Archive 2017

Inflammatory skin diseases

1. Layers of the host defense system

The host defense system of the skin is mainly composed of the following three layers: (1) barrier of the skin, (2) innate immunity, and (3) acquired immunity [1]. In general, these layers are aligned in this order chronologically, functionally, and phylogenetically. A disorder in a specific layer can arise from defects in the superior layer. Each layer has unique roles to protect the body against specific infectious agents and external/internal dangers. Inflammation is defined as a series of protective and regenerative responses of the body. Therefore, inflammatory skin diseases are originally a result of these protective and regenerative responses of the skin against infections and dangers. If primarily causative infections and dangers are ruled out, the dermatitis is due to hereditary or acquired disorder in a specific layer of the host defense system.

Descriptive dermatology of the morphological phenomena of skin has been developed for more than two thousand years. Despite recent and ongoing progress in immunology, innate immunity, and the skin barrier, inflammatory skin diseases have not yet been fully classified in terms of the defects in each layer of the host defense system.

In this review, we propose a new algorithm to understand the pathology of inflammatory skin diseases in terms of the specific roles of each three layer in host defense system of the skin (Box). We describe the disorder of these layers in reverse order from acquired immunity to barrier, for the better understanding (see Section 5).

2.1. Immunodeficiency

A number of hereditary diseases have been identified as a genetic lack of the specific molecules that are essential in acquired immunity. Many of them are associated with a variety of cutaneous infections and inflammation. For example, X-linked agammaglobulinemia (XLA) develops furunculosis, impetigo, and atopic-like eczematous eruptions. X-linked lymphoproliferative (XLP) disease is highly accompanied by infectious mononucleosis due to Epstein–Barr virus (EBV) infection. Chronic mucocutaneous candidiasis (CMCC) is composed of heterogeneous diseases, some of which have molecular defects in the acquired immunity, such as defects in the autoimmune regulator (AIRE) gene (see Section 2.3.1) [2]. Acquired immunodeficiency syndrome (AIDS) patients are highly susceptible to fungal and herpes virus infection, such as human herpes virus 8 (HHV8), and patients develop repetitive and severe herpes and Kaposi’s sarcoma in the skin.

How to treat cancer

A class of drugs is emerging that can attack cancer cells in the body without damaging surrounding healthy ones. They have the potential to replace chemotherapy and its disruptive side effects, reshaping the future of cancer care.

The complex biological medicines, called antibody drug conjugates (ADCs), have been in development for decades, and are now generating renewed excitement because of the success of one ADC in late-stage testing, a breast cancer treatment called DS-8201.

The fervor over ADCs is such that AstraZeneca Plc in March agreed to pay as much as $6.9 billion to jointly develop DS-8201 with Japan’s Daiichi Sankyo Co., the British drugmaker’s biggest deal in more than a decade. The investment was widely seen to be a validation of DS-8201’s potential — and the ADC class of drugs as a whole — as an alternative for chemotherapy, the most widely used treatment, for some types of cancer.

DS-8201, which will be filed for U.S. approval by the end of September, is so well-regarded that some analysts already predict it will surpass the $7 billion in annual sales for Roche Holding AG’s breast cancer drug Herceptin, which it aims to replace.

“DS-8201 may become one of the largest cancer biologic drugs,’’ said Caroline Stewart, an analyst at Bloomberg Intelligence, who estimates sales of the drug to eventually approach $12 billion globally — that’s a level attained by only a handful of biologics, which are drugs based on a living organism. “While the field has advanced and there are several companies focusing on ADCs, Daiichi in particular seems to have developed a unique expertise.”

Analysts say DS-8201 could triple the number of patients who get powerful targeted treatment for breast cancer, the most common tumor in women that kills more than half a million annually. As importantly, its ability to target cancer cells without affecting normal cells is a key advantage over the take-no-prisoners approach of chemotherapy.

Daiichi’s treatment has been seen to double survival time for advanced breast cancer patients to 20 months from 10, former UBS Securities Japan Co. analyst Atsushi Seki said in March. In trials, patients using DS-8201 experienced less nausea and hair loss compared with chemotherapy.

Magic Bullet

DS-8201’s full potential is still years away, as it will take time for data to validate the drug’s efficacy in a wide range of patients. Still, the potential of ADCs is already jolting Big Pharma. Roche, whose Herceptin loses patent exclusivity in the U.S. this year, has added ADCs to its portfolio with its Kadcyla breast cancer treatment. Pfizer Inc. has Mylotarg, an ADC that treats myeloid leukemia.

About 56 pharmaceutical companies are developing ADC candidates, including ImmunoGen Inc. and Seattle Genetics Inc., and they could be targets for acquisitions or licensing deals from global pharmaceuticals anxious for a piece of the ADC pie, according to Cowen Inc.

“ADCs are being positioned as a chemo replacement,’’ Cowen analysts including Boris Peaker wrote in an April note. “There is significant potential for partnership activity.’’

The global ADC market was valued at $1.57 billion in 2017 and is projected to grow 26% every year through 2025 to almost $10 billion, according to a report by Grand View Research.

The concept behind ADCs was envisioned in 1900 by German Nobel laureate Paul Ehrlich, who formed the idea of a “magic bullet” in which a single toxic molecule would be delivered to attack a diseased cell without damaging surrounding healthy cells.

The actual use of ADCs began in 2000, but the interest in the sector cooled down as many failed to live up to expectations. The therapies belong to a broader category of cancer immunotherapies that include Merck & Co.’s Keytruda and Novartis AG’s CAR T-cell therapy Kymriah that harness the immune system to kill tumors.

Another Level

Daiichi Sankyo’s drug takes ADCs to another level. Its advantage is that it carries eight payloads stably to cancer cells, double the number of the industry standard, said Toshinori Agatsuma, head of oncology research at Daiichi Sankyo who led a team that discovered the therapy.

“Currently available ADCs are far from being perfect technically because the payload linked to antibodies aren’t properly delivered to cancer cells,’’ said Agatsuma. “We wanted to challenge and improve that. We were a latecomer in biotech, but I knew it was an area where we could catch up, compete and win.’’

