Immunomodulators in warts: Unexplored or ineffective?

Cutaneous warts are known to be recurrent and often resistant to therapy. Resistant warts may reflect a localized or systemic cell mediated immune (CMI) deficiency to HPV. Many modalities of treatment are in use; most of the provider-administered therapies are destructive and cause scarring, such as cryotherapy, chemical cauterisation, curettage, electrodessication and laser removal. Most patient-applied agents like podophyllotoxin have the risk of application-site reactions and recurrence. Thus immunotherapy is a promising modality which could lead to resolution of warts without any physical changes or scarring and in addition would augment the host response against the causative agent, thereby leading to complete resolution and decreased recurrences. Immunomodulators can be administered systemically, intralesionally or intradermally, and topically. A few agents have been tried and studied extensively such as cimetidine and interferons; others are new on the horizon, such as Echinacea, green tea catechins and quadrivalent HPV vaccine, and their efficacy is yet to be completely established. Though some like levamisole have shown no efficacy as monotherapy and are now used only in combination, other more recent agents require large and long term randomized placebo-controlled trials to clearly establish their efficacy or lack of it. In this review, we focus on the immunomodulators that have been used for the treatment of warts and the studies that have been conducted on them.     

Methodology Series Module 3: Cross-sectional Studies

Cross-sectional study design is a type of observational study design. In a cross-sectional study, the investigator measures the outcome and the exposures in the study participants at the same time. Unlike in case–control studies (participants selected based on the outcome status) or cohort studies (participants selected based on the exposure status), the participants in a cross-sectional study are just selected based on the inclusion and exclusion criteria set for the study. Once the participants have been selected for the study, the investigator follows the study to assess the exposure and the outcomes. Cross-sectional designs are used for population-based surveys and to assess the prevalence of diseases in clinic-based samples. These studies can usually be conducted relatively faster and are inexpensive. They may be conducted either before planning a cohort study or a baseline in a cohort study. These types of designs will give us information about the prevalence of outcomes or exposures; this information will be useful for designing the cohort study. However, since this is a 1-time measurement of exposure and outcome, it is difficult to derive causal relationships from cross-sectional analysis. We can estimate the prevalence of disease in cross-sectional studies. Furthermore, we will also be able to estimate the odds ratios to study the association between exposure and the outcomes in this design.     

Drug Interactions in Dermatology: What the Dermatologist Should Know

A drug interaction is a process by which a drug or any other substance interacts with another drug and affects its activity by increasing or decreasing its effect, causing a side effect or producing a new effect unrelated to the effect of either. Interactions may be of various types-drug-drug interactions, drug-food interactions, drug-medical condition interactions, or drug-herb interactions. Interactions may occur by single or multiple mechanisms. They may occur in vivo or in vitro (pharmaceutical reactions). In vivo interactions may be further subdivided into pharmacodynamic or pharmacokinetic reactions. Topical drug interactions which may be agonistic or antagonistic may occur between two drugs applied topically or between a topical and a systemic drug. Topical drug-food interaction (for example, grape fruit juice and cyclosporine) and drug-disease interactions (for example, topical corticosteroid and aloe vera) may also occur. It is important for the dermatologist to be aware of such interactions to avoid complications of therapy in day-to-day practice.     

Evaluation and Management of Polymyositis

Polymyositis (PM) is one of the inflammatory myopathies, disorders characterized pathologically by the presence of inflammatory infiltrates in striated muscle. The principal clinical manifestation of PM is proximal muscle weakness. The cause of PM is unknown, but current evidence suggests that it is an autoimmune disorder. PM can affect people of any age, but most commonly presents between the ages of 50 to 70. PM is rarely seen in people younger than 18 years of age, and is twice as common among females than males. PM is more common in blacks than in whites. The overall prevalence of PM is 1 per 100,000. Muscle weakness may develop suddenly or more insidiously over a period of weeks to months. The classic symptom of PM is proximal weakness, which may manifest as difficulty holding the arms over the head, climbing stairs, or rising from a chair. Weakness of the striated muscle of the upper esophagus may result in dysphagia, dysphonia, and aspiration. The chest wall muscles may be affected, leading to ventilatory compromises. Involvement of cardiac muscle may lead to arrhythmias and congestive heart failure. Dermatomyositis (DM) is closely related to PM, and both are distinguished primarily by the occurrence of characteristic skin abnormalities in the former. PM and DM may be associated with a variety of malignancies. PM may also occur as part of the spectrum of other rheumatic diseases like systemic lupus erythematosus and mixed connective tissue disease. Moreover, inflammatory myopathy may be caused by some drugs (procainamide, D-penicillamine), and viruses, most notably the retroviruses. Corticosteroids and immunosuppressive agents are the mainstays of therapy for PM. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness.     

