Dr Shapiro, an expert in hair loss treatment, provided the audience with a practical approach to treating hair loss. Dr Shapiro practices in Vancouver, Canada and New York, New York. In Canada, he sees 60-70 patients per day and 70 percent of his patients are female. 35 percent are PHL and telogen effluvium, 30 percent are alopecia areata, and 35 percent are cicatricial alopecias.
In this summary, we will provide an overview of hair loss in women with a focus on Female Pattern Hair Loss.
Hair Loss in Women
It’s important to know that at least one third of women experience hair loss and the effect of hair loss on patients’ emotions is often greatly underestimated by physicians. As a clinician, it is imperative that you spend a good amount of time talking to your patients about their hair loss and trying to assess an approximate duration of time since their hair loss began. Of note, the youngest cases of MPHL and FPHL that Dr Shapiro has seen is age eight and it happens suddenly versus gradually. Another important step in evaluating hair loss is to assess the pattern. We should all be familiar with the Ludwig classification of Female Pattern Hairloss ranging from classes I to III. Also of importance is to address whether the hair loss is thinning or shedding. The key question for shedding is to ask “is there hair on your pillow” and “is there hair in your food.” You need to lose 50 percent of scalp hair to notice any change clinically. The next step in the evaluation is to determine whether the hair is falling out from the roots or whether it is breaking. Hair loss from the roots can be associated with AGA, telogen effluvium, or alopecia areata; hair breaking with tinea capitis, cosmetics/trichotillomania, or hair shaft abnormalities A thorough evaluation also includes taking a good family history and assessing hair care practices.
When talking to your female patients, you need to address any systemic illnesses, recent childbirth, recent surgery and any psychosocial stressors. Psychosocial stressors such as bereavement, break-up/divorce, and bankruptcy can initiate a telogen effluvium. New medications can initiate hair loss within one to three months. (Some of these medications include acetretin, heparin, interferon alfa, isotretinoin, and many more.)
Factors that might indicate an androgen excess and thus can contribute to hair loss include seborrheic dermatitis, acne, hirsutism, and irregular menstrual cycles. Other important questions include signs of hypo or hyperthyroidism, heavy menstruation, and a vegetarian diet.
Five Stages of the Clinical Evaluation
Distribution of hair loss
Inflammation, scale and erythema
Scarring vs. non-scarring
Quality of hair shaft
Pull test
There are several new diagnostic tools available for the scalp and these include dermascopy (10-fold magnification), videodermascopy (50-100-fold magnication), and folliscope which magnifies the scalp 50-100 times.
Alopecia in women can be categorized as Female Pattern Hair Loss, alopecia areata, and cicatricial alopecia: lichen planopilaris. In patients with Female Pattern Hair Loss, this is a crucial time to utilize the Ludwig Classification for FPHL.
Female Pattern Hair Loss
When assessing women with Female Pattern Hair Loss, it is important to test for any signs or symptoms of androgen excess. If there are no signs or symptoms, you can determine the class of hair loss based on the Ludwig stage. If there are signs or symptoms of androgen excess, an endocrine work-up should be performed. You may want to consider referral to either an endocrinologist or a gynecologist. From there, you can assess the Ludwig stage.
Ludwig stages I or II can be treated with topical minoxidil solution for one year. If there is no improvement, you may want to add:
Antiandrogen therapy + OCA (if childbearing age)
Hair transplation if donor area dense
Hair prosthesis
Hair cosmetics
If the patient has Ludwig stage III, a hair piece could be considered.
In conclusion, it is important to remember that patient education is crucial. There are websites available such as www.carfintl.org, www.naaf.org and www.nahrs.org.
Our great progress in understanding the underlying basis for immune-mediated and genetic diseases has led to breakthroughs in therapy beyond prenatal and preimplantation diagnosis. Newer technology, ranging from next-generation sequencing to microarrays to proteomics, has facilitated these breakthroughs. Gene replacement through skin grafts has been initiated for treating recessive dystrophic epidermolysis bullosa based on early mouse studies and our knowledge of the deficiency of collagen VII and stem cell therapy to replenish cells with collagen VII- or laminin 332-producing skin cells at wounds has been modified to decrease risk and increase efficiency.
The availability of technology to create induced pluripotent stem cells and direct their differentiation into skin cells means designable sources of both stem cells and skin cells for grafts. New technology, such as use of microneedles or topically applied interfering RNA, is being studied as well to suppress the abnormal protein product and correct dominant-negative skin disorders, such as epidermolysis bullosa simplex and dominant dystrophic epidermolysis bullosa. Laboratory-based technology has also delineated the alterations in RNA and protein expression that define cutaneous immune-mediated disorders and tumors.
