐dependent, and persisting immune effects of interleukin‐10 application in psoriasis

Cytokine and anticytokine treatments represent promising approaches for therapy of immune‐mediated diseases. In humans, however, regulatory consequences of interference with the cytokine network are only partially understood. Biomarker analysis in clinical studies may help to overcome this complexity and provide novel information about the in vivo relevance of individual cytokines. We report systemic immunological effects of IL‐10 therapy in 10 psoriasis patients during a 7‐week treatment period followed by a 7‐week observation period. IL‐10 was given s.c. at 8 μg/kg/day or 20 μg/kg/3×/week, and a broad range of immunological biomarkers was analyzed in an extended kinetics (17 time‐points) before, during, and after IL‐10 therapy. Besides the expected anti‐inflammatory effects (e.g., inhibition of LPS‐induced cytokine secretion), we found unexpected effects, such as activation of NK cells and an increase in parameters indicating proinflammatory activity (C‐reactive protein and soluble IL‐2R). Furthermore, cumulative effects (IgE and IgA), loss of effect (IL‐1R antagonist and IFN‐γ secretion), or counter‐regulation during and rebound after IL‐10 therapy (TNF‐α and IL‐12/IL‐23 p40) were found. Remarkably, some alterations were retained long after the 7‐week treatment period (IL‐4 secretion, monocytic CD86, and TGF‐β1). In summary, we found manifold effects of IL‐10 far beyond the immediate anti‐inflammatory activity considered initially. These findings may explain the rather disappointing clinical effects of IL‐10 therapy in exacerbated inflammation but also hint to its role for sustained immunological reshaping. They further exemplify the importance of analyzing an extended kinetics of an entire panel of biomarkers for understanding the effects of therapeutic interference with the cytokine network.

Persistent CMV infection correlates with disease activity and dominates the phenotype of peripheral CD8+ T cells in psoriasis

Background:  Previously, we have reported a frequent association of active plaque psoriasis with inflammation‐mediated cytomegalovirus (CMV) reactivation.