Category Archives: Issue 78 – Fall 2014

Our immune system is a killing machine. It consists of various types of specialized cells and proteins that function to destroy invaders and “non-self” or mutated “self” proteins, such as those that come from virus78_RH image_optes, bacteria, and cancer cells. In the autoimmune diseases such as the P/P diseases, this mechanism has gone awry and the immune system actually attacks its own cells.

In P/P patients, antibodies generated by B cells of the immune system block the function of desmoglein proteins Dsg1 and Dsg3 known to be important in binding together keratinocytes of the skin and mucous membranes, but it is not known how the rogue antibodies are generated by the immune system, how they escape the quality control mechanisms in place that only allow B cells with non-“self” specificities to survive, and why P/P patients are so rare.

New research led by Dr. Aimee Payne in the Department of Dermatology at the University of Pennsylvania (Nature Communications, http://www.nature.com/ncomms/2014/140619/ncomms5167/abs/ncomms5167.html) helps us begin to understand why.

In previous work, Dr. Payne and colleagues have identified antibodies that recognize Dsg1 and Dsg3 (so-called anti-Dsg1 and anti-Dsg3 antibodies) and have also identified regions of those antibodies that are important for the ability of those antibodies to be pathogenic — that is, to recognize their Dsg targets in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) and to disrupt their function. To extend this work and to better understand how PV autoantibodies arise, Dr. Payne and colleagues have performed a similar analysis of PV patients.

PV patients can present as either mucosal-dominant, where only the mucous membranes are affected or as mucocutaneous, affecting both the mucous membranes and the skin. Almost all mucosal-dominant PV patients have anti-Dsg3 autoantibodies, while the mucocutaneous patients have anti-Dsg3 autoantibodies as well as anti-Dsg1 autoantibodies. Since it is thought that Dsg1 and Dsg3 can compensate for each other’s function, the presence of functional Dsg1 in the skin in the presence of anti-Dsg3 autoantibodies can explain why mucosal-dominant patients do not have skin lesions.

The authors first isolated the full antibody repertoire from four different untreated PV patients, all with mucocutaneous disease. They isolated and characterized these in a multistep process that ultimately allowed them to determine the amino acid compositions (by cloning and DNA sequencing methods) of the patient’s PV antibodies. This led to the assignment of six unique antibodies from Patient 1 and five additional unique antibodies from the three other PV patients.

In total, the sequencing efforts identified 21 unique heavy chains among the four patients.

All 11 antibodies could bind to Dsg3 and this was mediated via a domain (called EC1) in Dsg3 that is known to be important for its adhesive interactions, suggesting that anti-Dsg3 autoantibody binding to Dsg3 leads to a direct block in Dsg3 function in keratinocytes (and subsequent skin blistering).

Curiously, not all of the antibodies that the authors identified that bound Dsg3 could cause blistering when added to human skin tissue samples; the VH1-46-containing antibodies did. They determined that these differences in functional effects were due to the inability of the nonpathogenic antibodies to bind to the functional domains of Dsg3.

Even more curiously, the authors found that all four patients had at least one PV antibody that consisted of an identical variable region termed VH1-46. They also found very little change in the VH1-46 amino acid sequence in the patient antibodies compared to the known sequence of VH1-46 that also exists in unaffected patients (considered the “wild-type” or germline sequence).

As noted by the authors, this is a pattern typical of a somatically mutated antibody sequence, meaning that very few changes were generated during the development of the B cells (each with its own single antibody that it makes, see Figure).

They did some additional experiments to define the ability of those amino acid changes to affect the binding to Dsg3. They conclude that VH1-46 autoantibodies in PV are generated during B cell development and require very little mutation to become pathogenic. This suggests that they appear early during the development of the disease and explains their prevalence in all of the patients tested here.

These autoantibodies may not be the most common later on (during full-blown disease), but they may provide a clue to why and how pemphigus arises. The ability of these autoantibodies to escape the quality control machinery at play during B cell development is likely due to the low levels of Dsg3 antigen available that would distinguish these antibodies as “self” antibodies and therefore the ability of the machinery to mark the cells and their rogue autoantibodies for destruction.

These data led the authors to speculate that the five pathogenic (disease-causing) VH1-46 anti-Dsg3 mAbs that they’ve identified in this study are among the earliest autoantibodies formed in PV patients, caused only by how simple they are to generate from germline sequences. They also define a mechanism for how these autoantibodies are made and most importantly, how they are missed by the quality control machinery – all low probability events that likely account for the rarity of PV.

One of the first things to remember about illnesses and the side effects of medications is the effects of illness are not just physical. There is an emotional component as well.

For example, the prednisone roller coaster is both physical and emotional. The ups and downs often have patterns and triggers, and these are not always predictable. The mere fact of having an illness can lead to depression, with or without side effects from medications.

