IMHO the idea of creating some disease specific threads has some pros and cons.
The problem as you mentioned is the lots of interesting trials and new research, which will continue to increase exponentially.
Regarding psoriasis for example, I had recently made a summary of recent studies for my own information and for WIMBW here is a copy:
Psoriasis is most probably an inherited disease characterized by cell proliferation, angiogenesis, and an inflammatory process.
The pathophysiology remains unknown, although an alteration in cell-cell and cell-matrix adhesion versus an autoimmune process has been proposed as the primary defect.
Both genetic and environmental factors are thought to contribute to the pathogenesis of the inflammatory and hyperproliferative components of the typical skin lesions.
Segregation analysis and twin studies together with ethnic differences in disease frequency all point to an underlying genetic susceptibility to psoriasis, which is both complex and likely to reflect the action of a number of genes.
Predisposing genetic influences include associations with human leucocyte antigens (HLA) of which that with HLA-Cw6 is the strongest.
In a recent study, all patients (100%) with guttate psoriasis carried the Cw*0602 allele compared with 20% of the control population (odds ratio = infinity; 95% confidence limits 25.00-infinity; Pcorrected < 0.0000002). The results were consistent with HLA-Cw*0602 playing a part directly in the pathogenesis of guttate psoriasis.
Some other recent studies have pointed to a linkage evidence in favor of a novel susceptibility locus for psoriasis and have provided evidence of the complex mechanisms underlying the genetic predisposition to this common skin disease.
For instance, significant excess (p=0. 004) paternal allele sharing was detected for markers spanning the PSORS1 locus. A further three regions reached NPL scores of 2 or greater, including a region at chromosome 7 (NPL 2.1), for which linkage for a number of autoimmune disorders has also been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favored linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and suggests evidence for epistasis between PSORS1 and genes at other genomic locations.
It has been suggested that mast cell play a role in the pathogenesis of psoriasis, but recent studies have not found any correlation.
The role of “activated neutrophiles”: Activated neutrophils are responsible for the release of serine proteases, which directly lead to tissue damage. Activated neutrophils also contain a newly assembled enzyme that produces tissue damaging free radicals.
It has been pointed out that a preliminary and necessary step is to attach the activated neutrophil on to the lining of the blood vessels, a process requiring proteolytic activity. This has led to the development by SuperGen of a drug, LEX 032, with a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface by blocking this proteolytic activity. In addition, they claim that this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine protease. If true, this approach may have a broad therapeutic potential in the treatment of neutrophil mediated diseases.
These diseases include inflammatory diseases which are, at least in part, caused or exacerbated by excessive neutrophil proteases, such as acute pancreatitis, arthritis, allograft rejection, sepsis, meningitis, acute pulmonary inflammation, psoriasis and damage caused by burns. This is in addition to reperfusion-related diseases such as myocardial infarction, stroke, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation, in which activated neutrophiles have also been shown to play a role. .
The role of elafin :
Elafin, an elastase inhibitor produced by keratinocytes, is overexpressed in the subcorneal region of skin affected by psoriasis, a major feature of which is epidermal infiltration by neutrophil leucocytes.
In recent studies, anti-elafin antibody showed a strong reaction with the subcorneal region of the epidermis in patients with Behcet's syndrome, Sweet's syndrome, pyoderma gangrenosum, cutaneous allergic vasculitis and acute bacterial infection (cellulitis), but showed no reaction in skin from patients with dermal lymphocyte infiltration such as is seen in chronic prurigo and discoid lupus erythematosus.
In vitro experiments demonstrated that treatment with IL-1beta and TNF-alpha resulted in 2.6-fold and 4-fold stimulation of elafin secretion, respectively, whereas IL-6, neutrophil elastase and IFN-gamma caused no significant changes in elafin release.
It was concluded that inflammatory mediators such as IL-1beta or TNF-alpha secreted by dermal neutrophils may be involved in overexpression of elafin in keratinocytes and that this could protect the epidermis from degradation by dermal neutrophil infiltration.
The discovery of peroxisome proliferator-activated receptor gamma (PPARgamma) as the molecular target for antidiabetic thiazolidinediones has heralded a new era in the approach to understanding the pathophysiology of insulin resistance and its relationship to cardiovascular disease.
However, the subsequent discovery of PPARgamma-dependent modulation of immune function and the cell cycle has led to a new paradigm in the approach to treating proliferative, inflammatory diseases.