By understanding pathways that are activated, new therapy has been developed to target specifically these pathways and suppress the overactive immune system or growth and survival pathways. Recognition of the key roles of TNF, IL-23, and IL-17 in psoriasis has revolutionized our intervention through the development of targeted biologics. The promising ongoing trials of IL-4 receptor antagonist and other blockers of Th2/Th22 pathways suggest that severe atopic dermatitis will similarly be treated with effective biologics. Already small molecules that target the activated signaling pathways in basal cell carcinomas (vismodegib), neurofibromatosis (imatinib for mast cells), and tuberous sclerosis (rapamycin) have suppressed tumor growth. Rapamycin is currently being applied to other disorders in which Akt/mTOR signaling is activated, such as venous malformations and could be considered for the subset of epidermal nevi with Akt pathway activation.
The other pathway leading to growth is the MAP kinase pathway, including through Ras and Raf activation. While a classic example of successful pathway suppression includes vemurafenib for Braf activation/ the Braf V600E mutation in melanoma, this MAP kinase pathway also plays a role in pediatric skin disorders of keratinocytes (e.g., epidermal nevi), melanocytes (e.g., several forms of pigmented nevi), and endothelial cells (e.g., portwine stains). Finally, protein or lipid replacement therapy is an option used for several noncutaneous genetic disorders and is finding its way to dermatology. Injected recombinant collagen VII protein is now in trials for adults with recessive dystrophic EB and the combination of a statin to suppress the accumulation of cholesterol pathway precursors and cholesterol to replete the deficiency from pathway blockade has been used topically to reverse the skin changes of CHILD syndrome (Congenital Hemidysplasia with Ichthyosis and Limb Defects), which results from an enzyme deficiency in cholesterol biosynthesis.
These examples are just the beginning of what laboratory breakthroughs can yield for our patients. The next frontier is epigenetics and scientists are now unraveling the mechanisms that control cell- and tissue-specific gene expression. We can only imagine what scientists will discover in the future to transform medicine through personalized mutation-based gene and pharmacologic therapy.
Dr Kavanaugh, a leading Rheumatologist, provides us with the top ten topics in vasculitis from his perspective.
There has been substantial change in the nomenclature for systemic vasculitides. Wegener’s granulomatosis is now being called GPA (granulomatosis with polyangiitis) and Churg Strauss syndrome is now being called EGPA (eosinophilic granulomatosis with polyangiitis). The 3rd similar systemic vasculitis is microscopic polyangiitis (MPA), which is distinct from polyarteritis nodosa (PAN).
GPA, EGPA and PAN are sometimes known as ANCA associated vasculitides because of their potential association with anti-neutrophil cytoplasmic antibodies (ANCA).
In addition to vessel size and ANCA, other factors relevant for vasculitides include the extent of involvement (limited vs diffuse) and the response to treatment.
Systemic Vasculitis can have diverse manifestations. The skin is involved in approximately 40-65% of patients with GPA, EGPA, MPA and PAN.
Internal organ involvement can be severe and serious and affect multiple organs. However, most areas of involvement will be apparent with only a directed history and physical examination, and a few straightforward laboratory tests and imaging procedures.
ANCA testing can be of value, but results MUST be interpreted in the correct clinical context. The quality of the lab is very important.
ANCA testing should not be relied upon as a predictor of disease activity for individual patients.
Treatment options for systemic vasculitides include methotrexate for many more limited disease manifestations, and cyclophosphamide for more severe disease. Treatment often must be continued to prevent relapses.
Rituximab has gained increasing attention as an effective therapy for severe systemic vasculitis.
There are mimics of vasculitis that clinicians should be aware of.
https://mauiderm.com/wp-content/uploads/2013/10/Kavanaugh-Photo.jpg520782Maui Derm Newshttps://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpgMaui Derm News2014-01-29 09:37:222014-02-20 17:53:48Top 10 Topics in Vasculitis from a Rheumatologist’s Perspective
Remember that acne can be categorized by age, i.e., neonatal (0-6wk), infantile (0-1), mid-childhood (1-7), preadolescent (7-12), and adolescent (12-19). Dr Eichenfield emphasizes that for dermatologists, mid-childhood (age 2 – 7) acne is the most worrisome. It can be associated with premature adrenarche, Cushings Syndrome, CAH, gonadal/adrenal tumors, and precocious puberty. Mid-child acne is very uncommon and dermatologists may want to consider a referral to an endocrinologist. The evaluation for mid-childhood acne includes testicular size (males), hirsutism, clitoromegaly, androgenetic alopecia, increased muscle mass, and deepening of the voice (males). If the acne is persistent, severe, or virilizing, tests/examinations include a growth chart, evaluation including bone age, tanner stage, Total/Free testosterone, DHEAS, androstenedione, LH, FSH, prolactin, and 17OH-progesterone.
