B-Cell Targeted Therapy in Autoimmunity

Written by: Judy Seraphine Based Upon a Presentation Delivered by Arthur Kavanaugh, MD at the 2012 Maui Derm 

Introduction

B cells may play a prominent role in a number of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, pemphigus/pemphigoid, vasculitis, and many others. The mechanisms by which B cells may play a role in autoimmunity include autoantibody secretion, modulation of immune/inflammatory reactions via ctyokines and other mediators, antigen presentation / co-stimulation of T cells, and  lymphoid organogenesis in target organs. The activity of B cells in autoimmunity represents a loss of immunologic tolerance. The targeting of B cells specifically is now possible; the first approved agent being the anti-CD20 monoclonal antibody, rituximab. Clinicians should be aware that B cells may be targeted in many other ways and the results on the efficacy and safety of these approaches are forthcoming. Safety issues related to targeting of B cells may be both agent-specific as well as target-specific and the major concerns include the potentially increased risk of infections.

B Cells – Autoimmunity: History

Paul Ehrlich, the “Grandfather” of autoimmunity, first studied B cells in autoimmunity via histologic staining and the identification of blood cells. More importantly, Dr Ehrlich came up with the side chain theory, i.e., a specific receptor for a counter-receptor on a type of cell. This really helped develop chemotherapy or the “magic bullet” theory, i.e., a single, very focused therapy would go straight to its target and not hurt the other tissue. However, scientists noted that this could go wrong and; therefore started what was known as “horror autotoxicus”, the idea that the body was attacking itself. In Rheumatology, the identification of autoantibodies, specifically rheumatoid factor (RF) and anti-nuclear antibodies (ANA) came about in the 1940s and really brought B cells into the forefront.  In 1952, Bruton researched  X-linked agammaglobulinemia, and the 1960s researchers began to the identify B cells. In the 1960s and 1970s, there was very important work done in autoimmunity, specifically, clonal deletion, clonal anergy and idiotypic network.  In 1975, monoclonal antibodies were developed which really paved the way for modern immunology. In 1997, rituximab was approved for NHL. In 2006, rituximab received approval for RA and in 2011 it was approved for WG/MPA.

B cells are the source of all immunoglobulins and can be activated by antigen in conjunction with co-stimulatory signals provided by antigen-presenting cells (APCs) and T lymphocytes. If successfully stimulated, activated B cells differentiate into antibody-secreting plasma cells. Most plasma cells generated during the initial phase of clonal expansion are short-lived and tend to produce IgM antibody.

In the second phase of clonal expansion, high-affinity (germinal center) B cells give rise to long-lived plasma cells and extremely long-lived memory B cells. When memory B cells re-encounter antigen, they rapidly differentiate into plasma cells and proliferate into more memory B cells. The plasma cells themselves are “terminally differentiated” and are no longer able to divide in response to antigen.

Reference:
Ahmed R, Lanier JG, Pamer E. Immunological Memory and Infection. In: Kaufman SH, Sher A, Ahmed R, eds. Immunology of Infectious Diseases. ASM Press; 2002:175–189.

What do B Cells do in Autoimmune Disease?
  1. Production of autoantibodies
  2. Co-stimulation/antigen presentation
  3. Immunomodulation/cytokine secretion
  4. Lymphoid organogenesis

In rheumatoid arthritis, the efficacy and safety of rituximab has been demonstrated in several studies. With the use of rituximab also comes B cell depletion; however, only about 60% of patients respond; therefore, there is no correlation with clinical response. So what is the mechanism of depleting B cells? Is it bone marrow B cells? Is it synovial B cells? Scientists are still not sure what the specific target is.  We’re not always sure why they work. A related issue in rheumatoid arthritis is a biomarker and the idea of personalized medicine. The patients who were positive for RF or ANA, tended to do better with rituximab.  

Many open studies showed that perhaps B cell therapy would work in SLE.

Why did the EXPLORER study fail?

There was no statistical significance between rituximab and placebo and there were no differences by AUC of total activity, landmark analyses, or flares in “responders”.

The study demonstrated that rituximab significantly depleted CD19+ B cells and there were significant reductions in adsDNA, ACL Abs; memory CD8+ T cells. In summary, high dose steroids with prolonged taper may have blunted the effects of rituximab, and longer term follow-up may have shown beneficial effect but open-label extension was cancelled due to PML concerns. Healthcare providers should also be aware that BILAG is a difficult instrument to use and/or adjudicate.

There is another line of thought that is dedicated to the differential effects of rituximab on serum autoantibody levels, i.e., some diseases are rituximab-sensitive; some are partially rituximab-sensitive and some are rituximab-resistant.

We are now thinking of our targets based on the types of B cells that we may be eliminating or modulating with different types of therapies.

Targeting B Cells
  • Anti-CD20:
    • Rituximab
    • Ofatumumab (HuMax CD20):
    • Ocrelizumab
    • Trubion synthetic anti CD20
    • B-cell growth factors
      • BR3-Fc
      • Atacicept [TACI-Ig
      • Belimumab (anti-sBLyS)
      • Anti-CD22
        • Epratuzumab
        • Anti-CD40L (CD154)
          • Studies halted
BLyS/BAFF: Ensuring B Cell Survival

BLyS/BAGG is potentially expressed by multiple immune cells, specifically neutrophils, monocytes, B cells, activated T cells, plasma cell, and dendritic cells. It exists in membrane-bound and soluble forms. Three molecules bind together to form the trimeric soluble protein; soluble BLyS is considered to be the active form. BLyS is important in ensuring that new B cells mature, survive, and differentiate themselves. BlyS (BAFF) levels are elevated in patients with SLE.

Belimumab

Belimumab received FDA approval in May of 2011. The only prior FDA approved drugs for SLE were aspirin, prednisone, and HCQ. Belimumab is considered to be relatively safe, but its efficacy is modest (cutaneous outcomes; only significant for rash, not alopecia, oral ulcers: improved BILAG rash seen in placebo – 30% / 1 mg – 42% / 10mg – 44%). There is a question as to its utility as a steroid-sparing agent in milder lupus. The long-term efficacy, safety and cost of belimumab are yet to be determined.

Epratuzumab, the anti-CD22 mAb, is currently under study in SLE.
Anti-neutrophil cytoplasmic antibody (ANCA) Associated Vasculitis (AAV)

What about using B cell therapy in the ANCA-associated vasculitides? In the RAVE study (RTX vs CTX), rituximab demonstrated increased efficacy (63.6% v 51.1%).  Looking at long-term efficacy, a single course of rituximab is as effective as 18 months of standard therapy with cyclophosphamide and azathioprine.

Clinicians should also note that rituximab has also had a dramatic effect in patients with MS.

Safety Issues with B Cell Targeted Therapies

There are a number of safety issues with the use of biologic DMARDs in RA, including serious infections, opportunistic infections such as tuberculosis (TB), malignancies, demyelination, hematologic abnormalities, administration reactions, congestive heart failure, and autoantibodies and lupus.

Target Related

•Impaired humoral immunity / B cell costimulatory function

•Infections / serious infections

•Impaired vaccine responses

Agent Related

•Infusion / administration reactions:

•RTX: mostly on 1st infusion; mild (common) à severe (rare)

•RTX: lesser frequency / severity, RA vs NHL

•Immunogenicity: antibodies to treating agent

•RTX: HACA ~ 1% NHL studies; ~ 4%-12% RA studies

•? Clinical relevance ?