Moreover, PPARgamma agonists can promote apoptosis, block angiogenesis and inhibit pathological remodelling in a variety of malignant and non-malignant pathological states.
With the availability of the PPARgamma protein crystal structure, the ligand binding domain co-ordinates and a better knowledge of the interaction of PPARgamma with co-factor assemblies, libraries of simple synthetic organic PPARgamma ligands can be constructed.
High throughput screening can identify the best candidates for targeting cellular phenotypic transition, cell cycle control, inflammation and apoptosis.
Instead of single agents for single pathologies, one can envisage the development of multifunctional therapeutic agents that target the multiple cellular processes that contribute to multifactorial diseases such as diabetes, hypertension, atherosclerosis, psoriasis and other inflammatory diseases, and carcinogenesis.
The role of angiogenesis, endothelial growth factor, trombospondin-1 and thrombospondin-2:
The vasculature in adult skin remains normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli.
However, skin retains the capacity for brisk initiation of angiogenesis, the growth of new blood vessels from preexisting vessels, during tissue repair and in numerous diseases, including inflammatory skin diseases such as psoriasis and skin cancers such as cutaneous squamous cell carcinomas.
Recent evidence suggests that vascular endothelial growth factor is the major skin angiogenesis factor. During skin angiogenesis, expression of vascular endothelial growth factor is induced in epidermal keratinocytes by several stimuli including transforming growth factor-alpha and hypoxia, leading to increased vascularization of the dermisThrombospondin-1 and thrombospondin-2 are endogenous inhibitors of angiogenesis that are expressed in normal skin, maintaining the quiescence of cutaneous vessels. Both inhibitors potently inhibit skin cancer growth via inhibition of tumor angiogenesis.
Targeting cutaneous blood vessels represents a promising new therapeutic approach for the treatment of a variety of skin diseases.
The role of immunocytes:
A few reports of patients undergoing allogeneic BMT for malignant conditions, observed the resolution of psoriasis after BMT, with minimal late morbidity.
T cells bearing natural killer receptors (NKRs) such as CD94 and CD161 are present in psoriasis. These immunocytes express several receptors for both classical and non-classical class I MHC molecules. Whether T cells bearing NKRs in psoriatic lesions represent immunoregulatory versus pathogenic immunocytes or are just bystander cells is unclear.
Recent in-vivo findings have demonstrated that this T cell line is pathogenic by creating a psoriatic plaque. In-vitro results also support a pathophysiologic role for interaction between T cells expressing NKRs and CD1d positive keratinocytes, with subsequent production of IFN-gamma.
It has been shown that upon injection in-vivo, the cytokine network produced was characterized by an immunological response polarized towards Th1 rather than Th2 cytokines. Thus, this pathogenic cell line provided evidence that T cells bearing NKRs can directly provoke a Th1 disease such as psoriasis.
A T cell receptor (TCR) peptide has been designed that mimics the intramembranous amino acid sequence of the TCR chain. Prior studies had shown that this mimic peptide would inhibit TCR signaling. . In humans, application of mimic peptide for the treatment of various diseases resulted in amelioration or even cure in patients suffering from atopic dermatitis, psoriasis or lichen planus.
The role of IGF-II and IL-6:
IGF-II is known to induce the growth of keratinocytes and the level has been found to be significantly elevated in the tissue fluid of psoriatic lesions. However, the role of IGF-II in psoriasis is not well defined. Because an inflammatory cytokine, interleukin-6 (IL-6) is overexpressed in psoriatic lesions, the possibility that IGF-II had some role in psoriasis through induction of IL-6, was recently studied and the results suggested a novel role of IGF-II in psoriasis possibly by inducing IL-6 through the activation of NFkappaB mediated by downregulation of IkappaB.
The role of (MMP)2 and the keratinocyte:
Recent reports from the National Institutes of Health, have shown evidence of a new mechanism involving basement membrane alterations accompanied by keratinocyte overexpression of matrix metalloproteinase (MMP) 2 and tissue inhibitor of MMP-2 (TIMP-2) in both uninvolved and involved psoriatic skin.
The overexpression of MMP-2 in uninvolved and involved psoriatic epidermis supports the concept that the primary alteration may reside in the keratinocyte. In addition, the presence of the activated form of MMP-2 could be responsible for cell-cell and cell-matrix changes noted in psoriatic epidermis.