What do the new guidelines say?
These guidelines were developed by the American Acne and Roseacea Society and endorsed by the American Academy of Pediatrics, which is the first time that the Academy has a set of guidelines for the management of acne. One of the main reasons this was done was to address the gap between pediatric dermatologists and pediatricians. It’s important to know that pre-adolescent (7 ≤ 12 years) acne is common and may precede other signs of pubertal maturation. Work-up beyond history and physical is generally unnecessary unless there are signs of androgen excess, polycystic ovarian syndrome, or other systemic abnormalities. There is evidence that acne, and possibly puberty, are now occurring at an increasingly earlier age.
A recent analysis of the National Ambulatory Medical Care Survey (NAMCS) database assessed trends in the age of children seeking treatment for acne. NAMCS data from 1979 through 2007 were analyzed for all physician visits in which acne vulgaris was listed as a diagnosis in children aged 6 to 18. The analysis revealed a significant decrease in the mean age of children seeking treatment for acne over this period.
Over the past several years, clinicians have noted an earlier onset of acne—that is, the appearance of acne in patients as young as 8 or 9 years. Indeed, it has been suggested that 12 years of age should no longer be considered the low end of the “normal” range for the onset of acne.
Acne may be the first sign of the onset of puberty in children aged 7 to 11 years. The general clinical impression of earlier puberty is, in fact, supported by epidemiologic data in the US and elsewhere. In general, the trend toward earlier puberty is stronger among girls than among boys. In any event, the earlier onset of acne has mirrored the downward trend in puberty timing.
Acne Guidelines: Highlights
Topical retinoids may be used as monotherapy or in combination products and in regimens of care for all types and severities of acne in children and adolescents of all ages. It is important to remember that topical antibiotics are not recommended as monotherapy and if a topical antibiotic treatment is to be used for more than a few weeks, topical benzoyl peroxide should be added, or used in combination products. The guidelines also suggest that fixed-dose combination topical therapies may be useful in regimens of care for all types and severities of acne. With regards to oral antibiotics, they are appropriate for moderate to severe inflammatory acne vulgaris at any age. Tetracycline derivatives should not be utilized in children 8 years of age and below. Second generation tetracyclines are sometimes preferred to tetracycline because of ease of use, fewer problems with absorption with food and minerals in vitamins and other supplements, and less frequent dosing. It’s very important that patients are educated and monitored for potential adverse events when utilizing oral antibiotics for acne. Combined oral contraceptives may also be useful as second-line therapy in regimens of care in pubertal females with moderate to severe acne; however, tobacco use and family history of thrombotic events should be assessed. Due to concerns about growth and bone density, many recommend withholding OCs for acne until one year after onset of menstruation. Isotretinoin is recommended for severe, scarring, and/or refractory acne in adolescents and may be utilized in younger patients. Remember that extensive counseling, particularly regarding the avoidance of pregnancy, as well as careful monitoring of potential side effects and toxicities, is recommended.
In this section, Drs Frieden and Friedlander reviewed coxsackie onychomadesis, the treatment of onychomycosis in children and a how to best obtain nail specimens in kids.
Healthcare providers should be aware that onychomadesis is a sequela of HFMD and fairly commonly seen after coxsackie A-6 infection. With onychomadesis, you typically see shedding of the fingernails and toenails within one to two months after HFMD. Onychomadesis can appear in the form of exaggerated Beau’s lines. It is not surprising that this happens with infection, but why can it occur with mild disease? Osterback R et al obtained shed nails from two siblings with onychomadesis who had HFMD eight weeks before the nail shedding. The nail clippings were enterovirus positive by RT-PCR and one case was identified as CVA6. Dr Frieden believes that this may, in fact, be an infection of the nail matrix and not merely a physiological response of stopping nail growth.
Onychomycosis
Fungal nail infections are more common in adults; however, they DO affect children (0.16%). The incidence of fungal nail infections in children may be increasing due to occlusive foot lifestyle. While families want their children to be “perfect”, they are reluctant to put their children on prolonged systemic therapy, and do they want their children to undergo lab studies. It is important to keep in mind that children have thinner nails and; therefore, grow faster.
How do we best approach fungal nail infections in children? A study by Lawry MA, et al. showed that the best approach to diagnosing fungal nail infections is through PAS and culture and the second best approach is PAS.
Clinical Pearl: Dr Frieden comments that one of the best ways to get a diagnosis of onychomycosis in a small child is by using a disposable curette. Kids are not as afraid of this versus a scalpel because this instrument is blunt and looks more like a spoon. This is a great technique for a KOH or culture specimen.
