Rishu Gupta

Memory regulatory T cells reside in human skin.

Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of anchoring fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning anchoring fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.

Biologic fatigue in psoriasis

Background: Over the past 15 years, biologic medications have greatly advanced psoriasis therapy. However, these medications may lose their efficacy after long-term use, a concept known as biologic fatigue. We sought to review the available data on biologic fatigue in psoriasis and identify strategies to help clinicians optimally manage patients on biologic medications in order to minimize biologic fatigue. Methods: We reviewed phase III clinical trials for the biologic medications used to treat psoriasis and performed a PubMed search for the literature that assessed the loss of response to biologic therapy. Results: In phase III clinical trials of biologic therapies for the treatment of psoriasis, 20–32% of patients lost their PASI-75 response during 0.8–3.9 years of follow-up. A study using infliximab reported the highest percentage of patients who lost their response (32%) over the shortest time-period (0.8 years). Although not consistently reported across all studies, the presence of antidrug antibodies was associated with the loss of response to treatment with infliximab and adalimumab. Conclusion: Biologic fatigue may be most frequent in those patients using infliximab. Further studies are needed to identify risk factors associated with biologic fatigue and to develop meaningful antidrug antibody assays.

Topical steroid risk analysis: Differentiating between physiologic and pathologic adrenal suppression

Abstract Background: Topical corticosteroids are a mainstay of therapy for inflammatory skin disorders. Hypothalamic–pituitary–adrenal (HPA) axis suppression is a potential systemic risk of topical steroid use. Our aim was to review available data on the risk of HPA axis suppression associated with long-term topical steroid use and to distinguish between pathologic and physiologic adrenal suppression. Methods: We performed a PubMed search for literature that evaluated the risk of HPA axis suppression associated with topical steroid use. Results: Fifteen of sixteen clinical trials reviewed did not report any pathologic adrenal suppression. In the single clinical trial that reported pathologic adrenal suppression, the patients used twice the maximum recommended amount of clobetasol propionate continuously for as long as 18 months. Physiologic adrenal suppression was seen as early as 1–2 weeks after treatment with class I–IV topical corticosteroids. In about half of these patients, cortisol levels spontaneously returned to normal within a few weeks, despite continuous therapy. Conclusion: Even when adrenal suppression occurs, topical corticosteroids are unlikely to be associated with clinical signs or symptoms of HPA axis suppression and are extremely safe as long as they are used within the current safety guidelines.

The Goeckerman regimen for the treatment of moderate to severe psoriasis.

Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting approximately 2-3% of the population. The Goeckerman regimen consists of exposure to ultraviolet B (UVB) light and application of crude coal tar (CCT). Goeckerman therapy is extremely effective and relatively safe for the treatment of psoriasis and for improving a patients quality of life. In the following article, we present our protocol for the Goeckerman therapy that is utilized specifically at the University of California, San Francisco. This protocol details the preparation of supplies, administration of phototherapy and application of topical tar. This protocol also describes how to assess the patient daily, monitor for adverse effects (including pruritus and burning), and adjust the treatment based on the patients response. Though it is one of the oldest therapies available for psoriasis, there is an absence of any published videos demonstrating the process in detail. The video is beneficial for healthcare providers who want to administer the therapy, for trainees who want to learn more about the process, and for prospective patients who want to undergo treatment for their cutaneous disease.

An update on drug–drug interactions with biologics for the treatment of moderate-to-severe psoriasis

Objective: Moderate-to-severe psoriasis is a chronic skin condition that often requires systemic therapy and biologics are the newest systemic treatment available. A favorable aspect of biologics is that they are thought to have minimal risks for drug–drug interactions compared to oral systemic medications such as cyclosporine and methotrexate. However, this assumption has not been recently or adequately reviewed. We reviewed the literature to identify possible drug–drug interactions with biologics and other medications. Methods: We searched PubMed for published case reports, clinical studies, reviews, and Food and Drug Administration (FDA) labels discussing possible drug–drug interactions with biologics for the treatment of moderate-to-severe psoriasis. Results: There were only a small number of published articles describing drug–drug interactions with biologics. Our review identified two case reports, five clinical studies, and three pharmacokinetics reviews. The majority of articles did not observe clinically relevant drug–drug interactions with biologics. FDA labels do suggest a possible relationship between tumor necrosis factor (TNF)-alpha inhibitors and cytochrome P450 (CYP) activity. Conclusion: The paucity of information regarding drug–drug interactions reaffirms the idea that biologics have limited susceptibility to drug–drug interactions compared to other oral medications. Further studies are needed to adequately assess drug–drug interactions with biologics.

