Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2).

BACKGROUND: Continuous maintenance therapy with infliximab 5 mg kg(-1) every 8 weeks is effective for moderate-to-severe plaque-type psoriasis. OBJECTIVES: To evaluate the efficacy and safety of continuous vs. intermittent infliximab maintenance therapy. METHODS: RESTORE2 was a long-term extension of RESTORE1. At baseline of RESTORE2, eligible patients who had received infliximab for 26 weeks and achieved Psoriasis Area and Severity Index (PASI) 75 in RESTORE1 were rerandomized 1 : 1 to continuous therapy (infliximab 5 mg kg(-1) every 8 weeks) or intermittent therapy (no infliximab until > 50% loss of PASI improvement). Safety and efficacy assessments occurred throughout the study. RESULTS: In total, 222 patients were randomized to receive continuous therapy, and 219 to intermittent therapy. More serious infusion-related reactions occurred with intermittent therapy (8/219 patients, 4%) than with continuous therapy (1/222 patients, < 1%), leading the sponsor to terminate the study. The mean duration of exposure to infliximab was 40·12 weeks (SD 27·55) with a mean of 5·8 infusions (range 0-16) for continuous therapy and 22·78 weeks (SD 22·98) with a mean of 3·4 infusions (range 0-16) for intermittent therapy. Although no formal efficacy analyses were conducted, continuous therapy led to greater PASI 75 at week 52 in the continuous group (81/101, 80%) than in the intermittent group (39/83, 47%); several other efficacy measures demonstrated similar patterns. CONCLUSIONS: For patients with moderate-to-severe plaque-type psoriasis, continuous therapy with infliximab may be more effective than intermittent therapy. The incidence of serious infusion-related reactions in the intermittent group suggests that clinicians should avoid intermittent therapy in this population.

[A decade of biologics in dermatology]. / Zehn Jahre Biologics in der Dermatologie.

Basic research on psoriasis has identified a number of molecular targets which can be of therapeutic interest. While the first two biologics--alefacept and efalizumab--were developed primarily for dermatologists, other agents like cytokine antagonists (TNFα antagonists) were introduced primarily by other medical fields. Knowledge has provided new impulses for research, so that today many therapeutic strategies are being developed, not exclusively limited to biologics. Others branches of dermatology also have benefitted greatly from biologics like ipilimumab or omalizumab.

Up-regulation of CCL11 and CCL26 is associated with activated eosinophils in bullous pemphigoid.

Eosinophils contribute to the pathogenesis of bullous pemphigoid (BP) by secretion of proinflammatory cytokines and proteases. Trafficking of eosinophils into tissue in animal models and asthma depends on interleukin-5 and a family of chemokines named eotaxins, comprising CCL11, CCL24 and CCL26. Up-regulation of CCL11 has been described in BP, but the expression of the other two members of the eotaxin-family, CCL24 and CCL26, has not been investigated. In addition to these chemokines, expression of adhesion molecules associated with eosinophil migration to the skin should be analysed. We demonstrate that similar to CCL11, the concentration of CCL26 was up-regulated in serum and blister fluid of BP patients. In contrast, the concentration of CCL24 was not elevated in sera and blister fluid of the same BP patients. In lesional skin, CCL11 and CCL26 were detected in epidermis and dermis by immunohistochemistry. In contrast to CCL11, CCL26 was expressed strongly by endothelial cells. In line with these findings, eosinophils represented the dominating cell population in BP lesional skin outnumbering other leucocytes. The percentage of eosinophils expressing very late antigen (VLA): VLA-4 (CD49d) and CD11c correlated with their quantity in tissue. Macrophage antigen (MAC)-1 (CD11b/CD18) was expressed constitutively by tissue eosinophils. In conclusion, these data link the up-regulation of the eosinophil chemotactic factor CCL26 in BP to the lesional accumulation of activated eosinophils in the skin. Thereby they broaden the understanding of BP pathogenesis and might indicate new options for therapeutic intervention.

Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1).