Human Demodex Mite: The Versatile Mite of Dermatological Importance

Demodex mite is an obligate human ecto-parasite found in or near the pilo-sebaceous units. Demodex folliculorum and Demodex brevis are two species typically found on humans. Demodex infestation usually remains asymptomatic and may have a pathogenic role only when present in high densities and also because of immune imbalance. All cutaneous diseases caused by Demodex mites are clubbed under the term demodicosis or demodicidosis, which can be an etiological factor of or resemble a variety of dermatoses. Therefore, a high index of clinical suspicion about the etiological role of Demodex in various dermatoses can help in early diagnosis and appropriate, timely, and cost effective management.     

Biostatistics Series Module 2: Overview of Hypothesis Testing

Hypothesis testing (or statistical inference) is one of the major applications of biostatistics. Much of medical research begins with a research question that can be framed as a hypothesis. Inferential statistics begins with a null hypothesis that reflects the conservative position of no change or no difference in comparison to baseline or between groups. Usually, the researcher has reason to believe that there is some effect or some difference which is the alternative hypothesis. The researcher therefore proceeds to study samples and measure outcomes in the hope of generating evidence strong enough for the statistician to be able to reject the null hypothesis. The concept of the P value is almost universally used in hypothesis testing. It denotes the probability of obtaining by chance a result at least as extreme as that observed, even when the null hypothesis is true and no real difference exists. Usually, if P is < 0.05 the null hypothesis is rejected and sample results are deemed statistically significant. With the increasing availability of computers and access to specialized statistical software, the drudgery involved in statistical calculations is now a thing of the past, once the learning curve of the software has been traversed. The life sciences researcher is therefore free to devote oneself to optimally designing the study, carefully selecting the hypothesis tests to be applied, and taking care in conducting the study well. Unfortunately, selecting the right test seems difficult initially. Thinking of the research hypothesis as addressing one of five generic research questions helps in selection of the right hypothesis test. In addition, it is important to be clear about the nature of the variables (e.g., numerical vs. categorical; parametric vs. nonparametric) and the number of groups or data sets being compared (e.g., two or more than two) at a time. The same research question may be explored by more than one type of hypothesis test. While this may be of utility in highlighting different aspects of the problem, merely reapplying different tests to the same issue in the hope of finding a P < 0.05 is a wrong use of statistics. Finally, it is becoming the norm that an estimate of the size of any effect, expressed with its 95% confidence interval, is required for meaningful interpretation of results. A large study is likely to have a small (and therefore “statistically significant”) P value, but a “real” estimate of the effect would be provided by the 95% confidence interval. If the intervals overlap between two interventions, then the difference between them is not so clear-cut even if P < 0.05. The two approaches are now considered complementary to one another.     

Methodology Series Module 4: Clinical Trials

In a clinical trial, study participants are (usually) divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care). We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1) parallel study design, (2) cross-over design, (3) factorial design, and (4) withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV) or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials). Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an “open trial.” However, many of the trials are not open – they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India.     

Latex allergy in clinical practice

A continuous exposure or contact to latex products may sensitize the human body by causing mild to fatal reactions. Despite the availability of the literature, medical personnel are still unaware of the implications of the use of latex materials. The increased awareness to prevent the transmission of infectious blood borne pathogens has lead to increased usage of medical gloves among health care workers. This increased usage of medical gloves, along with improved methods in diagnosing latex allergy, has been the reason for the rise in the number of reported cases. This has lead to recognition of latex allergy as a serious medical concern. Patients in high-risk groups must be assessed carefully, so that appropriate protocols can be used to protect them from contact with latex.     

Profiling and Hormonal Therapy for Acne in Women

Acne vulgaris is the most common condition treated by physicians worldwide. Though most acne patients remit spontaneously, for the ones that do not or are unresponsive to conventional therapy or have obvious cutaneous signs of hyperandrogenism, hormonal therapy is the next option in the therapeutic ladder. It is not strictly indicated for only those patients who have cutaneous or biochemical evidence of hyperandrogenism, but can be used even without any evidence of hyperandrogenism, for therapy-resistant acne. It can be prescribed as monotherapy, but when used in combination with other conventional therapies, it may prove to be more beneficial. Hormonal evaluation is a prerequisite for hormonal therapy, to identify the cause behind hyperandrogenism, which may be ovarian or adrenal. This article reviews guidelines for patient selection and the various available hormonal therapeutic options, their side-effect profile, indications and contraindications, and various other practical aspects, to encourage dermatologists to become comfortable prescribing them.     

