Cost-effectiveness of systemic treatments for moderate-to-severe psoriasis in the German health care setting.

Systemic treatments of moderate-to-severe psoriasis differ substantially in terms of effectiveness and costs. Comprehensive economic-evaluations of all systemic treatments for psoriasis from a societal perspective are missing. The objective of our study was to compare the cost-effectiveness all systemic treatments approved for moderate-to-severe psoriasis from a societal perspective, by including all cost categories. An incremental cost-effectiveness-analysis was performed for all systemic treatments for psoriasis, currently recommended by the German S3-Guideline i.e. methotrexate, cyclosporine, fumaric acid esters, and retinoids, adalimumab, etanercept, infliximab and ustekinumab. We used a Markov model with time-dependent transition probabilities and a time horizon of 2 years to investigate incremental cost-effectiveness ratios. Both direct and indirect costs were considered to reflect the societal perspective. Effectiveness outcome was PASI-75 response. One-way and probabilistic sensitivity analyses explored the effect of treatment duration, discount rate, effectiveness, and the perspective (societal vs. healthcare system) on the findings. According to the base-case analysis a cost-effective treatment pathway for moderate-to-severe psoriasis starts with methotrexate, followed by ustekinumab 90 mg and infliximab, if methotrexate does not achieve or maintain PASI-75 response. Sensitivity analyses confirmed the general robustness of these findings with methotrexate being most cost-effective. However, from a third-party-payer perspective (without indirect cost) conventional therapies were generally more cost-effective than biologics. From a value-based healthcare perspective, methotrexate should be the systemic treatment of first choice, ustekinumab 90 mg second choice and infliximab third choice for patients with moderate-to-severe psoriasis. From a societal perspective, the other treatments are less efficient according to our model. From a third-party-payer perspective conventional therapies are more cost-effective than biologics.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

German psoriasis registry PsoBest: objectives, methodology and baseline data.

BACKGROUND: The German psoriasis registry PsoBest records the long-term efficacy, safety, patient benefit and treatment regimens of psoriasis. PATIENTS AND METHODS: Patients with moderate or severe psoriasis are included in PsoBest when treatment with a conventional systemic agent or biologic is started for the first time. Observation time is five years. Standardized physician and patient case report forms are obtained every three to six months. Baseline data of patients included by 31 December 2012 are presented and compared to the national health care study PsoHealth 2007 (n = 2,009). RESULTS: 602 dermatology practices and clinics have been registered and 199 have recruited n = 2,556 patients (63 % by practices, 37 % by clinics). Initially, n = 808 received biologics (316 adalimumab, 34 efalizumab, 209 etanercept, 75 infliximab, 22 golimumab, 152 ustekinumab) and n = 1,651 conventional systemic therapy (928 fumaric acid esters, 518 methotrexate, 161 cyclosporine A, 191 other drugs or UV treatment). Compared to PsoHealth, patients in PsoBest had on average a higher disease severity (PASI 14.7 vs. 10.1; DLQI 11.0 vs. 7.5; EQ-5D VAS 54.0 vs. 64.5), shorter disease duration (18.2 vs. 21.3 yrs.), lower age (47.3 vs. 51.5), higher rates of psoriatic arthritis (20.5 vs. 19.1 %) and nail psoriasis (55.0 vs. 35.6 %). On average patients receiving biologics were younger, more often male and had higher disease severity and comorbidity. CONCLUSIONS: Patients in PsoBest represent patients with a high burden of disease.

Effectiveness of interdisciplinary vs. dermatological care of moderate-to-severe psoriasis: a pragmatic randomised controlled trial.

Psychiatric morbidity is frequent in patients with psoriasis. We compared the effectiveness of dermatological vs. interdisciplinary dermatological and psychiatric care for psoriasis. Adults with moderate-to-severe psoriasis were randomly allocated to dermatological (n = 24) or interdisciplinary care (n = 23) and treated accordingly. Primary endpoint was the mean change in Dermatology Life Quality Index (DLQI) at 6 months. Data was analysed by intention-to-treat. Mean ± SD change in DLQI was 7.5 ± 7.3 and 10.5 ± 9.9 after 6 months of dermatological and interdisciplinary care, respectively (p = 0.27). At baseline, 10 patients in the interdisciplinary treatment group (43%) had at least one psychiatric disorder. These patients showed significantly better DLQI response (DLQI change 14.8 ± 9.7) than patients receiving dermatological care only (p = 0.03). Ninety percent of psoriasis patients with DLQI scores exceeding psoriasis area and severity index (PASI) scores had comorbid psychiatric disease. Although psychiatric co-treatment is not generally required for patients with moderate-to-severe psoriasis, those patients with higher DLQI scores than PASI scores might benefit from interdisciplinary care.

Dapsone in dermatology and beyond.