About 2.1 million women are diagnosed with breast cancer each year, according to the World Health Organization. Some 18% of cases are driven by a protein called HER2, and their first treatment is chemotherapy alongside Roche’s Herceptin and Perjeta, a related drug. While DS-8201 is currently in testing for later-stage cancer, the plan is to go up against the first-line treatment in the next two years.

“It would be transformative” if the drug were to become the sole first-line treatment, said David Fredrickson, president of AstraZeneca’s oncology business. “If we can eliminate the side effects associated with chemotherapy, that would be a tremendous benefit for women.”

Drugs like Herceptin only target high levels of HER2, and women with lower levels must rely on hormone therapy or chemotherapy. That’s where DS-8201 has the potential to serve far more patients, treating those with both higher and lower levels of HER2.

‘It’s Different’

“We need more evidence, but my gut feeling is that DS-8201 is the most effective among existing medicines targeting HER2 positive patients, including Herceptin and chemotherapy,’’ said Shunji Takahashi, deputy director at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, who took a part in an early-stage DS-8201 trial. He noted that interstitial pneumonia is a concern as a side effect, and needs to be monitored.

For Daiichi Sankyo, the development of DS-8201 has helped resurrect the Japanese company after it struggled for years to set a path for growth, weighed down by a failed acquisition of India’s Ranbaxy Laboratories Ltd. and a shortage of blockbuster products.

“A single drug has a potential to transform Daiichi Sankyo and I didn’t expect it a year ago,’’ SMBC Nikko Securities Inc. analyst Yasuhiro Nakazawa said. “Daiichi Sankyo had a track record of betraying market expectations with previous drug developments. But with this one, I can really feel that it’s different this time.’’

Evolution of Cancer Treatment Therapies

Cancer therapy has been characterized throughout history by ups and downs, not only due to the ineffectiveness of treatments and side effects, but also by hope and the reality of complete remission and cure in many cases. Within the therapeutic arsenal, alongside surgery in the case of solid tumors, are the antitumor drugs and radiation that have been the treatment of choice in some instances. In recent years, immunotherapy has become an important therapeutic alternative, and is now the first choice in many cases. Nanotechnology has recently arrived on the scene, offering nanostructures as new therapeutic alternatives for controlled drug delivery, for combining imaging and treatment, applying hyperthermia, and providing directed target therapy, among others. These therapies can be applied either alone or in combination with other components (antibodies, peptides, folic acid, etc.). In addition, gene therapy is also offering promising new methods for treatment. Here, we present a review of the evolution of cancer treatments, starting with chemotherapy, surgery, radiation and immunotherapy, and moving on to the most promising cutting-edge therapies (gene therapy and nanomedicine). We offer an historical point of view that covers the arrival of these therapies to clinical practice and the market, and the promises and challenges they present.

Keywords: cancer, immunotherapy, nanotechnology, gene therapy, nanomedicine
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1. Introduction

Chemotherapy, surgery and radiotherapy are the most common types of cancer treatments available nowadays. The history of chemotherapy began in the early 20th century, but its use in treating cancer began in the 1930s. The term “chemotherapy” was coined by the German scientist Paul Ehrlich, who had a particular interest in alkylating agents and who came up with the term to describe the chemical treatment of disease. During the First and Second World Wars, it was noticed that soldiers exposed to mustard gas experienced decreased levels of leukocytes. This led to the use of nitrogen mustard as the first chemotherapy agent to treat lymphomas, a treatment used by Gilman in 1943. In the following years, alkylating drugs such as cyclophosphamide and chlorambucil were synthesized to fight cancer [1,2]. Kilte and Farber designed folate antagonists such as aminopterin and amethopterin, leading to the development of methotrexate, which in 1948 achieved leukemia remission in children [3]. Elion and Hitchings developed 6-thioquanine and 6-mercaptopurine in 1951 for treating leukemia [4,5]. Heidelberger developed a drug for solid tumors, 5-fluorouracil (5-FU), which is up to now an important chemotherapy agent against colorectal, head and neck cancer [6]. The 1950s saw the design of corticosteroids, along with the establishment of the Cancer Chemotherapy National Service Center in 1955, whose purpose was to test cancer drugs. At that time, monotherapy drugs only achieved brief responses in some types of cancers [7]. By 1958, the first cancer to be cured with chemotherapy, choriocarcinoma, was reported [8]. During the 1960s, the main targets were hematologic cancers. Better treatments were developed, with alkaloids from vinca and ibenzmethyzin (procarbazine) applied to leukemia and Hodgkin’s disease [9-11]. In the 1970s, advanced Hodgkin’s disease was made curable with chemotherapy using the MOMP protocol [12,13], which combined nitrogen mustard with vincristine, methotrexate and prednisone, and the MOPP protocol [14,15], containing procarbazine but no methotrexate. Patients with diffuse large B-cell lymphoma were treated with the same therapy and, in 1975, a cure for advanced diffuse large B-cell lymphoma was reported using protocol C-MOPP, which substituted cyclophosphamide for nitrogen mustard [16].

Surgery and radiotherapy were the basis for solid tumor treatment into the 1960s. This led to a plateau in curability rates due to uncontrolled micrometastases. There were some promising publications about the use of adjuvant chemotherapy after radiotherapy or surgery in curing patients with advanced cancer. Breast cancer was the first type of disease in which positive results with adjuvant therapy were obtained, and also the first example of multimodality treatment, a strategy currently employed for treatment of numerous types of tumors. In the late 1960s, the use of adjuvant chemotherapy changed the concept of localized treatment.

