Shiu-chung Au

NF-κB: an essential transcription factor in psoriasis.

Nuclear factor kappa B (NF-κB) is a protein transcription factor that orchestrates inflammation and other complex biological processes. It is a key regulatory element in a variety of immune and inflammatory pathways, in cellular proliferation and differentiation and in apoptosis. Therefore NF-κB is a crucial mediator involved in the pathogenesis of psoriasis. Psoriasis, an inflammatory dermatosis, is marked by elevated levels of active, phosphorylated NF-κB. Genomic studies have also linked psoriasis with mediators in the NF-κB pathway. NF-κB has been hypothesized to connect the altered keratinocyte and immune cell behavior that characterizes the psoriatic milieu. Several anti-psoriatic therapies, including tumor necrosis factor-α blockers and glucocorticoids, reduce active NF-κB levels and related down-stream elements, and other biologics currently in development, including interleukin-17 blockers, may also target this pathway. Compounds that specifically target NF-κB signaling may be developed as novel therapeutics for chronic inflammatory disorders including psoriasis. However, chronic NF-κB inhibition could also result in immunodeficiencies. Therefore, a delicate balance must be found that maximizes therapeutic potential while limiting harmful effects, and may be achieved through several possible approaches, including localized therapy, selective inhibition of NF-κB signaling in pathologic cells, incomplete pathway inhibition or short treatment durations.

Etanercept: efficacy and safety for approved indications

Introduction: Etanercept is a tumor necrosis factor alpha (TNF-α) inhibitor, which is approved for the treatment of immune-mediated inflammatory conditions including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and psoriasis (PsO). Areas covered: Clinical efficacy and safety data of etanercept for the approved indications are reviewed in this paper. Data were obtained from published clinical trials, registries, post-marketing data as well as information provided by Amgen. Expert opinion: Etanercept is a generally well-tolerated treatment for the approved inflammatory diseases. The most common adverse effect of etanercept treatment is injection site reaction, which is generally self-limiting and often does not require treatment. Etanercept may be associated with an increased risk for infection, the development of malignancy, demyelinating disease and congestive heart failure. Fewer patients withdraw from etanercept due to adverse events than with other biologics. For pediatric patients, there are more data for etanercept than other biologics, and etanercept may have lower rates for the development of malignancy.

Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis

Abstract Background: Palmoplantar psoriasis is a variant of psoriasis resistant to many forms of treatment. Methods: Twenty subjects with moderate-to-severe psoriasis of the palms and soles, 50% with pustules at baseline, were treated with ustekinumab at weeks 0, 4, and 16. All subjects had previously failed topical corticosteroids. Dosing was 45 mg subcutaneously for subjects weighing <100 kg and 90 mg for subjects weighing ≥100 kg. The primary endpoint was the percent of subjects achieving clinical clearance at week 16, defined as Palm–Sole Physicians Global Assessment ≤1. The study received Tufts Medical Center IRB approval. Results:After 16 weeks of treatment, 35% (7/20) of subjects achieved clinical clearance. Sixty percent (12/20) improved two or more points on the Palm–Sole Physicians Global Assessment scale. Sixty-seven percent (6/9) of those receiving the 90 mg ustekinumab dose achieved clinical clearance compared with nine percent (1/11) receiving 45 mg (p = 0.02). At 24 weeks, mean values showed 56% improvement in Dermatology Life Quality Index, and 34% improvement in pain Visual Analogue Scale score (all p < 0.05). Limitations: Assessment tools for palmoplantar psoriasis are not yet validated. Five subjects withdrew or were lost to follow-up. Conclusion: This study demonstrates that ustekinumab dosed at 90 mg is effective in controlling signs and symptoms of palmoplantar psoriasis.

