IVIg (FDA approved)-Controversial for Toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (SJS)
IVIg (off label)-Scleromyxedema
IgE and Omalizumab (off label)
Rituximab has demonstrated positive efficacy for the treatment of both pemphigus and mucus membrane pemphigoid. Intravenous Immune Globulin (IVIg) is FDA now approved for a variety of dermatologic disorders, and because of the thousands of donors, it is rather accessible. The efficacy of high dose IVIg in the treatment of TEN has been studied and it has demonstrated positive results in adults; however, it is important to keep in mind that IVIg is not benign and adverse effects can occur.
What about scleromyxedema? Scleromyxedema is a rare disease with mucin deposition in the skin and other organs with monoclonal IgG protein. In a case series report, the data on IVIg therapy for scleromyxedema was positive. Finally, Dr Zone feels that in the next ten years IgE will really “catch on.” Omalizumab can treat diseases such as urticaria, pemphigoid, atopic dermatitis and many more disorders.
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Our expert panel of pediatric dermatologists reviewed various topics in the field of pediatric dermatology including, hemangiomas, nail diseases, atopic dermatitis, inflammatory disorders, and skin lesions.
Drs Friedlander and Frieden began the pediatric dermatology session with a discussion on infantile hemangiomas (IH). Dermatologists need to continue to understand the incidence and pathogenesis of IH and when to recognize when intervention is required. A large prospective study showed that overall 4.5% of infants were affected by IH. Where do infantile hemangiomas come from? There are three theories: 1. Placenta embolization; 2. Somatic mutation in gene mediating endothelial cells (VEGF); 3. A hypoxic location elicits production of HIF.
How do we treat IH?
Over the last four years, Beta Blockers have emerged as a novel therapy for the treatment of IH. Guidelines were recently published for the use of propranolol in patients with IH. (Drolet et al. Pediatrics 2012 December 24. Epub ahead of print) A recent systematic review compared the improvement of IH with propranolol versus steroids and the results were 98 percent and 71 percent, respectively. The adverse events were also higher in the steroid group versus the propranolol group. All patient vital signs should be monitored when given propranolol; the most frequent side effect is hypoglycemia.
What if propranolol is not an option? The topical beta blocker, Timolol (which has been use for years in glaucoma patients with great safety), has encouraging results and appears to be well tolerated. This has been effective in facial lesions particularly around the eye. For lesions near the eye in neonates 1 drop BID is the generally accepted dose.
Other therapy for IH includes corticosteroids, systemic therapy, pulsed dye laser, cryotherapy and Imiquimod. An important concept with the overall management of hemangiomas is that management is not a “one size fits all” approach and therapy needs to be individualized.
Hand-Foot-Mouth and Beyond…
Over the last few years, atypical cases of HFMD have been reported to the CDC. Many of these cases looked like eczema herpeticum, but oral erosions and palmar lesions looked like HFMD. Coxsackie A-6 infection seems to be a virus that is now appearing in clinical practice. Fortunately, multiple PCR panels are commercially available and can aid dermatologists in the detection of these worrisome viruses.
What about onychomycosis?
Dermatologists need to remember that fungal nail infections DO affect children and the incidence may be increasing due to occlusive foot lifestyle and genetics. **Utilizing a curette is a good way to obtain a nail specimen in a child without provoking fear or fuss. Terbinafine 5mg/kg/d is an effective systemic therapy used to treat onychomycosis as well as fluconazole. Data has also shown that that children, with Onychomycosis not involving the matrix, can be effectively treated with topical ciclopirox lacquer.
Atopic Dermatitis
Dr Eichenfield addressed atopic dermatitis in the pediatric population. Key takeaway messages included:
What is the association between filaggrin and AD? Not all patients have filaggrin mutations and fillagrin mutations vary in AD patients from country to country. However, filaggrin expression decreases with inflammation even in AD patients without filaggrin mutations. When treating these patients, address the barrier, i.e., hydration. How do we best treat pediatric AD patients? Anti-inflammatory treatment is effective and proper education can help to improve therapeutic outcomes. It is also important to remember that microbes are not just bacteria, inflammation decreases diversity and increases staph infection; bleach baths and other products can be used as reasonable adjuvant therapy. Mental health conditions, such as ADHD, are associated comorbidities among AD patients. Family attention and appropriate screening may be necessary. In conclusion, don’t forget about allergy in AD patients; selective testing for foods may be beneficial.
Inflammatory Disorders
Dr Cordoro discussed inflammatory disorders in pediatric patients and what to do when creams aren’t enough to effectively manage these conditions. Because of the lack of data and treatment guidelines currently available for the pediatric population, managing these disorders with systemic and biologic therapies can be challenging for dermatologists. Different factors can affect and determine the appropriate therapeutic choice.
Practical Pearls for the Use of Systemic Therapy in the Pediatric Population
Let explosive –onset psoriasis evolve a bit before committing to systemic therapy
When you need speed, choose cyclosporine
Oral retinoids are often the best initial choice for sever guttate and pustular psoriasis in children
Is there a place for biologic therapy in children with psoriasis? The answer is yes.
Remember to assess which is worse: the disease or the treatment. Do not withhold treatment because “nothing is approved for use in children”
Dr Hensin Tsao, Director of the Melanoma Clinic at Massachusetts General Hospital, lead off the 2013 Maui Derm meeting by providing the audience with an overview of the top stories in dermatology in 2012-2013.
New Observations
Melanoma is the 5th most common cancer in males and the 6th most common cancer in females affecting one in 36 men and one in 55 women. Melanoma incidence and mortality continue to increase, there is a disparity in survival among races (higher level of mortality in African Americans), and women seem to have better survival rates than men.