The role of 39 psoriasis risk variants on age of psoriasis onset.

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (P = 0.94). The imputed HLA-C∗06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C∗06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset.

Supraerythemogenic excimer laser in combination with clobetasol spray and calcitriol ointment for the treatment of generalized plaque psoriasis: Interim results of an open label pilot study.

Abstract Background: The combination of phototherapy and topical therapy is one of the most widely used treatment modalities for moderate to severe psoriasis. The development of targeted phototherapy with excimer laser and new topical spray formulations has made these therapies both more convenient and more effective. In this open label pilot study, we aim to assess the efficacy of combination therapy using 308-nm excimer laser, clobetasol propionate spray and calcitriol ointment for the treatment of moderate to severe generalized psoriasis. Methods: In this 12-week study, patients with moderate to severe psoriasis received twice weekly treatment with XTRAC® Velocity 308-nm excimer laser combined with clobetasol propionate twice daily followed by calitriol ointment twice daily. Results: To date, 21 patients have completed the protocol. By week 12, 76% of the patients had a reduction in Psoriasis Area and Severity Index by at least 75% (PASI-75) and 52% had a Physicians Global Assessment of “clear” or “almost clear”. Conclusions: Excimer laser therapy combined with an optimized topical regimen that includes clobetasol spray followed by calictriol ointment appears to be an effective treatment for moderate to severe generalized psoriasis that avoids the risk of serious internal side effects associated with many systemic agents.

Review of recommendations for dermatologic therapy in pregnancy

To the Editor: We read with interest the article by Tyler and Zirwas in the April 2013 issue of the journal entitled ‘‘Pregnancy and dermatologic therapy.’’ The use of dermatologic medications in pregnancy is an important issue, and we commend the authors for creating a resource detailing therapeutic options in this unique population. There are, however, additional considerations that we would like to address regarding ultraviolet light therapy, biologics, cyclosporine, oral antifungals, and the use of hydroxychloroquine in lupus. Ultraviolet B therapy is considered a first line treatment during pregnancy. However, the authors neglect discussion regarding the risk of folate depletion. High cumulative doses of UVB ([118.16 J/cm in 36 treatments) resulted in a decrease of serum folate, increasing the potential risk of a neural tube defects in the first trimester if the patient is not adequately supplementing folic acid. Moreover, there are case reports of early pregnancy exposure in tanning beds and subsequent infantile neural tube defects. In regard to the use of biologics during pregnancy, one key recommendation is to avoid live vaccination of infants for the first 6 months of life due to the infant’s inability to mount an immune response. There is a report of a fatal case of disseminated tuberculosis from BCG vaccination at 3 months of age with in utero infliximab exposure. The authors also state that there have been no specific congenital malformation risk associated with the biologics; however, 2 publications by Carter et al point to a possible association with VACTERL (vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limb abnormalities). Based on animal models, there is a biologically plausible connection between tumor necrosis factor inhibition and these abnormalities, but critics of the reports argue that the data is retrospective, uncontrolled, and that no published cohorts have confirmed this association. The article also states that long-term data on cyclosporine exposure are lacking; however, several studies follow infants years after exposure, indicating minimal to no long-term adverse effects. Studies following children after in utero exposure to cyclosporine in transplant patients showed no adverse nephrotoxic effects when followed 3 years

Tumor Necrosis Factor-α Triad: Psoriasis, Cardiovascular Disease, and Depression:

Tumor necrosis factor-α (TNF-α) plays an intricate role in immune defense mechanisms. Over the past decades, studies have demonstrated that inflammatory cytokines, such as TNF-α and interleukin-6, may play an important role in the pathophysiology of psoriasis and depression. More recently, studies suggested an additional association of TNF-α with cardiovascular disease, which has attracted much attention. People with psoriasis, cardiovascular disease (i.e., heart failure or myocardial infarction [MI]), and depression have been found to have higher levels of proinflammatory cytokines, especially TNF-α. This article reviews the roles of TNF-α in psoriasis, cardiovascular disease, and depression.