How do we treat children?
Benign neglect (this is certainly still a reasonable approach)
Ciclopirox, amorolfine lacquer, bifonazole-urea
Griseofulvin 20/kg for at least 6 months; don’t exceed 1 gram (compliance can be difficult as well as side effects)
Terbinafine 5mg/kg/d don’t exceed 250mg; FN 6 wks; TN 12 wks (Families can get a month supply for $3-$6)
Fluconazole 6mg/kg/week once a week; FN 12 weeks; TN 26 wks
Dermatologists should know that onychomycosis does not always require systemic treatment for a cure. Dr Friedlander and her colleagues conducted a prospective trial of forty children with non-matrix nail disease. 30 patients (25 male and 15 female with a median age of 9.8) were placed on active topical ciclopirox lacquer and 10 patients on vehicle. The lacquer was applied daily and nails were trimmed weekly for 32 weeks. If the patients had a poor response, they were rolled over to active treatment at week 12. The only known AE was a transient discoloration of the nail.
The graph above shows that 77 percent of these patients had mycologic cure, 71 percent had effective treatment and 34 percent had a complete cure. These numbers are much higher than what we see in adults. These patients were followed over one year and the vast majority of them did not relapse. When asked about quality of life and whether or not the patients would undergo this treatment again, over 90 percent responded “definitely yes” or “probably yes.” (Friedlander SF et al. Ped Dermatology. 2012;Dec28)
This trial was just a a small pilot study, and thus needs to be repeated. Non-lunula nail disease can remit without medication (n =2); and topical therapy appears to work better in young nails than in adult nails. This data suggests that topical therapy may be a reasonable option as first-line therapy for some children with fungal nail disease.
There are new products currently being studied for the treatment of nail disease. Nuvail, for example, is an innovative approach in that it is a poly-urethane vapor permeable substance. It is currently marketed for dystrophic/brittle nails. A small prospective study of Nuvail in 62 patients demonstrated 60 percent improvement in six months and a 62 percent mycologic cure in six months. Stay tuned for more information….
https://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpg00Maui Derm Newshttps://mauiderm.com/wp-content/uploads/2013/04/MD-WebLogo.jpgMaui Derm News2013-12-17 11:44:032014-01-13 08:31:09Pediatric Dermatology: Nail Diseases
Dr Frieden discusses the new manifestations of an old disease. Classic HFMD presents with exanthem (skin) and (enanthem) mouth symptoms. Skin symptoms include grey-white vesicles on the palms and soles and occasionally on the buttocks, diaper area, knees and elbows. Mouth symptoms include vesicles and erosions on anterior oral mucosa and are very painful.
From November of 2010 to February 2011, 63 cases of atypical HFMD were reported to the CDC. 34 cases had vesicle, stool, blood, and/or respiratory samples. 74 percent of these cases were PCR positive for coxsackie A6, whereas in the past in North American most cases were due to coxsackie A16. These patients differ from those with classic HFMD in that there was a wider age range, greater than ten percent of the body surface area was involved, these patients had fevers and a rash that appeared “severe”, and they had findings of “locus minoris resistentiae.”
Mathes E and colleagues published a report on coxsackie exanthems characterizing the 2011 outbreak of the emerging viral type, A6. There were 64 children and 18 and ot 19 were positive for PCR enterovirus. 58 percent of the children had atopic dermatitis, 56 percent had ecema herpeticum-like eruptions which were termed “eczema coxsackium”. Additionally 22 percent had findings of locus minoris, 35 perecent had Gianotti-Crosti-like eruptions and 18 percent had hemorrhagic purpuric or petechial skin lesions. (Mathes E, et al. Pediatrics. 2013;132(1):e149-157.) This virus can also affect adults. An important sequellae is onychomadesis which can develop two to four weeks after infection.
New Ways to Diagnose Viruses
Traditionally, it was difficult and expensive to find out which/whether a specific virus was pathogen. Viral cultures are expensive and the question remained as to what to look for. Acute and convalescent titers were the “gold standard”, but follow-up studies were required so you didn’t receive the answers you were looking for right away. Dr Friedlander comments that we are now lucky enough to have commercially available multiplex PCR diagnostic panels for viruses. These panels are available in some labs or hospitals. They can typically detect influenza A and B, adenovirus, parainfluenza 1-3, respiratory syncytial virus A and B, human metapneomovirus and human rhinovirus. Other panels can detect coronavirus, coxsackie/echo virus, bocavirus, adenoviruses, parainfluenza and seasonal influenzas. This is a positive step as it provides clinicians with the ability to have answers more rapidly than previously.
In this presentation, Drs Frieden and Friedlander discuss infantile hemagiomas, coxsackie and beyond, and nail disease.