Psychologists have been called “an angry bunch of shrinks” (Newsweek, December 2013) because of their collective response to new and unsettling upcoming changes in current diagnostic criteria and standards. The Diagnostic and Statistical Manual (DSM-IV) of the American Psychological Association has been the “bible” of the psychiatric profession for more than a decade, with the new version (DSM-V) going into effect in October 2015. The physicians’ ICD-10 (or International Statistical Classification of Diseases and Related Health Problems) will also be issued at that time.

In this article I will review some current diagnoses and criteria related to depression. With the aforementioned changes more than a year away, now is a good time to go over the diagnostic criteria for depression as outlined by the DSM and ICD standards. Lenore Sawyer Radloff’s Screening Test for Depression (see p. 17) can be used to monitor your own symptoms and patterns.

One mood disorder in the current DSM-IV is simply called “Mood Disorder Due to ____________.” The blank is filled in with a specific general medical condition, such as pemphigus vulgaris. The diagnosis may develop into a clinical depression over time, which has a different etiology. The diagnostic criteria for these generic mood disorders include:

A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following: Depressed mood or markedly diminished interest or pleasure in all, or almost all, activities. Elevated, expansive, or irritable mood.

There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition.

The disturbance is not better accounted for by another mental disorder so as to distinguish this general mood disorder from “Adjustment Disorder With Depressed Mood” in response to the stress of having a general medical condition, another clinical diagnosis.

The disturbance does not occur exclusively during the course of a delirium.

The symptoms cause clinically significant distress or impairment in social, occupational, or important areas of functioning.

Common symptoms of depression look different in each circumstance and with each individual. A diagnosis may be given if there is a prominent and persistent disturbance in mood that predominates in the clinical picture, and it is further characterized by five or more of the following:

Persistent feelings of sadness

Difficulty sleeping or excessive sleeping78_psychspeaking_opt

Poor or increased appetite

Weight loss or weight gain

Anxiety, restlessness and agitation

Inertia: feeling “slowed down” or low in energy

Tearfulness or an inability to cry

Difficulty concentrating, remembering, or making decisions

Loss of interest in sex and other normal activities

Social withdrawal

Difficulty functioning at work, at home and/or in social situations

Irritability

Suicidal thoughts or passive thoughts of death.

Ill people will often try to hide their symptoms until they lose the energy necessary to keep up the act. After all, the last thing most people want is more prescription medications or treatments. This is more so when their bodies have already “betrayed” them and medications are necessary just to not get sicker. It is important to understand what is happening emotionally and to get a proper diagnosis. With a diagnosis can come appropriate treatment.

The simple 20-question screening test for depression can be self-administered. I often recommend that anyone who is concerned or has symptoms they do not understand make copies and re-test themselves roughly every two weeks. This particular screen looks at the feelings and thoughts for the previous seven days, so you could use it weekly if you wanted to.

I often use this tool as a handout at presentations. Patients (and caregivers) usually come up to me and express surprise at how many statements they have endorsed. Many have no idea these particular feelings and thoughts were actually signs of depression. As I noted above, with diagnosis there is treatment.

My philosophy is to refer patients to a knowledgeable psychiatrist for evaluation for possible psychotropic medication. The psychotherapy component may be a fairly short-term cognitive-behavioral model, or a more lengthy psychodynamic approach. The bottom line is that everyone is unique, and no one needs to feel worse than absolutely necessary. For some people this means medication, especially in the beginning, or more frequent therapy appointments. The doctor will monitor and make changes as necessary. Having said that, the sooner the emotional diagnosis and the sooner treatment begins, the better and faster the positive effects will be in stopping any potential downward spirals.

It is often easier to speak with a professional than with someone in your personal network. The key is to identify any problem areas and to address them, not just put on a band-aid when emotional surgery is necessary.

The average P/P patient sees five doctors over 10 months to obtain a diagnosis. The IPPF Awareness Campaign strives to change this statistic by reducing the amount of time it takes a patient to receive a pemphigus vulgaris (PV) or mucous membrane pemphigoid (MMP) diagnosis.

We are excited to share the Awareness Campaign’s new logo and slogan, Put it on Your RADAR. The IPPF will encourage dental professionals to put PV and MMP on their radar. To do this, we are using different methods to increase awareness, such as conference presentations, community outreach, and dental expert reviewed materials.

The Dental Detective

The IPPF partnered with four other autoimmune disease foundations and submitted a joint conference presentation proposal. We are happy to announce our proposal was accepted and will be presented at the American Dental Association’s Annual Meeting on October 9, 2014, in San Antonio, TX. This was a very competitive process and we are thrilled to use this opportunity to spread awareness.

Dr. Vidya Sankar, DMD, MHS, and Sjögren’s Syndrome Foundation Board Member, will present on “The Dental Detective: Investigating Autoimmune Diseases.” This is a wonderful way to get information on PV and MMP, as well as other autoimmune diseases, out to an entire dental team.