Dapsone (4,4'-diaminodiphenylsulfone) is an aniline derivative belonging to the group of synthetic sulfones. In 1937 against the background of sulfonamide era the microbial activity of dapsone has been discovered. Shortly thereafter, the use of dapsone to treat non-pathogen-caused diseases revealed alternate antiinflammatory mechanisms that initially were elucidated by inflammatory animal models. Thus, dapsone clearly has dual functions of both: antimicrobial/antiprotozoal effects and anti-inflammatory features similarly to non-steroidal anti-inflammatory drugs. The latter capabilities primarily were used in treating chronic inflammatory disorders. Dapsone has been investigated predominantly by in vitro methods aiming to get more insights into the effect of dapsone to inflammatory effector cells, cytokines, and/or mediators, such as cellular toxic oxygen metabolism, myoloperoxidase-/halogenid system, adhesion molecules, chemotaxis, membrane-associated phospholipids, prostaglandins, leukotrienes, interleukin-8, tumor necrosis factor α, lymphocyte functions, and tumor growth. Moreover, attention has been paid to mechanisms by which dapsone mediates effects in more complex settings like impact of lifespan, stroke, glioblastoma, or as anticonvulsive agent. Additionally, there are some dermatological investigations in human being using dapsone and its metabolites (e.g., leukotriene B4-induced chemotaxis, ultraviolet-induced erythema). It could be established that dapsone metabolites by their own have anti-inflammatory properties. Pharmacology and mechanisms of action are determining factors for clinical use of dapsone chiefly in neutrophilic and/or eosinophilic dermatoses and in chronic disorders outside the field of dermatology. The steroid-sparing effect of dapsone is useful for numerous clinical entities. Future avenues of investigations will provide more information on this fascinating and essential agent.

Reduction of inflammatory slan (6-sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept.

Dermal dendritic cells (DCs) play a central role in the immunopathology of psoriasis. We previously identified slanDCs as pro-inflammatory TNF-α, IL-23- and IL-12-producing DCs in human blood and as prominent inflammatory dermal TNF-α secreting and CD11c-positive DC subset in psoriasis. Here, we ask for the effects of TNF-α-inhibition on inflammatory slanDCs in skin and blood of 10 patients with psoriasis during 24 weeks of treatment with etanercept. Treatment with etanercept reduced the frequency of dermal slanDCs but did not induce apoptosis as determined by lack of increased active caspase-3-expression. In parallel, we found increased frequencies of slanDCs in blood which expressed lower levels of HLA-DR. Stimulating slanDCs isolated from the blood of healthy donors in vitro induced a strong production of IL-1ß, IL-6, IL-23 and IL-12p70. This capacity was efficiently reduced in the presence of etanercept, thereby indicating that TNF-α is an autocrine stimulus for maturation and pro-inflammatory cytokine production of slanDCs. In vivo, we noticed that treatment with etanercept did reduce the number of dermal slanDCs in parallel to the overall expression of TNF-α and IL-23p19. However, successful treatment did not down-regulated the percentage of dermal slanDCs that stained positive for TNF-α and IL-23p19 indicating that remaining slanDCs kept their pro-inflammatory capacity. This study provides novel insights into the immune regulatory properties of etanercept at the level of inflammatory slanDCs in vivo in skin and blood as well as in vitro.

Hypersensitivity reactions to dapsone: a systematic review.

Dapsone is widely used in the treatment of leprosy and several chronic inflammatory dermatological conditions. Hypersensitivity reactions to dapsone are potentially fatal adverse drug reactions with unknown prevalence and risk factors. We performed a systematic review covering all reported cases of hypersensitivity reactions, in order to systematically summarize the published evidence on prevalence, clinical course and fatality rate. Articles were identified through standardized search strategies. Included studies were reviewed for hypersensitivity characteristics and odds ratios were calculated in univariate and multivariate regression models to assess the risk factors for fatal outcome. A total of 114 articles (17 epidemiological studies, 97 case reports) totalling 336 patients with hypersensitivity reactions were included for analysis. From the epidemiological studies a total hypersensitivity reaction prevalence rate of 1.4% (95% confidence interval 1.2­1.7%) was determined. Mucosal involvement, hepatitis, higher age and disease occurrence in non-affluent countries were associated with higher risk of fatal outcome. Overall, the fatality rate was 9.9%.

Diagnostics of autoimmune bullous diseases in German dermatology departments.

