Yearly Archives: 2010

The nonprofit world is stewing over the ban Apple has put on making donations on the iPhone via charity apps.

No one, including Apple, has data on how many nonprofits have created apps for the iPhone. Organizations like the Monterey Bay Aquarium and American Cancer Society have them, but none can be used to make gifts. Prospective donors instead are directed out of a nonprofit’s app and to its Web site, which the organizations say makes the process of contributing more cumbersome.

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Pharmaceutical (drug) and biotech companies are constantly researching and developing new medications to treat medical conditions, and new drugs come on the market frequently. People who have rare diseases or disorders, however, have not had as much research attention in past decades. This is because their numbers are small and therefore the potential market for new drugs to treat them (commonly referred to as “orphan drugs”) is also small. A rare disease occurs in less than 200,000 individuals in the United States, or less than 5 per 10,000 individuals in the European Union. Government regulatory agencies in the United States and the European Union have thus taken steps to reduce this disparity.

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Pemphigus is a term used to describe blistering of the skin caused by binding of antibodies to the surface of the cells of the outer layer of the skin, the epidermis. In pemphigus vulgaris, the most common form of pemphigus, there are IgG antibodies that bind to the cell surfaces of epidermis of the skin as well as the epithelium lining mucosal surfaces such as the mouth. As a result, patients develop severe oral ulcerations, and may also have inflammation or erosions of the lining of the eye and eyelids (conjunctiva), the nasal mucosa, or the genital mucosa. Half of the patients also develop blisters or erosions of the skin, often in the head and neck area.

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Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of pemphigus patients. Common terms and endpoints of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and

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advance clinical trials This consensus statement from the International Pemphigus Committee represents two years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

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The risk of death in patients with pemphigus
vulgaris has been substantially reduced by treat-
ment with systemic corticosteroids.5 Current therapy consists of high doses of corticosteroids plus immunosuppressive agents.6 This combination frequently causes long-term immunosuppression, the consequences of which are now the most
common cause of death in patients with pemphigus vulgaris.7 Patients who do not have a response to corticosteroids plus immunosuppressive agents
or who

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have severe side effects from this therapy have been successfully treated with intravenous immune globulin,8,9 which can be used as monotherapy and can produce long-term remissions.

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Pemphigus VulgarisCurrently, available technologies are limited in their power to characterize autoreactive T cells, which are necessary for the generation of autoantibodies in PV and the development of disease. The research team of the Department of Dermatology at the Weill Medical College of Cornell University is developing two newly emerging technologies to identify, enumerate, and analyze autoreactive T cells.  They are undertaking fine specificity characterization of autoreactive T cell populations and precise mapping of T cell epitopes responsible for disease induction and progression.  These studies are expected to illuminate novel and specific targets for immunoprevention and therapy.

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“This new science is forcing the medical community to take more seriously the popular notions of the mind-body connection,” says Esther M. Sternberg, M.D., director of the Integrative Neural Immune Program at the National Institute of Mental Health. In response to stressful events, our bodies pump out hormones. These hormones aren’t necessarily harmful and can be very useful, says Dr. Sternberg, author of The Balance Within: The Science Connecting Health and Emotions. “The problem is when the stress response goes on for too long,” she says. “That’s when you get sick. Hormones weaken the immune system’s ability to fight disease.”

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The Unseen Problem With Drugs

Judith Graves developed a rare medical condition called jawbone death after taking Fosamax, a drug used by millions of American women with thinning bones.

The F.D.A. said the optimal period for using drugs like Fosamax was unknown.

In a civil trial now under way in Manhattan, Mrs. Graves is suing Merck, the maker of Fosamax. Her lawyer, Timothy M. O’Brien, told the jury that Fosamax had caused such debilitating jawbone deterioration that Mrs. Graves required five major operations, including a lengthy surgery to replace her broken jaw with bone from her left arm.

Merck has argued that Fosamax is not the culprit. In its defense, Merck contends that Mrs. Graves took other prescriptions — like steroids to treat rheumatoid arthritis — that weakened her immune system, leading to her jaw infection and healing problems, said Paul F. Strain, outside counsel for the company.