There was significant progress in 1978 when higher cure rates of metastatic germ cancer were achieved by combining cisplatin, bleomycin and vinblastine [17-19]. The experience with polychemotherapy in hematologic cancer brought to light the fact that different drugs act against tumor cells in different phases of their cellular cycle. One of these solid tumor drugs was CMF (cytoxan, methotrexate and fluorouracil), a standard therapy for treating breast cancer for over 30 years. Understanding of molecular changes in cancer cells quickly developed after the 1970s. As a consequence, numerous drugs with various mechanisms of action were introduced during the 1980s. Subsequent advances and developments led to liposomal therapy, which places drugs inside liposomes (vesicles made of lipid bilayers), decreasing some of the side effects of chemotherapy such as cardiotoxicity. Examples of liposomal drugs include liposomal doxorubicin and daunorubicin, one of the first steps in nanotechnology-based approaches. The 1990s sparked the beginning of targeted chemotherapy by screening for specific critical molecular targets. These advances in modern chemotherapy and studies on genetics and molecular biology contributed to the ongoing decline in death rates. Data from the genome sequence suggested that many dysfunctions associated with cancer could be due to the abnormal function of some protein kinases. The current pharmacological trend has been to develop kinase inhibitors [20,21]. The first tumors targeted with drugs approved by the FDA (Food and Drug Administration) and the EMEA (European Medicines Agency) were renal cell cancer, hepatocellular cancer and gastrointestinal stromal tumors. In recent years, numerous specific tumors have been tested with various kinase inhibitors and there is a trend towards combining chemotherapy with these new targeted therapies.

Chemotherapy is curative in some types of advanced cancer, including acute lymphoblastic and acute myelogenous leukemia, Hodgkin’s and non–Hodgkin’s lymphoma, germ cell cancer, small cell lung cancer, ovarian cancer and choriocarcinoma. In pediatric patients, curable cancers include acute leukemia, Burkitt’s lymphoma, Wilms’ tumor and embryonal rhabdomyosarcoma. Although treatment is not always curative for these cancers, there has been significant improvement in progression-free and overall survival. Another modality of treatment is neoadjuvant therapy, which aims to reduce the size of the primary tumor and prevent micrometastases. This type of treatment improves on more conservative surgical techniques in preserving the functionality of important organs. Neoadjuvant chemotherapy is indicated for anal, breast, lung, gastroesophageal, rectal, bladder and head and neck cancer, as well as some types of sarcoma. There are many cancers for which adjuvant chemotherapy has been established with curative effect, and with the new effective drugs and combinations the curability rates are expected to rise even more. Since 1990, the incidence and mortality of cancer have been declining and despite the increase in the elderly population [22], mortality rates for the United States declined from 2005 to 2007.

In 1890, Halsted performed the first radical mastectomy, believing that cancer would be more curable if surgical techniques were more aggressive, thus avoiding regional recurrences. He had many followers at that time, but thanks to advances in chemotherapy, radiotherapy, biology and technology, the outlook now is quite different. Radical surgery has now been replaced by less extensive operations.

The turn of the 20th century marked the beginning of the development of cancer surgery techniques, with the first abdominoperineal resection performed in 1908 by Miles [23], the first lobectomy being performed in 1912 [24,25] and the first radical hysterectomy performed by Wertheim in 1906, all carried out under oncological criteria. Additionally, in 1904, Young made the first radical suprapubic prostatectomy. Modern surgery has changed significantly, with Halstedian techniques replaced by non-invasive procedures such as laparoscopic colectomy (for the removal of colon cancer) [26], videothoracoscopy, radiofrequency ablation and radiosurgery techniques such as Cyberknife® [27]. Breast-conserving surgery with sentinel-node removal has been used to improve esthetic results and avoid lymphedema [28]. Another example of conservative surgery is the use of laryngoscopic laser surgery in early laryngeal cancer [29]. The most recent development is the Da Vinci®, a robotic system for the removal of cancer from prostate and kidney [30].

The discovery of X-rays and radiation by Becquerel and Rontgen in the late 19th century was the first step towards radiation treatment. Marie Curie’s work greatly contributed to the development of radiotherapy. The first cancer case cured exclusively by radiation occurred in 1898. After World War II, technological progress allowed charged particles to be propelled through a vacuum tunnel called linac, or linear accelerator. In 1960, Ginzton and Kaplan began to use a rotational linac radiotherapy called “Clinac 6”, which was used to concentrate X-rays more deeply thereby they not affecting the skin as much. The development of modern computers enabled three-dimensional X-ray therapy, such as intensity-modulated radiation therapy (IMRT) using mapping information from Computed Tomography (CT) scans. This provides a three-dimensional reconstruction, which helps avoid toxicity since the contours of the tumor are targeted and separated from healthy tissues. In 2003, a specific type of IMRT was developed called the TomoTherapy® system. This treatment uses CT-guided IMRT technology that directs the radiation source by rotating it around the patient, which makes the morphological limits of a tumor easier to trace with the beam [31]. Another significant trend is the use of charged particle radiotherapy with proton or helium ions for specific types of patients with melanoma of the uveal tract. It is also used as adjuvant therapy for skull base chondroma, chondrosarcoma and spine (usually cervical). In summary, the lines of development have been fractionated dose delivery, technological advances in X-ray production and delivery and improvement of computer-based treatment planning.

The latest advance in scanning technology with radiotherapy therapy is four-dimensional (4D) conformal radiotherapy [32], which records a video sequence of tumor movement. This therapy uses dynamic CT images of the body that compensate for any movement by the target, including movements when patients breathe. There are two forms of this therapy: Image-guided radiation therapy (IGRT) and Image-guided adaptive radiation therapy (IGART).

Skin diseases and people’s health

In modern society, more and more people are attacked by a variety of diseases. In medicine, relevant skin diseases seriously affect people’s health. As one of the common diseases, skin diseases such as leprosy, scabies, fungal disease, bacterial skin infections appear frequently. With the form, structure and functions changing, skin (including hair and armor) is influenced by external and internal factors, which produce the pathological process, and the corresponding produce all sorts of clinical successively performance. This is the cause of skin diseases. They have a high incidence of dermatitis, but relatively the symptoms are not serious, they often do not affect health, but a few heavier are even life-threatening.

As a typical kind of skin diseases, photodermatoses are among the most common skin disorders in the world. Some of them acquired a particular importance in some regions because of their high frequency, severity, and also be­cause of their different diagnostic and therapeutic ap­proaches.