Prevalence of the Metabolic Syndrome in Children with Psoriatic Disease

Adults with psoriasis have a greater risk of developing metabolic syndrome (MetS) and cardiovascular disease (CVD), but few studies have investigated the prevalence of MetS and other risk factors for CVD in children with psoriasis. In an assessor‐blinded study, 20 children ages 9–17 years with a current or previously documented history of psoriasis involving 5% or more of their body surface area or psoriatic arthritis were compared with a cohort of age‐ and sex‐matched controls with benign nevi, warts, or acne. MetS, our primary endpoint, was defined by the presence of abnormal values in at least three of the following measures: triglycerides, high‐density lipoprotein cholesterol (HDL‐C), fasting blood glucose (FBG), waist circumference, and blood pressure. Secondary endpoints included high‐sensitivity C‐reactive protein (hs‐CRP), total cholesterol (TC), and low‐density lipoprotein cholesterol (LDL‐C). Thirty percent (6/20) of children with psoriasis met the criteria for MetS, compared with 5% (1/20) of the control group (p < 0.05). Subjects with psoriasis had higher mean FBG (91.1 mg/dL) than the control group (82.9 mg/dL) (p = 0.01). There were no statistically significant differences in the other four components of MetS, BMI, BMI percentile, hs‐CRP, TC, or LDL‐C. The results of this trial demonstrate that children with psoriasis have higher rates of MetS than age‐ and sex‐matched controls. It may therefore be important to evaluate children with psoriasis for components of MetS to prevent future CVD morbidity and mortality.

Parvovirus B19–associated Systemic Lupus Erythematosus: Clinical Mimicry or Autoimmune Induction?

To the Editor: Recent research has focused on the role of parvovirus B19 in the etiopathogenesis of systemic lupus erythematosus (SLE). The acute manifestations of B19 infection, including symmetric polyarthritis, cytopenia, and macular erythema, bear striking similarity to those found in SLE. Further, infection with B19 elicits autoantibodies to antigens commonly found in patients with SLE, including nuclear antigens, dsDNA, and phospholipids1. These symptoms and laboratory abnormalities are transient in some cases, yet persist in others, sparking debate over whether the similarities observed between acute B19 infection and SLE are mere coincidence, or whether the virus does in fact induce chronic autoimmunity. We describe a case of SLE possibly triggered by parvovirus B19, and we conducted a literature search to identify other cases in which B19 infection induced either transient or persistent SLE symptoms. To identify potential prognostic factors for the development of persistent disease, we performed a 2-tailed t test (p value for statistical significance = 0.05) to analyze differences in mean antinuclear antibody (ANA) titers in patients with transient versus persistent symptoms. A 59-year-old woman was referred for a history of urticarial plaques in the setting of fatigue, facial flushing, and polyarthritis of the hands and elbows. Her joint symptoms first developed 2 years ago; at the time, she was treated for presumed rheumatoid arthritis. However, she subsequently developed urticarial plaques on the torso, back, and arms. Biopsy of a plaque revealed an upper dermal angiocentric mixed polynuclear and mononuclear cell inflammatory infiltrate with … Address correspondence to M.T. Hession; E-mail: mth2114{at}columbia.edu

Psoriatic Eye Manifestations

The relationship between the eye and psoriasis has been recognized for decades, but the precise eye manifestations in patients with psoriasis and psoriatic arthritis are only recently coming to light. Psoriatic eye findings may include conjunctivitis, dry eye, episcleritis, and uveitis, all of which may precede articular changes. Uveitis, seen in 7% to 25% of psoriatic arthritis patients, may be recognized by the presence of conjunctival injection, photophobia, pain, lid swelling, or otherwise unexplained visual changes. Early recognition is paramount because its natural course may lead to vision loss. Immunopathogenesis has shown evidence for T-helper cell (Th) type 1 (Th1) and Th17 involvement in the pathogenesis of uveitis according to the murine experimental autoimmune uveitis model. Corticosteroids are the primary treatment modality; however, increasing emphasis has been placed on immunomodulators and biologics for more intractable cases. Referral to an ophthalmologist is essential for definitive diagnosis and treatment.

