Burden of Moderate-to-Severe Plaque Psoriasis and New Therapeutic Approaches (Secukinumab): An Italian Perspective.

UNLABELLED: Psoriasis is a chronic immune-mediated inflammatory skin disease commonly categorized as mild, moderate, or severe. Moderate-to-severe psoriasis is associated with significant comorbidity and has been shown to severely impair quality of life. Moreover, psoriasis is associated with high costs, including those associated with treatment, which have increased recently with the inclusion of biological systemic agents (most recently secukinumab) as available treatment options. However, despite clear evidence of their value in the treatment of moderate-to-severe plaque psoriasis, in Italy access to the biological agents remains limited to dermatological centers originally involved in the Psocare network. The impact of secukinumab entry into the market in Italy is still to be determined, but we believe that it will be associated with significant changes in the way in which biological treatments for psoriasis are accessed and prescribed in Italy. It is noteworthy that in January 2015, the European Medicines Agency approved secukinumab as first-line systemic therapy in this indication. FUNDING: Novartis, Italy.

Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.

Factors and comorbidities associated with central nervous system involvement in systemic lupus erythematosus: a retrospective cross-sectional case-control study from a single center.

To evaluate, by a retrospective cross-sectional case-control study from a single center, the distribution of a number of factors and comorbidities potentially related to central nervous system involvement in SLE Italian patients, a number of "generic" (i.e. not strictly SLE related) and "specific" (i.e. SLE related) risk factors were checked and their distribution analyzed in SLE patients with (NPSLE) and without (SLE) neuropsychiatric (NP) involvement. One hundred and fifty-three SLE patients with NP involvement observed from 1999 to 2008 and 247 SLE patients without NP manifestations, matched for sex, age and disease duration were included in the study. A neuropsychiatric (NP) event represented the heralding symptom of the disease in 40.5% of NPSLE. Headache, cerebrovascular events, mood disorders and seizures were the most frequent NP manifestations. NPSLE patients had a major cumulative number of the investigated factors than controls without NP involvement. Antiphospholipid antibodies (aPL), lupus anticoagulant (LA), Antiphospholipid antibodies syndrome (APS), Raynaud's phenomenon, smoke, assumption of contraceptives and higher cumulative dose of glucocorticosteroids (GC) were significantly more commonly observed among NPSLE. APS and systemic arterial hypertension were more frequently detected among patients with focal NP manifestations, especially cerebrovascular events. aPL, LA, APS, Raynaud's phenomenon, smoke, contraceptives intake and higher cumulative dose of GC did prove more frequently detected in NPSLE patients than in controls. In particular, overall, arterial hypertension should be regarded as a potential independent "risk factor" for focal involvement, especially for cerebrovascular events.

The use of uterine artery doppler as a predictive tool for adverse gestational outcomes in pregnant patients with autoimmune and thrombophilic disease.

OBJECTIVES: To verify whether Doppler velocimetry on the uterine arteries can be used to single out abnormal hemodynamic adjustments in the uteroplacental district and to prognose adverse gestational outcomes in pregnant women with autoimmune and trombophilic disease. METHODS: The study included 67 patients divided into 3 groups selected by a developed pathology. Attention was given to the performance of the Resistance Index (RI) in Doppler velocimetry checks at 10th, 16th-18th, 21st and 28th weeks of gestation. RESULTS: A significant correlation between Doppler values at week 21st and development of preeclampsia was observed (p <0.05) in the three patient groups. High Doppler values at the 21st week were found to be strongly associated (p <0.01) with preterm delivery. We also observed a significant correlation (p <0.05) between high Doppler values at week 21st and low weight at birth. Doppler was found to have a predictive power for gestational adverse outcomes already at week 16th. CONCLUSION: RI values of more than 0.58 (taken as a cut-off) at 16/18th weeks allowed us to identify the category most at risk, if confirmed at 21 weeks.

Central nervous system involvement in Sjögren's syndrome: unusual, but not unremarkable--clinical, serological characteristics and outcomes in a large cohort of Italian patients.

