Marco Galluzzo

Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab

Our understanding of the genetic basis of predisposition to psoriasis is increasing exponentially due to the progress of genetic studies. However, so far little is known about genetic predisposition in relation to the response to psoriasis treatments. Recent data identified genetic predictors for the clinical outcome of conventional treatments such as methotrexate, acitretin and vitamin D derivatives, but few studies are available on genetic predictors of response to biologics. We hypothesized that genetic variations associated with increased risk of developing psoriasis may also act as predictors for the outcome of biologic therapy.

Role of the HLA-C*06 allele in clinical response to ustekinumab: evidence from real life in a large cohort of European patients

Little is known about the role of the HLA‐C*06 allele in the response to psoriasis treatments.

Brodalumab for the treatment of psoriasis

ABSTRACT Introduction: Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association. Expert commentary: By blocking the IL-17 receptor A, brodalumab antagonizes signaling from IL-17A, IL-17F, IL-17A/F and IL-25, and this probably contributes to the high efficacy observed in clinical trials. Considering the different therapeutic target and the potential biological implications that blocking IL-17RA instead of IL-17A might have, brodalumab may not necessarily belong to the same class that includes secukinumab and ixekizumab, but it may be classified in a distinct group.

Tofacitinib for the treatment of psoriasis.

ABSTRACT Introduction: The identification of a number of psoriasis-susceptibility genes and a better understanding of the pathogenesis of the intracellular metabolic pathways, have generated new perspectives on psoriasis treatment, in particular new compounds that inhibit certain intracellular proteins involved in the immune response. In contrast to biologic agents, these compounds block intracellular targets such as transcriptional factors or enzymes. Areas covered: Tofacitinib is a small molecule that acts as a reversible, competitive inhibitor of ATP in the ATP binding site of JAK proteins, determining their inactivation, thus prevents the downstream activation of the STAT proteins, which are then unable to up-regulate the pro-inflammatory genes implicated in psoriasis. The authors present an overview of Phases I - III clinical trials of tofacitinib for psoriasis based on peer-reviewed literature. Expert opinion: In clinical practice, it is important to assess the response of psoriasis to tofacitinib and identify possible clinical, genetic, and immune biomarkers to predict the response. Comorbidities associated with psoriasis, in particular metabolic syndrome and obesity, are also an important aspect of using tofacitinib in clinical practice. There are some evidences that a drug such as tofacitinib could be used to improve not only psoriasis, but also some of its important comorbidities.

Tildrakizumab for treating psoriasis

ABSTRACT Introduction: Agents that block inflammatory pathways other than tumor necrosis factor (TNF) have represented new options for treating psoriasis in recent years. IL-23 is involved in regulating Th17 cells and is a potent activator of keratinocyte proliferation. Targeting IL-23p19 alone may be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis, with a downregulation of Th17 and Th22 cell responses, while IL-12 blockade is not required to achieve efficacy in these patients. Areas covered: The authors review and provide an update on tildrakizumab, a humanized IgG1 monoclonal antibody that blocks the p19 subunit of IL-23. Expert opinion: Total skin clearance is an important treatment goal that has both measurable and clinically meaningful benefits. Meeting patient needs about total clearance, IL-23p19 inhibitors will obtain a specific position in the crowded psoriasis market. On the other hand, PASI 75 and PASI 90 response achieved by tildrakizumab in the phase II and III trials are less than the response achieved by the IL-17A inhibitors and other p19 competitors, possibly due to a less intensive dosing regimen, although direct comparisons cannot be made without a head-to-head randomized clinical trial. The main advantage of tildrakizumab is that it is dosed in a maintenance regimen of 12 weeks, and similar to ustekinumab, this is likely to encourage adherence and aid persistence to the drug.

The Role of Pharmacogenetics in Chronic Plaque Psoriasis: Update of the Literature

Psoriasis is a chronic inflammatory disease triggered by both genetic and environmental factors. Systemic and biologic therapies used to treat moderate-to-severe psoriasis show significant variability in efficacy, are associated with various degrees of toxicity, and, for biologic therapies, are expensive. There is a great need for non-invasive biomarkers to predict treatment outcomes of these therapies and to individualize care for patients with psoriasis. This article reviews currently recognized pharmacogenetic targets related to the treatment of chronic plaque psoriasis, in particular to biologic therapies. The use of pharmacogenetic and pharmacogenomic approaches to genetically profile patients will allow therapies to be targeted more precisely and safely to individual patients, to optimize the treatment of psoriasis, and minimize unnecessary costs. Characterizing patients with psoriasis according to common molecular mechanisms rather than by clinical phenotype may also allow more selective therapeutic agents to be targeted to genetically distinct groups of patients.