BACKGROUND: No consistent data are available on the currently employed diagnostic tools for autoimmune bullous diseases in Germany. The aim of this survey was to describe currently performed diagnostic methods for bullous autoimmune diseases in German dermatology departments. METHODS: A standardized questionnaire evaluated the available diagnostic methods i. e. direct immunofluorescence microscopy (IFM), indirect IFM, commercial ELISA systems, and non-commercial serological tests as well as the number of samples per year in all 34 university and 39 non-university dermatology departments. RESULTS: The overall return rate was 89 %, 100 % and 79 % for the university and non-university departments, respectively. Direct IFM was the most frequently used method and was applied in 98 % of the responding departments. In 74 % of the responding departments, indirect IFM was used mainly on monkey esophagus and human salt-split skin. Commercial ELISA systems were employed in 58 % of the clinics; all of them used anti-desmoglein ELISA, while anti-BP180 and anti-BP230 ELISA were established in 49 % and 48 % of departments, respectively. Non-commercial analytic methods were only performed in 22 % of the departments. CONCLUSIONS: The high return rate of this survey allows a relatively precise description of the current diagnostic methods used in German dermatology departments. Standard diagnostic tests are available nationwide and in bullous pemphigoid and pemphigus, the antigen-specific detection of autoantibodies is routinely performed in half of the departments. Rare disorders may be diagnosed by cooperation with some specialized centers.

Cutaneous side effects of inhibition of VEGF signal transduction.

The VEGF signaling pathway (including ligands, surface-bound receptors and intracellular downstream signaling cascades) is critically involved in angiogenesis under normal and pathological conditions, in particular in malignant tumors. As a consequence, several therapies that target specific components of this pathway have been approved for clinical use or are in various stages of clinical development. Currently, the monoclonal antibodies bevacizumab and ranibizumab, as well as the small-molecule kinase inhibitors sorafenib and sunitinib, have been approved for cancer therapy. The spectrum of cutaneous side effects elicited by bevacizumab is considerably less pronounced than that seen with EGF inhibitors and includes peripheral sensory neuropathy, stomatitis, skin dryness, skin discoloration and exfoliative dermatitis. In contrast, unwanted cutaneous side effects seen with the less specific small molecule compounds include pruritic exanthems, nail changes, cheilitis and the painful hand-foot-syndrome.

Targeted treatment of psoriasis with adalimumab: a critical appraisal based on a systematic review of the literature.

Psoriasis is a chronic inflammatory disease affecting 2% to 3% of the population in Western countries. Psoriasis is associated with limited quality of life, cardiovascular disease, and depression. The approval of injectable biological agents has revolutionized the management of moderate to severe psoriasis. Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF) alpha approved for moderate-to-severe plaque-type psoriasis and psoriatic arthritis (PsA). This systematic review summarizes the evidence concerning the efficacy, clinical effectiveness, safety, and cost-effectiveness of adalimumab in the treatment of psoriasis. Five randomized controlled trials demonstrated the efficacy of adalimumab in moderate-to-severe plaque-type psoriasis and PsA with PASI-75 response rates of 53% to 80% and ACR-20 response rates of 39% to 58% after 12 to 16 weeks of treatment. In clinical practice patients who have not responded to one TNF antagonist may respond to another TNF antagonist. Adalimumab has similar or better cost-effectiveness than other biologics, but is less efficient than methotrexate and cyclosporine. Adalimumab is generally well tolerated. Patients should be evaluated for active/latent tuberculosis, serious infections, and other contraindications prior to initiation of adalimumab therapy. Future studies should investigate the comparative efficacy of adalimumab and other biologic and prebiologic agents. Recently established registries will yield additional data on the effectiveness and long-term safety of adalimumab.

[Treatment of plaque psoriasis with biologics. A meta-analysis of randomized controlled trials]. / Behandlung der Plaque-Psoriasis mit Biologics. Eine Metaanalyse randomisierter kontrollierter Studien.

BACKGROUND AND PURPOSE: The development of different biological therapies (so-called biologics) is a great progress for the treatment of the psoriasis vulgaris. The evidence from randomized controlled trials (RCTs) of biologics, which have been licensed in Germany for the treatment of moderate-to-severe psoriasis vulgaris, were pooled in this meta-analysis. MATERIAL AND METHODS: Systematic review and meta-analysis of all RCTs, in which biologics licensed in Germany as of January 2008 for the treatment of moderate-to-severe psoriasis vulgaris were examined. Relevant trials were identified by systematic electronic literature search in MEDLINE, EMBASE, Cochrane Library, and Scopus. Primary endpoint: proportion of patients achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI) Score (PASI75 responder), secondary endpoints: clinically relevant improvement in the quality of life, monthly incidences of study withdrawals and adverse events. PASI75 response rates were statistically pooled and represented as risk differences (RD). RESULTS: 25 articles on 16 RCTs totaling 8,057 patients with moderate-to-severe psoriasis vulgaris were qualitatively analyzed. 15 double-blind and placebo- controlled trials were compared by meta-analysis. Infliximab had the highest efficacy in the short-term therapy of moderate-to-severe psoriasis vulgaris (RD [95% confidence interval, CI] 76% [72-80%]). Adalimumab (RD [95% CI] 59% [45-73%]) was more effective than efalizumab (RD [95% CI] 24% (19-30%]) and etanercept. Treatment with etanercept showed a clear dose-response effect (50 mg twice weekly: RD [95% CI] 44% (40-48%]; 25 mg twice weekly: RD [95% CI] 30% (25-35%]). All biologics improved the quality of life of psoriasis patients. Monthly incidence rates of withdrawals due to adverse events were 1.2% for infliximab, 0.5% for etanercept, 1.0% for efalizumab, and 0.5% for adalimumab. CONCLUSION: A patient's chance to reach considerable clinical benefit differs significantly between the different biological therapies currently approved for moderate-to-severe psoriasis vulgaris. Infliximab is most effective, followed by adalimumab. Large controlled studies indicate a high safety of all biologics in the short-term treatment. Recently established registers will provide additional important safety data under real-life conditions.