Conclusions

There is a lot of promise with targeting B cells. There are lots of potential mechanisms that may have varying efficacy and different safety concerns. There is a lot of excitement in the future for B cell directed autoimmune diseases. 

Pediatric Pearls Perfectly Repolished: Part 4 The Vitamin D Dilemma

Sheila Fallon Friedlander, MD

Dr Friedlander reviews the many questions that face clinicians regarding vitamin
D in their pediatric patients.  Patients still come in and ask and about what do regarding Vitamin D and sun protection;  as dermatologists it is important to provide them with accurate and useful information.

Historical Perspective

Why do we or should we care about Vitamin D? In the 1700s, it was noted that some children had “bowed” legs. Some of them also developed  tetany and laryngeospasm. This was more frequent during the industrial revolution  likely due to less exposure to direct sunlight. In 1921, sunlight was found to be a treatment for Vitamin D deficiency , in1922 cod liver oil was found to be helpful and in 1925 scientists identified Vitamin D1 and Vitamin D2. The concept that has evolved over the last few years is that of Vitamin D as the “super hormone.”  It is well established that Vitamin D is important for bone mineral density and bone strength and appropriate levels  decrease risk for fracture.  Over the last decade, several studies have demonstrated that Vitamin D may also protect us from certain types of cancer, multiple sclerosis and cardiovascular mortality; however, there is still much controversy around these studies.

How can Vitamin D do so much?

Vitamin D binds to cell surface receptors and nuclear receptors (VDR). The presence of polymorphisms in the receptor may be a reason why not all studies show the same results with the same Vitamin D levels. Vitamin D has an impact on gene expression and regulates growth and differentiation.

Vitamin D Synthesis

Vitamin D synthesis is a complicated process. The overall concept is that  precursors are present on the skin surface, and when the precursors are exposed to sunlight, we get one form of Vitamin D3, cholecalciferol That is then metabolized in the liver to another  form that can be measured. Finally, in the kidney, the final , active form is synthesized. This  active form, 1,25-Vitamin D3, does not have a long half-life, and therefore levels of this form are not used in clinical practice.

Vitamin D Deficiency—How much?

A recent study found that 70% of children in the United States have low levels of Vitamin D.  What is really a low level? This can be confusing and puzzling. as “normal” values vary depending on the expert discussing the isse and  healthcare providers have no perfectly clear standards . There were also some studies that rickets may also be increasing. In a study conducted in Glasgow, the researchers looked at all children with suspected Vitamin D deficiency from 2002-2008. There were a total of 160 cases, the median age was 24 months, the majority of the patients were dark skinned and 40% of the patients presented with bowed legs. (There was one seizure). There were twice as many cases of Rickets in 2008 as in the previous six years. The question is, are people looking harder now because they are more aware?

Why are dermatologists concerned about this?

As dermatologists, we tell our patients to protect themselves from the sun; therefore,  we are interfering with “the natural order” of getting sunlight. Are we putting our patients at risk with this advice? Is there really a problem?

The problem is that the ultraviolet action spectrum for Vitamin D photosynthesis is identical to that for DNA damage and skin cancer, so we cannot  separate out this action spectrum.

Known Facts

Ultraviolet radiation from the sun is a carcinogen. It is responsible for the  majority of 1.3 million cases of skin cancer in the United States every year. In animal models, ultraviolet radiation is directly related to squamous cell carcinoma, basal cell carcinoma and metastatic melanoma. The use of sunscreen decreases one’s risk of malignant melanoma. Ultraviolet radiation compromises the skin’s function and can negatively affect one’s appearance.

Sunscreen, Vitamin D & Skin Cancer

In a 2011 review by Burnett and Wang, they found that sunscreen use has little or no impact on clinically relevant Vitamin D levels. Eide et al, in 2011, showed us that an increased baseline serum 24-OH Vitamin D level was significantly associated with an increased non-melanoma skin cancer risk. Basically, the more Vitamin D people had, the more skin cancer they had.

Natural Sources of Vitamin D Other Than the Sun

It can be hard to get enough Vitamin D from food.

  • Milk (but  4 glasses needed to get 400 IUs)
    Not such a good idea for the lactose-intolerant
  • Salmon, mackerel – but you need wild for the highest amount (600-1000 IU  &   $$$$)
  • Shittake mushrooms
  • Cod liver oil (grandma was right!)
  • Eggs
  • Could make it if you eat mushrooms & salmon a lot

Some feel that a little sun may be helpful to get the extra Vitamin D, but how much?

We know that white skin is more efficient than dark skin at “procuring” Vitamin D conversion from the sun. White skin is also more vulnerable to the bad, cancer-associated effects of the sun. How much one needs really depends from patient to patient.

So where do experts  stand on this issue? In New Zealand, they feel that sun exposure depends on the time of year and UV index along with one’s skin type. In the summer months, they believe that people receive sufficient Vitamin D through incidental sun exposure outside peak UV times (11am-4pm). For skin types 1 or 2, the recommendation is 5 minutes per day to the face, hands and forearms. For skin types 5-6, the recommendation is up to 20 minutes per day. (www.dermnetnz.org) However, according to the AAD and the AAP, this is a no-go. They feel it is inappropriate to recommend intentional exposure to natural or artificial UV light in order to obtain Vitamin D.  These two organizations believe the risks clearly outweigh the benefits and Vitamin D should come from diets and supplements.

So, to the rescue came  supplemental Vitamin D3; however, it is still not clear  how much to give, but  researchers began to demonstrate the positive effects of Vitamin D3 and its potential to reduce many health risks; therefore, people began to supplement and supplement and supplement….In 2001, $40 million was spent on Vitamin D supplements, in 2009, $425 million was spent and the federal government took notice.

The government got involved and asked the Institute of Medicine (IOM) to provide some answers regarding Vitamin D:

  1. What health outcomes are impacted by Vitamin D levels?
  2. How much Vitamin D is needed for a beneficial effect?
  3. How much is too much?

The IOM determined that, with no sun exposure, 600 units of supplement is a good idea for just about everyone. Babies need a little less and older patients (70+) will do well with 800 units.  There many experts who felt that these levels were inappropriately low. Why would the IOM be so rigid about how much Vitamin D people need?…because the  risk-benefit data are not clear. The colorectal data is the most supportive; that is Vitamin D is protective. Prostate, pancreatic, and cardiovascular data is conflicting, i.e., there is data that shows an increased risk with higher doses. There is an increased risk of renal stones with modest (400mg) supplements. Some of these problems, as Dr Friedlander mentioned before, could be due to Vitamin D receptor polymorphisms.  There may be a U-shaped curve of response where a little is bad, a moderate amount is good, and too much is also bad.

The IOM and Their Conservative Recommendations

We should not base recommendations on imprecise, suboptimal data. Risks are also possible with increased dose.

It is important to remember that there is data that shows an increased risk of prostate and other cancers, increased cardiovascular mortality and stones with increased doses of Vitamin D. A little Vitamin D is bad, moderate amounts is good, and too much can be bad. For now, patients should stick with 600 IU/day, unless they are considered to be in a high-risk population. This includes breast fed infants, older adults, individuals who have limited sun exposure, people with dark skin, and those with fat malabsorption. Healthcare providers should consider blood levels and higher supplemental intake for  elderly adults and those with dorders putting them at risk for Vitamin D malabsorption..