Photo medicine is a rapidly developing subspe­cialty of dermatology concerned with skin diseases caused by radiation in the UV and visible spectra. Initiation or exacerbation of a rash after sun exposure that occurs in typical light-ex­posed areas is features that point toward a sun­light-induced condition. The diagnosis of photosen­sitive conditions may be difficult, and the use of investigations such as light, patch, and photopatch testing may be necessary to confirm the diagnosis. [1]

Background and history

With the development of modern medicine, every Teaching Hospital Department is in treat­ment development dilemmas. For becoming involved in a new therapy, they still need to promise to be at the speculative stage. In the early 1990s, the problem about whether to actively become involved in the development of PDT for skin cancers was discussed by the Photobiology Unit within the Department of Dermatology in Dundee. As a new invest significant re­sources, it’s so difficult for PDT to have a fairly certain outcome. By 1998, with the position changed and enough good quality data existed, treatment outcomes justi­fied become involved in the development of both PDT and photodiagnosis (PD) for pre-malignant and malignant skin lesions. From a clinical re­search and therapeutic point of view, the skin has two huge advantages. Firstly, it can be easily ex­amined with the naked eye, and secondly, it is the most accessible organ for investigation, biopsy and treatment. Although PDT firmly has its roots at the beginning of the last century, it is only over the last 15 years that it has gained considerate popularity as a topical treatment of great promise for the treatment of skin cancers.[2]

In 1900 a German medical student Oscar Raab famously reported the concept of cell-induced death subsequent to light interacting with chemicals. In subsequent exper­iments he demonstrated that this effect was greater that with alcidine red alone, light alone or alcidine red exposed to light and then added to the paramecium. He postulated that in vitro toxicity occurred as a result of fluorescence caused by the transfer of energy from the light to the chem­ical. Professor von Tappeiner soon after predicted the future of fluorescent substances in medicine.

In 1904 von Tappeiner and Jodlbauer identified that oxy­gen was integral component in photosensitisation reactions and termed the phrase ”photodynamic action” in 1907. Since its incidental discovery in 1900 photodynamic ther­apy (PDT) and all aspects relating to it from mechanism of action, differing photosensitisers through to clinically based applications have been studied. Three components are required for PDT to occur; a photosensitiser, oxygen and a light source. [3]

The Photobiology Unit (photobiology = the study of tight on living systems) has the purpose in Scotland of diagnosing tight sensitive skin disease (the photodermatoses) and the development of new forms of tight therapy (phototherapy). This Centre, which has been in existence since 1973, has always combined clinical skills (photodermatology) with a strong scientific base (photophysics) and laboratory biology (photobiology). This combination of applied science and clinical service in the same unit has pro­vided exciting research opportunities. Applied photo physics, through the Medical Physics Department, has dedicated members of staff whose only rote is optical physics. The necessary expertise in tight de-tivery and measurement is essential for predictable PDT and PD.

Basic knowledge of sun and the skin

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X-rays

UVC

UVB

UVA

Visible light

Figure 1 the place of ultraviolet radiation in the electromagnetic spectrum

Figure 1 illustrates the relationship between ultraviolet radiation and the other types of non-ionizing radiation, such su natural light an infra-red radiation. It will be seen that ultraviolet radiation from the sun is divided into three different wavelengths-UVA, UVB, and UVC. The UVA waves are the longest and the UVC the shortest.

At present, UVC is prevented from reaching the earth’s surface by the ozone layer, and is not therefore a natural hazard. There is, however, concern that the loss of the protective layer of ozone above the earth’s atmosphere will continue, and that in future more UVB might reach the earth. The main ultraviolet component of travel of natural that does each the earth’s surface is UVB. This penetrates the epidermis and reaches the more superficial layer of the dermis—the papillary dermis. UVA is also present in sunlight and ,in the early spring, a high proportion of natural sunlight in countries at latitudes 50 degrees or more north of south of the equator is composed of UVA. As the summer develops the proportion of UVA falls. UVA is the main, but not the only, wavelength found in the long tubes in UVA sunbeds. The effects of UVA go deeper into the skin than those of UVB. A very simple rule of thumb is that chronic over-exposure to UVB causes wrinkles, chronic over-exposure UVA causes sagging, and chronic over-exposure to both increases the risk of developing skin cancer. One of the important points of difference between UVB and UVA exposure is that acute over-exposure to UVB causes the redness and soreness recognized as sunburn. This is maximal 12-24 hours after the exposure has taken place, and is a useful warning that the skin should be protected for a few days until the redness has disappeared.

The chemicals in sun-screens that protect against UVA and UVB can be divided into those that absorb ultraviolet radiation and those that reflect it away. The absorbing chemicals include para-aminobenzoic acid-PAMA- cinnamates, and salicylates, which protect against UVB alone. Benzophenones protect against both UVB and UVA and are also chemical sun-screeners.[4]

Photosensitivity

The skin is our main defense against light, and in particular against ultraviolet (UV) radiation. Sometimes the skin reacts abnormally to light by becoming inflamed. This is called photosensitivity.

There are many causes of photosensitivity. Some of the most important are below:

Acute parts like Sunburn Xeroderma pigmentosum, Porphyria, Solar urticaria, Pellagra, and Photosensitivity disorders like Polymorphic light eruption, Juvenile spring eruption, Hydroa vacciniforme, actinic prurigo. Disorders exacerbated by light include Drug reactions, Lupus erythematosus, Rosacea Darier’s disease Eczema (including actinic dermatitis and photo contact dermatitis Psoriasis Lichen planus.

These reactions are either a direct toxic effect of light, or have an immunological component, either provoked by light alone or in conjunction with something else such as a drug.

Diagnosis and treatment of common causes of photosensitivity

The acute effects of sun on the skin are all too familiar. They are caused largely by medium wavelength UV radiation (UVB), but the “dose” required producing sunburn depends on:

(1)An individual’s skin type

(2)The intensity of the radiation (greatest near the equator and around midday)

(3)The length of exposure to UVB

Mild sunburn causes erythema: more severe damage leads to extensive blistering and epidermal boss. Treatment makes little difference to the acute changes, but symptomatic relief can be obtained with soothing lotions, such as calamine. These include avoiding the midday sun, seeking shade, wearing appropriate clothing and eyewear, and using sunscreens, this is more important for those with skin type I and II than for those with a more radiation skin.

