Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 11, Issue 2, 2011

Graves' orbitopathy occurs in around 30&percnt of patients with Graves' disease and ranges in clinical severity from mild to severe. Even mild disease can affect quality of life significantly while severe disease can be sight threatening. This issue of Immunology, Endocrine and metabolic Agents in Medicinal Chemistry explores the therapy of this condition. Before considering therapy however, the pathogenesis must be appreciated. Draman and Ludgate update our understanding in this regard as well as indicating where our knowledge is deficient. While the clinical presentation of this condition may be obvious to some clinicians the experience from The European Group on Graves' Orbitopathy (EUGOGO) has reported that many patients are diagnosed late as the early signs may be mistaken for other conditions. Heggie and Petros Perros, the current chairman of EUGOGO, review the clinical features of the condition as well as commenting on the psychosocial aspects. It is important to note that The Amsterdam Declaration (2009) seeks to achieve greater access of patients to centres of excellence. Until recently the treatment of Graves' orbitopathy has included symptomatic measures, immunosuppression and surgical intervention.. Steroids have been the mainstay of immunosuppressive therapy; Zang and Kahaly review this modality concentrating on the immunological action as well as the mode of administration. Developments in our understanding of the immune system have given rise to new possibilities in therapy for autoimmune diseases. Rituximab, which depletes memory CD20+ B cells has been used with success in rheumatoid arthritis: Salvi and colleagues report their experience with this targeted immune modulator in Graves' orbitopathy. Further discussion of potential targets for immunotherapy is presented by Smith who explores different facets of the immune system in this regard. One of the features of this issue was that it should incorporate a communication from the pharmaceutical industry on which we depend for drug development. The review by van Maurik and colleagues illustrates the wide variety of new immune modulators that are currently available; it is to be hoped that at least some of them will be studied in the management of orbitopathy in the near future. I would like to thank sincerely all the contributors to this volume for their work and patience. I believe the end result amply justifies the effort.

About 5% of patients with Graves' disease (GD) develop Graves' orbitopathy (GO) of sufficient severity to require treatment. GD is an autoimmune condition caused by thyroid stimulating antibodies (TSAB) mimicking the action of TSH, although the mechanisms leading to loss of tolerance to the TSHR remain unknown. In GO, tissue remodeling increases the volume of the orbital contents by several mechanisms including adipogenesis and overproduction of glycosaminoglycans (GAGs). The increased volume produces proptosis, chemosis and increased intraocular pressure. GO is also an autoimmune disease and the timing of its onset (relative to GD) suggests a thyroid/orbit shared antigen. Data in favour of the antigen being the TSHR include demonstration of its increased expression during adipogenesis and the fact that the most severe GO occurs in GD patients having the highest TSAB titres. Evidence against its role are patients with euthyroid GO (devoid of TSAB) and its widespread expression. However, recent reports demonstrate a direct role for TSHR autoantibodies in GAG production, but it is likely that other antigens, such as IGF-1R, may also contribute to pathogenesis. In vitro models have demonstrated the heterogeneity of orbital fibroblasts, some destined for adipogenesis and/or secretion of GAGs in response to stimulation by inflammatory cytokines or patient immunoglobulins. GO may be exacerbated by e.g. PPARγ agonists, but PPARγ antagonists (inhibit adipogenesis) may provide novel treatment options. Of interest, B cell depletion, which does not consistently reduce TSAB levels, also shows some promise but further adds to the puzzle of the relevance of the TSHR.

GO is common in patients with Graves' disease and is associated with significant morbidity. The clinical presentation is varied and often the diagnosis is delayed. Careful clinical assessment usually leads to an accurate diagnosis, though in a minority of atypical presentations imaging and other diagnostic tests may be necessary. The natural history is well-documented, but work is still required in developing measures of grading of the disease to assist in clinical decision-making.

Steroids act via suppression of the immune system in two different ways: a genomic and a non-genomic pathway. While the non-genomic pathway appears to be responsible for the quick effects only a few minutes after application, the genomic pathway determines the long-time effects. Since decades, systemic steroids have been applied in the management of severe Graves' orbitopathy (GO). In GO, steroids effectively modulate both the effector cells as well as the orbital targets cells, i.e. fibroblasts and pre-adipocytes. They inhibit the release of inflammatory mediators i.e. cytokines and prostaglandins. Also, systemic steroids significantly reduce the titer of the disease relevant thyroid-stimulating immunoglobulins. A few studies only, dealing with difference in mechanisms depending on the way of administration (intravenous, oral or peribulbar) are available. Efficacy of the three ways of application is statistically different. The systemic administration of steroids has a higher efficacy than the local peribulbar application. Furthermore, evidence based and compared to the oral form, the intravenous steroid administration shows both a significantly higher response rate as well as markedly less adverse events. Thus, high dose intravenous steroid pulses are currently considered the first line-treatment for active and severe GO.

