Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Comparison between classical polyarteritis nodosa and single organ vasculitis of medium-sized vessels: a retrospective study of 25 patients and review of the literature.

BACKGROUND: Polyarteritis nodosa (PAN) is a rare form of systemic vasculitis, characterized by necrotizing inflammation of medium-sized vessels. In clinical practice, the distinction is made between a limited, mostly cutaneous, form and a generalized form. The Chapel Hill Consensus Conference of 2012 on the classification of the vasculitides classifies PAN as a medium vessel vasculitis, whereas the limited forms fall under the heading 'single-organ vasculitis' (SOV), with subdivions such as 'cutaneous arteritis' (formerly called cutaneous PAN) and 'others'. In this last category, forms of PAN limited to a single organ (e.g. testicle, gall bladder or appendix) should be categorized. The relation between classical and limited forms of PAN remains enigmatic. OBJECTIVE: To compare demographics, clinical characteristics and prognosis between SOV and generalized PAN. METHODS: Clinical files of all patients with a diagnosis of classical or limited PAN made in the departments of general internal medicine and dermatology between 1983 and 2013 in a tertiary care university hospital were reviewed. RESULTS: The patients of the SOV group tend to be younger, with a female predominance, while we observed a male predominance in the generalized PAN group. Relapses were more common in SOV than in classical PAN. None of the patients initially diagnosed with cPAN/SOV progressed to generalized disease. DISCUSSION: Though SOV and classical PAN share a lot of similarities, they are probably different disease entities, based on their different demographical, clinical and prognostic characteristics. The 1990 ACR-criteria for classical PAN are too broad since they allow patients with limited disease to be classified as classic PAN.

IgG4-related skin lesions: case report and review of the literature.

IgG4-related disease (IgG4-RD) is a systemic disease, mostly affecting the pancreas. It presents as accumulation of IgG4-producing plasma cells in various tissues. Other possible affected organs include the lacrimal glands, salivary glands, lungs, kidneys, liver, bile duct, retroperitoneum, breast, aorta, pituitary gland and prostate. A cutaneous presentation has also been described in the literature, and might be the initial presenting feature of IgG4-RD. We describe a 73-year-old white man who presented with two infiltrated, erythematous nodules on his abdomen. The histopathological characteristics were highly suggestive of IgG4-related cutaneous disease. Immunohistochemical stains were positive for IgG4. In the past, the patient's other organs had also been affected by IgG4-RD. Cutaneous presentation of IgG4-RD has been described previously in the literature but only in Asian patients (both East and South Asian). We also provide an overview of previously reported cutaneous manifestations of IgG4-RD.

Acute response of human skin to solar radiation: regulation and function of the p53 protein.

p53 is a tumor suppressor gene and mutation of p53 is a frequent event in skin cancer. The wild-type p53 encodes for a 53-kD phosphoprotein that plays a pivotal role in regulating cell growth and cell death. The wt-p53 gene is also called "guardian of the genome", for its role in preventing the accumulation of genetic alterations, observed in cancer cells. The wild-type p53 protein plays a central role in the response of the cell to DNA damage. UV, present in sunlight, is one of the most ubiquitously present DNA damage inducing stress conditions to which skin cells are exposed. The wt-p53 protein accumulates in human skin cells in vitro and in human skin in vivo upon UV irradiation. This upregulation mounts a protective response against permanent DNA damage through transactivation of either cell cycle arrest genes and DNA repair genes or genes that mediate the apoptotic response. The molecular events which regulate the activity of the wt-p53 protein activity are only beginning to be described.

Inability of antipsychotics to antagonize the cueing properties of cocaine in rats.

In this study the possible antagonistic effects of five different antipsychotics on the discriminative stimulus properties of 10 mg/kg cocaine were evaluated by use of a two-lever food-reinforced drug discrimination procedure in rats. To do so, rats were treated with several doses of haloperidol, risperidone, seroquel, sertindole, and olanzapine, either at 60 or 120 min prior to testing. With all compounds tested, no substantial antagonism of the cocaine cue was observed. Only with haloperidol (maximum 60%), risperidone (maximal 20%), and olanzapine (maximal 20%) a partial antagonism without clearcut dose-response was observed. Clozapine, seroquel, and sertindole did not influence the discriminative stimulus properties of cocaine. These results indicate that antipsychotics with different pharmacological profiles are unable to antagonize more than partially the cueing properties of 10 mg/kg cocaine in rats, pointing to the unique underlying stimulus properties of this stimulant.

Antagonism of the discriminative stimulus properties of cocaine with the combination of a dopamine D1 and D2 antagonist.

Antagonism of the discriminative stimulus properties of 10 mg/kg cocaine was studied in rats by use of the dopamine D1 antagonist SCH 23390 and the D2 antagonist haloperidol. Whereas SCH 23390 and haloperidol were by themselves unable to antagonize the cueing properties of cocaine, the combination of both dopamine antagonists resulted in a complete blockade of the cocaine cue. In the presence of a fixed dose of 0.01 and 0.04 mg/kg haloperidol, the ED50's (it is the effective dose in 50% of the animals) of SCH 23390 for cocaine antagonism were 0.043 and 0.012 mg/kg, respectively. Similarly, the ED50's of haloperidol in combination with 0.01 and 0.04 mg/kg SCH 23390 were 0.021 and 0.024 mg/kg. The combined treatment of haloperidol and SCH 23390 resulted in strong response-rate reductions. At all combination regimens resulting in a complete blockade of the cocaine cue, response rate was reduced to less than 20% of the control values. These results indicate that the cueing properties of cocaine are both dopamine D1- and D2-mediated and that a combined antagonism of both receptor subtypes can lead to a complete antagonism of the cueing properties of cocaine which is associated with severe attenuation of response rate.

Risperidone (R 64 766), a potent and complete LSD antagonist in drug discrimination by rats.

Risperidone was studied in a 0.16 mg/kg LSD-saline drug discrimination test procedure. At doses varying from 0.0025 to 0.63 mg/kg, no LSD-like agonist effects were observed. Studies on the antagonism of the LSD-cue indicated that risperidone was able to completely block the discriminative stimulus properties of LSD with a minimum ED50-value of 0.028 mg/kg. Risperidone was also very active over time with reference to LSD antagonism, the ED50S after 2, 4 and 8 h pretreatment being 0.028, 0.064 and 0.44 mg/kg. Response rate reductions were only observed at doses greater than or equal to 0.16 mg/kg after 1 h and at 0.63 mg/kg after 2 h pretreatment. Four and 8 h after treatment, no rate-reducing effects were apparent at doses up to 2.50 mg/kg. Thus at pretreatment intervals ranging between 2 and 8 h, complete antagonism of LSD without any rate effects was obtained. As compared to other LSD antagonists, risperidone was quantitatively better than setoperone and ritanserin and longer acting than pirenperone. Based on the pharmacological profile of risperidone and the other LSD antagonists, it was concluded that a potent central 5-HT2 and catecholamine antagonism is needed for a potent and complete antagonism of the 0.16 mg/kg LSD-cue. The potential clinical effect of risperidone in the positive and negative symptoms of schizophrenia is discussed.