Infantile Hemangiomas (IH): What We’ve Learned
At USC, Dr Friedlander and her colleagues followed 500 babies in a prospective study looking at the incidence and risk factors for IH. They found that overall 4.5 percent of infants were affected. The risk factors included placental anomalies (35 percent of IH deliveries) and gestational age (extreme prematurity). One of the unexpected findings was that of location (53 percent were located on trunk, only 12 percent on the head and neck), this would make sense with what one would expect as the trunk is a larger body surface area. They also found that 91 percent of the hemangiomas were focal and 23 percent were abortive/telangiectatic. The most important thing that was discovered was that only one of the 34 lesions discovered on the 500 babies needed intervention. This is reassuring information and can help guide clinicians to “worry less” about small truncal lesions: however facial and larger lesions should be evaluated early to determine if intervention would be appropriate. .
IH: Where do they come?
Dr Friedlander comments that the worrisome cases are those where the potential for functional deformity or cosmetic disfigurement exist. There are three major theories that most experts are comfortable with regarding the pathogenesis of IH. The first is placental embolization; supporting evidence for this includes the following: IH share surface characteristics with placental tissue (glut-1, HPL). In addition, placental markers (hCG and hPL) are expressed on endothelium of proliferating, but not involuting IH tissue. Other similarities between placental and IH tissue have been identified through DNA profile clustering analysis.
The second theory concerns a somatic mutation in a gene mediating endothelial cell proliferation (VEGF receptor). VGEF (vascular endothelial growth factor) can be likened to a stimulus package for endothelial cells. Most of the time VEGF will complex with an inhibitory receptor. If there is not enough of the inhibitory receptor (VEGF 1) around, then VEGF will complex with other “more stimulatory type” VEGF receptors and proliferation then results. Angiogenesis is a tightly regulated balance of promoting and inhibitory factors. In the simplified model below, complexing of VEGFR2 with VEGF activates EC proliferation.
The third theory, which is the most popular right now, is that IH may result from a combination of factors, including the presence of an area of localized hypoxia Vascular cells in this area of low oxygen tension produce hypoxia inducible factor (HIF). HIF sends a message to endothelial progenitor cells in the bone marrow, which then “home” to the hypoxic area and proliferate there.
Why do the endothelial progenitor cells (EPCs) misbehave in the first place? Perhaps they possess a mutation such as mentioned in theory 2, perhaps it is just the hypoxic endothelial cells, in a particular area, expressing “recruitment” factor for EPCs. . It has been found that infants with IH have an increased number of circulating EPCs, supporting this latter theory.
The general belief is that all of these theories could be involved with IH.
Therapy for IH
Dr Frieden comments that extrapolating from the data from Dr. Friedlander’s study, about one in every thousand infants will need an intervention for a hemangioma. For several years, beta-blockers have been studied as a treatment for IH. There are more than 240 articles published. Dr Frieden and her colleagues conducted a systematic review of 41 case series, with greater than ten patients, looked at a total of 1264 patients. 28 percent of the patients received prior treatment, most commonly oral prednisolone. Propranolol was initiated at the mean age of 6.6 months at a mean dose of 2.1 mg/kg/day. The mean duration of treatment was 6.4 months. The results of this systematic review demonstrated a response rate of 98 percent (range 82-100 percent). The response rates were comparable irrespective of anatomic sites. There was rebound growth in 17 percent. Adverse events occurred in about three to five percent, with sleep changes and acrocyanosis being the most common. Serious AEs were rare. (Marqueling et al. Pediatr Dermatol. 2013; 30(2):182-91.
In Dr Frieden’s experience, this response rate really parallels that of isotretinoin, i.e. it works so well that you don’t really need statistics to prove that it works. Dr Frieden also comments that in her practice, they have been treating IH with propranolol for several years and have seen remarkable results.
Steroids versus Propranolol
Another systematic review compared steroids to propranolol. The review of literature was conducted from studies from 1965-2012; 16 studies (2,629 patients) versus 25 studies (795 patients). The overall efficacy rate for systemic steroids was 71 percent compared to 97 percent for propranolol. AEs for steroids were 17.6 percent versus 13.7 percent in propranolol. This review concluded that propranolol has greater efficacy and acceptable AEs for the treatment of IH. (Izadpanah A, et al. Plast Reconstr Surg. 2013;131(3):601-613.)
Propranolol Consensus Guidelines
Dr Frieden and her colleagues developed guidelines in order to come up with best practices for treating these patients. It is important that dermatologists understand whether patients should be treated inpatient or outpatient. Inpatient hospitalization is suggested for infants younger than eight weeks of age including gestationally-corrected age for preterm infants, any infant with inadequate social support, and any age infant with comorbid conditions affecting the cardiovascular or respiratory systems. Outpatient treatment with monitoring can be considered for infants/toddlers over eight weeks of age with adequate social support and no significant comorbid conditions.