OBJECTIVES: To perform an observational retrospective cross-sectional case-control study to evaluate prevalence, clinical patterns and outcomes of CNS involvement in a large cohort of primary SS (pSS) patients. METHODS: A total of 424 pSS patients, diagnosed according to the 2002 criteria proposed by the American-European Consensus Group, were checked for CNS involvement after exclusion of secondary causes. Demographic, clinical, seroimmunological data were compared between patients with and without CNS involvement. Neuroimaging data were also analysed. RESULTS: CNS involvement was detected in 25 (5.8%) patients (24 females and 1 male) both at disease onset (52%) and later (48%) with a mean latency after diagnosis of 7 years. Diffuse (40%), focal/multifocal (36%), multiple sclerosis (MS)-like disease (20%) and isolated optic neuritis (4%) were the most common CNS clinical pictures. Disease duration, lung involvement and decreased C(4) were associated with CNS involvement, while articular manifestations were more frequently observed in patients without neurological complications. Most cases had an acute, often recurrent course with spontaneous remission or only mild neurological impairment. CONCLUSIONS: CNS involvement represents a rare but not negligible complication of pSS, which may occur with a bimodal temporal pattern, both at onset and later, prompting attention in the differential diagnosis of apparently isolated neurological syndromes. Lung involvement emerged as the strongest risk factor for CNS involvement with a relative risk of 7.9, along with disease duration and decreased C(4).

Baseline serum concentrations of TRAIL in early rheumatoid arthritis: relationship with response to disease-modifying antirheumatic drugs.

OBJECTIVE: To assess the relationship between serum concentrations of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) and the therapeutic response to disease-modifying antirheumatic drugs (DMARD) in patients with early rheumatoid arthritis (RA). METHODS: Circulating levels of TRAIL and its soluble receptor OPG were measured by ELISA in paired serum samples obtained from 66 patients with early RA at their first visit (baseline) and after 1 year of therapy. Levels of TRAIL and OPG were analyzed in relation to the clinical response, defined by the 28-joint count Disease Activity Score (DAS28). RESULTS: Both serum TRAIL and OPG increased after DMARD therapy. Baseline levels of TRAIL, but not OPG, were significantly higher (p < 0.05) in the patients that achieved a clinical response by DAS28 after 1 year of therapy, versus patients without clinical response to DMARD. Baseline serum levels of TRAIL were higher (p < 0.01) in rheumatoid factor-negative patients. CONCLUSION: Our data suggest that the basal level of circulating TRAIL is an important determinant in the therapeutic response to DMARD in patients with early RA.

The tumour necrosis factor-related apoptosis-inducing ligand-osteoprotegerin system in limited systemic sclerosis: a new disease marker?

OBJECTIVE: To investigate the role of the TNF-related apoptosis-inducing ligand-osteoprotegerin (TRAIL-OPG) system in the pathogenesis of limited SSc (lSSc). METHODS: Circulating levels of TRAIL and of its soluble receptor OPG were measured by ELISA in serum samples obtained from 50 lSSc patients and 50 healthy controls. RESULTS: TRAIL serum levels in lSSc patients were similar to those of healthy controls, whereas the OPG serum levels were significantly increased (P < 0.0001). According to different subgroups of lSSc patients, TRAIL was not statistically different between each group and healthy controls; concerning OPG, the statistically different value was also maintained when comparing each single lSSc group with the whole control population. CONCLUSIONS: OPG serum levels, but not TRAIL, are elevated in lSSc patients. Since OPG binding to TRAIL inhibits TRAIL-TRAIL receptor interaction, the relative concentrations of these two molecules in the local micro-environment has to be considered. In this setting, OPG increase in lSSc patients may produce a detrimental effect by counteracting the vasoprotective activity of TRAIL. The TRAIL : OPG ratio and their relative levels of expression in lSSc patients should be taken into consideration as a possible novel marker of vascular damage.

The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression and release by endothelial cells: implications in rheumatoid arthritis.

OBJECTIVE: Complement activation products contribute to a large number of inflammatory diseases, including RA. We have investigated whether osteoprotegerin (OPG) may concur with the soluble terminal complement complex (SC5b-9) to the inflammatory cascade characterizing RA. METHODS: Levels of SC5b-9 and OPG in the plasma and SF of patients with active RA were determined by ELISA. The presence of SC5b-9 and OPG in RA synovial lesions was analysed by immunohistochemistry. Cultured endothelial cells were used for in vitro leucocyte/endothelial cell adhesion assays. In addition, endothelial cells were exposed to SC5b-9 in order to evaluate the effects on the production of OPG protein, as well as the activation of the OPG promoter. RESULTS: Patients affected by active RA are characterized by elevated levels of both SC5b-9 and OPG in plasma and/or SF. Of note, we have observed a co-localization of SC5b-9 and OPG in endothelial cells of post-capillary venules of RA synovial lesions. Data on endothelial cell cultures showed that exposure to SC5b-9 induced the up-regulation of OPG expression/release, stimulating the transcriptional activity of the OPG promoter, and synergized with TNF-alpha in up-regulating OPG production. CONCLUSIONS: Our findings demonstrate that SC5b-9 induces OPG production by endothelial cells and we propose that the SC5b-9-mediated up-regulation of OPG may be an important mechanism whereby complement contributes in promoting and/or enhancing the inflammation in RA.