BACKGROUND: Infliximab is indicated for treatment of moderate-to-severe plaque psoriasis in adults whose disease cannot be controlled with other systemic therapies, including methotrexate (MTX). To date, no studies have directly compared the efficacy and safety of infliximab and MTX. OBJECTIVES: To compare the efficacy and safety of infliximab vs. MTX in adults with moderate-to-severe plaque psoriasis. METHODS: MTX-naïve patients (n = 868) were randomized 3:1 to receive infliximab 5 mg kg⁻¹ at weeks 0, 2, 6, 14 and 22 or MTX 15 mg weekly with a dose increase to 20 mg weekly at week 6 if the Psoriasis Area and Severity Index (PASI) response was < 25%. At week 16, patients with < PASI 50 response could switch treatment groups. The primary efficacy endpoint was PASI 75 response at week 16. Major secondary efficacy endpoints were PASI 75 response at week 26, and the proportion of patients achieving a Physician's Global Assessment (PGA) score of cleared (0) or minimal (1) at weeks 16 and 26. Others included Dermatology Life Quality Index, 36-Item Short Form Health Survey, and PGA, PASI 50, PASI 75 and PASI 90 responses over time. RESULTS: The primary endpoint was achieved by a significantly greater proportion of infliximab-treated patients (508/653, 78%) than MTX-treated patients (90/215, 42%; P < 0·001). Key secondary endpoints also were achieved by a greater proportion of infliximab-treated patients. Similar responses were observed at week 26 in patients who switched from MTX to infliximab at week 16. Overall adverse event (AE) incidence was comparable between groups, but incidence of serious and severe AEs was slightly higher in the infliximab group. CONCLUSIONS: Infliximab was well tolerated and more efficacious than MTX in patients with moderate-to-severe plaque psoriasis. Infliximab also was efficacious in patients who failed MTX and switched to infliximab.

Evaluation of methylprednisolone aceponate, tacrolimus and combination thereof in the psoriasis plaque test using sum score, 20-MHz-ultrasonography and optical coherence tomography.

BACKGROUND: Despite new treatment options with systemic disease modifiers, topical therapy - especially as combination therapy - plays an important role in psoriasis treatment. METHODS: Antipsoriatic efficacy of methylprednisolone aceponate ointment (MPA), tacrolimus 0.1% ointment (FK506) and their combination (MPA+FK506) were investigated in a double-blind randomized pilot study using the psoriasis plaque test. Agents and corresponding placebos were applied once daily under occlusion for 11 days. Test sites were evaluated by sum score (erythema, scaling, infiltration), objective assessment by 20-MHz-sonography and optical coherence tomography (OCT). RESULTS: After 11 days, the sum score significantly improved from baseline value in FK506-treated skin (9.6 vs. 2.9, p < 0.0001). MPA led to a significant improvement of the sum score (9.4 vs. 0.6, p < 0.0001). Combination therapy showed results similar to MPA monotherapy (9.4 vs. 0.4, p < 0.0001). These findings were confirmed by 20-MHz-sonography and OCT data. CONCLUSION: FK506 is moderately effective in chronic plaque-type psoriasis in our model. Combination therapy with FK506+MPA has no additive effect compared to MPA alone.

Psoriatic arthritis: a diagnostic challenge?

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis vulgaris. Making the diagnosis is not trivial even today. In contrast to older data, relatively high rates of disease progression and joint damage have been found in recent trials. Whether this originates from erroneously included patients with rheumatoid arthritis or true severity of PsA needs to be confirmed. The ClASsification criteria for Psoriatic Arthritis criteria are now widely accepted and used in the setting of clinical studies. Their further validation and development is conducted by Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Correct diagnosis and classification is a prerequisite for valid conclusions from therapeutic and prognostic clinical trials and optimal care for individual patients. This article reviews clinical presentation, diagnostic tools, classification criteria, differential diagnosis and treatment options in PsA.

[Therapeutic strategies for psoriasis and psoriatic arthritis]. / Behandlungsstrategien bei Psoriasis vulgaris und Psoriasisarthritis.

Psoriasis is a chronic, immune-mediated inflammatory disorder with a genetic background, whose treatment is currently undergoing a paradigm shift. For many patients clinical signs and symptoms of psoriatic skin and joint disease are most important. From the public health perspective, however, recent findings that suggest a high degree of co-morbidity is becoming increasingly relevant. Because it is also highly significant from the patients' perspective, the improvement of health-related quality of life should be considered as the third treatment goal. Modern therapeutic concepts interact with specific pathogenetically relevant molecular targets. The development of such"targeted therapies" reflects our increasing understanding of the pathogenetic principles of psoriasis. Provided that the whole spectrum of approved remedies is employed as indicated, psoriasis has become a condition that is amenable to early intervention and can be treated effectively in the long run.

[Therapy-resistant "psoriasis vulgaris"]. / Therapierefraktäre "Psoriasis vulgaris".