Possible IL-10 deficiency
According to some studies by Schering in Germany, in psoriasis a relative deficiency in cutaneous IL-10 expression is observed. IL-10, plays a crucial role in several immune reactions. Several lines of evidence suggest that IL-10 could have antipsoriatic abilities. IL-10 administration over 3 - 7 weeks in patients with moderate to severe psoriasis have supported this hypothesis. The therapy was well-tolerated and clinical efficiency was found in the majority of patients. These investigations suggest that IL-10 is of major importance in psoriasis and show that IL-10 administration represents a new therapeutic approach.
Topical applications:
On recent experiments, Isis Pharmaceuticals, topically applied 20 nucleotide phosphorothioate intercellular adhesion molecule-1 anti-sense oligodeoxynucleotide in a cream formulation. It effectively inhibited tumor necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 in human skin transplanted on severe compromised immunodeficient mice. The effects were concentration dependent, sequence specific, and resulted from reduction of intercellular adhesion molecule-1 mRNA levels in the skin. Topical delivery produced a rapid and a significantly higher accumulation of oligodeoxynucleotide in the epidermis and dermis. The results strongly suggested that topically applied anti-sense oligonucleotides can be delivered to target sites in the skin and may be of considerable value in the treatment of psoriasis and other inflammatory skin disorders.
Limited application of fluticasone propionate ointment over a period of 10 weeks is effective and delays lesion recurrence without causing skin atrophy in patients with moderate to severe psoriasis in areas at risk for corticosteroid application, such as facial and intertriginous areas.
In a recent large-scale observation study the optimal treatment regimen was combination therapy of tazarotene and a corticosteroid. Overall results from a multicenter study involving more than 1000 patients with plaque psoriasis treated with tazarotene 0.1% gel plus a topical corticosteroid are soon to be published Considerable additional reductions (38%-50%) in overall severity of plaque psoriasis, plaque elevation, scaling, were reported.
The results of a multicenter, open-label observation study evaluating the use of tazarotene in 1393 patients being treated for plaque psoriasis also have been reported recently.The severity of each of these parameters was reduced from mild-to-moderate at baseline to trace-to-mild after a mean of 10 weeks' treatment with tazarotene plus a corticosteroid.
Phototherapy has been shown to be one of the most effective treatment modalities for patients with psoriasis. Nevertheless, photocombination therapies capable both of reducing cumulative ultraviolet (UV) doses and of accelerating clearance of skin lesions are important and of high interest.
At Mass. General Hospital, laser phototherapy is also been used in dermatology. The 308 nm excimer laser has recently been shown to clear psoriasis faster than conventional phototherapy. Scalp psoriasis may soon be treated by fiber-optic delivery of this UV laser.
Recent reports on dermatological phototherapy, showed that . UVA1 phototherapy (340-400 nm) is effective in the treatment of inflammatory skin diseases such as acutely exacerbated atopic dermatitis, localized scleroderma, urticaria pigmentosa and disseminated granuloma annulare.
Narrowband UVB radiation (311-313 nm) is used successfully as monotherapy or combined with dithranol, oral retinoids or 8-MOP in psoriasis, atopic dermatitis (AD) or photosensitivity disorders such as polymorphic light eruption.
The combination of salt water brine baths in different concentrations and subsequent UVA/B irradiation is been used increasingly for the treatment of psoriasis or AD.
Extracorporeal photopheresis (ECP) has proven to be a very effective treatment modality for cutaneous T cell lymphoma, chronic graft-versus-host disease and certain autoimmune diseases such as systemic scleroderma or pemphigus
Systemic therapy:
A variety of systemically administered drugs have been and are used to treat psoriasis, including among others, methotrexate, cyclosporine, acitretin, and hydroxyurea. Unfortunately, some patients are unresponsive to these agents. For others, side effects and cumulative toxicity prevent continued use.
Thioguanine appears to be an effective treatment for patients with severe recalcitrant psoriasis. Myelosuppression is a significant, but easily monitored side effect that can now be more accurately predicted by determining thiopurine methyltransferase levels before starting thioguanine
Liarozole, an inhibitor of the metabolism of all-trans-retinoic acid was recently administered systemically and the increase in tissue levels of this endogenous retinoid reportedly improved psoriatic lesions in an open, uncontrolled study. The data of the report suggested that liarozole is an effective treatment for psoriasis and indicate that the lowest effective dose is 75 mg twice daily. The drug reportedly was generally well tolerated. |