Regarding monitoring, the peak effect of oral propranolol on HR and BP is one to three hours after administration. Patients should be monitored with HR and BP measurement at baseline and at one and two hours after receiving the initial dose. This should be repeated with significant dose increases, i.e., greater than 0.5 mg/kg/day, including at least one set of measurements after the target dose has been achieved. If HR and BP are abnormal, then the child should be monitored until the vitals signs normalize and if necessary the dosage adjusted. The cardiovascular effects are usually most pronounced after the first dose so there is no need to repeat monitoring for the same dose again unless the patient is very young or has comorbid conditions. Of note, HR is usually easier to accurately obtain than BP.
With regards to hypoglycemia, routine glucose testing is not recommended. The risk of hypoglycemia is age-dependent and is related to the effects of propranolol on gluconeogenesis and glycogenolysis. Hypoglycemia ia more likely to occur if a child has had a prolonged period of time without oral intake and is age dependent. Infants less than six weeks of age should be fed at least every four hours, infants six weeks to four months should be fed every five hours and infants greater than four months every six to eight hours. Propranolol should be temporarily discontinued during intercurrent illness, especially in the setting of restricted oral intake.
Providers must remember that these guidelines are based on current knowledge and should be considered provisional. Martin. et al have written an article providing written instructions re: propranolol therapyr for parents and caregivers. It is a useful educational tool and resource for these parents and includes extremely helpful information. (Martin K, et al. Pediatr Dermatol. 2013;30(1):155-159.
How do beta blockers work?
Both speakers agree that we don’t fully understand how this class of medications works for IH. One of the theories is that they decrease rennin production. The second theory is the regression via HIF-1-alpha-mediated inhibitor of VEGF-A and the third theory is the inhibition of “homing” of endothelieal progenitor cells to hemangioma sites, as Dr Friedlander previously discussed.
Topical Beta Blockers
Sometimes the risk-benefit ratio of propranolol is of concern. We now have an option with the topical beta blocker, timolol, which has been previously approved for adult and pediatric glaucoma. There have been at least twenty articles since February 2010 with approximately 175 patients evaluated. Nearly all of these studies were retrospective with the largest series being of 73 patients. Most of the studies utilized timolol ophthalmic solution but two reports used compounded propranolol. There were varied concentrations and frequency, however timolol 0.5% gel-forming solution is most commonly used, typically with a – duration of three months or more.
Collectively, reports in the past two and a half years have shown encouraging results with topical beta blockers. Lesions on the eyelid tend to do particularly well, as do hemangiomas which are more superficial and smaller in size. Preliminary reports suggest that timolol is well tolerated, in that there have been no significant toxicity reports to date. The drug is also relatively inexpensive. It is important; however, to remember that timolol has a relatively higher potency and there is a risk of achieving significant blood levels, particularly in small premature infants. The quantity used should be limited; some healthcare providers use a maximum of one drop two times per day.
Multimodal Therapy
We have seen beneficial effects of early pulsed dye laser (PDL) therapy in individuals with infantile hemangiomas. (Admani S et al. Dermatologic Surgery. 2012;1-7)Multiple cases have demonstrated that in some cases you can do better with combination therapy, such as steroid use and PDL or beta blockers and PDL. Mixing and matching with regards to treating IH is a reasonable approach.
Dr Zone has treated over one thousand patients with Dermatitis Herpetiformis (DH). It usually presents as itchy, red bumps in the elbows and knees. DH should be diagnosed through a biopsy and Dr Zone recommends biopsying in the area close to redness, but not directly on the red bumps.
There have been several studies looking at the prevalence of DH. The numbers in Europe are very similar to those of the United States. It is a genetic disease but it is distributed throughout life. We don’t know what the factors are that set off the onset of disease. We do, however, know that people with DH express the entire range of intestinal abnormalities. Some people will have Grade IV and others will only have Grade I.
Dr Zone stresses another important point that people with DH develop antibodies to epidermal transglutaminase (TG3). Dr Zone states that roughly one in six celiac patients will develop DH.
What about people who have intestinal inflammation, but don’t have DH or symptomatic CD?
It is important to consider that celiacs may have:
Only aphthous stomatitis
Only eczema
Only alopecia areata
Only psoriasis
Diabetes
Only fatigue or anemia
What this means is that all of the diseases mentioned above might be associated with celiac disease, it is pretty rare, but those people who have it might get better on a gluten free diet.