There are several special examples which are listed and explained:

(1) Porphyria:

Some forms of porphyria are associated with photosensitivity. In a European child the most common is erythropoietic protoporphyria, whereas an adult presenting for the first time probably has porphyria cutanea tarda. The latter is often associated with alcoholic liver disease. Screening tests involve blood ,urine and stool samples and are best undertaken in a specialist setting.

(2)Solar Urticaria: Rarely, exposure to light leads to urticarial weals.

(3)Pellagra:

In western societies, nicotinic acid deficiency is seen most commonly in alcoholics. It presents a triad of changes: Diarrhoea Dementia Dermatitis, which is light sensitive.

(4)Polymorphic light eruption

This is perhaps the most important, and certainly the commonest of the primary photosensitivity disorders. Patients often refer to their skin changes as”prickly heat”, but true prickly heat (or miliaria rubra)is quite different.

Polymorphic light eruption presents a day or two after sun exposure, with changes on light exposed areas, for example the forearms, legs the “V” of the neck and the face. The lesions are itchy and morphologically variable (hence “polymorphic”). There may be papules, plaques, and blisters of areas resembling eczema. They increase in intensity over a week or so before subsiding.

Treatment with topical steroids provides some relief, but some patients require systemic steroids to control an acute attack. Prevention is a better approach. Unfortunately, sunscreens are often not effective, but pre-season PUVA works well and can last for a whole summer. An alternative is the use of antimalarial medication (notably hydroxychloroquine) taken during sunny periods, or while abroad. A variety of polymorphic light eruption occurs almost exclusively in boys. Clusters of small blisters appear on the topes of the ears, especially in early spring. The condition settles spontaneously with age.

Skin Diseases in the Era of Highly Active Antiretroviral Therapy

With the increasing number of HIV-infected patients receiving highly active antiretroviral therapy (HAART), the shift in their dermatologic profile becomes less characteristic of AIDS-defining illnesses.

Retrospective review of mucocutaneous pathology among patients seen at HIV-Dermatology Clinic from January 2009 to December 2013.

Among 534 patients, there were 68.4% males and 31.6% females, with 8.7-year average duration of infection; 82.8% were receiving HAART. Kaposi sarcoma was the only relatively frequent AIDS-defining disease. Fungal and viral infections were common, with human papilloma virus (HPV) as the most frequent overall. Benign and premalignant tumors were associated with HAART and CD4 >200/mm3 (P < .05). Psoriasis was prevalent among patients without HAART (P < .05). Prurigo was associated with lower CD4 count (P < .001).

Patients receiving HAART are faced with chronic skin problems such as benign and premalignant tumors, and HPV infection adds to their neoplastic predisposition. Further research is recommended to develop protocols for treating psoriasis and screening for HPV-associated neoplasia among patients.

Keywords skin diseases, HIV, HAART

Patients living with HIV infection are usually afflicted with skin diseases, and their variability and severity often reflect their level of immune deficiency. Ranging from infections, inflammations, and neoplasms, these can lead physicians to the initial diagnosis of HIV infection or can manifest the various stages of its disease evolution. In addition to this is the problem of drug reactions and iatrogenic effects as well as the reactivation of certain diseases alongside immune reconstitution while receiving highly active antiretroviral therapy (HAART).1

The epidemiologic profile of dermatologic illnesses in relation to HIV varies between countries. This is mainly affected by economic and political factors pertaining to the availability of HAART, as well as the risk-taking behavior of patients. In Portugal, a few years after the recognition of HIV (1985-1991), the mucocutaneous manifestations were dominated by AIDS-defining conditions, such as oropharyngeal candidiasis and Kaposi sarcoma, as well as the aggravation of more common conditions, such as herpes simplex virus (HSV) infection, herpes zoster, dermatophytosis, seborrheic dermatitis, and drug-related skin disorders.2 However, for the past 5 years, there has been a decreasing trend in terms of the number of new HIV-infected cases but with an increasing number of people living with the infection alongside the increasing number of patients receiving HAART.3 These observations result to a less number of opportunistic infections, but instead there is the emergence of medical problems that were less common before4 and a shift to more chronic forms of illnesses.

This study aims to have a descriptive measure of the current epidemiology of mucocutaneous pathology among HIV-positive patients, based on the referrals to the dermatology clinic of a tertiary hospital in Lisbon, Portugal, from 2009 to 2013. By understanding the trend and identifying shifts in the epidemiologic burden of disease, the authors hope to identify areas that can be bases for future research in assessing the economic burden of HIV in the field of dermatology and hence aid in the formulation of new policies and planning of resource allocation.5

Clinical Data

We accessed data from the electronic records of all HIV-infected patients on their first consult at the Specialized HIV Clinic of the Dermatology Service of Hospital de Santa Maria during the period of January 2009 to December 2013. These include in-hospital referrals as well as those referred from other hospitals in Greater Lisbon area. Dermatologic diagnoses were based on clinical data and, if needed, laboratory and pathologic correlations as in the case of malignant neoplasms. The medical ethics board of the hospital approved the study.

Statistical Analysis

The primary outcome variable was the frequency rate of identified skin diseases among the study participants, classified according to those receiving and not receiving HAART. We also determined the mean CD4 count for each diagnosis. The secondary outcome variables were the significant correlation of each diagnosis with the patient’s HAART status and the significant difference in the mean CD4 count among the diagnoses.

We analyzed the data statistically using IBM Statistical Package for the Social Sciences (SPSS) version 22. We used summary statistics, where N is the total number of HIV-infected patients included in the study. For the analysis of the secondary outcome variables, we used Pearson χ2 test (P < .05) to check for correlations between categorical data. For parametric data, we used independent samples t test at the same significance level.