Alexithymia and Plaque Psoriasis: Preliminary Investigation in a Clinical Sample of 250 Patients

Background/Aims: Psoriasis as a dermatological disorder has complex effects on mental health and the psychological status of the patient. Many authors proposed that assessing how psoriasis affects a patients life is better than a body surface area measurement for delineating psoriasis severity. Alexithymia is a personality dimension characterized by difficulty identifying feelings, difficulty describing feelings, and externally oriented thinking observed in many clinical conditions, especially in psychosomatic disorders. This study aimed to determine the prevalence of alexithymia in patients with plaque psoriasis compared with healthy participants, while taking into consideration demographic and clinical variables. Methods: We enrolled 250 patients with chronic plaque psoriasis, naïve to any systemic treatment, and 215 healthy individuals. The 20-item Toronto Alexithymia Scale (TAS-20) was used to assess alexithymia. Data analysis was done. Results: The mean TAS score was 53.5 (±15.3) for the patient group and 45.1 (±10.8) for controls (p < 0.0001). Compared to controls, the psoriasis group showed significant alexithymic features (32.4 vs. 9.3%), and no significant differences of alexithymia between patients with severe and mild psoriasis were observed. A significant relationship was determined between alexithymia and female gender and sensitive area involvement, such as the face, hands, and genital area. Conclusion: This study suggests that the assessment of alexithymia should be a part of the comprehensive care of patients with moderate to severe psoriasis. For this purpose, the TAS-20 is a useful and simple tool to be used in daily clinical practice.

Long-term ustekinumab therapy of psoriasis in patients with coexisting rheumatoid arthritis and Sjögren syndrome. Report of two cases and review of literature

BACKGROUND Inteleukin (IL)12 and IL23 are two main cytokines involved in the pathogenesis of immune-mediated disease. IL12 is produced by macrophages and B lymphocytes and mediates differentiation of Th1 lymphocytes, while IL23 is a pro-inflammatory cytokine essential for the differentiation of Th17 cells. Ustekinumab is a human monoclonal antibody directed against the p40 protein subunit shared by IL12 and IL23, therefore it blocks the signal transmission of both cytokines. MAIN OBSERVATIONS We present two cases and discuss the long-term efficacy of ustekinumab as a treatment of psoriasis in patients affected by autoimmune diseases, rheumatoid arthritis and Sjögrens syndrome, who presented with severe psoriasis after anti-TNF treatment. CONCLUSIONS To the best of our knowledge, these are the first cases reported in the literature describing the long-term good efficacy of ustekinumab not only on paradoxical forms of psoriasis induced by anti-TNF-α drugs, but also on the articular involvement in a patient affected by RA and in a patient affected by Sjögren syndrome.

Ustekinumab Treatment of Erythrodermic Psoriasis Occurring after Physical Stress: A Report of Two Cases

Erythrodermic psoriasis (EP) is a severe form of psoriasis precipitated by numerous factors, including physical stress, infections, and drugs. The disease represents a therapeutic challenge, and little is known about its response to ustekinumab. Though the efficacy of ustekinumab has been extensively studied in chronic plaque psoriasis, no trials have been carried out in EP. We report the case of 2 patients, 1 male and 1 female, who showed EP despite being treated with etanercept and methotrexate for chronic plaque psoriasis, respectively. The patients were treated with ustekinumab at a dosage of 45 mg s.c. They showed a significant improvement in their Psoriasis Area and Severity Index score after only 4 weeks of ustekinumab therapy, and further improvements were observed throughout the treatment. In our experience, ustekinumab has been proven safe and effective, without increasing the dosage, in controlling and preventing the occurrence of erythrodermic flares. Ustekinumab therapy may therefore be considered a valid therapeutic option for the treatment of EP, even in cases where other biological agents have failed.

HLA-C*18:01: A Rare Allele in the European Caucasian Population Coinciding with Difficult-to-Treat Plaque Psoriasis

BackgroundAdvances in knowledge about the metabolic pathways involved in the pathogenesis of psoriasis and related diseases have led to a search for new therapeutic targets and the development of new biological drugs. Several studies have focused on HLA-C*06 and investigated correlations between the genetic risk factors of psoriasis and clinical parameters such as the severity of the disease and the response to treatment.ObjectiveOur objective is to share experience from our institution in the observation of two patients with severe chronic plaque psoriasis who were unresponsive to any anti-TNF-α treatment and only partially responsive to ustekinumab. The patients are carriers of a rare allele of HLA-C that occurs in Caucasians.MethodsThe patients with moderate-to-severe chronic plaque psoriasis, and candidates for biological therapy were typed for the HLA-C locus at high resolution via polymerase chain reaction sequence-specific oligonucleotide probes (PCR-SSOP) using a commercial kit (LAB®Type, One Lambda Inc., Canoga Park, CA, USA). The socio-demographic variables and clinical data were collected.ResultsIn our cohort of 134 patients, only two showed the presence of the allele HLA-C*18:01. To our knowledge, a coincidence between HLA-C*18 and severe psoriasis in Caucasian patients has not previously been described. The fact that both of these patients showed the same clinical history (unresponsive to any anti-TNF-α treatment and partially responsive to ustekinumab) cannot be attributed to a random observation because HLA-C*18 is extremely rare in Europe. As a consequence, at this latitude, it probably indicates a severe disease for which the proper therapy has still not been identified.