Thrombocytosis in systemic lupus erythematosus: a possible clue to autosplenectomy?

OBJECTIVE: Thrombocytosis can be due to a myeloproliferative disorder or to a reactive or secondary process; among these are connective tissue disorders, in particular systemic lupus erythematosus (SLE). Besides being an expression of active disease, this unusual finding has also been described in SLE complicated by autosplenectomy. We evaluated the prevalence of thrombocytosis in a series of SLE patients and its relationship to functional asplenia. METHODS: Platelet count was evaluated in 465 consecutive Caucasian patients with SLE (387 women, 78 men, median age 54 yrs). Thrombocytosis was defined as platelet count > 400 x 10(9)/l in at least 3 blood samples. All patients with thrombocytosis underwent peripheral blood smears for erythrocyte abnormalities and instrumental spleen evaluation. RESULTS: Seventeen patients (3.7%) with thrombocytosis were observed. Peripheral blood smear showed Howell-Jolly bodies, spherocytes, and target cells in 3/17 patients (17.6%). In the same 3 patients, ultrasound and computed tomography failed to evidence the spleen, and liver-spleen scans showed absence of splenic uptake (a finding indicative of functional autosplenectomy). One satisfied criteria for antiphospholipid syndrome (APS), and the other 2 patients had positive IgG antiphospholipid antibodies (aPL) at medium titer. CONCLUSION: The sudden appearance and persistence of thrombocytosis or even the apparent reversal of thrombocytopenia in patients with SLE should raise suspicion of autosplenectomy, in particular if secondary APS or aPL is present.

Late onset systemic lupus erythematosus: no substantial differences using different cut-off ages.

To compare the clinical, laboratory and immunological features of a group of Caucasian systemic lupus erythematosus (SLE) patients in relation to age at disease onset. Three groups of patients with different ages at disease onset were analysed and compared: group A (30 patients, >or=65 years); group B (62 patients, 50-64 years) and group C (163 patients, <50 years). All patients were regularly followed-up for a mean period of 6.5 years. Female predominance was reduced in groups A and B. Time-lapse between disease onset and diagnosis was longer in group A and B. There were no statistically significant differences in clinical features. The only relevant difference was observed in peripheral nervous system (PNS) involvement, more frequent in group A. Anti-dsDNA and RF were more frequent in group A. Complement levels were reduced more frequently in group C. No differences were observed in disease activity scores, while SLICC/ACR score was higher in group A. In Caucasian SLE patients, age at disease onset is not associated with differences in clinical features apart from a more frequent PNS involvement in elderly patients. In the same group, the organ damage seems to develop more rapidly mostly due to higher susceptibility to jatrogenic side effects.

The treatment of the rheumatological manifestations of the inflammatory bowel diseases.

The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations. However, the therapeutic approach is still empirical. For symptomatic therapy it is better to favour the use of steroids and avoid non-steroidal anti-inflammatory drugs because they may induce intestinal ulcerations and can activate inflammatory bowel disease. Second line drugs (sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide) should be used for selected indications. In some cases (severe spondylitis, severe and persistent enthesopathy) anti-TNF-alpha agents (infliximab) should be considered as first line therapy. In all cases it is mandatory to select the best therapeutic option for each individual patient, considering that the optimal treatment of bowel inflammation may induce "per se" a remission of the musculo-skeletal manifestations.

Multicentric reticulohistiocytosis.

Multicentric reticulohistiocytosis (MR) is an uncommon disease with joint and cutaneous manifestations most commonly affecting women in middle age. The diagnosis must be confirmed by the histological evidence of typical mononuclear histiocytes and multinucleated giant cells. Many conditions have been described in association with MR, and the clinician should be aware that in many cases the disease is associated with malignancy. This eventuality must be accurately ruled out. If the typical nodular manifestations are missing at the onset, the arthritic complaints-usually localized but not confined to the interphalangeal joints-may be confused with those of more common rheumatic disorders. At this stage, a careful clinical and radiological evaluation may offer the key to the correct diagnosis. The natural course of the disease may develop into a severe, destructive arthropathy and disfiguring cutaneous lesions. In these cases an aggressive treatment with immunosuppressive drugs is strongly recommended. On the basis of recent reports, anti-tumor necrosis factor alpha agents and alendronate may also be added to the list of the drugs used in the treatment of this disease.