Epidermolysis bullosa acquisita with moderately severe Dysphagia due to esophageal strictures

Epidermolysis bullosa acquisita (EBA) is a chronic, autoimmune condition involving the skin and mucous membranes. Symptomatic mucosal involvement is rare, but can impact on quality of life, due to esophageal strictures and dysphagia. We report a case involving a 60-year-old male presenting with bullous skin lesions on areas of friction on his hands, feet and mouth. Milia were visible on some healed areas. Biopsy showed a subepidermal vesicle. Direct immunofluorescence showed intense linear junctional IgG and C3 at the dermo-epidermal junction. Serological tests also supported the diagnosis of EBA. Screening tests for underlying malignancies were negative. Despite treatment with systemic steroids, the patient developed increasing dysphagia, requiring further investigation with esophagoscopy and a barium swallow. Confirmation of extensive esophageal stricturing prompted adjustment of medications including an increase in systemic steroids and addition of azathioprine. Currently, the patient's disease remains under control, with improvement in all his symptoms and return of anti-basement membrane antibody levels to normal, whilst he remains on azathioprine 150 mg daily and prednisolone 5 mg daily. This case highlights the fact that the treatment of a given patient with EBA depends on severity of disease and co-morbid symptoms. Newer immunoglobulin and biological therapies have shown promise in treatment resistant disease. Considering that long-term immunosuppressants or biologicals will be required, potential side effects of the drugs should be considered. If further deterioration occurs in this patient, cyclosporin A or intravenous immunoglobulin (IV Ig) will be considered. Vigilance for associated co-morbidities, especially malignancies, should always be maintained.     

Methodology Series Module 2: Case-control Studies

Case-Control study design is a type of observational study. In this design, participants are selected for the study based on their outcome status. Thus, some participants have the outcome of interest (referred to as cases), whereas others do not have the outcome of interest (referred to as controls). The investigator then assesses the exposure in both these groups. The investigator should define the cases as specifically as possible. Sometimes, definition of a disease may be based on multiple criteria; thus, all these points should be explicitly stated in case definition. An important aspect of selecting a control is that they should be from the same ‘study base’ as that of the cases. We can select controls from a variety of groups. Some of them are: General population; relatives or friends; and hospital patients. Matching is often used in case-control control studies to ensure that the cases and controls are similar in certain characteristics, and it is a useful technique to increase the efficiency of the study. Case-Control studies can usually be conducted relatively faster and are inexpensive – particularly when compared with cohort studies (prospective). It is useful to study rare outcomes and outcomes with long latent periods. This design is not very useful to study rare exposures. Furthermore, they may also be prone to certain biases – selection bias and recall bias.     

BIOLOGICS: TARGET-SPECIFIC TREATMENT OF SYSTEMIC AND CUTANEOUS AUTOIMMUNE DISEASES

Biologics are becoming important in the treatment of systemic and cutaneous autoimmune diseases. They are designed to target specific components of immune system. As the new drugs are capable of targeting proteins in a more specific fashion, yet have lower risks of systemic side-effects, they have considerable advantages over the older immunomodulators. The development of TNF-alpha blockers in the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn''s disease and ankylosing spondylitis have been major breakthroughs. Likewise, B-cell depletion has proved to be equally revolutionary for the treatment of lupus, pemphigus, certain vasculitides etc. But all said and done, the development of these molecules and their clinical usage are still at evolving stages. Consensus needs be formed to further categorize the clinical profiles of the patients in whom biologics are to be used in the future, given that the long-term safety profiles of these agents are very much unknown at present.     

Methodology Series Module 1: Cohort Studies

Cohort design is a type of nonexperimental or observational study design. In a cohort study, the participants do not have the outcome of interest to begin with. They are selected based on the exposure status of the individual. They are then followed over time to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are (1) Framingham Cohort study, (2) Swiss HIV Cohort study, and (3) The Danish Cohort study of psoriasis and depression. These studies may be prospective, retrospective, or a combination of both of these types. Since at the time of entry into the cohort study, the individuals do not have outcome, the temporality between exposure and outcome is well defined in a cohort design. If the exposure is rare, then a cohort design is an efficient method to study the relation between exposure and outcomes. A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study. Follow-up of the study participants is very important in a cohort study, and losses are an important source of bias in these types of studies. These studies are used to estimate the cumulative incidence and incidence rate. One of the main strengths of a cohort study is the longitudinal nature of the data. Some of the variables in the data will be time-varying and some may be time independent. Thus, advanced modeling techniques (such as fixed and random effects models) are useful in analysis of these studies.     