A 61-year-old patient had a 25-year history of erythematous scaling lesions, diagnosed and treated as psoriasis vulgaris. He presented with a growing nodule within the erythematous plaque. Biopsy shows epithelioid cell granulomas with prominent Langhans giant cells. There was no sign of a squamous cell carcinoma. The tuberculin test was strongly positive and M. tuberculosis complex was detected in the biopsy material by PCR. He was diagnosed with lupus vulgaris, the most frequent form of cutaneous tuberculosis. Other types include tuberculosis verrucosa cutis, tuberculosis cutis orificialis and disseminated military tuberculosis. The patient was treated with rifampicin, isoniazid, pyrazinamide and ethambutol for two months, following a four month treatment with rifampicin and isoniazid. The skin lesions rapidly resolved under antituberculotic treatment.

Efficacy and tolerability of biologic and nonbiologic systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials.

BACKGROUND: The comparative efficacy and tolerability of conventional and biologic treatments for moderate-to-severe plaque psoriasis are unknown. OBJECTIVES: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) reporting efficacy of systemic treatments approved for moderate-to-severe psoriasis by means of the Psoriasis Area and Severity Index (PASI). METHODS: We identified relevant articles by systematic electronic searches (Cochrane Library, Medline, Embase, Scopus). Efficacy was defined as proportion of participants with >or= 75% decrease in PASI (PASI-75) at primary efficacy measurement (week 8-16). PASI-75 response rates of double-blind placebo-controlled trials were summarized as risk differences (RDs) and pooled using random effects models. Tolerability was assessed from rates of withdrawals and adverse events. RESULTS: Twenty-four RCTs totalling 9384 patients were analysed qualitatively. Sixteen double-blind placebo-controlled trials were eligible for meta-analysis. Infliximab was significantly superior to all other interventions [RD 77%, 95% confidence interval (CI) 72-81%]. Adalimumab (RD 64%, 95% CI 61-68%) was superior to ciclosporin (RD 33%, 95% CI 13-52%), efalizumab (RD 24%, 95% CI 19-30%), etanercept 50 mg twice weekly (RD 44%, 95% CI 40-48%) and etanercept 25 mg twice weekly (RD 30%, 95% CI 25-35%). Efalizumab was significantly less efficacious than fumaric acid esters (RD 48%, 95% CI 32-64%). Rates of withdrawals due to adverse events were highest for methotrexate and fumaric acid esters. CONCLUSIONS: The efficacy of systemic agents approved for moderate-to-severe psoriasis differs considerably both within and between biologics and nonbiologics. Infliximab is most efficacious, followed by adalimumab. Patients receiving infliximab have an excess chance of 77% over placebo to achieve PASI-75 response. Published evidence questions regulatory guidelines that recommend biologics as second-line therapy for moderate-to-severe plaque psoriasis.

Scalp psoriasis: a review of current topical treatment options.

The scalp is the most common site of disease involvement at the onset and throughout the course of psoriasis. For many patients, psoriasis of the scalp is the most difficult aspect of their disease; yet, despite a wide range of therapy options and an extensive literature base, scalp psoriasis remains difficult to treat, highlighting a long-standing unmet need for the effective treatment of scalp psoriasis. A review of past and current medical literature reveals that a number of interesting therapeutic approaches have been used in the treatment of scalp psoriasis. The diverse and sometimes extreme therapeutic approaches, the marginal benefit of many topical agents, the paucity of controlled studies evaluating the efficacy of topical agents in the treatment of scalp psoriasis and the high level of patient dissatisfaction with currently available treatments for psoriasis all support the need for new, effective and well-tolerated treatment options for scalp psoriasis.

[Systemic psoriasis therapy - the next step. Adalimumab]. / Systemische Psoriasistherapie - der nächste Schritt. Adalimumab.

Adalimumab is the first fully human monoclonal antibody against TNFalpha and has been approved for treatment of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Its efficacy for both joint and skin involvement has been confirmed in clinical trials. The recommended dose is 40 mg administered every other week subcutaneously. It may be combined with methotrexate and all topical psoriasis treatment modalities. User-friendly administration devices make self-injection possible. Patients should be evaluated for active/latent tuberculosis and serious infections prior to initiation of therapy. Adalimumab rapidly reduces joint symptoms within a few days. Adalimumab is used for the management of adult psoriatic arthritis patients who have had an inadequate response to disease-modifying antirheumatic drugs. Adalimumab is yet another biological for the treatment of psoriasis. Since the TNFalpha antagonists can be switched if one is ineffective, this agent broadens the therapeutic spectrum.

[Eosinophilic dermatoses]. / Eosinophile Dermatosen.