Another hot topic is that of blood-borne viral infections linked to tattooing. M. chelonae infection has been associated with tattoos. Molecular analysis showed M. chelonae was found in 11 clinical isolates and in an unopened bottle of ink. 18 out of 19 patients responded to macrolides and or doxycycline depending on sensitivities. Contamination likely occurred before distribution.
Sun avoidance is a crucial component of all skin cancer prevention campaigns. Scientists have studied the effects of direct light, diffuse light, and reflected light. Modeling revealed that a large amount of diffuse UV radiation occurs. Recent studies indicate that direct UV occurs mostly on exposed sites during summer months; reflected irradiation occurs during winter months. SimuVex software estimates UV from various ambient sources. Diffuse radiation accounted for 75-85% of the annual sun exposure. It is not clear whether or not shading can protect against diffuse light.
87% increased risk of melanoma if tanning [beds] are first used before age 35. Sunbeds account for about ten percent of melanomas in women and five percent in men. This is becoming a significant public health problem. Tanning bed use now contributes to about 10% of melanomas. Public health response is more aggressive these days, but we’re not there yet.
Murcormycosis is a rare infection caused by molds that are ubiquitous in soil, decaying wood and organic material. Immune incompetent patients are more susceptible. Outbreaks of rare saprophytic infections occur after catastrophes, such as tornadoes, have been reported. Infections need to be considered early so proper treatment with Amphotericin B can be instituted.
New Treatments
Most BCCs are removed by surgery or with radiation or topical therapies
The small molecule hedgehog pathway inhibitor is effective for metastatic advanced and generalized BCCs. Side effects are pretty significant, recurrences after drug discontinuation, and costs are limiting factors.
The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Ivermectin 0.5% (topical) for the treatment of head lice has a higher success rate versus the control vehicle. It is pediculocidal and ovacidal. This means that nit combing post treatment is not necessary.
Targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction and may be less toxic than ipilmumab.
The use of Sirolimus (rapamycin) has proven effective in secondary skin cancer in the transplant population.
New Insights
Germline and mosaic versions of cancer mutations lead to developmental and harmartomatous conditions. Sequencing these can lead to emerging treatment.
The increased use of antibiotics has lead to increased diarrhea. Duodenal infusion of donor feces for recurrent clostridium difficile has demonstrated positive efficacy and data suggest that fecal transfer is superior to vancomycin for recurrent C. difficile.
Biologics and small molecules are going to change the way we continue practice medicine.
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Infliximab (initial response, with subsequent failure)
History of:
Hypertension
Hypercholesterolemia
Hypertriglyceridemia
Obese, 120 kg, BMI = 33
[poll id=”2″]
There is concern for this patient because he is at a relatively high risk for cardiovascular disease. However, he has not responded to various treatments and needs therapy in order to function.
How do you discuss ustekinumab with this patient prior to initiation of therapy?
Discuss his risks of cardiovascular disease and conduct a benefit/risk assessment of ustekinumab prior to starting therapy
[poll id=”3″]
[poll id=”4″]
[poll id=”5″]
Case Study 2- Topical Therapy
42 year-old man
Psoriasis affecting 4% of BSA
Inverse pattern
Inguinal
Intergluteal and perianal
Refractory to alclometasone dipropionate cream
No psoriatic arthritis
[poll id=”6″]
Case Study 3- Scalp Psoriasis
22 year-old woman
Severe scalp psoriasis, affects 50% of scalp surface area, failed:
OTC preparations (T-gel)
Fluocinolone acetonide topical scalp oil 0.01%
Clobetasol shampoo, solution and foam
[poll id=”7″]
Case Study 4- Refractory Local Psoriasis in a Patient on Biologic Therapy
46 year-old man with > 20 years of severe psoriasis and psoriatic arthritis
Baseline: 20% BSA, PGA = 4
Currently managed effectively with:
TNF-inhibitor in combination with MTX 10 mg per week
BSA currently 4%, with residual disease on the elbows and lower extremities
Refractory to topical class 1 corticosteroids
[poll id=”8″]
Case Study 5- Latent TB
52 year-old man with 40% BSA
Active psoriatic arthritis
Only treated with UV Phototherapy and topicals, neither of which is effective
PPD is positive to 12 mm induration
Chest X-ray shows no infiltrate and chest CT is normal
What if this patient had previous BCG vaccination?
Verify latent TB status with Quantiferon Gold test
What are your steps to starting therapy for this patient?
Quantiferon Gold test
If positive, treat with a full course of latent TB infection prophylaxis prior to initiation of immunosuppressive/immunomodulatory therapy. Therapy for psoriasis may be begun 1 month into treatment for latent TB.
Discuss various treatment options review the benefits/risks
How do you follow/monitor a patient with treated latent TB while on a TNF-inhibitor?
Be vigilant of signs and symptoms of TB
[poll id=”9″]
[poll id=”10″]
Case Study 6- New Onset Psoriasis
53 year-old woman
Crohn’s disease on TNF-inhibiting antibody with gastrointestinal disease is well-controlled
Develops palmoplantar pustular dermatitis
Could the psoriasis have been induced by the TNF-inhibitor?
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?
Production of autoantibodies
Co-stimulation/antigen presentation
Immunomodulation/cytokine secretion
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.
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.
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:
What health outcomes are impacted by Vitamin D levels?
How much Vitamin D is needed for a beneficial effect?
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
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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.
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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.
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.
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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 ocularpemphigoid. 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.
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