A 1998 paper studied oral ulcers and celiac disease. They found that approximately five percent of patients with “idiopathic” apthous stomatitis have been found to have positive endomysial antibody tests and then CD on small bowel biopsy. Stomatitis will clear with a gluten free diet. (Jokinen J et al: Celiac sprue in patients with chronic oral mucosal symptoms. J Clin Gastroenterol.1998; 26:23-26) In a 2008 study, the researchers looked at 269 kids ages 3 to 17 with CD and 575 otherwise healthy subjects. They found apthae in 61 of the 269 kids (22.7%) and 41 of the 575 normals (6%). 33 out of 46 CD kids on a strict gluten-free diet reported significant improvement or clearing of apthae. (Campisi et al. Dig Liver Disease. 2008 40:104-107)
Alopecia Areata (AA)
Alopecia areata is a T-cell mediated disorder that produces hair loss. Some studies have shown that patients with AA and CD have regrown hair with a gluten free diet (GFD) others have seen no effect of GFD. Also of note, chronic diseases can make the response to a GFD less likely. Dr Zone states that there is probably about one in 100 chance of having celiac disease. The questionable association between CD and AA and hair regrowth will only be answered by a prospective trial of testing new onset AA kids for total serum igA and tTG, establishing CD rate, and then comparing the outcome on GFP compared to non CD kids on a normal diet.
CD and Psoriasis
Take Home Point—CD occurs at a slightly increased frequency in psoriasis patients and response to a GFD has been reported.
A 2002 study of patients with long standing psoriasis who were found to have CD all had marked improvement on a GFD. Psoriasis patients with positive anti-gliadin antibodies have improved on a GFD. The prevalence of positive EMA and tTG antibodies is no greater than the rest of the population (1:133). The question is “is gluten a source of chronic antigen stimulation in psoriasis?” (Cardinali et al. Br J Derm. 2002.147:187-188)
CD and Atopic Dermatitis
There is no increased incidence of atopy in CD patients but patients with dermatitis who are shown to have CD will improve on a GFD. This was a large case controlled study of 82 CD patients and 180 matched controls and their first-degree relatives. The researchers found increased prevalence of asthma, eczema, rhinitis, or elevated IgE levels. However, patients with eczema and Cd did improve their eczema on a GFD. (Greco L, et al. Paediatr Scand. 1990 79:670-74)
Take Home Points
Screening in patients with these disorders (serum IgA and IgA tTG(TG2)) will result in 1-2% positivity (low yield)
But: Patients with a (+) result who are then treated with a Gluten Free Diet will likely likely have response of their skin disorder to dietary restriction of gluten
What about people who are “gluten sensitive?”
There is a group of people who have gone on gluten free diets and say that they feel better. These are people with normal IgA tTG and normal small bowel biopsies. Up to 50 percent of these people do have the high-risk genotype (higher than the 25 percent in normals). A 2012 studied demonstrated that certain symptoms can improve with dietary gluten restriction including GI symptoms, neurological symptoms, skin symptoms and “brain fog” (the most common symptom). These were all patients with a normal intestinal biopsy. (Lundin EA and Alaedini A:Non-gluten sensitivity. Gastrointest Endosopy Clin N Am. 2012. 22: 723-734) A study at the University of Maryland documented that symptoms could be induced by gluten through a blinded challenge that they performed at the university.
In patients with non-celiac gluten sensitivity, adaptive immune response (IgA, tTG, IgE anti wheat and cellular response to gliadin, etc.) cannot be identified. These patients have normal intestinal biopsies and multiple symptoms in response to gluten ingestion that do not occur with placebo. These people may have an innate immune response that can occur in the absence of HLA DQ2. There are also no serologic markers.
Dapsone Treatment
This is the most common question that Dr Zone hears from colleagues. Dapsone is a major oxidant stress to red blood cells. It is important to make patients aware of hemolytic anemia and the blue/gray color associated with methemoglobinemia. Clinical management should stress the maintenance of the smallest dose necessary to control the disease. Occasional new DH lesions (2-3/week) are to be expected, and are not an indication for raising the dose. Before initiating Dapsone treatment, you should perform a baseline CBC and Chem profile; G-6-PD in asians, blacks or those of southern mediteranean descent. You should start your patients at 25 mg. daily and increase 25 mg. weekly until the symptoms are controlled. CBC should be performed weekly for four weeks, then monthly for six months, then semi-annually. Chem profile should be performed at six months and then annually.
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Dr Zone has been studying gluten since the 1970s. He comments that recently, all we hear about is gluten sensitivity and gluten free diets. In fact, there are entire sections in the supermarket that are dedicated to gluten sensitivity. This used to be considered rare and now, it appears, that everyone has it. There are now improved methods for diagnosing celiac disease and so the number of people diagnosed has increased. However, there is also a population of people who have self diagnosed gluten sensitivity.