Morphological and functional properties of the eosinophilic granulocyte (e. G.) feature this haematopoietic stem cell-derived cell type as an important cellular component of defense mechanisms, immunologic reactions and proinflammatory/neoplastic processes. Over the last decade significant advances of the molecular pathophysiology of eosinophilic disorders enable increasingly the distinction between the more common reactive (secondary) and clonal eosinophilia including the hypereosinophilic syndrome. This review features a comprehensive clinical summary of dermatological disorders that are frequently associated with transient or persistent eosinophilia belonging to the reactive eosinophilia. The hypereosinophilic syndrome is a subset of idiopathic eosinophilia frequently associated with major tissue targets as skin, heart and others. Therefore, the hypereosinophilic syndrome has to be considered as important differential diagnosis. Most recently, the identification of selective targets (e. g. IL-5, CD52) has translated into therapeutic approaches with monoclonal antibodies such as mepolizumab, alemtuzumab or SCH55700.

Efficacy results of a 52-week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris.

BACKGROUND: The calcipotriol/betamethasone dipropionate two-compound product is safe and effective in the short-term treatment of psoriasis. OBJECTIVE: The primary objective was to investigate the safety of two treatment regimens involving use of the two-compound product over 52 weeks. The efficacy results are presented here. METHODS: Six hundred and thirty-four patients were randomised double-blind to treatment (once daily, when required) with either: 52 weeks of two-compound product (two-compound group), 52 weeks of alternating 4-week periods of two-compound product and calcipotriol (alternating group), or 4 weeks of two-compound product followed by 48 weeks of calcipotriol (calcipotriol group). RESULTS: There was a trend towards a difference between treatments from the overall treatment effect for the percentage of satisfactory responses for each patient during the study (p = 0.071). This appeared to be due to the comparison of the two-compound and calcipotriol groups (p = 0.025). CONCLUSION: There was a trend towards the efficacy of the two-compound product used for up to 52 weeks being better than that of 4 weeks of the two-compound product followed by 48 weeks of calcipotriol.

[Is the psoriasis plaque test still relevant in the age of biologicals?]. / Ist der Psoriasis-Plaque-Test im Zeitalter der Biologics noch aktuell?

A variety of approaches (in vitro-/ex vivo studies, animal models, human studies and clinical trials) are available to assess compounds with potential antipsoriatic properties. Over the past few years various rodent models that mirror aspects of psoriasis phenotypes and/or pathogenesis have been created (e. g. knockout rodents, xenotransplantation models). Unfortunately these animal models do not reflect the complete pathogenesis of psoriasis. Therefore, screening procedures involving psoriatic lesions in humans are necessary. Even in the era of biologicals, the psoriasis plaque test (PPT) remains an important in vivo tool. In addition to screening potential antipsoriatic substances, the PPT can help answer other questions (frequency of use, dose-response relationship). A prerequisite for correct performance of PPT is knowledge of the toxicological and pharmacological data of the investigational compounds. The PPT is relatively simple, not time-consuming and allows the simultaneous testing of multiple substance. All the results from PPT must be confirmed by controlled clinical trials.

A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris.

BACKGROUND: The calcipotriol/betamethasone dipropionate two-compound product Dovobet/Daivobet/Taclonex(LEO Pharma A/S, Ballerup, Denmark) has been shown to be safe and effective in the treatment of psoriasis for up to 8 weeks. As psoriasis is a chronic disease, long-term treatment may be required, so there is a need to investigate the safety of its use over a longer period of time. OBJECTIVES: To investigate the safety of two treatment regimens involving use of the two-compound product over 52 weeks in the treatment of patients with psoriasis. METHODS: Patients (n = 634) were randomized double-blind to treatment with: (i) 52 weeks of the two-compound product (two-compound group); (ii) 52 weeks of alternating 4-week periods of the two-compound product and calcipotriol (alternating group); or (iii) 4 weeks of the two-compound product followed by 48 weeks of calcipotriol (calcipotriol group). Treatments in all groups were used once daily when required. RESULTS: Adverse drug reactions (ADRs) occurred in 45 (21.7%) patients in the two-compound group, 63 (29.6%) in the alternating group and 78 (37.9%) in the calcipotriol group. The odds ratio for an ADR in the two-compound group relative to the calcipotriol group was 0.46 (95% confidence interval 0.30-0.70; P < 0.001). ADRs of concern associated with long-term topical corticosteroid use occurred in 10 (4.8%) patients in the two-compound group, six (2.8%) in the alternating group and six (2.9%) in the calcipotriol group; those with the highest incidence were skin atrophy, occurring in four (1.9%), one (0.5%) and two (1.0%) patients, respectively, and folliculitis, in three (1.4%), one (0.5%) and no patients, respectively. CONCLUSIONS: Treatment with the two-compound product for up to 52 weeks appears to be safe and well tolerated whether used on its own or alternating every 4 weeks with calcipotriol treatment.