Summary FAQs
  • Does everyone need to be supplemented?Not a bad idea
    Age IU
    <1 400
    1-70 600
    70+ 800
  • Should everyone get Vitamin D levels?No, it can be expensive.
    Yes, for high risk populations.
  • What kind of supplement is best?
    • Food
    • Vitamin D3

     

  • Is more Vitamin D better?Perhaps not
  • Does Vitamin D support bone Health?Absolutely
  • Does Vitamin D protect us from MS, cardiovascular disease and cancer?Evidence is imprecise, inconclusive, inconsistent and insufficient at this time
  • Should I get Vitamin D from the sun?Not needed
Vitamin D “Pseudo-controversy”

Sunlight (UVR) is a known carcinogen. You can’t make Vitamin D in your skin without inducing DNA damage. Vitamin D is certainly good for you and you can get a sufficient amount with incidental sun exposure and a reasonable diet +/- supplements.

What’s a clinician to do?
  • Adhere to IOM guidelines – for now
    • <1yr = 400 IU
    • 1-70 = 600 IU
    • 70+  = 800 IU,
    • Identify high risk groups, test prn,
      • Breast fed, dark skin, elderly, malabsorbers
      • Counsel your patients that supplements are more dependable & safer than sun exposure

 

 

 

 

Pediatric Pearls Perfectly Repolished: Part 3 Worry or Not Worry: Which Vascular Birthmarks Need Further Evaluation?

Ilona J. Frieden, MD

 

Sturge-Weber Update

Sturge-Weber syndrome (SWS) is the triad of a port wine stain involving a V1 distribution as well as brain vascular malformations and often times glaucoma along with other ocular sequalae.  A recent report, published in December of 2011, from the Brain Vascular Malformation Consortium and the Sturge-Weber Syndrome National Workgroup. The experts discussed the disease in a broader sense to really examine what is going on now with the disease, what can physicians do currently and what does future look like as far as new developments in science.

Neurologic  Status

Usually with PWS, the patient has roughly a 30% chance of having unilateral, ipsilateral brain involvement to the PWS; however, in some cases with bilateral PWS there can be bilateral brain involvement that can correlate to a poorer prognosis. Epilepsy was found in 75-80% of patients with SWS and the vast majority will have an onset by age one (75%). It important to know that if a child over the age of two presents with a PWS and have been asymptomatic neurologically they are unlikely to have SWS.  When looking at outcomes, cognition was variable but it was worse in patients with seizures. In older patients, migraines or migraine-like headaches were a major issue. Endocrine disorders, especially growth hormone  deficiency and central hypothyroidism, have also been seen in some  patients.

Imaging Studies: Which to Do and What They Tell Us

There really isn’t a right answer as to whether or not one should be doing routine imaging in all infants with PWS in a V1 distribution to assess for the possibility of Strurge-Weber. The standard imaging modality used MRI with contrast; however, that is not always diagnostic in young infants because it is not adequately sensitive. The newly developed Susceptibility Weighted Imaging (SWI) MRI may make earlier detection possible and is more sensitive for venous disease which also may be present as a part of SWS.   Currently, Dr Frieden typically does not routinely do imaging as this will not necessarily change management in otherwise asymptomatic children.  However she  does routinely send these at-risk children to an ophthalmologist.

Another important part of imaging studies, however, is in helping to  better understand the disease. Imaging has shown us that brain disease is progressive, not static in SWS and that though initially increased blood vessels and hyperperfusion are present, over time,  hypoperfusion of parenchyma develops and this  correlates with functional impact. Functional PET imaging is also playing an increasing role in prognosis and pre-surgery planning for patients with intractable seizures.

Future Diagnostic Directions

Quantitative EEG (qEEG) in a non-invasive test that uses math signal processing for interpretation, rather than looking at just the morphology of the spikes and waves. qEEG was able to distinguish young infants with and without SWS correctly with high reliability (but small numbers). Transcranial Doppler is a non-invasive flow measure used in Sickle-Cell disease and there are ongoing studies looking at this modality for studying SWS.

Infantile Hemangiomas

Infantile hemangiomas cause multiple potential risks. This infant has a risk of eye disease as well as PHACE syndrome.

How do we begin to approach infants like this early on?

PHACE Syndrome
  • P: Posterior fossa and other brain anomalies
  • H: Large facial hemangiomas
  • A: Arterial anomalies especially CNS anterior circulation
  • C: Cardiac anomalies and aortic coarctation
  • E: Eye defects especially retinal vascular anomalies

PHACE Syndrome is the most common neurocutaneous vascular syndrome and is more common than SWS.  This is present in 30% of infants with large facial hemangiomas (> 5 cm in diameter).

Segments 1 and 3 have a much higher risk (50% or higher) compared to segment 2.

Elements of a PHACE Work-up
  • At risk if facial infantile hemangioma ≥ 5 cm
  • MRI and MRA with contrast
  • Eye exam (even if no perioccular vascular lesions)
  • Cardiac echo (looking for coarctation of the aorta in particular)
  • Consider other tests
    • ENT evaluation if “beard area”
    • Hearing tests (sensory-neural hearing loss independent of ear canal occlusion from a hemangioma)
    • Thyroid functions (occasionally central hypothyroidism is an issue)

The MRI and the MRA need to be individualized by patients due to the need to perform general anesthesia to due these procedures.

 Beard Area Segmental IH

Dermatologists should realize that hemangiomas distributed in the so-called “beard-area  pose a high risk of both airway disease and of PHACE.

Multifocal Hemangiomas

A prospective study by Horii et al, published in 2011, looked at the risk of liver hemangiomas in patients with multiple infantile skin hemangiomas. Abdominal ultrasound was performed on infants 6 months of age or less with 5 or more skin IH. They were compared with 50 infants who had 1-4 IH (control group). 24 (16%) of the 151 infants with 5 or more skin hemangiomas had hepatic hemangiomas (HH) versus 0/50 with less than 5 cutaneous (p = 0.003).

HH are similar to skin IH, in that, not all HH need treatment. More cutaneous IH are associated with a greater overall risk of HH but they are not necessarily more severe. In the prospective study mentioned above, only two of the 24 patients who had HH needed treatment specifically for the HH because they caused symptoms.

Risk of Life-Threatening “Diffuse” Disease

This is the feared complication of liver hemangiomas; whereby the liver is replaced by hemangiomas. In a recent study, the researchers found that the time to presentation for these patients is between a few weeks and 4 months. Symptoms include abdominal distention and poor feeding. If children have this, it is imperative to consider severe hypothyroidism, as it is commonly associated. The hemangioma itself causes a consumptive hypothyroidism by de-iodinating T3.

Do I need to worry about GI bleeding?

Dr Frieden states that most of us were taught that we needed to worry about GI bleeding when we saw patients with multiple hemangiomas. That actually turned out to be false. Large facial such as those seen in PHACE Syndrome, not multifocal IH, is a major risk factor for GI hemangiomas; usually in the small intestine.  In contrast, when you see multiple vascular lesions together with visceral involvement in sites such as the  brain, gastrointestinal tract, kidney, spleen, or adrenal glands this is more likely to be due to other multifocal vascular tumors such as multifocal lymphangioendotheliomatosis, rather than infantile hemangiomas.

Lumbosacral Hemangiomas

Regarding lumbosacral hemangiomas, dermatologists should worry about tethered cord and other anomalies.  In a 2010 prospective study by Drolet et al, the researchers studied 41 infants with IH greater than 2.5 cm midline overlying lumbar or sacral spine. The patients were imaged with ultrasound, MRI or both. The spinal abnormalities that were noted included lipoma or hemangioma and structural malformations of cord/tethered cord. Nearly 50% (21/41) had tethered cord, intraspinal hemangiomas, or both. High-resolution ultrasound was not optimal for evaluation (sensitivity 50%; specificity 78%).