B-cell contributions to human autoimmune disease have recently been emphasized due to the therapeutic benefit of B-cell depleting therapies. B cells are involved in the production of autoantibodies, by CD4+ T-cell activation and control of T-cell function and inflammation, through cytokine production. Although autoantibodies alone may not initiate autoimmune disease, their relationship with the disease course suggests that they are the key mechanisms of disease pathogenesis. In addition to antibody production, B cells are important antigen presenting cells. Maturation of B cells develops through various steps characterized by the expression of several cell surface markers that are potential targets on which B cell-depleting agents can act directly. Rituximab (RTX) has been used off-label in various autoimmune disorders but is approved for clinical use in non-Hodgkin's lymphoma (NHL) and RA only. RTX treatment effectively depletes mature and memory CD20+ B cells, but not long-lived plasma cells. The availability of RTX has provided the rationale of its use in GD, since blockade of pathogenic autoantibody generation might bring about Graves' hyperthyroidism remission. The effects of RTX in patients with active GO have also been studied. Although, caution is suggested before proposing RTX as a novel therapeutic tool in this disease, data collected show that RTX significantly affect the inflammatory activity and severity of GO. Therefore, we envisage that the optimal strategy to controlling the progression of a disease like GO would be to pursue B-cell depletion shortly after diagnosis and not as an additional therapeutic option when standard immunosuppression has failed.

Graves' disease comprises a syndrome involving the thyroid, orbit and skin. The unifying components that tie together these anatomically diffuse manifestations remains uncertain as do the genetic and environmental factors initiating and propagating disease. The orbital process, termed thyroid-associated ophthalmopathy or Graves' orbitopathy, is not effectively managed because we do not yet understand enough about its pathogenesis to develop specific and safe therapeutic agents. Moreover, we lack complete and robust pre-clinical models of Graves' disease. In this brief review, I will attempt to discuss the potential targets to which new agents might be developed and others that are already available and could be utilized in clinical trails. The wide array of biological agents recently introduced to the marketplace and those currently under development offer an opportunity to identify productive treatment strategies for this vexing disease.

Although over the years an improved understanding in the etiology of Graves' orbitopathy has been obtained, conventional medical therapy for the treatment of this autoimmune disorder has changed very little and remains essentially based on approaches of non-specific immunosuppression. There is great potential for this to change as novel disease-modifying therapies have been developed which have been proven effective in the treatment of other autoimmune inflammatory disorders. These recent developments offer a strong rationale to evaluate such immune-targeting drugs for the treatment of Graves' orbitopathy. This article provides an overview on new drugs that act specifically on the pathogenic immune-mechanisms of the disease that are currently being developed for autoimmune disorders and could be considered for use to treat Graves' orbitopathy including immune-interventions that inhibit lymphocyte responses through depletion or modulation, and block cytokine secretion or action.

Most prostate cancers (PCa) are critically reliant on functional androgen receptor (AR) signaling. At its onset, PCa is androgen-dependent and although temporarily halted by surgically or pharmacologically blocking the AR (androgen ablation), the disease ultimately recurs as an aggressive, fatal castration resistant prostate cancer (CRPC). FDAapproved treatments like docetaxel, a chemotherapeutic agent, and Provenge, a cancer vaccine, extend survival by a scant 3 and 4 months, respectively. It is clear that more effective drugs targeting CRPC are urgently needed. The ErbB family (EGFR/ErbB1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) of receptor tyrosine kinases (RTKs) have long been implicated in PCa initiation and progression, but inhibitors of ErbB1 and ErbB2 (prototypic family members) fared poorly in PCa clinical trials. Recent research suggests that another family member ErbB3 abets emergence of the castrationresistant phenotype. Considerable efforts are being directed towards understanding ErbB3-mediated molecular mechanisms of castration resistance and searching for novel ways of inhibiting ErbB3 activity via rational drug design. Antibody- based therapy that prevents ligand binding to ErbB3 appears promising and fully-humanized antibodies that inhibit ligand-induced phosphorylation of ErbB3 are currently in early development. Small molecule tyrosine kinase inhibitors are also being vigorously pursued, as are siRNA-based approaches and combination treatment strategies- the simultaneous suppression of ErbB3 and its signaling partners or downstream effectors - with the primary purpose of undermining the resiliency of ErbB3-mediated signal transduction. This review summarizes the existing literature and reinforces the importance of ErbB3 as a therapeutic target in the clinical management of prostate cancer.