Assessing the Impact of Efalizumab on Nail, Scalp and Palmoplantar Psoriasis and on Quality of Life: Results from a Multicentre, Open-label, Phase IIIb/IV Trial.

This post-approval, open-label trial (n = 1266) assessed the efficacy of efalizumab, administered in accordance with the European label at that time, in patients with concomitant nail, scalp or palmoplantar psoriasis. Patients received subcutaneous efalizumab 1.0 mg/kg weekly for up to 20 weeks. By Week 12, an improvement from baseline of 50% or more was observed in 21.4% (181/844) of patients with nail psoriasis, 62.4% (718/1150) of patients with scalp psoriasis, and 51.4% (127/247) of patients with palmoplantar psoriasis. Quality of life improved throughout the trial, with a 50% median improvement in DLQI score after 12 weeks of treatment. Efalizumab showed promising efficacy in the treatment of nail, scalp and palmoplantar psoriasis, which was reflected in improvements in quality of life.

Palmoplantar pustular psoriasis: successful therapy with efalizumab after non-response to infliximab.

Palmoplantar pustular psoriasis (PPP) is a chronic inflammatory skin condition mainly characterized by recurrent eruptions of sterile pustules on erythematous skin; hyperkeratosis and fissures on the palms and soles are additional clinical features. Treatment options for PPP are unsatisfactory. We present a patient with a typical course of PPP that had previously received a broad range of topical and systemic antipsoriatic therapies. They all had to be discontinued due to ineffectiveness or side effects. Being aware of the high efficacy of infliximab in generalized pustular psoriasis, we initiated this therapy. An initial improvement was followed by a substantial flare after 7 months, during which a combination treatment of infliximab with methotrexate was administered. Only subsequent monotherapy with efalizumab led to complete clearing up of PPP after 10 to 12 weeks of treatment without any adverse effects. This indicates that efalizumab is potentially effective in PPP.

Psoriasis treatment in difficult locations: scalp, nails, and intertriginous areas.

Psoriasis comprises a broad spectrum of different clinical courses among which the chronic stable psoriasis by far occurs most frequently. The clinical presentation ranges from mild disease to more serious forms involving large areas of skin and/or joint disease. A number of modifying factors may impact on treatment choice in individual cases (eg, location of the lesions, disease phase, treatment history, response to previous treatments, comorbidity). Aside from this consideration, there are special localizations that remain some of the most difficult regions to control. Such entities are the scalp, nails, and intertriginous areas. Topical treatment of such different-to-treat areas has to be considered as a first-line intervention strategy, at least in those patients who are presenting an exclusively isolated involvement. In some situations (eg, in severe psoriasis or in patients who are refractory to topical treatment), however, a systemic treatment is indicated. Most obvious difficulties in treating these locations are due to unrealistic expectations from the patients' perspectives, time-consuming applications, side effects, cosmetic injuries, and restricted bioavailability of active compounds. Aside from hair care, initial use of keratolytics for scalp psoriasis, corticosteroids, and vitamin D3 and analogues are currently standard treatments. Recently developed new formulations of both active ingredients such as foam or gel appear to be more acceptable to patients than traditional creams or ointments. Current treatment options for nail psoriasis are very often poorly efficacious, associated with undesirable effects, or time consuming. Success has to be measured in terms of months. Topical treatments (eg, corticosteroids, vitamin D analogues, tazarotene) are mainly used, but impressive improvement rates mostly will be achieved by systemic treatment of conventional and biologic agents. Finally, the usefulness of corticosteroids, vitamin D and analogues, and calcineurin inhibitors in treating intertriginous psoriasis clearly is demonstrated. Especially the use of calcineurin inhibitors exhibits efficacy in intertriginous regions and therefore may be seen as a promising treatment option in the future. Besides the important innovations in the last years, there is a need for new effective and well-tolerated treatment modalities, especially for long-term use in the 3 difficult-to-treat locations, which encompass cosmetic acceptability.