Epidemiologic Profile

We initially assessed a total of 564 patients, of which 5% did not have CD4 count available on record. In the end, we included a total of 534 patients, of which 68.4% were males and 31.6% were females. They were mostly Caucasians with 18% non-Caucasians. The mean age at the time of dermatologic consult was 44.6 years (standard deviation [SD] = 11.9), whereas the mean age at initial HIV diagnosis was 36 years (SD = 11.9), both values with no significant difference between the genders. The average duration of HIV infection was 8.7 years (SD = 6.4). The primary mode of HIV transmission was heterosexual, with 18% being men having sex with men (MSM). History of intravenous (IV) drug use was identified in 21.8%, of which 96.6% were Portuguese and 98.3% were heterosexuals. Also, the majority of the study population had HIV-1, with 3.9% HIV-2, of which 76% were non-Caucasians.

In this study, around 82.8% were receiving HAART at the time of their dermatologic consult. Almost all (96.4%) of them were compliant, with no significant difference between genders. The 3.4% of those who were not compliant were all heterosexuals. In this case, noncompliance was significantly correlated with the history of IV drug use (P < .05).

Staying Healthy in Your 70s, 80s, 90s…

Aging can be defined as: “progressive changes related to the passing of time.” While physiological changes that occur with age may prevent life in your 70s, 80s and beyond from being what it was in your younger years, there’s a lot you can do to improve your health and longevity and reduce your risk for physical and mental disability as you get older.

Research shows that you’re likely to live an average of about 10 years longer than your parents—and not only that, but you’re likely to live healthier longer too. According to the U.S. Department of Health and Human Services, 40.4 million Americans (about 13 percent) were 65 years of age or older in 2010 and by the year 2030, almost 20 percent of the total U.S. population will be 65+.

So how do you give yourself the best possible chance for a long, healthy life? Although you aren’t able to control every factor that affects health as you age, many are in your hands. Some keys to living a long, healthy life include:

  • Make healthful lifestyle choices—don’t smoke, eat right, practice good hygiene, and reduce stress in your life
  • Have a positive outlook
  • Stay as active as possible—mentally and physically
  • Take safety precautions
  • See your health care provider regularly and follow his or her recommendations for screening and preventative measures

One of the most important things you can do to stay healthy in your golden years is to maintain your sense of purpose by staying connected to people and things that matter to you. However, this isn’t always easy—especially in a society that all-too-often views older people as a burden.

Visit your local senior center. Spend time with at least one person—a family member, friend or neighbor—every day. Volunteer in your community, attend a local event, join a club or take up a new hobby.

According to our sister publication REMEDY’s Healthy Living Fall 2014, walking may help prevent physical disability later in life. In a large study of older Americans, researchers focused on sedentary men and women between the ages of 70 and 89 who either met twice a week for a supervised walk around a track and received instruction to walk or do balance and flexibility exercises three to four times a week at home or attended weekly workshops on healthy aging.

After an average of 2.6 years, the walkers were 28 percent less likely to have become persistently physically disabled than the non-walkers, suggesting that it’s never too late to start.

Stress and Aging

Stress can have an enormous impact on your health and your quality of life at any age—and even more so as you get older. In fact, according to a recent study published in the Journal of the American Geriatrics Society, depression and anxiety are linked to physical decline in seniors. Concerns like: “Will there enough money now that I’m retired?” and “What will happen if I get a serious illness or become disabled?” are common in older adults.

Elderly Woman Stress Image

As you age, you’re also more likely to experience emotional trauma associated with loss—the deaths of people close to you (friends, family members, spouse), your own health, and/or your independence. For many seniors, dealing with the loneliness caused by multiple losses can lead to a diminished investment in life—especially when combined with other issues, like financial concerns.

Try these tips to help deal with difficult changes:

  • Focus on being thankful. Appreciate and enjoy your life and don’t take people or things for granted.
  • Acknowledge your feelings and express them. Talk to a friend, family member or health care professional, write in a journal or join a support group.
  • Embrace your spirituality.
  • Accept that some things are out of your control.
  • Try to keep your sense of humor.

Seniors are at increased risk for depression. If you’re feeling overwhelmed, or unable to cope or deal with stress, it’s important to reach out to family, friends, caregivers and health care providers. To locate services for older adults (and family members) in your area, visit the Eldercare Locator provided by the U.S. Administration on Aging or call 1.800.677.1116.

Health Concerns in Your 70s and Older

The risk for certain medical conditions—including heart attack, stroke, dementia, diabetes, lung disease, chronic pain, some types of cancer and other health concerns increases with age. However, healthy lifestyle choices can help reduce your risk for many of these issues. Helpful tip: Put “ICE” (in case of emergency in your cell phone contact list in front of the name(s) of family member(s)/friend(s) to call if something happens to you so bystanders or first responders will know who to get in touch with.

Here are some other common problems that can develop, even in relatively-healthy seniors:

Elderly Man Image

Balance Disorders—Many older people experience problems with balance and dizziness (vertigo). There are many different causes for balance disorders, so contact your health care provider if you feel unsteady or dizzy. Falls and fall-related injuries (including hip fractures) are serious concerns that can have a significant impact on your life and your ability to live independently. According to the Centers for Disease Control and Prevention (CDC), more than one-third of adults 65 years of age and older fall each year, and falls are the leading cause of injury-related death in seniors.

Memory Problems—It’s important to know: While some degree of forgetfulness is normal with age, significant memory loss or cognitive decline is not an inevitable part of normal aging. If you experience mental lapses that interfere with daily life, contact your health care provider. Serious memory problems or a decrease in cognitive function may be caused by a treatable, underlying condition—such as dehydration, malnutrition or sleep deprivation—or a medical problem like Alzheimer’s disease or dementia.

Inadequate Nutrition—As you get older, it’s more important than ever to eat right to stay healthy and maintain energy levels. However, good nutrition is a challenge for many seniors. Changes in your senses of taste and smell can affect your appetite. Slower digestion and metabolism can change how your body processes food. You may have difficulty shopping for, purchasing or preparing nutritious foods and meals.

If you’re having trouble maintaining a healthy diet, talk to a family member or your health care provider. Many communities have programs that provide healthy meals to seniors.

