Robert Bissonnette

The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010-2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.

A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis

Tofacitinib (CP‐690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.

Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study

Background  Ongoing evaluation of biological agents in patients with moderate‐to‐severe psoriasis is needed to support their long‐term use.

Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial

Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.

Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis

The response of psoriasis to antibodies targeting the interleukin (IL)‐23/IL‐17A pathway suggests a prominent role of T‐helper type‐17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate‐to‐severe psoriasis receiving 3 different intravenous dosing regimens of the anti‐IL‐17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL‐17 and may store the cytokine preformed, as IL‐17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL‐17‐inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c‐positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest‐dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil–keratinocyte axis in psoriasis that may involve neutrophil‐derived IL‐17 and is an early target of IL‐17A‐directed therapies such as secukinumab.

Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population

BACKGROUND Etanercept is well tolerated and effective in moderate to severe plaque psoriasis. However, effectiveness and safety data beyond 2.5 years have not been reported. OBJECTIVE We sought to assess the effectiveness and safety profile of up to 4 years of etanercept therapy in psoriasis. METHODS We analyzed prospective data from previous trials and open-label extensions, including 506 patients who initiated etanercept therapy in either of two phase III trials. Patients received etanercept, 25 mg twice weekly, 50 mg weekly, or 50 mg twice weekly, depending on which trial therapy was started. Dosage adjustments were allowed in open-label extensions, but no patients exceeded 50 mg twice weekly. Outcomes included change from baseline for the static Physician Global Assessment and Dermatology Life Quality Index scores. Exposure-adjusted adverse event (AE) rates were calculated. RESULTS In all, 75.9% (95% confidence interval 67.9-84.0) and 27.8% (95% confidence interval 19.3-36.2) maintained Dermatology Life Quality Index response (≥ 5-point improvement from baseline) and static Physician Global Assessment response (clear or almost clear) at 48 months, respectively. AE and serious AE rates were 243.5 and 7.8 events per 100 patient-years, respectively. No serious AE rates exceeded 1.0 event per 100 patient-years. Overall infection and serious infection rates were 96.9 and 0.9 events per 100 patient-years, respectively. No cases of tuberculosis or lymphoma were reported. LIMITATIONS Effectiveness data were limited to static Physician Global Assessment and Dermatology Life Quality Index scores. Analysis of AE rates was limited to available comparator databases. CONCLUSION Etanercept demonstrated sustained effectiveness and a favorable safety profile with no cumulative toxicity for up to 4 years, representing, to our knowledge, the longest published study on etanercept use in psoriasis to date.

Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate‐to‐severe plaque psoriasis.

A randomized, double-blind, placebo-controlled, phase I study of MEDI-545, an anti–interferon-alfa monoclonal antibody, in subjects with chronic psoriasis

BACKGROUND Interferon-alfa (IFN-alpha) has been implicated in the pathogenesis of psoriasis. OBJECTIVE To evaluate the safety profile of MEDI-545, a fully human anti-IFN-alpha monoclonal antibody and to explore its effect on the involvement of type I IFN-alpha activity in the maintenance of established plaque psoriasis. METHODS We conducted an 18-week, randomized, double-blind, placebo-controlled, dose-escalating study in 36 subjects with chronic plaque psoriasis. Subjects received one intravenous dose of MEDI-545 (0.3-30.0 mg/kg) or placebo. Study outcomes were safety profile, pharmacokinetics, immunogenicity, and clinical effects. RESULTS There was no difference in adverse events between MEDI-545 and placebo. Two serious adverse events were reported; one drug-related hypotensive infusion reaction occurred in one subject in the 30.0 mg/kg MEDI-545 dose group, causing discontinuation of study drug in that subject and study dismissal of the other subjects in the same cohort; and a myocardial infarction occurred in one subject in the 10 mg/kg MEDI-545 dose group, which was considered to be unrelated to treatment. MEDI-545 was nonimmunogenic, had a half-life of 21 days, showed no significant inhibition of the type I IFN gene signature, and had no clinical activity. LIMITATIONS The study addressed only IFN-alpha and chronic psoriatic lesions. CONCLUSION The safety profile of MEDI-545 supports further clinical development. IFN-alpha does not appear to be significantly involved in the maintenance of established plaque psoriasis.

CURRENT STATUS OF PHOTODYNAMIC THERAPY IN DERMATOLOGY

The accessibility of skin to light treatment, as well as the expertise developed by dermatologists in laser surgery and phototherapy, creates an exciting opportunity for dermatologic PDT to become part of our standard therapeutic armamentarium. PDT appears to be viable alternative to conventional therapy for superficial BCC and Bowens disease, although definitive controlled studies are lacking. The introduction of ongoing research developments, new photosensitizers, and better light sources into clinical PDT trials in the coming years will undoubtedly expand the range of indications for this novel form of therapy, particularly for nononcologic conditions.

Socioeconomic Burden of Immune-Mediated Inflammatory Diseases — Focusing on Work Productivity and Disability

Chronic disabling conditions, such as immune-mediated inflammatory diseases (IMID), adversely affect patients in terms of physical suffering and pain, impaired function, and diminished quality of life. These persistent relapsing diseases have a significant influence on individual employment status and work-related productivity. In addition to the significant burden on patients and their families, IMID represent a sizable burden to society due to high healthcare and non-healthcare related costs. Non-healthcare related, or indirect, costs — primarily associated with decreased work productivity, disability payments, and early retirements — are typically greater contributors than direct healthcare costs to the total costs associated with IMID. This article discusses the socioeconomic impact of several IMID, including rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, and psoriasis.