Secukinumab treatment in new-onset psoriasis: aiming to understand the potential for disease modification - rationale and design of the randomized, multicenter STEPIn study.

BACKGROUND: To date, biological treatments have been assessed in subjects with a long-term history of psoriasis and previous failures to systemic and topical therapies. In rheumatoid arthritis and other immune-mediated inflammatory diseases, early intensive systemic treatment prolongs treatment-free remission. We hypothesize that, by treating patients with psoriasis early with an effective systemic therapy, we may be able to alter the clinical outcome and the natural course of the disease. The STEPIn study (NCT03020199) investigates early intervention with secukinumab versus narrow-band ultraviolet B (nb-UVB) phototherapy in subjects with new-onset psoriasis. OBJECTIVE: To determine whether early intervention with either nb-UVB treatment or secukinumab in subjects with new-onset plaque psoriasis might modify the natural course of the disease. METHODS: One hundred and sixty subjects aged 18-50 years with new-onset (≤12 months) moderate-to-severe plaque psoriasis and naïve to systemic treatment and phototherapy will be randomized to secukinumab 300 mg or nb-UVB. The Main Study has two treatment arms: Arm A1, subcutaneous secukinumab 300 mg at baseline, Weeks 1, 2, 3 and 4, and every 4 weeks thereafter until and including Week 52; Arm B1, one/two cycles of nb-UVB for 12 weeks each (maximum 28-week break between cycles). After treatment discontinuation, patients will be followed up and monitored for disease activity up to Week 208. A Mechanistic Sub-study will assess immunological changes and pathogenic tissue-resident memory T cells in skin biopsies. CONCLUSIONS: STEPIn is the first study to investigate whether early intensive treatment in new-onset psoriasis can modify the long-term natural course of the disease and thus become a novel treatment strategy for patients with psoriasis.

Definition of treatment goals for moderate to severe psoriasis: a European consensus.

Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) ≤10 and psoriasis area and severity index (PASI) ≤10 and dermatology life quality index (DLQI) ≤10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (ΔPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is ≥75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved ≥50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is ≤5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians.

Evaluation of the effects of topical clobetasol propionate by visual score, electrical impedance and laser Doppler flowmetry.

BACKGROUND/PURPOSE: The intensity of steroid-induced skin blanching is usually evaluated subjectively by a trained observer using a visual score although a few methods have been described for doing this objectively. In this study we wished to establish whether the effects of topical steroids can be detected by measuring the electrical impedance of the skin. METHODS: Ten healthy volunteers were treated with three concentrations of clobetasol propionate (0.005, 0.05, and 0.5 mg/mL) on the forearm covered by a dressing overnight. On the following morning, we assessed dermal blanching using a visual score, laser Doppler flowmetry and electrical impedance. RESULTS: Using the visual score, we found dose-response blanching at all concentrations of clobetasol propionate. The laser Doppler flow values declined significantly after the application of clobetasol propionate (0.005 mg/mL (P<0.01) and 0.5 mg/mL (P<0.05)), as compared with the test site treated with the vehicle alone. Electrical impedance showed a significant increase in phase index after the application of 0.05 mg (P<0.01) and 0.5 mg (P<0.01) of clobetasol propionate, and a significant reduction in real part index after of 0.05 mg/mL (P<0.05) and 0.5 mg/mL (P<0.05) compared with the test site treated with the vehicle alone. The magnitude index and imaginary part index were not affected by this steroid. CONCLUSION: Our findings indicate that the dermal blanching induced by topical corticosteroids can be evaluated with a skin impedance spectrometer.

Biophysical assessment of atopic dermatitis skin and effects of a moisturizer.

BACKGROUND: The mechanisms of the skin barrier impairment in patients with atopic dermatitis (AD) are still unknown and need further studying. OBJECTIVE: We evaluated the skin of healthy subjects and of patients having atopic dermatitis with an instrument measuring electrical impedance and other noninvasive methods (transepidermal water loss, capacitance) and studied the effects of a new emollient [Proderm (Pro-Q in the USA)]. METHODS: After a 2-week washout period, we treated clinically noneczematous skin on the forearm of 24 patients with AD and assessed the effects with the noninvasive methods. 22 healthy subjects were used as controls. RESULTS: The findings indicate that barrier function and hydration, and certain patterns of electrical impedance of AD skin are abnormal compared with normal skin. Moreover, there was an increase in hydration in patients' skin after treatment and a reversal of certain impedance indices towards normal. CONCLUSIONS: Our findings demonstrate that the moisturizer we used changes some biophysical parameters when applied to atopic skin. In addition, a technique based on electrical impedance seems to give valuable information in atopic skin studies, especially the effects of moisturizers.

