Assessing the Adjuvant Effect of Layered Double Hydroxides (LDH) on BALB/c Mice.

The discovery and validation of new adjuvants are critical areas for vaccinology. Mineral materials (e.g., alum microparticles) have been used for a long time as adjuvants in human vaccine formulations. Nonetheless, the use of nanosized materials is a promising approach to diversify the properties of adjuvants. Nanoclays are potential adjuvants proposed by some research groups. However, their adjuvant mechanisms and safety have not been fully elucidated. Herein, we aimed at expanding the knowledge on the potential adjuvanticity of layered double hydroxide (LDH) nanoparticles by reporting a detailed method for the synthesis and characterization of LDHs and the adsorption of a model antigen (bovine serum albumin, BSA). LDHs varying in diameter (from 56 to 88 nm) were obtained, and an in vitro evaluation revealed that the LDHs are not inherently toxic. BSA was passively adsorbed onto the LDHs, and the immunogenicity in mice of the conjugates obtained was compared to that of free BSA and BSA co-administered with alum (Alum-BSA). The LDH-BSA conjugates induced a higher humoral response that lasted for a longer period compared with that of free BSA and Alum-BSA, confirming that LDH exerts adjuvant effects. The 56 nm LDH particles were deemed as the more efficient carrier since they induced a higher and more balanced Th1/Th2 response than the 88 nm particles. This study is a contribution toward expanding the characterization and use of nanoclays in vaccinology and justifies further studies with pathogen-specific antigens.

The combination of IL-6 and its soluble receptor is associated with the response of rheumatoid arthritis patients to tocilizumab.

BACKGROUND: IL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA). Tocilizumab, a humanized anti-human IL-6 receptor antibody that blocks the signaling originated by the IL-6/IL-6R complex, is an effective treatment. However, predictors of the response to tocilizumab are still required. We aimed to combine IL-6 and soluble IL-6R (sIL-6R) levels to identify groups of responses. METHODS: Heparinized blood and clinical data from 63 RA patients were collected before treatment and after 3 and 6 months. Two-step clustering (SPSS v.18) was used to establish the relationship between IL-6 and sIL-6R. Then, we compared European League Against Rheumatism (EULAR) response criteria with remission achievement in the groups of patients. RESULTS: Three statistical significant clusters of RA patients (i.e., g1, g2, and g3) were defined by serum concentrations of IL-6 and sIL-6R at baseline. All groups of RA patients had higher IL-6 and sIL-6R levels than healthy donors. The levels of IL-6 expressed as median (IQR) in g1 patients were 124(90-183)pg/ml, in g2 12.3(4.4-24)pg/ml, and in g3 60.1(30-146)pg/ml (p < 0.001). The levels of sIL-6R expressed as mean ± sd in g1 patients were 250.5 ± 72ng/ml, in g2 269.1 ± 125ng/ml, and in g3 732.7 ± 243ng/ml (p < 0.001). Disease activity score (DAS)28, C-reactive protein, and erythrocyte sedimentation rate were comparable in the three groups at baseline. Disease duration in g3 was the longest (median(IQR) years: g1 = 11(5-15), g2 = 12(8-20), and g3 23(16-26); p = 0.006), with years of disease evolution being correlated with sIL-6R levels (R = 0.417, p < 0.001). Simple and Clinical Disease Activity Index (SDAI and CDAI) decreased significantly in the three groups. However, EULAR response criteria and remission achievement at 6m was different in the three groups (p = 0.03 and 0.04, respectively). In all. 17 out of the 18 patients in g1 had a good or moderate response to tocilizumab. Conversely, the percentage of patients with no response to tocilizumab was higher in g3 than in g1 and g2. We also observed different changing patterns of IL-6 and sIL-6R levels among the three groups. CONCLUSIONS: RA patients could be easily stratified prior to therapeutic intervention with two molecules related to the pathway blocked by tocilizumab. G1 patients, who had the best response to tocilizumab, had the highest level of IL-6 and the lowest level of sIL-6R.

Diagnostic and therapeutic delay of rheumatoid arthritis and its relationship with health care devices in Catalonia. The AUDIT study. / Retraso diagnóstico y terapéutico de la artritis reumatoide y su relación con dispositivos asistenciales en Catalunya. Estudio AUDIT.

OBJECTIVE: Diagnosis and therapy of patients with early onset rheumatoid arthritis (RA) is influenced by accessibility to specialized care devices. We attempted to analyze the impact of their availability. METHODS: We analyzed time related to diagnosis delay measuring: 1) Time from first clinical symptoms to the first visit with the Rheumatologist; 2) Time from referral to the first visit of Rheumatology; 3) Time between first symptom until final diagnosis; 4) time between first symptom until the initiation of the first disease-modifying antirheumatic drug (DMARD). The presence of these 6 rheumatology devices was defined: 1) early arthritis monographic clinics, 2) RA monographic clinics, 3) Mechanisms for fast programming, 4) Algorithms for referral from primary care (PC), 5) rheumatology consultation services in PC and 6) consulting services in PC. RESULTS: The mean time from onset of symptoms to diagnosis or the establishment of a DMARD in RA patients in Catalonia is very long (11 months). Patients seen in rheumatology devices such as RA monographic clinics, rheumatology consultation in PC and specially in early arthritis clinics are treated early with DMARDs. CONCLUSION: the existence of monographic clinics or consulting in primary care centers is essential to improve early care of RA patients.

Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship?