Changes in digestion also increase choking and food-borne illness risk in older adults. As you age, your body produces less saliva and stomach acid and your digestion slows down. These changes make it easier to choke on foods and make it harder to get rid of harmful bacteria in your system. Also, changes in smell and taste may impair your ability to know when a food is spoiled.

Slower digestion also can cause constipation. Make sure to get enough fiber—found in fruits, vegetables and whole grains—in your diet.

Lack of Exercise—Exercise is an important part of a good health at every age; however, many older adults don’t get the recommended amounts of physical activity. Staying active can boost vitality, help maintain strength and flexibility, improve mental function, reduce your risk for health problems, and even help relieve chronic pain. Be sure to talk to your health care provider before beginning an exercise program.

Senior Man Woman Tennis Image

Find an activity you enjoy and begin slowly. Try to incorporate endurance activities, strengthening exercises, stretching and balancing exercises into your exercise program. Good choices include walking, swimming, biking, gardening, tai chi and exercise classes designed for seniors.

Trouble Sleeping—Many older adults do not get enough sleep. Insomnia (difficulty falling or staying asleep) and excessive daytime sleepiness are common problems. Benign prostatic hyperplasia (BPH, enlarged prostate), which affects as many as 90 percent of men in their 70s and 80s, can cause frequent nighttime urination that disrupts sleep.

If you’re having problems sleeping, talk to your health care provider. These good sleep hygiene tips might be helpful:

  • Make sure your bedroom is dark and quiet and that it’s not too warm.
  • Adjust your bedtimes. Go to bed when you feel tired and get up at the same time each day.
  • Turn off the TV at least one hour before going to bed.
  • Wind down before bed by taking a bath or listening to soft music.

Other Concerns in Your 70s and Older

Safety is a serious issue for many seniors—especially those who are living alone and experiencing varying degrees of physical and/or mental decline. In addition to falls and choking hazards, concerns include the following:

  • Driving safety (Giving up driving means giving up a measure of independence. Seniors may be unwilling to stop driving, even though continuing to drive can pose a safety risk for themselves and for others.)
  • Fire/smoke safety (Memory lapses, which are more common in older adults, increase the risk for household fires caused by cooking, candles or smoking. It’s important to have working smoke detectors and carbon monoxide detectors in your home.)
  • Extremely hot or cold weather. (Seniors are at increased risk for health problems caused by hot or cold temperatures, especially when the cooling or heating systems in their homes aren’t functioning properly.)

Older adults are at increased risk for certain types of crime, including burglary and fraud—identity theft, fake check and wire transfer scams, investment and credit card fraud and fake online charity solicitations.

Unfortunately, many also are at risk for another type of crime that takes place in their home, in the home of a family member, or in a living facility or nursing home and is committed by people responsible for their care. Called elder abuse, this type of crime can take many forms. Elder abuse can be physical, emotional (psychological) or sexual. It may involve neglect, abandonment or financial exploitation. Physical elder abuse is the non-accidental use of force against an elderly person that causes injury or pain. It includes hitting, shoving and kicking, as well as misusing drugs, restraints or confinements on a person who is elderly.

  • Emotional or psychological elder abuse can be verbal or non-verbal. It includes intimidation (e.g., through yelling or threatening), humiliation and ridicule, as well as ignoring, terrorizing or isolating the elder from family and friends.
  • Sexual elder abuse involves sexual contact with a senior without his or her consent, as well as forcing the elder to view pornographic material, watch sexual acts or undress.
  • Neglect and abandonment are the most common type of elder abuse. They involve failing to fulfill care-taking obligations—either intentionally or unintentionally.
  • Financial exploitation elder abuse involves the unauthorized use of the elder’s assets—funds or property. It also includes health care fraud and abuse, which is carried out by unethical health care providers and involves charging for health care services not provided, overcharging for services, over- or under-medicating, and insurance fraud.

Health Care Recommendations in Your 70s and Older

Senior Couple Healthy Image

The risk for a number of medical conditions increases with age. In fact, some studies show that the average person 75 years of age has three chronic medical problems—ranging from minor to serious. If you have concerns or questions about your health, talk to your health care provider. You may find it helpful to have a trusted family member or friend accompany you to your medical appointments.

One of the most important ways to stay healthy in your 70s and beyond is to seek the care of a geriatric physician, also called a geriatrician. Geriatric physicians are medical doctors who specialize in the diagnosis, treatment and prevention of disease and disability in older adults. They are specially-trained in the aging process and provide comprehensive health care.

According to the Centers for Disease Control and Prevention (CDC), indicators that can be used to help assess health in older adults have been identified. These indicators are related to health status, health behaviors and compliance with preventative care recommendations and include the following:

  • Number of physically unhealthy days reported per month (due to illness or injury)
  • Frequent mental distress (depression, stress, anxiety or emotional problems reported on 14 or more days per month)
  • Complete loss of natural teeth
  • Current smoking status (smoker or non-smoker)
  • Lack of leisure time/physical activity
  • Regularly eating fewer than 5 fruits and vegetables per day
  • Obesity (body mass index [BMI] of 30 or greater)
  • Reported disability (physical, mental or emotional) that limits activity or requires special equipment (cane, walker, wheelchair, hearing-impaired telephone)
  • Hip fracture
  • Receiving a yearly flu vaccine
  • Following routine health care / screening procedure recommendations (cancer, high cholesterol)

General health care recommendations in your 70s and older include the following:

  • Blood pressure screening—every 2 years or as recommended
  • Bone mineral density test—as recommended to screen for osteoporosis (bone loss)
  • Cholesterol screening—every 5 years or as recommended
  • Colorectal cancer screening—as recommended
  • Dental exam—every 6 months or as recommended
  • Diabetes screening—every 3 years or as recommended
  • Eye exam—every 1 – 2 years or as recommended by an ophthalmologist
  • Hearing test—yearly or as recommended
  • Immunizations—yearly flu vaccine, herpes zoster vaccine (to prevent shingles; if not previously vaccinated), pneumonia vaccine (as recommended, if not previously vaccinated), tetanus (every 10 years)
  • Mammogram (women)—as recommended by your health care provider
  • Pelvic exam (women)—yearly or as recommended
  • Pap test (women)—as recommended by your health care provider (Most women over the age of 65 usually do not need this test.)
  • Prostate cancer screening (men)—as recommended by your health care provider
  • Thyroid test (TSH)—as recommended by your health care provider