The lawsuit is one of a handful of bellwether cases against Merck representing litigation involving about 1,400 people across the country who say they developed jawbone ailments after taking Fosamax, Mr. O’Brien said. Merck won an earlier case; but in another, a judge proposed to reduce a plaintiff’s jury award to $1.5 million from $8 million (both sides plan to appeal).

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A questionDosage and indication “creep” with the new biologics to treat inflammatory diseases have payers enforcing strict utilization policies. Physicians counter that payers can’t dictate treatment. With even more biologics on the horizon, and drug spend spiralling upward, both sides need to seek a middle ground. The question is how?

“It’s a bit like solving a Rubik’s Cube” when dealing with new immunomodulators, says Helen Sherman, PharmD, with RegenceRX. “We keep track of all the science and potential uses, but this is a complex category.”

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Bullous pemphigoid (BP) is a prototypical organ-specific autoimmune disease. Autoantibodies unfold their blister-inducing potential by triggering an Fcγ-dependent inflammatory reaction. The study by Iwata et al.  in this issue provides the first direct evidence that IgG autoantibodies from BP patients may also weaken cell–matrix adhesion by depleting BP180/type XVII collagen from cultured keratinocytes. These novel findings shed new light on additional mechanisms of blister formation in pemphigoid diseases and open the way for further informative studies.

Bullous pemphigoid (BP) is a subepidermal blistering disease that typically affects the elderly and is associated with an autoimmune response against hemidesmosomal proteins (Liu and Diaz, 2001; Mihai and Sitaru, 2007; Olasz and Yancey, 2008). Extensive clinical and experimental evidence strongly suggests that autoantibodies cause the pathology in this disease (Sitaru and Zillikens, 2005; Leighty et al., 2007). Circulating autoantibodies in BP patients exhibit a heterogeneous specificity to several hemidesmosomal components, including BP230, an intracellular constituent of the hemidesmosomal plaque, and the transmembrane protein BP180/type XVII collagen (Sitaru and Zillikens, 2005; Leighty et al, 2007). Mutations in COL17A1 in patients with generalized atrophic benign epidermolysis bullosa and in knockout mice result in low or absent expression of BP180/type XVII collagen and subepidermal blistering (McGrath et al., 1995; Nishie et al., 2007). These findings suggest that a decrease in the expression of this hemidesmosomal antigen may weaken cell–matrix adhesion in the skin and eventually result in dermal–epidermal separation.

Autoantibodies to the transmembrane antigen BP180, but not to the intracellularly located BP230, were hypothesized to be pathogenically relevant (Liu and Diaz, 2001; Sitaru and Zillikens, 2005). Indeed, experimental evidence generally supports the pathogenic role of autoantibodies to BP180 for blister formation. IgG autoantibodies, affinity purified against recombinant BP180 from patients with BP and pemphigoid gestationis, induce dermal–epidermal separation in cryosections of human skin when co-incubated with leukocytes from healthy donors (Sitaru and Zillikens, 2005). In 1993, Liu et al. first provided evidence for a pathogenic role of autoantibodies to type XVII collagen/BP180 in vivo (Liu et al., 1993). The authors demonstrated that rabbit antibodies generated against murine BP180 induce subepidermal blisters when passively transferred into neonatal mice. More recently, further animal models reproducing blister formation in BP have been developed using mice that express the human form of the BP180 antigen injected with BP patient autoantibodies. Studies performed mainly with the experimental model developed by Liu et al. (1993) revealed that subepidermal blistering triggered by rabbit IgG specific to murine BP180 depends on complement activation, mast cell degranulation, macrophage activation, and neutrophilic infiltration. Reactive oxygen species and proteases, such as gelatinase B/MMP-9 and elastase, are critically involved in blister formation

IgG autoantibodies deplete BP180 from keratinocytes.