Somatostatin is a specific inhibitor of SDF-1alpha-induced T cell infiltration.

The chemokine stromal cell-derived factor 1alpha (SDF-1alpha) is a potent stimulator of T cell infiltration into three-dimensional type I collagen matrices as demonstrated using T cells freshly isolated from blood and an activated T cell clone. The neuropeptide somatostatin selectively inhibits SDF-1alpha induced T cell infiltration by the same T cells including CD4 as well as CD8 positive cells, while somatostatin does not inhibit 'spontaneous' T cell infiltration. A number of other neuropeptides and opioids do not inhibit SDF-1alpha-induced T cell infiltration, indicating that the inhibitory effect is somatostatin-specific. The neuropeptide antagonist cyclosomatostatin abrogated the inhibitory effect of somatostatin on T cell infiltration, indicating that the effect of somatostatin is mediated via specific somatostatin receptors. Somatostatin does not inhibit SDF-1alpha-induced T cell attachment to the collagen substrate, which indicates that this neuropeptide specifically inhibits the process of chemokine-induced T cell penetration and migration through the collagen.

Somatostatin receptor (SSTR) expression and function in normal and leukaemic T-cells. Evidence for selective effects on adhesion to extracellular matrix components via SSTR2 and/or 3.

We have examined normal T-cells and T-cell lines with respect to expression of various somatostatin receptor subtypes (SSTR1--5) using RT-PCR and PCR. To evaluate the function of these receptors we have further studied the effects of subtype specific signalling on T-cell adhesion using somatostatin analogs specific for various receptors as probes. Human T-lymphocytes showed SSTR expression related to activation and stage of differentiation. Normal T-cells (peripheral blood, T-cell clone) and T-leukaemia cell lines expressed SSTR2, SSTR3 and SSTR4. Normal T-cells expressed SSTR1 and SSTR5 while T-leukaemia lines did not. SSTR5 was selectively expressed in activated normal T-cells. T-lymphocytes produced no somatostatin themselves. Somatostatin and somatostatin analogs specific for SSTR2 and/or SSTR3 enhanced adhesion of T-cells to fibronectin (FN), and to a certain extent, also to collagen type IV (CIV) and laminin (LAM). T-lymphocytes express multiple SSTR and somatostatin may therefore regulate lymphocyte functions via distinct receptor subtypes as shown here for adhesion to extracellular matrix components (ECM) via SSTR2 and SSTR3. SSTR expression also distinguishes normal and leukaemic T-cells. Our findings suggest that SSTR subtypes may be useful targets for therapy during inflammatory diseases and malignancies affecting lymphocytes.

Somatostatin- and factor XIIIa-immunoreactive cells in psoriasis during clobetasol propionate and calciprotriol treatment.

This study describes the changes in number and distribution of somatostatin- and factor XIIIa-immunoreactive dendritic cells in the epidermis and dermis of psoriatic lesional skin during topical treatment with clobetasol propionate or calcipotriol. Immunohistochemical analysis showed that the number of each cell type was increased in lesional skin as compared to normal skin. Investigation of serial biopsies from psoriasis lesions revealed a significant reduction in the number of somatostatin- and factor XIIIa-positive dendritic cells during the treatments. The reduction rate of the somatostatin-positive cells differed between the two groups and closely paralleled the healing process induced by the two treatments. These findings and the fact that somatostatin has been used in several studies as treatment for psoriasis may indicate that the somatostatin-positive cells are specifically involved in the healing process of psoriasis. The reduction of the factor XIIIa-positive cells was associated with the healing process as a whole, but showed no relation to either treatment.

Colocalization of somatostatin- and HLA-DR-like immunoreactivity in dendritic cells of psoriatic skin.

This study presents an immunohistochemical characterization of somatostatin-positive dendritic cells in psoriatic lesions. Somatostatin is a neuropeptide with inhibitory action on several neuropeptides and hormones, but also with immunomodulating properties, and has been used in several studies as treatment for psoriasis. The number of somatostatin-positive dendritic cells was found to be larger in psoriatic lesions than in normal skin of psoriasis patients and healthy controls. Colocalization of somatostatin and HLA-DR immunoreactivity was demonstrated in a subgroup of dendritic cells of psoriatic skin, whereas double-labelled cells were not found in uninvolved skin. The somatostatin-positive cells in the epidermis and dermis did not co-express CD1a, CD35, CD45RB, CD45RO, CD68, factor XIIIa or S-100. On the basis of these findings, the somatostatin-positive cells seem to represent a specific population of dermal dendritic cells, distinct from Langerhans' cells and factor XIIIa-positive cells, which are found in elevated amounts in chronic plaque psoriasis.