Life expectancy in patients with rheumatoid arthritis (RA) is reduced compared to the general population owing to an increase in cardiovascular diseases (CVD) not fully explained by traditional cardiovascular risk factors. In recent years, interest has been focused on the alterations in lipid metabolism in relation to chronic inflammation as one of the possible mechanisms involved in the pathogenesis of atherosclerosis of RA patients. Research regarding this issue has revealed quantitative alterations in lipoproteins during the acute-phase reaction, and has also demonstrated structural alterations in these lipoproteins which affect their functional abilities. Although many alterations in lipid metabolism have been described in this regard, these structural changes associated with inflammation are particularly important in high-density lipoproteins as they affect their cardioprotective functions. In this respect, excessive oxidation in low-density lipoprotein (LDL) and increased lipoprotein(a) with a predominance of smaller apolipoprotein(a) isoforms has also been reported. This article will discuss proinflammatory high-density lipoproteins (piHDL), oxidized LDL and lipoprotein(a). Elevated concentrations of these lipoproteins with marked pro-atherogenic properties have been observed in RA patients, which could help to explain the increased cardiovascular risk of these patients.

Specific cutaneous involvement in Whipple disease.

Cutaneous lesions in Whipple disease (WD) are infrequent, and the histological findings are usually nonspecific. Specific cutaneous lesions have rarely been described and usually involve the subcutaneous fat. We report a patient diagnosed with WD, who developed multiple small subcutaneous nodules after antibiotic treatment was administered. In addition to septal panniculitis, the cutaneous biopsy showed a mild granulomatous dermal reaction with PAS-positive macrophages characteristic of WD. A positive polymerase chain reaction in the cutaneous sample confirmed the presence of Tropheryma whipplei in the skin. Dermatopathologists should be aware that not only subcutaneous lesions but also dermal lesions may exhibit specific findings of WD.

Rituximab therapy in refractory neuropsychiatric lupus: current clinical evidence.

OBJECTIVE: To review and summarize published information on the effectiveness and safety of rituximab (RTX) in adult patients with refractory neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: We describe a patient with persistently active NPSLE, despite conventional therapy, who responded dramatically to RTX. Current evidence on the therapeutic use of RTX in this complex situation is also analyzed through a systematic review of the English-language literature, based on a PubMed search. RESULTS: Available data on the use of RTX in refractory NPSLE come from a large number of case reports and some open-label studies. Including our case, 35 patients have been well documented. A complete or partial therapeutic response was achieved in 85% of patients after 1 cycle of treatment. A positive correlation between serological markers of disease activity and clinical outcome has also been demonstrated in some of these patients. Clinical improvement was accompanied by a significant reduction in the daily dose of oral corticosteroids. Relapse after RTX treatment was noted in 45% of cases (median 9.5 months; range, 4-33 months). Infections were observed in 29% of patients. CONCLUSION: Evidence for the effectiveness of RTX as induction therapy in NPSLE is based solely on several case reports and noncontrolled trials. Although it is not yet possible to make definite recommendations, the global analysis of these cases supports the off-label use of RTX in cases of severe refractory NPSLE.

Pancreatitis, panniculitis, and polyarthritis.

BACKGROUND AND OBJECTIVE: Lobular panniculitis, together with polyarthritis and intraosseous fat necrosis, may occasionally complicate pancreatic disease. This triad is known in the literature as the pancreatitis, panniculitis, and polyarthritis (PPP syndrome). We describe a case of the PPP syndrome and review the available literature to summarize the clinical characteristics of patients with this condition. METHODS: A patient with the PPP syndrome, with evidence of extensive intraosseous fat necrosis in the joints involved revealed by magnetic resonance imaging, is described and the relevant literature based on a PubMed search from 1970 to February 2008 is reviewed. The keywords used were pancreatitis or pancreatic disease, panniculitis, arthritis, and intraosseous fat necrosis. RESULTS: Including our case, 25 well-documented patients with the PPP syndrome have been reported. Our patient had few abdominal symptoms despite high serum levels of pancreatic enzymes. In our review of the literature, almost 2/3 of patients had absent or mild abdominal symptoms, leading to misdiagnosis. The delay in diagnosis and specific treatment of the underlying pancreatitis worsens the prognosis of this condition, which has a mortality rate as high as 24%. In nearly 45% of the patients, the arthritis follows a chronic course with a poor response to nonsteroidal anti-inflammatory drugs and corticosteroids, and the rapid development of radiographic joint damage. CONCLUSION: Certain forms of pancreatic disease can very occasionally cause arthritis and panniculitis. Although uncommon, physicians should be alert to the possible presence of this syndrome for 2 reasons: first, unrecognized pancreatic disease can be fatal if not treated promptly; second, to avoid inappropriate and risky therapy to improve joint symptoms.

Multicentric Castleman's disease mimicking adult-onset Still's disease.

Castleman's disease is a rare lymphoproliferative disorder having two types of presentation: the localized and the multicentric form. Multicentric Castleman's disease (MCD) typically presents with constitutional symptoms, generalized peripheral lymphadenopathy, hepatosplenomegaly, and laboratory markers of inflammation. Rash and arthritis may also be initial complaints of this disease. In these cases, MCD can resemble adult-onset Still's disease (AOSD), especially if the arthritis precedes other manifestations. We describe a patient with initial clinical suspicion of AOSD. Eighteen months later evidence of MCD was ascertained when the patient developed insidiously growing axillary lymphadenopathies. Despite its rarity, MCD should be borne in mind in the differential diagnosis of patients with suspicion of AOSD.