Nevus Simplex (Salmon Patch)

The incidence of the nevus simplex also known as the salmon patch, is quite high (greater than 15%; range 19-82%). How do we know that this isn’t a Port Wine Stain? Clues to this diagnosis include its medial location and very blotchy, less well-demarcated borders.   We know that the classic locations include the glabella, the eyelids as well as the nape. Dr Frieden and colleagues have reported on some cases of extensive nevus simplex that included additional sites such as the scalp (67%), the nose (67%), the lip (60%), lumbosacral skin (56%) and the upper and mid back (15%). In this case series, most of the children were referred to Dr Frieden’s group because of the vascular anomalies. There were no associated abnormalities and imaging was not needed.

“Nevus Simplex Complex”

Infants with widespread nevus simplex were termed “Nevus simplex complex”. The patients had no other conditions. In a literature search, however, prominent NS was found to be associated with some rare syndromes such as:

  • Beckwith-Wiedemann
  • Macrocephaly-Capillary Malformation
  • Ondotodysplasia
  • Roberts-SC phocomelia
  • Nova syndrome

We also know that there is also an increased incidence of NS in infants with IH. Of note, patients with NS respond very well to pulsed dye laser treatment.

In 2011, Sillard et al published on a condition they termed  “Medial Fronto-Facial Capillary Malformation.” This was a retrospective study of 84 children. The distribution was the same as that of nevus simplex complex with “extended forms” in 26%. Neurologic anomalies were found in 9.5% of the patients. The researchers argue that this “looks like salmon patch” but it is not the same; it is darker, wider, slower, and there is less complete resolution.

 

 

 

Pediatric Pearls Perfectly Repolished: Part 2 Rapamycin Sheila Fallon Friedlander, MD

In this presentation, Dr Friedlander  discusses the many clinical applications of rapamycin, a target of the P13K pathway which was previously discussed by Dr Frieden.

Is Rapamycin the new wonder drug for kids?

Rapamycin (sirolimus) is an immunosuppressant used to prevent rejection. It is a macrolide and derives from a  Streptomyces species. Rapamycin was first discovered on Easter Island (Rapa Nui) and was originally used an antifungal.. It  blocks the mammalian target of rapamycin (mTOR) pathway by affecting  cyclin-dependent pathways .  These pathways are essentially messengers which can mediate cell  proliferation, metabolism and angiogenesis.

If you think of mTOR as a conductor that is mediating the effect of various growth factors, then  if we have a substance  which can inhibit mTOR, we can impair cell proliferation, cell metabolism and angiogenesis.

Why do dermatologists care about Rapamycin?

There are several diseases with cutaneous manifestions in which  proliferation is a major component of the pathology, for which we have no safe effective treatment. There is evidence that Rapamycin may be effective in treating at least a few of these disorders; in particular  tuberous sclerosis, port wine stains have been investigated,  Rapamycin has also been utilized in an animal model of infantile hemangiomas.

It has been  established that Rapamycin significantly improves facial angiofibroma lesions in patients with TS.  What about port wine stains (PWS)? We know that PWS can recur after PDL treatment. It is hypothesized that the cell trauma of treatment stimulates new blood vessel growth.  Dr Stuart Nelson and others have conducted studies in animal models which show that rapamycin can inhibit regrowth of vessels following laser therapy.

 

Rapamycin is currently under investigation by Nelson and his colleagues to determine if PWS treatment outcomes can be improved with the use of rapamycin in addition to pulsed dye laser.

One of the challenges with Rapamycin, as found by De Klotz et al, is that of compounding the agent into the right formulation. Scientists are working on optimizing the formulation. Rapamycin is also rather expensive.

Side Effects

Because Rapamycin is an immunosuppressant we have to worry about oral ulcers, diarrhea, and infections, to name just a few concerns. Topical Rapamycin appears to have less side effects.

Rapamycin and Infantile Hemangiomas

In an animal infantile hemangioma model, rapamycin was able to suppress the growth of the tumor via the inhibition of stem cell renewal capability, vasculogenesis, and differentiation.  What’s the difference between angiogenesis and vasculogenesis?  Many healthcare providers are confused regarding angiogenesis and vasculogenesis.  Angiogenesis occurs when new  vessels sprout  and develop  from an existing vessel. Vasculogenesis is de novo new formation of a  vessel presumably from stem cells. The effect of Rapamycin is distinct from that of corticosteroids, i.e., the pathways are  very different.

The Promise of Rapamycin

Rapamycin is a topical  as well as systemic formulation that can inhibit angiogenesis, proliferation and perhaps vasculogenesis. Rapamycin also inhibits stem cell renewal. Given these characteristics, , it could well be an excellent therapy in topical formulation for both angiofibromas and PWS., and perhaps infantile hemangiomas.  However, we  do need to better investigate its possible  side effects before  utilizing on a wide scale basis.

 

 

Pediatric Pearls Perfectly Repolished: Part 1 Molecular Pathways: Towards a Better Understanding of Genetic Disorders Ilona J. Frieden, MD

In this presentation, Dr Frieden discusses molecular pathways and how the science can be applied into clinical practice in order to optimize the outcomes for patients with dermatologic diseases.

 The concept of Molecular Pathways

Dr Frieden’s concept of molecular pathways is described here. Signaling pathways are essential in regulation and growth development. These pathways are the key to understanding of the phenotypic overlap of many genetic disorders because even diseases with distinct genetic causes can show overlap if they involve a molecular pathway because the defect can be present either upstream or downstream of another condition and thus show similar features.  Understanding these pathways can  also help to bring us closer to more rational therapies because if we find things that inhibit overactivity of an element of a pathway, it may work not just for one disease but for several.

 RAS/MAP Kinase Pathway

The RAS/MAP kinase pathway is essential to our central understanding of melanoma genetics, for example melanomas with mutations in NRAS and BRAF. This pathway also plays a major role in NF1 and other genetic syndromes.

 

Collectively germ-line genetic diseases in this pathway can be referred to as “Rasopathies”.  They include Noonan syndrome, cardiofaciocutaneous syndrome, NF1, and Legius syndrome.  All share in common features of developmental delay and most also have café-au-lait macules as a common feature.

 

Geneticists call this group (CFC, Noonan, NF-1, and Costello) of overlapping disorders RASopathies.

Another Important Pathway: PI3K

PI3K stands for phophatidylinositol-3-kinase, and the pathway in which PI3K is involved  is sometimes called the PI3K/AKT/mTOR pathway. This pathway is critical to cell growth and survival. It is intimately involved in normal vascular development and angiogenesis. The mammalian target of Rapamycin (mTOR) integrates signals from the pathway to coordinate cell growth and proliferation both in the fetus and continues to work later in post-natal life as well.

 

PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by P13K. There is also crosstalk between P13K pathways and other tumorigenic signaling pathways, such as those that involve Ras, p53, TOR (target of rapamycin) or DJ1, can contribute to this deregulation.

Genetics of Proteus Syndrome

Based on a paper published by Lindhurst et al in 2011, we now know that the cause of Proteus Syndrome is due to mutations in the oncogene AKT1 that is found right in the center of the P13K pathway. The researchers in this study conducted exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome—158 samples from 29 patients. 26 out of the 29 had a somatic activating mutation in the oncogene AKT1. Tissues and cell lines harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Two of the 38 peripheral-blood DNA samples were positive for the mutation compared with affected tissue (75 of 97, P<0.001) and unaffected samples that were positive (13 of 41, P = 0.004). This was a very important breakthrough as it determined that AKT1 was the cause of Proteus syndrome.