Histopathological and immunohistochemical changes in psoriatic skin during peptide T treatment.

Ten patients with plaque-type psoriasis were treated with 2 mg peptide T i.v. for 28 days. Six patients responded with a substantial clinical improvement. Sequential biopsies from skin lesions were taken before, during and after treatment. The histological score (defining the activity of the psoriasis), the epidermal thickness and the number of infiltrating dermal lymphocytes were all reduced in the six patients who responded to the treatment. An increase in the number of CD1+ dendritic cells was detected immunohistochemically in the epidermis of the responders. The nonresponders did not display any pronounced changes.

Rearrangement of S-100 immunoreactive Langerhans' cells in human psoriatic skin treated with peptide T.

Dendritic cells marked by protein S-100 (S-100) antiserum in the suprabasal layers of the epidermis have previously been identified to be Langerhans' cells. In this study, S-100 immunoreactive cells have been investigated in psoriatic lesioned skin during and after peptide T treatment. Peptide T is an octapeptide with affinity for the CD4 receptor. Nine patients were intravenously infused with peptide T, 2 mg in 500 ml saline per day for 28 days. Sections from involved skin before, every week during, and after the treatment were processed by indirect immunofluorescence using S-100 antiserum. Before the treatment the epidermal Langerhans' cells were numerically decreased or even completely gone in the involved skin of psoriasis as compared to skin from normal healthy controls, while the dermal dendritic cells instead were increased and gathered in cell clusters around vascular structures. Four of the nine patients had histopathological improvements after the peptide T treatment, and, in those cases, the dendritic cells in the dermis were reduced in number, and the Langerhans' cells in the epidermis were numerically increased as well as even reversed to normal position and morphology. These changes in the distribution and density of Langerhans' cells represent their rearrangement during the course of psoriasis and/or the remission after peptide T treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin immunoreactive cells in lesional psoriatic human skin during peptide T treatment.

Peptide T has been shown to be an effective treatment in psoriasis. The mechanism through which peptide T works in psoriasis is at present unknown. Furthermore, a clearance of psoriasis has also been registered using the inhibitory peptide somatostatin. These observations all focus on the fact that peptide T, somatostatin, and/or other peptides, might provide a clue to understanding the etiology and pathogenesis of psoriasis. Therefore, the effect of peptide T administration on somatostatin containing cutaneous cell populations was investigated. Ten psoriatic patients were treated with peptide T (D-Ala-peptide T amide; 2 mg/day i.v.) for 28 days. Serial biopsies were obtained from the psoriatic lesions before, once weekly during and 4 weeks after discontinuation of the peptide T treatment. An indirect immunofluorescence procedure was performed using a polyclonal antiserum against somatostatin. Clinically, most of the patients responded successfully to the treatment. Immunohistochemical investigations of the serial biopsies revealed the appearance of extensive changes in the number of dermal somatostatin immunoreactive dendritic cells. We believe that peptide T may stimulate the local synthesis and/or release of somatostatin, or proliferation and/or migration of certain dendritic cell populations in psoriatic lesions during healing. Since the benefits of peptide T treatment of psoriatic patients parallel earlier investigations using somatostatin infusions, it is likely that somatostatin given exogenously or synthesized/released endogenously plays a vital role in inducing the healing process.(ABSTRACT TRUNCATED AT 250 WORDS)

Speculations around the mechanism behind the action of peptide T in the healing of psoriasis: a minireview.

Peptide T, the HIV envelope-derived fragment Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr, has already been used to successfully treat psoriatic patients without major side-effects. The underlying reason for the positive effect is, however, at present unknown. In the following minireview, we summarize today's knowledge regarding peptide T's interaction with other chemical messenger molecules, such as somatostatin, vasoactive intestinal polypeptide (VIP) and epidermal growth factor (EGF), within the human skin, and, finally, speculate about their relationship to each other. In summary, we believe that the clearance effect of peptide T on psoriasis will open up new avenues with regard to the concept of the pathogenesis of as well as the clinical attendance to this disease.

Peptide T a new treatment for psoriasis? A study of nine patients.

Nine patients with recalcitrant and long-standing psoriasis were treated over a period of 28 days with 2 mg Peptide T iv, once daily (22-34 micrograms/kg bodyweight). Eight of them showed an improvement of less than 50% by day 28 and one deteriorated. The patients were evaluated for a further 3 months when no topical or systemic treatment was given. Five patients recovered by more than 50%, during the months following termination of the therapy. Two patterns of healing were noted: firstly, a steady clearance beginning immediately with the Peptide T infusions; secondly, a clearance pattern preceded by deterioration. No serious side effects were noted.