Management of Cutaneous Human Papillomavirus Infection: Pharmacotherapies

A plethora of different treatment modalities for treating human papillomavirus (HPV) are available, offering a range of efficacies and balancing several patient needs. Here we discuss pharmacotherapies for HPV, focusing in particular on the mechanism of action and treatment efficacy. Immunomodulators such as Candida antigen, imiquimod and squaric acid stimulate cell-mediated immunity and induce production of antiviral cytokines. Proapoptotic and antiviral treatments such as podophyllin resin, podophyllotoxin gel, bleomycin, 5-fluorouracil, cidofovir and interferon α interfere with the viral reproduction cycle. Other therapies include trichloroacetic acid, acitretin, cantharidin and sinecatechins, some of which operate by epidermal destruction, effects on cellular proliferation and other mechanisms of which are poorly understood. Overall, given the high HPV recurrence rates, adjunctive use of antiviral agents should be considered in treatment, especially when managing severe or complicated presentations.

Analysis of Trial Data for Infliximab and Golimumab: Baseline C‐Reactive Protein Level and Prediction of Therapeutic Response in Patients With Psoriatic Arthritis

Anti–tumor necrosis factor medications have demonstrated good efficacy in treating psoriatic arthritis (PsA). Clinical responses at the primary end point in recent clinical trials of golimumab in PsA subjects yielded lower American College of Rheumatology 20% criteria for improvement (ACR20) responses than those seen in the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 infliximab study. However, baseline C‐reactive protein (CRP) levels of PsA subjects enrolled in these trials differed significantly. We hypothesized that baseline CRP levels predict the observed differing clinical response rates at the primary end point.

Analysis of Gender Differences in the Efficacy of Psoriasis Treatment Modalities Resulting in Clearance

Background/Objective Characterize gender differences in efficacy of psoriasis treatments, as this has not been well studied. Methods In this retrospective cohort study, data were collected on patients with psoriasis seen at Tufts Medical Center between 2008 and 2014. Treatment courses lasting ≥ 4 weeks in patients with baseline moderate to severe psoriasis were included. Clearance was defined as an S-MAPA (simple measure for assessing psoriasis activity, the product of body surface area and physician global assessment) ≤ 3. Results Of the 172 biologic treatment courses, 81 (47%) resulted in clearance, 56% of females and 39% of males (RR=1.43, p=0.032). Women were more likely to clear on infliximab (88% compared to 27% of males, RR=3.21, p=0.02) despite a significantly higher baseline S-MAPA in females in this subgroup (166.63 versus 94.86 in men, p=0.05). There was no statistically significant gender difference in clinical outcomes for patients on conventional systemics or combination treatment courses. Conclusion Clinical outcomes are better for biologics, especially infliximab, in females compared to males with moderate to severe psoriasis. Further investigation of possible biologic or pharmacokinetic explanations for this finding is warranted.

The Comparative Efficacy of Traditional Systemic, Biologic, and Combination Therapies in the Treatment of Psoriasis: An Expansion Study:

Background There is a lack of comparative effectiveness research, particularly in the clinical setting, guiding psoriasis therapy. Objective To compare the efficacies of the traditional systemic, biologic, and combination therapies. Methods This retrospective cohort study analyzed psoriasis patient visits to the Tufts Medical Center Department of Dermatology. The outcome measure used was the validated simple measure for assessing psoriasis activity (S-MAPA). Results Patients treated with biologic or combination therapies had a significantly larger improvement in S-MAPA than patients treated with a traditional systemic medication at 24 weeks (biologic: 62.69% vs. 36.20%, p=0.021; combination: 83.28% vs. 36.20%, p=0.011). Multivariate analysis demonstrated the superiority of biologics to traditional systemic therapy was independent of patient demographics and comorbidities. Conclusions In the clinical setting, the biologic and combination therapies are superior to the traditional systemic therapies in the treatment of psoriasis. Emphasis should be placed on future trials that compare current active therapies.