PI3K Syndromes: Overgrowth is a Common Motif

  • Cowden and Bannayan syndrome (PTEN)
  • Proteus (ALK)
  • Tuberous Sclerosis
  • Capillary Malformation-AVM and Parkes Weber
  • Familial venous malformations

Diseases Probably in the Pathway (but not proven)

  • Macrocephaly-Capillary Malformation
  • CLOVE syndrome
  • Diffuse capillary malformation with overgrowth
  • Probably others…

Clinical Pearls– Pathways help to explain the overlapping phenotypes of distinct genetic diseases. They help us to think about candidate genes for unknown disorders because they can lead us to look at certain candidate genes to see if they may be the cause of other phenotypically similar conditions. Pathways may also provide important molecular targets for treating previously untreatable diseases.

Combining Technology for Facial Rejuvenation

Suzanne L. Kilmer, MD

 Clinical Pearls: When Combining Devices with Injectables and Other Devices

In this presentation, Dr Kilmer reviews the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.

Dr Kilmer stresses the importance of remembering the 4 Rs:

  • Relax
  • Refill
  • Resurface
  • Redrape

During her initial consult with patients Dr Kilmer discusses the 4 Rs and how the various techniques that she uses in combination for facial rejuvenation can aide in maximizing the outcomes. It is also important, as dermatologists that full disclosure regarding outcomes is presented. Dr Kilmer informs her patients that she does not “have a magic wand or a crystal ball”; therefore, she can’t predict the outcomes of any given patient.

Relax

It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.

Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.

 Refill-Restore Volume Loss

When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, and the nasal bridge. Fillers can also be used globally in the cheeks and temples.  It is important to remember that there may be a lag time resulting in delayed gratification.

It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.

If all of these procedures are being done in one patient, Dr Kilmer typically tries to slow down the movement and relax the muscles. Discussions with patients regarding the overall procedures that could be performed are very important. Considerations for patients include money, down time, and fear factor, i.e., what are they willing to go through? In these consultations, Dr Kilmer and her patients decide on the best approach based upon their issues and the issues that she sees.

 Combination Treatments

  • Best order
    • Start with toxins to stop movement and relax muscles.
      • Relax frown, smile and lip lines when doing facial rejuvenation
      • Relax DAOs and neck bands when doing fillers, tightening or resurfacing
        • May need less filler and patients are happy sooner with tightening devices
        • Then filler or laser depending on a patient’s specific needs (and ability for downtime)
          • Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
          • Typically end with filler if still needed after toxins and laser
            • Sometimes the combination will diminish the need for filler
            • If able to tell that will need volume, can do before or at same time as laser

Caveats of Combining Treatments

  • Toxin with Filler
    • Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
    • Toxin with Laser
      • Can’t do toxin same day as Fractional lasers – swelling can lead to migration
      • Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
      • Filler with Laser
        • Can do filler same day but do first if doing fractional as swelling can mask need for filler.
        • Fractional with nonablative RF tightening
          • Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive. (wait an hour or two because the sensation will decrease with time)

Combining Fractional with other Devices

  • Fractional laser with other lasers/txs
    • Lentigines – pre-tx QS lasers, KTPs, etc
    • AKs – LN2
    • Sebaceous hyperplasia, nevi – 1450 nm
    • Vascular lesions – PDL, KTP, Alex
    • Downtime from other treatment is simultaneous and shortened
    • Fractional resurfacing with ablative resurfacing
      • Almost always do fully ablative to upper eyelids
        • More tightening/more predictable – do inner canthi
  • Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
  • Ablative fractional and nonablative fractional resurfacing
    • Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion

Other Combination Therapy

Other combination therapy includes fat loss and tissue tightening (CoolSculpting + RF tissue tightening, lipo/laser lipo + tissue tightening); Fractionated RF ((ePRime) + QS/KTP/PDL); and Fractionated US ((Ulthera) + QS/KTP/PDL).

Now that the 4Rs have been implemented, dermatologists need to be particularly aware of reassessing. Combination treatments may minimize the need for other treatments; therefore, increasing the interval for maintenance. For example, one can decrease the need for the amount and frequency of dermal fillers and one can conduct fewer fractional treatments when lentigines are specifically targeted. There may also be the possibility of foregoing vascular laser treatment if the fractional laser used to treat facial vessels was sufficient. Patient concerns should be addressed, i.e., were his/her expectations met? Is there anything new on the patient that has become noticeable since the initial treatment needs have been performed and met? Normally, with time, additional needs will become apparent.

 Summary

In summary, botulinum toxins, fillers and lasers can be used synergistically to minimize the signs and sun damage and aging. To produce the optimal results, expertise in the techniques are required, one should use the best possible modalities and watching and treating for any possible complications is imperative. Combining these modalities may obviate the need for more invasive procedures.

Managing Pemphigus and Pemphigoid: How to Avoid Getting Sued

John J. Zone, MD

In general, Dermatologists see very few blistering diseases. Therefore, managing these autoimmune conditions can often be a challenge in practice.  Dr Zone, an expert in the field of autoimmune blistering diseases, discusses these conditions and optimal strategies for managing these patients from his perspective.

Dr Zone came upon this topic because over the years he has managed a large number of people with both pemphigus and pemphigoid. He always asks himself “what would I do if I was sitting here?”

Virtually, all medications for the treatment of pemphigus and pemphigoid are used off’-label.

 

Case Study 1

In this first case, we can see a lot of acnatholysis and one would assume that it looks like pemphigus.

The above picture shows the direct immunoflourescence, the epidermis is at the top and is totally black.

This case was actually Hailey Hailey disease; therefore, histology alone does not make a diagnosis. According to Dr Zone, treating people on the basis of histology alone is a mistake.

Pemphigus- How do I biopsy people?

Biopsy of the wrong location for direct immunofluorescence is the single greatest problem that is seen in the specimens that are received. Dr Zone would not biopsy in the crusty area; he would biopsy the clinically normal appearing skin (see circle above) near the lesion. That is where one would find the classical cell surface antibody of pemphigus.


Dr Zone also sees a lot of mucosal pemphigus and pemphigoid. Again, it is important to biopsy the normal appearing mucous membrane immediately adjacent to the lesion. There is antibody all around the lesion so there is no need to get involved in in areas with intense inflammation that disrupt the antibody deposition pattern.


Ocular and Esophageal Pemphigoid

In the case of ocular pemphigoid (above), it is important to biopsy the reddish area NOT the bands of scar tissue called symblepharon that are usually negative on immunofluorescence. This should be done by an ophthalmologist.

Clinical Pearl- Dr Zone believes that rituximab should be used as initial therapy for ocular pemphigoid. Dr Zone has seen seven patients who have gone blind from this disease. Dermatologists should biopsy for direct Immunofluorescence if considering immunobullous disease. It is imperative that the biopsy is performed on clinically normal appearing skin adjacent to a lesion. 

 Pemphigus Antigens

Pemphigus foliaceus  (PF) and pemphigus vulgaris (PV) have different desmoglein antigens. The PF antigen is Dsg 1 and the PV antigen is Dsg 3, both of which are calcium-dependent adherence molecules. Desmoglein causes epithelial cells to stick one to another. Dr Zone finds that these antibody levels correlate extremely well with disease activity.  (see figure below)

In this case, Dr Zone treated this patient with azathioprine; however, he wasn’t fully responding.  The  “dip” in antibody levels reflects plasmapheresis. From there, he stopped the azathioprine and the patient was started on CellCept and the levels went up. Dr Zone, remembering that azathioprine induces thiopurine methyl transferase and patients become resistant to the drug, went back to azathioprine at very large doses, to the point of leucopenia, and eventually the patient went into remission.