Acrocyanosis: An Overview

Introduction:

It is a functional peripheral vascular disorder characterized by bluish discoloration of skin and mucous membrane due to diminished oxyhemoglobin. It may be due to central or local tissue oxygenation defects. It is a painful episodic disorder, where trophic changes and ulceration are very rare except in necrotizing variant. By definition, it refers to persistent abnormally deep blue or cyanotic discoloration of skin over extremities (hand and feet most commonly) due to decreased oxyhemoglobin.

Etiology:

It can be both primary and secondary to psychiatric, neurologic, autoimmune, infective, metabolic and other causes. The existing hypothesis suggests the prevailing role of vasospastic reaction over possible blood rheology impairment.[1] As per the current line of thinking, it is due to chronic vasospasm of small cutaneous arteries, and arterioles along with compensatory dilatation in the capillary and post capillary venules causes cyanosis and sweating.

Clinical Features:

Acrocyanosis is an uncommon condition. It usually presents with coolness and violaceous dusky discolorations of hands and less frequently the feet. Other peripheral part like ear, nose, lips and nipple can also be affected.[2] The changes may be transient after cold exposure but frequently persist during winter and even in summer.

Management:

There is no standard and curative medical or surgical treatment of acrocyanosis. In mild cases, it is unnecessary to give any drug treatment. Life style modification, dietary and hygiene counseling, avoidance of cold and reassurance that the bluish skin discoloration does not indicate any serious illness is all that is necessary.     

SCID MOUSE MODEL OF PSORIASIS: A UNIQUE TOOL FOR DRUG DEVELOPMENT OF AUTOREACTIVE T-CELL AND TH-17 CELL-MEDIATED AUTOIMMUNE DISEASES

In both skin and synovial tissues of psoriatic arthritis (PsA) patients, there are prominent lymphocytic infiltrates localized to the dermal papillae in the skin and the sublining layer stroma in the joint. T-cells, with a predominance of CD4+ lymphocytes, are the most significant lymphocytes in the tissues; in contrast, this ratio is reversed in the epidermis, synovial fluid compartment, and at the enthesis, where CD8+ T-cells are more common. This differential tropism of CD8+ T-cell suggests that the CD8+ T-cells may be driving the immune response in the joint and skin. This is supported by an association with MHC class I. The cytokine network in the psoriatic skin and synovium is dominated by monocyte and T-cell-derived cytokines: IL-1β, IL-2, IL-10, IFN-γ, and TNF-α. In PsA synovium, higher levels of IFN-γ, IL-2, and IL-10 have been detected than in psoriatic skin. An analysis of T-cell receptor beta-chain variable (TCRβV) gene repertoires revealed common expansions in both skin and synovial inflammatory sites, suggesting an important role for cognate T-cell responses in the pathogenesis of PsA and that the inciting antigen may be identical or homologous between the afflicted skin and synovium. Traditionally, T-cells have been classified as T helper 1 (Th1) or Th2 cells by production of defining cytokines, IFN-γ and IL-4, respectively. Recently, a new type of T-cell, Th17, has been linked to autoimmune inflammation. T-helper 17 (Th17) cells are a unique effector CD4+ T-cell subset characterized by the production of interleukin (IL)-17. Murine diseases that were previously considered to be pure Th1-mediated responses have been shown to contain mixed populations of Th1 and Th17 cells. Also, in humans, a critical immunoregulatory role of Th-17 cells in infectious and autoimmune diseases has been identified. It has been postulated that IL-17 may be important in psoriasis. Our initial observations demonstrate that IL-17 and its receptor system are important for PsA also. In in vivo and in vitro studies we have demonstrated that IL-17/IL-17R are enriched in skin, synovial tissue, and synovial fluid of psoriatic arthritis patients and Th17 cells are functionally significant in the pathogenesis of psoriasis and psoriatic arthritis. Here we will share our experience of the SCID mouse model of psoriasis in respect to its use in investigating psoriatic diseases and development of immune-based drugs for psoriasis, psoriatic arthritis, and other autoimmune diseases.     

Immunotherapy with Intralesional Candida Albicans Antigen in Resistant or Recurrent Warts: A Study

Background:

Warts are sometimes resistant or they tend to recur after every possible destructive therapy. Immunotherapy with skin-test antigens has been used as a viable therapeutic option in such recalcitrant cases.