Awareness Ambassadors

Tina Lehne, Volunteer Awareness Ambassador Coordinator, is working hard to bring the Awareness Ambassador program to life. The first set of activities will include outreach to dental professionals. This may include one-on-one meetings or presentations to dental classes or societies.awareness78_opt

Ambassadors sign up for a one-year commitment and receive training prior to engaging in awareness activities. If you are interested in becoming an Ambassador, contact awareness@pemphigus.org.

Dental Advisory Council

We are pleased to introduce the formation of the IPPF Dental Advisory Council (DAC). The DAC provides critical review of dental materials related to the Awareness Campaign. It is comprised of both dental professionals and students. We are very lucky to have such an expert panel devoted to PV and MMP awareness.

And the Oscar goes to…

Becky Strong, IPPF Patient Educator (pictured below), is the first recipient of the IPPF Awareness Award, appropriately shaped like an Oscar for her starring role in the Patient Awareness Video (release date coming soon). Becky has devoted countless hours to P/P awareness by presenting to dental schools and sharing her diagnosis story to help reduce diagnostic delays. Thank you, Becky!

Funding Announcement

The IPPF is happy to announce continued funding from the Sy Syms Foundation (www.sysymsfoundation.org). The Sy Syms Foundation awarded the IPPF’s Awareness Campaign with a check for $75,000. These funds will go a long way in our efforts to spread awareness and reduce diagnostic delays for all pemphigus and pemphigoid patients.

Thank you to the Sy Syms Foundation!

The IPPF encourages our Community to get involved with the Awareness Campaign. If you are interested in learning more about the campaign or getting involved, contact awareness@pemphigus.org.

78_mac-slider2_optFall is a time most clothing designers live for. They spend months creating new styles to be modeled on runways in New York, Milan, and Paris hoping to have the “must have” look of next Spring or Summer.

This Fall we present a new look from Sacramento tech-firm Uptown Studios (uptownstudios.net) for the IPPF that will be on computers, tablets, and phones around the world. After months of sketches, wire-frames, and coding, I am very excited to announce our new website: www.pemphigus.org.

The new site is easier to navigate and features resources and support at your fingertips. The “responsive” design keeps its look and feel no matter what screen size. We added accessibility features like variable text sizing and a high-contrast display. Our social media links, search box, and donation button are conveniently located at the top of each page. Our home page features a testimonial section. Read what others have to say about the IPPF. You can also submit your own story to be shared on our site!

A big part of our mission is support. In addition to the Email Discussion Group, RareConnect community, and social media sites, we added Desk.com support.

Our Patient Support team can now provide fast, awesome customer service on a modern, flexible platform over various channels. Patients and caregivers can find answers in the self-service portal using existing FAQs, email questions to our PHCs, or post to the general community. And when they are online, you can chat live with a PHC!

I am also excited about the Awareness Campaign portal currently being developed. It will contain resources and information for dental professionals and Awareness Ambassadors. Our goal is to keep P/P on the RADAR of dentists and provide them with tools and training needed to reduce P/P diagnosis time and increase your quality of life.

For some people, the end of Summer means the start of school. Here at the office “Back to School” means helpful happy interns. Several interns from Sacramento State University and Cristo Rey High School (Sacramento) are working on website articles, informational materials, the Awareness Campaign, and more. Our Sac State interns are in health-related programs and our high school interns are part of a Work-Study program. The work done by them saves the IPPF thousands of dollars each year while giving them real-world experiences.

Volunteerism is on the rise! Daphna Smolka is working with us on a P/P friendly cookbook that will be also be a P/P Community effort. Tina Lehne is spearheading the Awareness Ambassador effort and preparing the program’s requirements and materials. Marketing guru Edie DeVine is helping with our public messaging and press releases. Dr. Maulik Dhandha is working on a paper reporting on the diagnostic delays of P/P we hope to publish in an academic journal.

And speaking of journals, members of our Medical Advisory Board joined 30 other physicians in finalizing an MMP consensus statement providing clearer definitions and outcome measures for accurate and reproducible definitions for disease extent, activity, outcome measures, end points and therapeutic response. Thank you Prof. Dedee Murrell and Dr. Victoria Werth for leading this effort.

This issue of the Quarterly is another great one! PV patient Martha Cusick was so happy with the help she received from her Peer Health Coach, she set a goal to fundraise for research and awareness (p. 4). And what do you do when you need a cancer treatment, but getting it will cause a severe flare? Read Joan Blender Ominsky’s story on page 15.

The Awareness Campaign has a new look, more help, and a catchy slogan. Kate Frantz keeps you up to date starting on page 6. Clinical psychologist and PV patient Terry Wolinsky McDonald explains the Nuts & Bolts of Depression (p. 7). The discovery of VH1-46 is the topic of two articles (pp. 8 and 9). Two P/P experts discuss the importance of measuring patient quality of life (p. 11). And we have another delicious Vicky Starr recipe on page 19!

Lastly, I hope to see you in New York for our 2015 Patient Conference. The Committee is busy finalizing the date (end of April) and venue (near Central Park). Keep an eye on your mailbox and inbox for more information in the coming months! I promise this event will be BIG!