These levels allow Dr Zone to predict how the patient is responding to therapy.

This (above) case represents a case where the antibodies were presumably against non-pathogenic epitopes.  Dr. Zone used plasmapheresis at the beginning of her clinical presentation (seen in the antibody titer drop)  In this particular case the high titer antibodies were likely against non pathogenic epitopes, and the patient went into remission without a corresponding decrease in antibody levels.

Indirect Immunofluorescence (IIF). Dr. Zone commented that the pemphigus antibody titers on IIF were found to correlate roughly with disease activity however the correlation with clinical activity was not as good as we now see with the ELISA technique. IIF has low accuracy and reproducibility .

Clinical Pearl- Dermatologists should biopsy for direct Immunofluorescence if  they are considering immunobullous disease. Biopsy clinically normal appearing skin adjacent to a lesion. It is important to monitor response with serial antibody level.

Pemphigoid

For antigen identification it is important testing using salt-split skin or ELISA.  This allows identification of specific antibodies that can then be used as an index of response to therapy. BP180(BPAg2) is the most common antigen and can be quantified using ELISA.

This patient’s BP180 antibody levels correlated very well with her disease activity.

Several studies have shown the correlation of disease activity with these antibodies.

Why is this important to test for antibodies?

Research has suggested that ant-epiligrin (laminin 332)  usually found in mucous membrane pemphigoid has a strong association with cancer. In a study of 35 patients with laminin V (332) mucous membrane pemphigoid there were 10 solitary solid cancers. There was a temporal association (14 months before or after the onset of the tumor in 9 out of 10 patients). The control groups indicated a relative risk of 15.4 (5.7-33.6). Ascertainment bias and treatment bias are unlikely because of time course. If a patient’s antibody goes the dermal side of salt split skin on indirect immunoflourescence, and binds to laminin 332 on immunoblot, that patient has a one in three chance of having cancer.

Type VII Collagen

The epidermolysis bullosa acquisita antigen (type VII collagen), which is present in the skin, is also present in the wall of the normal human colon. Research has shown that type VII collagen antibodies are associated with Crohns disease.  What does this mean? If you have antibodies to type VII collagen and epidermolysis bullosa acquisita (IgG antibodies that go to the dermal side of salt split skin on indirect immunoflourescence ) then you have a very significant chance of having Crohn’s disease or ulcerative colitis. If Dr Zone finds out that these people have antibodies to type VII collagen, then he screens them for Crohn’s and ulcerative colitis .

Clinical Pearls- Biopsy for direct Immunofluorescence if considering immunobullous disease; Biopsy clinically normal appearing skin adjacent to a lesion; Identify antigen if possible; Monitor response with serial antibody levels

Dr Zone prefers a topical steroidal therapy to control mild disease, especially in the mouth, and little to no systemic steroids. Dr Zone has found that over the years, systemic steroids have caused more problems to patients. If systemic steroids are required, Dr Zone suggests starting patients on a bisphosphonate, prior to starting the steroids, possibly alendronate (70 mg/wk). Patients should also be started on an H2 blocker or a proton pump inhibitor, the risk of gastritis is very high and it is very real.  A study from the New England Journal of Medicine looked at the comparison of oral and topical corticosteroids in elderly patients with bullous pemphigoid. Since the elderly have a low tolerance for oral corticosteroids the researchers evaluated whether potent topical steroids could decrease mortality and morbidity while controlling disease. Topical steroids were associated with significantly fewer problems with infection, diabetes and psychiatric symptoms.

The above table illustrates all the more reason to utilize topical steroids.

Dr Zone’s Algorithm for the Treatment of Pemphigoid

The dose for doxycycline (if tetracycline is not available) is 100 mg PO BID and niacinamide is 500 mg PO BID. This can be used effectively in mild pemphigoid.

Rituximab should be for any ocular or esophageal pemphigoid. For moderate and severe pemphigus rituximab has a definite benefit and Dr. Zone uses it in this clinical situation.

Rituximab and its Use in Autoimmune Disorders

  • Vaccinations before hand for pneumococcus, influenza, DPT boost 4 weeks earlier if possible
  • Stop immunosuppressives if possible (may have increased complications when used in conjunction with rituximab)
  • Premedicate with steroids and antihistamines to minimize infusion reactions
  • Dosing: 375g/m2 weekly x 4
  • OR 1000mg twice – 2 weeks apart (dosing most often used by rheumatologists)

A study by Joly, et al in the New England Journal of Medicine looked at a single cycle of rituximab for the treatment of severe pemphigus vulgaris in resistant patients (14 PV and 7 PF). The patients received a single cycle of rituximab, 18 of the 21 patients were in complete remission at 3 months and 2 of the 21 patients were in complete remission by 12 months. 9 patients experienced a relapse at 12 months and 2 of the patients required a second cycle. 8 of the 21 patients required no systemic therapy afterward. The Dsg antibody levels correlated with treatment response.

In another study looking at rituximab and autoimmune disorders, the researchers found that serious infections do not appear to be substantially increased but isolated reports are bothersome. Progressive Multifocal Leukoencephalopathy in non-HIV autoimmune patients treated with rituximab has created a significant concern.  Their total serum IgG was not significantly lowered.  When studying rituximab for patients with refractory mucous membrane pemphigoid, Le Roux-Villet et al, looked at 25 patients given 1 or 2 cycles of rituximab (375 mg/m2 weekly for 4 weeks). There were complete responses in all affected sites (ocular and/or extraocular) in 17 patients (68%) by a median time of 12 weeks after the first cycle and 5 additional patients responded completely after a second cycle, yielding an 88% complete response rate. 9 of the 10 patients became noninflammatory within a mean of 10 weeks. Severe infection occurred in 3 patients (12%) who developed severe infectious complications, 2 (8%) died; they had been receiving concomitant conventional immunosuppressants and high-dose corticosteroids. The immunosuppressants were discontinued in all other patients and no other infections were observed. 10 patients experienced a relapse after a mean of 4 (range, 1-16) months after achieving a complete response and were re-treated.

In 2009, Jones, et al published a multicenter survey of ritxumab therapy for refractory anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis) in Arthritis and Rheumatism. 49 of the 65 patients (75%) achieved complete remission. 15 of the 65 (23%) achieved a partial response and 1 (2%) had no response. The median time to remission was 2 months (range, 1-5 months). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). 28 of 49 patients experienced a relapse (median 11.5 months) and B cell return preceded the relapse in 14 of 27 patients (52%).  Serious adverse events seemed to be associated with the underlying disease so it is important to remember that the underlying disease is still a problem for several months. 46 SAEs occurred in 25 patients, and some patients experienced more than 1 SAE. Most patients received immunosuppression either immediately before (37) or during (14) rituximab therapy.  This study was reviewed to allow understanding of potential side effects of rituximab independent of the presence of pemphigus or pemphigoid.

Take Home Points

  • Make certain of the diagnosis
    • DIF and serology
    • Identify specific antigen whenever possible and follow antibody levels
    • Minimize systemic steroids
      • Use bone and stomach protection
      • Rituximab for severe disease
        • Sooner rather than later
        • Rituximab is the best initial treatment in ocular pemphigoid
        • The underlying disease is still a problem for months
        • Beware of simultaneous immunosuppressive therapy

 

 

The future of personalized medicine could be monoclonal antibodies that are directed against antigen specific B cells. Dr Zone feels that we will see a lot more of this over the years to come.