Clean Eating

You’ve probably heard of clean eating, but you may not know what it is exactly or how to go about cleaning up your diet. It’s about eating more of the best and healthiest options in each of the food groups—and eating less of the not-so-healthy ones. That means embracing whole foods like vegetables, fruits and whole grains, plus healthy proteins and fats. It also means cutting back on refined grains, additives, preservatives, unhealthy fats and large amounts of added sugar and salt. And avoiding highly refined foods with ingredients you’d need a lab technician to help you pronounce.

Some clean-eating plans call for eliminating lots of food groups—think coffee, dairy, grains and more. We don’t believe in being that restrictive. Not only will you take away some of the enjoyment of eating, but there isn’t much science to back up any benefits. You need to find a clean eating style that works for you, even if that means eating a little “dirty” sometimes. If you only take a few steps toward eating cleaner—cutting back on processed foods, for example, or eating more fruits and veggies (and, if it works for you, buying a few more organic)—it can still make an impact on your health. Here are some helpful tips to get you started.

Zucchini Lasagna Rolls in a white baking pan

1. Load Up On Fruits and Vegetables

When it comes to fruits and vegetables, most of us aren’t getting enough. Per the Centers for Disease Control and Prevention, 76 percent of Americans don’t get enough fruit each day and a whopping 87 percent aren’t eating enough servings of vegetables. Eating more fruit and vegetables can help significantly reduce your risk for a number of chronic diseases, including high blood pressure, type 2 diabetes, heart disease, obesity and cancer. The fiber in whole produce also helps keep your microbiome (the collection of good bacteria that live in your gut) happy, which can reduce your risk for autoimmune diseases, fight off pathogens and infections and even improve your mood. Choose organic produce where you can, focusing on buying organic foods from the EWG’s Dirty Dozen list and cutting yourself some slack with the Clean 15 foods list.

Lemon-Pepper Linguine with Squash

2. Go Whole Grain

The cleanest whole grains are the ones that have been touched the least by processing. Think whole grains that look most like their just-harvested state—quinoa, wild rice, oats. While some people abstain from eating any processed grains, we think that whole-wheat pasta and whole-grain bread made with simple ingredients are part of eating clean. Sometimes you just need a hearty slice of avocado toast or a bowl of pasta. Don’t get duped by “whole-grain” claims on labels though, to eat clean packaged whole grains you’re going need to take a closer look at the ingredients. Whole grains should always be the first ingredient, the ingredient list should be short and recognizable, and it should have minimal (if any) added sugar. When you swap out refined carbs (like white pasta, sugar, and white bread) for whole grains you’ll get more fiber, antioxidants and inflammation-fighting phytonutrients. Plus, people who eat more whole grains have an easier time losing weight and keeping it off long term.

Kale Salad with Spiced Tofu & Chickpeas

3. Eat Less Meat

More and more research suggests cutting back on meat is healthier for you and the planet. Veganism isn’t a requirement for clean eating though—just eating less meat can help reduce your blood pressure, reduce your risk of heart disease and help keep your weight in check. Plus, eating more plants helps bump up the fiber, healthy fats and vitamins and minerals in your diet. And if you’re worried about getting enough protein by cutting down on meat—that shouldn’t be an issue. Most Americans get much more than the recommended 0.8 grams of protein per kilogram of body weight (approximately 56 grams daily for men and 46 grams daily for women) and it’s easy to get that much protein eating a vegetarian or even vegan diet. Eggs, dairy (for a clean option, choose dairy with no added sugar and simple ingredients) beans and nuts all offer protein—see our list of top vegetarian protein sources for even more options. When you do eat meat, choose options that haven’t been pumped with antibiotics and even better if they’ve lived and eaten like they would in the wild (think grass-fed beef, wild-caught salmon). Clean eating also means cutting down on processed meats like cold cuts, bacon and sausage.

Homemade Trail Mix

4. Watch Out for Processed Foods

We’re not opposed to all processed foods. Technically when we chop, mix and cook at home we are processing foods. The trouble is that so much of processed food at the grocery store is processed beyond the point of recognition. Nature certainly didn’t color those chips that neon color of orange or make blue candy-colored cereal. Keep an eye out for anything with lots of sugar and refined grains, super-long ingredient lists with foods you don’t recognize and anything with partially hydrogenated oils. Clean processed foods exist like plain yogurt, cheese, whole-wheat pasta, and packaged baby spinach. And while you can make salad dressings, pasta sauce, mayo, hummus and broth at home you can also find clean versions at the store. Just read the ingredient list. Our bodies digest processed and unprocessed foods differently. In the case of white bread vs. whole wheat bread the machine has already started to process the white bread for you—stripping away the bran and germ—and leaving your body with less work to do. Limiting packaged foods can also reduce your exposure to BPA (found in some canned foods) and other chemicals found in plastics.

No-Sugar-Added Oatmeal Cookies

5. Limit Added Sugar

Most people eat too many added sugars. The American Heart Association recommends no more than about 6 teaspoons per day for women and 9 teaspoons per day for men. The average American gets about 4 times that amount—28 teaspoons of added sugar per day. To clean up your diet, cut down on added sugars by limiting sweets like soda, candy and baked goods. But it’s more than just desserts—keep an eye on sugars added to healthier foods like yogurt (choose plain), tomato sauce and cereal. Look for foods without sugar as an ingredient, or make sure it’s listed towards the bottom, which means less of it is used in the food. And you don’t have to worry as much about naturally occurring sugars in fruit and dairy. They come packaged with fiber, protein or fat to help blunt the effect of sugar on insulin levels. They also deliver nutrients so you’re not just getting empty, sugary calories.