What is gluten?
Gluten is a group of proteins from grains that are insoluble in water. It is made up of prolamins and glutelin. Prolamins are high in proline, alcohol soluble, and monomeric. Glutelin, which we know less about, is soluble in dilute acid or alkali and is comprised of aggregated polymers. Dr Zone mentions that the initial studies feeding people various fractions of gluten were conducted during the 1950s and 1960s, prior to IRBs, “we could feed people a lot of things that we can’t feed people now” and they found that a particular fraction of gluten, the prolamins, were toxic. (The glutelin fraction was never studied) Existing prolamins include gliadin (wheat), hordein (barley), and secalin (rye), all of which may induce celiac disease. Glutenin (wheat), which is a glutelin, may be pathogenic in celiac disease, but this has not yet been confirmed.
Wheat Allergy
In dermatology, we don’t always think about food-induced allergies. Wheat allergy is IgE mediated, i.e., crosslinking of IgE molecules bound to basophils and mast cells. It is repeat sequences in gluten peptides, e.g., serine-glutamine-glutamine-glutamine-glutamine-proline-proline-phenylalanine—not necessarily gliadin. This subsequently releases chemical mediators such as histamine.
The reason why patients with urticaria don’t always respond to anti-histamines is because they are also releasing TNF, proteases, heparin, and IL-5. This is why some people with urticaria will get better with TNF inhibitors.
Wheat Dependent Exercise Induced Anaphylaxis
Dr Zone has seen this on two occasions and it can be quite dramatic. One of his patients had a severe reaction after exercising and they deduced that it occurred because he had eaten gluten; as he didn’t eat gluten before execising, he could continue playing squash. This is caused by omega gliadin and the way to test for this is through a skin test or challenge.
Celiac Disease
Celiac disease is also known as gluten sensitive enteropathy, celiac sprue, and non-tropical sprue. One in 100 Caucasian Americans do have celiac disease. This is an HLA-associated disease. 90 percent of celiac disease and DH patients express HLA DQ2; 9 percent express DQ8. 20-25 percent of Caucasians have DQ2 or DQ8. The receptors coded by the HLA genes are essential for the processing of the gliadin antigen in celiac disease. So if you think about the people out there buying gluten-free foods, 20-25 percent of them have the gene makeup to process the gliadin antigen and develop an immune response. So, essentially, lsss than 5% of the people with the correct HLA genes will develop clinical celiac disease, others may have silent or latent celiac disease and some healthy individuals have all of the genetic makeup to develop celiac disease, yet they will never get it.
It’s important to remember that celiac disease clusters with other autoimmune disorders such as Addison’s disease, autoimmune thyroiditis, atrophic gastritis, SLE, RA, myasthenia gravis, and vitiligo. The interesting thing about this is that we know the antigen that precipitates the autoimmunity. Celiac disease is also common in Down’s syndrome.
Dr Zone comments that it is a “huge mistake” to go on a gluten free diet without first being tested for celiac disease. There is range of pathology in celiac disease that can be seen by proximal small intestinal mucosal immunopathology. Dr Zone also states that he and many of his colleagues were taught that to have celiac disease, you have to have a bloated abdomen, be malnourished and short and skinny…this is how it was described in the past.
What is celiac disease?
Celiac disease is an inflammatory injury of the small intestinal mucosa after ingestion of gluten in wheat, rye, or barley. We can see improvement once gluten is withdrawn from the diet. It is important to remember that many patients with histological inflammation have atypical intestinal symptoms or no symptoms at all. Clinical studies have shown that only 15-20 percent of CD and DH patients identified by serology and confirmed by biopsy have classical symptoms of diarrhea and malabsorption.
So how do you diagnose celiac disease? IgA tissue transglutminase (TG2) is the hallmark of celiac disease and correlates with the severity of intestinal inflammation. A 2003 study looked at the prevalence of CD in the United States based on IgA tTG testing of serum found the following ratios:
1:133 in not at risk individuals
1:56 in symptomatic patients
1:39 in second degree relatives
1:22 in first degree relatives
This demonstrates that CD is common, and not rare. (Fasano et al: Prevalence of Celiac Disease in at Risk and Not at Risk Groups in the United States. Arch Intern Med. 2003; 163: 286 – 292)
Conclusions
Celiac disease is as common as psoriasis and can be found in one to two percent of the Caucasian population. CD profoundly affects the immune system, which is the modulator for inflammatory skin disease.
It is important to remember that most celiac patients have few or no symptoms at all. There is a wide range of intestinal abnormality and the high risk genotype is essential for pathogenesis.
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