[Pancreatic panniculitis with neuroendocrine pancreatic carcinoma]. / Pankreopathische Pannikulitis bei neuroendokrinem Karzinom des Pankreas.

Pancreatic panniculitis is a rare complication occurring in 0.3-3% of patients with pancreatic disease. Clinical features include erythematous painful subcutaneous nodules usually on the lower leg and foot. A 72-year-old man was diagnosed in 2002 with a neuroendocrine carcinoma of the head of the pancreas. In 2003 following surgery and radiation therapy, he developed liver metastases and painful nodules on his legs. Lipase was found to be markedly elevated; amylase and alpha1-antitrypsin were in the normal range. Histopathologic examination of a nodule showed subcutaneous fat necrosis with ghost cells surrounded by an acute inflammatory infiltrate. The pathogenesis of pancreatic panniculitis is unclear. The pancreatic enzyme lipase may induce lipolysis and fat necrosis with secondary tissue inflammation.

[Etanercept. An effective TNF alpha-antagonist in the treatment of psoriatic arthritis and chronic plaque psoriasis]. / Etanercept. Ein effektiver TNF-alpha-Antagonist zur Behandlung von Psoriasisarthritis und Psoriasis vulgaris.

Etanercept, an inhibitor of TNF alpha, has been found effective in the treatment of psoriatic arthritis and psoriasis vulgaris. Etanercept is a fusion protein made up of domains of the soluble, fully human p75-TNF alpha receptor and the F(c) portion of human IgG(1). The drug is a protein which must be administered subcutaneously. Several controlled studies have highlighted its efficacy for both skin symptoms and joint involvement. The usual dose is 25 mg s.c. twice weekly. Higher dosages of 50 mg twice weekly may be used in severe cases. Before starting the therapy with etanercept, infections including tuberculosis have to be excluded. Methotrexate and other pharmacological immunosuppressive agents can be combined with etanercept, as can all standard topical agents. Etanercept in off-label use has been found to also be useful in several other inflammatory dermatologic conditions. If patients are carefully monitored, etanercept is generally well-tolerated and has a good safety profile. The development of novel biologic agents such as etanercept is one of the most important therapeutic innovations of recent years.

[Alefacept. Successful long-term therapy of a severe psoriasis]. / Alefacept. Erfolgreiche Langzeittherapie einer schweren Psoriasis.

Alefacept, a recombinant protein produced by fusion of human LFA(3 )and IgG(1), was the first biologic specially designed and approved for the treatment of psoriasis. Results of clinical trials reveal both an efficacy comparable to established systemic therapies and a high drug safety. A 62-year old male patient with psoriasis and incomplete response to several standard therapies was treated with alefacept (baseline PASI 23.1). After three courses of 15 mg alefacept i.m. weekly for 12 weeks, each followed by a 12 week post-dosing observation period, the PASI regressed to 2.0. Adverse drug reactions were not observed.

Leflunomide as a novel treatment option in severe atopic dermatitis.

BACKGROUND: Based on the increasing knowledge of T-cell-mediated pathogenesis in atopic dermatitis (AD), systemic immunosuppressive drugs are increasingly applied. The chronic, relapsing course of severe AD necessitates a drug, both efficacious and safe in long-term application. Leflunomide is a pyrimidine de novo synthesis-inhibiting immunosuppressant exhibiting an extremely long in vivo half life of its active metabolite. OBJECTIVES: To evaluate the efficacy of leflunomide in long-term treatment of AD. METHODS: As a proof of principle, we treated two patients with severe AD, recalcitrant to different systemic treatment modalities, for 20 months with leflunomide (loading dose 100 mg daily during 3 days; maintenance dose 20 mg daily). At regular visits physical examination, eczema area and severity index (EASI), visual analogue scale (VAS) for itching, and laboratory findings were assessed with according adjustment of the leflunomide dose. RESULTS: At the initiation of leflunomide therapy, both patients presented with almost erythrodermic AD (patient 1, EASI 40.0, VAS 10; patient 2, EASI 43.0, VAS 8). Partial remission was observed within 4 and 7 weeks, respectively, and maintained over 20 months (patient 1, median EASI 4.2, median VAS 2; patient 2, median EASI 8.4, median VAS 2) except for one episode of exacerbation in each case. In one patient, remission was stable even after cessation of drug dosing. Severe adverse events were not observed. CONCLUSIONS: Leflunomide was efficient in the long-term treatment of recalcitrant AD. Controlled studies will be necessary to evaluate the subset of severe AD patients benefiting most from this drug.