Psoriasis is a multifactorial disease of uncertain etiology that affects approximately 2% of the population (1). Psoriatic lesions are characterized by a clinical triad consisting of skin induration, scaling, and erythema. The histologic correlates of these clinical findings include inflammation, abnormal keratinocyte proliferation/terminal differentiation, and dermal angiogenesis. The inflammatory infiltrate, particularly pronounced at the dermal-epidermal junction, consists largely of activated T cells and antigen-presenting cells (APCs) and precedes the development of epidermal hyperproliferation (2). Increased levels of inflammatory cytokines have been detected in lesional psoriatic epidermis, which may result in the potentiation of T-cell activation (3) as well as hyperproliferation and accelerated differentiation of keratinocytes (4, 5). These and other data derived from T cell-based therapeutics (6-8) suggest that activated T cells play an important role in triggering and perpetuating the disease. Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage φX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC–lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

The relationship between cardiovascular risk factors and the incidence of peripheral neuropathy (PN) was examined in type 1 diabetic subjects from 27 centres participating in the EURODIAB Prospective Complications Study. PN was assessed at baseline and follow-up using a standardised protocol involving combinations of neuropathic symptoms, absent tendon reflexes, age related vibration perception thresholds (VPT) and autonomic function tests. Serum lipidsllipoproteins, HbA,, and albumin excretion rate (AER) were measured in a central laboratory. Of 1195 subjects with no PN at baseline (mean age 30.6 years; mean duration 12.4 years), 24.5% developed PN over the follow up period (average 7.3 years). In those with no baseline abnormalities 24.4% developed neuropathic symptoms, 19.5% had absent reflexes, 21.2% had abnormal VPT and 15.5% abnormal autonomic function at follow up. The incidence of PN was significantly positively associated with age, duration of diabetes and HbA,, at baseline. After statistical adjustment for these three factors the following baseline variables were significantly predictive of the development of PN; BMI, AER, triglyceride (p

Unintentional intra-arterial injection of medication, either iatrogenic or self-administered, is a source of considerable morbidity. Normal vascular anatomical proximity, aberrant vasculature, procedurally difficult situations, and medical personnel error all contribute to unintentional cannulation of arteries in an attempt to achieve intravenous access. Delivery of certain medications via arterial access has led to clinically important sequelae, including paresthesias, severe pain, motor dysfunction, compartment syndrome, gangrene, and limb loss. We comprehensively review the current literature, highlighting available information on risk factors, symptoms, pathogenesis, sequelae, and management strategies for unintentional intra-arterial injection. We believe that all physicians and ancillary personnel who administer Intravenous therapies should be aware of this serious problem.