Inflammatory Diseases in Little Kids: Part 2

Pediatric Psoriasis

Lawrence F. Eichenfield, MD

Obesity appears to be a common comorbidity in pediatric patients with psoriasis.   It is uncertain if the cardiovascular risks seen in adults with psoriasis is fundamentally related to obesity, skin inflammation, or other factors.  It is reasonable to discuss these issues with families of children with psoriasis, though much research is needed about long-term risks and modifying them.

Regarding psoriatic arthritis (PsA) in children, consider asking children with psoriasis about morning stiffness, as this can be a sign of PsA.  Pediatric psoriasis is typically treated with topical corticosteroids and Vitamin-D analogues; however, clinicians should not forget the appropriate placement of light therapy (NB-UVB is the most studied), which can be very effective.  The National Psoriasis Foundation has a pediatric site that is kid-friendly and provides much needed information and resources.

Systemic treatment is appropriate for severe psoriasis in children and adolescents, though it can be much work to have third party payers cover the costs of systemic therapies including biologic agents as there are no specifically approved systemic treatments for children and adolescents with psoriasis.

In summary, there is a fair amount of new information for both Atopic Dermatitis and psoriasis and, in the future, hopefully more treatments will become available for pediatric patients.

 

 

Inflammatory Diseases in Little Kids: Part 1

Inflammatory Disease in Little Kids

Lawrence F. Eichenfield, MD

 

In this presentation, Dr. Eichenfield discussed inflammatory diseases in children in a clinically relevant manner.  Dr. Eichenfield provided a review of the pathogenesis of atopic dermatitis (AD), the role of filaggrin, and allergies in AD.  He also updated us on new findings in pediatric psoriasis.

Atopic Dermatitis

When reviewing AD, it is important to consider the issues noted below:

  • Barrier dysfunction
  • Infection
  • Inflammation
  • Allergy
  • Itching

PEARL:  The phenotype, associated with ichtyhosis vulgaris, is associated with peanut allergy.  Be careful when you take your atopic child or nephew to a baseball game or circus.

Filaggrin Insufficiency

Filaggrin haploinsufficiency is defined as a 50% reduction in the expression of the filaggrin protein, an important functional protein that influences epidermal function.   Filaggrin mutations are associated with decreased filaggrin production, as well as higher rates of development of associated conditions.  The odds ratios for the risk of peanut allergy, asthma, or atopic dermatitis with Filaggrin mutations are greater as compared to individuals without Filaggrin mutations. The odds ratios for atopic dermatitis and asthma, from meta-analyses involving several thousand patients display that FLG mutations confer an overall risk of asthma of 1.5, but this risk is restricted to patients with atopic dermatitis. The odds ratio for the complex phenotype of asthma plus atopic dermatitis is 3.3. The odds ratio for peanut allergy is 5.3 and is based on data from a single study.  Of interest is that there is no filaggrin in the mucosal surfaces of the mouth or esophagus so it likely that the peanut allergy is the result of epicutaneous sensitization. (Irvine AD, McLean I, Leung DYM. N Engl J Med 2011;365:1315-27)

The question is how does filaggrin deficiency affect the skin barrier?  The answer is a decrease in filaggrin expression increases skin permeability, increases skin pH, decreases natural moisturizing factor and decreases cell-to-cell cohesion impacting barrier function.

Of importance, even in individuals who do not have the filaggrin mutation, there are decreased filaggrin byproducts in actively, inflamed eczema.

Atopic dermatitis can be triggered by the chronic exposure of barrier-disrupted skin to percutaneous antigens due to abnormalities in fillaggrin; however, only 30-50% have FLG mutations and most outgrow AD.  40% of patients with FLG-null alleles do not get AD. Therefore, there are other factors that influence AD development and course other than just filaggrin.

What are some of the traditional approaches and targeted therapies?

  • Moisturizing after bathing
  • Use of emollients
  • Targeted barrier repair products

These measures are part of maintenance care for all patients, and primary intervention for mild AD in infants.

What are some of the things that can be done for the prevention of Atopic Dermatitis? In the past, physicians have considered:

  • Formula
  • Maternal diet
  • Infant diet
  • Allergen avoidance (both environmental and food)
  • Probiotics
  • Prebiotics

So far, none of strategies mentioned above have solid data for their efficacy. Several international studies are currently looking at the role of early intervention in skin care in order to stop AD.

Anti-inflammatory therapy

There are typically two ways that a dermatologist handles a child with AD.

1. “As low as you can go (or just above where they were)”, i.e., the least strong topical steroid that can be used and 2: “Stronger steroids” to start, with tapering to less potent corticosteroids as the AD improves. Both of these approaches are reasonable. Many clinicians tend to “mix and match” the topical corticosteroids with the non-steroid topicals and utilize wet wraps with topical corticosteroids in patients with more difficult remissions.

Over the next few years, dermatologists will be seeing some new agents for the treatment of AD. These therapies include selective glucocoid agonist receptor stimulants, histamine 4 blockers as well as other molecules.

Wet Wrap Dressing with TCS Use: Effective, Rapid Control of Severe AD

Dawn Davis and colleagues conducted a study on wet wrap dressing in 218 patients who were hospitalized. The mean age of application was 6 years (2 months-17 years), the mean duration of hospital stay was 3.61 days (range 1-16) and all patients showed improvement.  45% of the patients showed 75-100% improvement; 38% of patients showed 50-75% improvement and 6% of patients showed a 25-50% improvement.

There are many methods to the use of wet wrap with topical corticosteroids and the benefits are clearly demonstrated.

Another important therapeutic intervention for AD, now recognized internationally, is education.   A struggle that clinicians face is how to educate patients within the limited time of busy office settings, so that patients understand how to utilize their medicines while also managing their fears with respect to the utilization of steroids and medications.

Pediatric Pearls and Conclusions

  • Prescribe specific amounts
  • Assess quantities of time
  • Discuss strengths and safety
  • Use educational and instructional materials
  • Handouts, web-sites, video training modules:  www.eczemacenter.org
  • Follow-up soon!  Studies show that there is more chance that patients will follow their regimen and will have better clinical outcomes

Maintenance Therapy

  • Emollients alone? In 30-40% of infants, this may be sufficient
  • Intermittent corticosteroids
  • TCIs (delicate areas, persistent, frequently recurrent)
  • Targeted-Barrier-repair products
  • BRING THEM BACK while they are still under control

What about the patients who are better, but not great or have persistent, frequent flaring?

  • Ask about feeding practices, atopic history
  • Establish aggressive maintenance plan
    • Intermittent CS and/or TCIs
    • Assess sleep and itching as endpoints
    • Trials of TBRP (targeted barrier repair products) and/or emollients
    • Consider anti-infectives, bleach baths/products
    • Check growth, infection history, differential diagnosis
    • Consider allergy referral

TCI Safety Information

New information has been collected with regards to TCI safety, but the data have not yet been published. The FDA Pediatric Advisory Committee evaluated emerging data as part of a routine evaluation of TCI safety and use.   They looked at the epidemiology studies, the clinical studies, Data Safety Monitoring Boards and Post-marketing surveillance/Adverse Events Reporting System (AERS). The FDA found that there is no evidence of an association between TCIs and B-cell lymphomas but because of the limited data available, one cannot necessarily form conclusions from the published literature. The FDA also said that a literature review suggests a possible association between topical tacrolimus use and an increased risk of T-cell lymphoma.  The T-cell lymphoma association, however, may be due to use of the TCI in individuals reported as having eczema prior to the diagnosis of cutaneous T-cell lymphoma (known as protopathic effect).