Aim:

The aim of the study was to evaluate the response of resistant or recurrent warts to intralesional Candida albicans antigen immunotherapy.

Materials and Methods:

A total of 40 patients with resistant or recurrent warts who showed a positive test reaction to C. albicans antigen were given intralesional injections of purified C. albicans antigen solution in a single wart at 3-weekly intervals for a total of three doses. The patients were monitored for resolution of the injected wart as well as other untreated warts. The patients who responded positively were then followed up for any relapses over the next 6 months. Adverse events, if any, were also documented.

Results:

Of the 40 patients enrolled in the study, 34 completed the total treatment protocol of three injections and 6 months of follow-up. In these 34 patients, 19 (56%) showed a complete resolution of warts at all places on the body. In addition, two patients (6%) showed a partial or complete resolution of the treated wart, but there was no effect on the untreated warts. Thirteenpatients (38%) failed to show any response to the treatment regimen. In all patients showing resolution of all the warts, there were no relapses at any site over the next 6 months of follow-up. The most common adverse effect seen was pain during the intralesional injection.

Conclusions:

Intralesional Candida immunotherapy seems to be an effective treatment option in more than half of the patients who fail to show a positive response to destructive modes of treatment or in whom there are multiple recurrences.

Limitations:

The small sample size and lack of control group are the main limitations of the study.     

Methodology Series Module 6: Systematic Reviews and Meta-analysis

Systematic reviews and meta-analysis have become an important of biomedical literature, and they provide the “highest level of evidence” for various clinical questions. There are a lot of studies – sometimes with contradictory conclusions – on a particular topic in literature. Hence, as a clinician, which results will you believe? What will you tell your patient? Which drug is better? A systematic review or a meta-analysis may help us answer these questions. In addition, it may also help us understand the quality of the articles in literature or the type of studies that have been conducted and published (example, randomized trials or observational studies). The first step it to identify a research question for systematic review or meta-analysis. The next step is to identify the articles that will be included in the study. This will be done by searching various databases; it is important that the researcher should search for articles in more than one database. It will also be useful to form a group of researchers and statisticians that have expertise in conducting systematic reviews and meta-analysis before initiating them. We strongly encourage the readers to register their proposed review/meta-analysis with PROSPERO. Finally, these studies should be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis checklist.     

Multiple Dermatofibromas: Dermoscopic Patterns

Dermatofibromas are benign skin lesions that consist of pigmented papules or nodules. They produce the dimple sign when laterally squeezed and are usually found on the legs. These clinical features lead to the diagnosis in most cases. However, the differential diagnosis with other lesions, such as atypical nevi and melanoma can be difficult, and the dermoscopy may help the diagnosis. There are several dermoscopic patterns associated with dermatofibromas, the most common being a central white scar like patch with delicate pigment network at the periphery. This article describes the case of a patient who had eleven clinically similar dermatofibromas, with four distinct patterns when submitted to dermoscopic examination.     

Cutaneous Manifestations of Multiple Myeloma

Multiple myeloma (MM) is a proliferative disorder of plasma cells which produce abnormal immunoglobulin proteins. Skin involvement is rarely found in this disorder. They are either specific or nonspecific lesions. We report four such interesting patients who presented to us initially with common dermatoses such as leukocytoclastic vasculitis, pyoderma gangrenosum, and vesiculobullous disorders and were subsequently diagnosed to have MM. There were no skeletal involvements or renal function abnormality at the time of presentation. Unusual presentation, nonresponsiveness to conventional therapy, and abnormal blood parameters prompted us to suspect some underlying systemic conditions which were later confirmed to be MM after serum immunoelectrophoresis for M-band and bone marrow biopsy.     

Allergic Contact Dermatitis (Type IV Hypersensitivity) and Type I Hypersensitivity Following Aromatherapy with Ayurvedic Oils (Dhanwantharam Thailam,Eladi Coconut Oil) Presenting as Generalized Erythema and Pruritus with Flexural Eczema

Herbal and Ayurvedic medications, believed to be “mild” and “natural” are usually sought as the first line of treatment before resorting to “stronger” allopathic medication. There are very few reports of adverse reactions to either topical and/or systemic Ayurvedic medications. Massage aromatherapy with ayurvedic oils plays an important role in alleviation of pain, but may cause allergic contact dermatitis. This is the second case report of allergic contact dermatitis to ayurvedic oil.