in vivo and in vitro (Liu and Diaz, 2001; Liu, 2004; Sitaru and Zillikens, 2005; Leighty et al., 2007). These findings partially match the pathology observed in BP patients and support the prevailing view that triggering an Fcγ-dependent inflammatory reaction is necessary for blister induction by autoantibodies in BP (Figure 1).
Figure 1.
Figure 1 – Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Mechanisms of blister formation in bullous pemphigoid (BP). The left lower panel illustrates several structural proteins of the epidermal basement membrane that function as major autoantigens in autoimmune subepidermal bullous skin diseases. The main autoantigens in BP patients include the BP antigen 230 (BP230) and the BP antigen 180 (BP180)/type XVII collagen. BP autoantibodies accumulate in tissue and bind to antigens at the epithelial basement membrane. Binding of pathogenic autoantibodies triggers an inflammatory reaction, including fixation of complement and Fc-dependent activation of leukocytes. In addition to granulocytes, mast cells likely contribute to the antibody-induced inflammation at the dermal–epidermal junction. Activated granulocytes release reactive oxygen intermediates and proteases, leading to epithelial damage and blister formation. Alternatively, as shown by Iwata et al. (2009), IgG autoantibodies may deplete BP180 from basal keratinocytes and thus contribute to blister formation. LN 332, laminin 332; ROS, reactive oxygen species.
Full figure and legend (158K)

Although the description of the relatively uncommon variant of BP with a paucicellular dermal infiltrate suggested the existence of alternative noninflammatory mechanisms of blister formation, until now experimental data did not support this hypothesis. A further hint that a full inflammatory response may not be required for subepidermal blistering by autoantibodies against BP180/type XVII collagen was provided by Yamamoto et al. (2002). They demonstrated that rabbit antibodies generated against hamster BP180 induced subepidermal blisters when passively transferred into neonatal hamsters. The blister formation in this model necessitates complement activation, but not the recruitment and activation of leukocytes (Yamamoto et al., 2002).

In this issue, Iwata et al. show that IgG autoantibodies from patients with BP deplete keratinocytes of BP180/type XVII collagen. When IgG from BP patients was added to cultured keratinocytes, the authors found that this treatment depleted BP180, but not α6β4 integrin, from cells as assessed by densitometric analysis of immunoblots. In addition, keratinocytes treated with IgG from BP patients showed a reduction in their adhesive strength as revealed by a standardized detachment assay (Iwata et al., 2009).

These findings describe new and potentially relevant mechanisms of blistering in BP and may have important consequences for the development of new treatment modalities. The fact that autoantibodies from patients with BP deplete BP180 from keratinocytes strongly suggests that alternative noninflammatory mechanisms contribute to blister formation in the pemphigoid diseases. Animal models of BP allow the in vivo relevance of these findings to be addressed and the relative contributions of the noninflammatory and inflammatory mechanisms of blister formation by autoantibodies to be dissected.

Autoantibodies in BP are thought to be heterogeneous with respect to their blister-inducing potential. Major intrinsic determinants of autoantibody pathogenicity include their specificity and their ability to activate complement and leukocytes (Sitaru and Zillikens, 2005). Future research should answer the question of whether the specificity of antigen-depleting autoantibodies differs when compared with that of autoantibodies that activate putative inflammatory mechanisms. BP autoantibodies belong to different isotypes, which may be associated with distinct effector functions. On the basis of previous experimental evidence, it has been proposed that blistering is induced primarily by IgG1, whereas IgG4 autoantibodies are less pathogenic or even protective (Liu, 2002; Sitaru et al., 2007). In light of the novel noninflammatory mechanisms of blister formation by autoantibodies as suggested by the study by Iwata et al. (2009), the role of different isotypes of autoantibodies in the pathogenesis of BP requires reappraisal.

In conclusion, this study strongly suggests the existence of noninflammatory mechanisms of blister formation by autoantibodies in BP. Further exploration of this line of research should provide relevant mechanistic insights into BP pathogenesis and greatly facilitate the development of more effective therapeutic approaches.