It is important to remember that these are retrospective studies; so drawing conclusions can be difficult for the clinician.

An epidemiologic survey published by Tennis and Gelfand came to the same conclusions, i.e., there is little to no evidence of an increased risk of lymphomas overall or specific sub-types of lymphoma with topical TCI use and there is no evidence indicating that melanoma or non-melanoma skin cancer is associated with topical TCI use.

Microbes

Dr Eichenfield posed the following question to the audience…

Staph aureus in patients with atopic dermatitis:

A.  Is more likely to be MRSA than staph in infections in non-atopics

B.  Is less common than streptococcal infection

C.  Is less likely to be MRSA than staph in infections in non-atopics

D.  None of the above

MRSA and Atopic Dermatitis

Dermatologists should be aware that atopics have lower rates of MRSA infection than community-acquired staph infections. From an ecological perspective, the question is “does MSSA protect against MRSA?”

Translation into Clinical Practice

Bleach Baths and Alternatives*

  • ¼ to ½ cup for ½ to full tub of standard bleach (6%).
    • 5 cup for 40 gallon full tub is 0.005% concentration
    • Dilute Na hypochlorite and hypochlorous acid (Aurstat: marketed with HylatopicPlus)*
    • Na Hypochlorite body wash (CLn BodyWash)*

The AD market has responded to this and there are now at least two alternatives currently available to bleach baths. One of which is a tube of sodium hypochlorite and hypochlorous acid and it is paired with a ceramide-containing moisturizer. The other product is available over the internet that is a sodium hypochlorite body wash in a can.ir

Comorbidities and Atopic Dermatitis

Over the last few years atopic dermatitis has been associated with higher rates of attention deficit disorder and other mental health disorders.  Recent evaluation of a large healthcare database displayed higher rates of ADD in individuals with atopic dermatitis as compared to those without atopic dermatitis, with evidence of higher rates proportionate to severity of ADD.   Depression was also higher in teens and adults with AD.  While there is may not be enough evidence to mandate screening of atopic dermatitis patients, clinicians should be aware of the association.

Food Allergy and Eczema

About 17% of children with mild AD and 30-40% of moderate to severe children have at least one clinically relevant food allergy.  Food allergy testing (skin testing and IgE testing), however, yields many false positive tests; in fact, it is estimated that 4 out of 5 positive tests may not be associated with true food allergy, but only with IgE sensitization (e.g. Milk: 238 of 1000 tested will have false + ;  vs. 50 having clinically relevant allergy). 

Highlights from the NIH Food Allergy Guidelines

The current guidelines suggest that children less than 5 years of age with moderate to severe AD be considered for FA evaluation for milk, egg, peanut, wheat, and soy, if at least one of the following conditions is met:

  • The child has persistent AD in spite of optimized management and topical therapy.
  • The child has a reliable history of an immediate reaction after ingestion of a specific food

Dr Eichenfield feels that it is appropriate to ask about food allergies; if a child has had a food allergy, then an EPIPEN or EPIPEN Jr. should be prescribed.

Clinical Pearls for Atopic Dermatitis

  • Great skin care
  • Anti-inflammatory medication as needed, with most care as topical regimens
  • Maintenance care “as needed”
  • Keep regimens simple
  • Educate…in the office, on the net, wherever!
  • If really hard, seek help!

Diet and Acne & Rosacea

Diet and Acne & Rosacea
Alan Shalita, MD

In this presentation, Dr Shalita discusses the role of one’s diet and its relationship to acne and rosacea. Unfortunately, there is not a lot of information about diet and acne; however, there is a tremendous amount of interest in this subject. Dr Whitney Bowe conducted various aspects of this review, during the time she spent at SUNY Downstate with Dr Shalita.

With regards to rosacea, recent research by Dr. Richard Gallo and co-workers suggests an important role for innate immunity. Patients should avoid foods that cause vasodilatation, e.g. spicy, hot, etc. This has not been demonstrated in clinical trials; however, Dr Shalita feels it is something that should be studied.

Acne and Diet
Historically, any food that teenagers enjoyed were said to provoke or aggravate acne, e.g. chocolate, sodas, french fries, other candy. We know that the common denominator was that all of these foods were rich in sugars. In the 1970’s, Fulton et al conducted a study looking at chocolate bars versus control bars (carob), and they found no difference, i.e., both had same sugar and fatty acid content. The glycemic index between both bars was about the same. The researchers concluded that chocolate does not cause acne.

Dr Anderson studied 27 students assigned to consume chocolate, peanuts, milk or coca cola for one week. He, too, found no relationship to acne; however, the study was too short, underpowered, there were no lesion counts and no statistics.

In 1931, published in the British Journal of Dermatology, Dr Campbell showed that there was impaired glucose tolerance in patients with acne. In 1951, Dr Belisario, who published research in the Australian Journal of Dermatology, found that acne patients should avoid excessive carbohydrates and food that was high in sugar. Unfortunately, these reports were largely ignored. More recently, the relationship between diet and acne has been called back into question. It appears that carbohydrates and dairy products are considered by some to be the “real offenders.”
Researchers are examining the glycemic index and the glycemic load of various foods.

Examples of Low and High Glycemic Foods

In more recent studies, Dr Cordain et al, in 2002, examined 1300 subjects in Kitavan Islanders of Papua New Guinea or Ache hunter-gatherers of Paraguay. The researchers found no acne among the subjects. The reason, they feel, is due to diets low in carbohydrates and low glycemic loads. There are ways to criticize this study, in that, there were no controls and perhaps this group is not genetically predisposed to acne. Nonetheless, their conclusions led them to believe that the western diet may lead to hyperinsulinemia resulting in hormonal effects on acne.

A studied conducted in Australia by Dr Smith among students with acne found a positive correlation between glycemic index and acne; yet, a study by Dr Kaymak et al, in Turkey found no relationship in acne patients with a high carbohydrate load versus those on a low carbohydrate diet.

Dr Brian Berman, at the University of Miami, conducted a preliminary study looking at the South Beach Diet. In a survey, individuals who were on the South Beach Diet claimed to have had less acne.

It is important for Dermatologists to remember that a true low-carbohydrate diet can be very difficult to follow and requires very careful monitoring. Patients may benefit from food diaries and reminders. Dr Shalita mentions that he has seen a failure in compliance among the Caribbean population at Downstate because they do not want to give up certain foods.

Many believe in the effect of dairy on acne because of the hormones; however, it may very well be due to the sugar in the diary products. In 2005, a paper published in JAAD, showed the correlation between dairy products and acne. Dr Shalita believes that it may be due to the sugar content but this has not been confirmed.

There are other dietary factors that have been studied such as zinc. Dr Shalita conducted a study many years ago looking at whether or not zinc could be beneficial in acne. The study looked at students in a reform school in Hartford, CT. It was a placebo washout study and demonstrated that after one month of placebo there was a 50% improvement, so the question is could they have gotten better if they had taken zinc? They did not.

Vitamin A, when taken in high doses, can have the same effect as isotretinoin. No one has established whether or not fish oil and antioxidants have an effect on acne.

In conclusion, there may very well be a role for diet and acne, but at this point we do not know what it is. Dr Shalita suspects that it is related to the glycemic index of foods, but further studies are needed.