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ID PMID Title PublicationDate abstract
19790055 Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee ost 2009 Oct OBJECTIVE: Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. METHODS: OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. RESULTS: CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. CONCLUSION: CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.
19933857 The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T 2009 Dec 15 IL-27 is formed by the association of a cytokine subunit, p28, with the soluble cytokine receptor EBV-induced gene 3 (EBI3). The IL-27R comprises gp130 and WSX-1. The marked difference between EBI3(-/-) and WSX-1(-/-) mice suggests that p28 has functions independent of EBI3. We have identified an alternative secreted complex formed by p28 and the soluble cytokine receptor cytokine-like factor 1 (CLF). Like IL-27, p28/CLF is produced by dendritic cells and is biologically active on human NK cells, increasing IL-12- and IL-2-induced IFN-gamma production and activation marker expression. Experiments with Ba/F3 transfectants indicate that p28/CLF activates cells expressing IL-6Ralpha in addition to the IL-27R subunits. When tested on CD4 and CD8 T cells, p28/CLF induces IL-6Ralpha-dependent STAT1 and STAT3 phosphorylation. Furthermore, p28/CLF inhibits CD4 T cell proliferation and induces IL-17 and IL-10 secretion. These results indicate that p28/CLF may participate in the regulation of NK and T cell functions by dendritic cells. The p28/CLF complex engages IL-6R and may therefore be useful for therapeutic applications targeting cells expressing this receptor. Blocking IL-6R using humanized mAbs such as tocilizumab has been shown to be beneficial in pathologies like rheumatoid arthritis and juvenile idiopathic arthritis. The identification of a new IL-6R ligand is therefore important for a complete understanding of the mechanism of action of this emerging class of immunosuppressors.
20594343 Curcumin mediated suppression of nuclear factor-κB promotes chondrogenic differentiation 2010 INTRODUCTION: Osteoarthritis (OA) and rheumatoid arthritis (RA) are characterised by joint inflammation and cartilage degradation. Although mesenchymal stem cell (MSC)-like progenitors are resident in the superficial zone of articular cartilage, damaged tissue does not possess the capacity for regeneration. The high levels of pro-inflammatory cytokines present in OA/RA joints may impede the chondrogenic differentiation of these progenitors. Interleukin (IL)-1β activates the transcription factor nuclear factor-κB (NF-κB), which in turn activates proteins involved in matrix degradation, inflammation and apoptosis. Curcumin is a phytochemical capable of inhibiting IL-1β-induced activation of NF-κB and expression of apoptotic and pro-inflammatory genes in chondrocytes. Therefore, the aim of the present study was to evaluate the influence of curcumin on IL-1β-induced NF-κB signalling pathway in MSCs during chondrogenic differentiation. METHODS: MSCs were either cultured in a ratio of 1:1 with primary chondrocytes in high-density culture or cultured alone in monolayer with/without curcumin and/or IL-1β. RESULTS: We demonstrate that although curcumin alone does not have chondrogenic effects on MSCs, it inhibits IL-1β-induced activation of NF-κB, activation of caspase-3 and cyclooxygenase-2 in MSCs time and concentration dependently, as it does in chondrocytes. In IL-1β stimulated co-cultures, four-hour pre-treatment with curcumin significantly enhanced the production of collagen type II, cartilage specific proteoglycans (CSPGs), β1-integrin, as well as activating MAPKinase signaling and suppressing caspase-3 and cyclooxygenase-2. CONCLUSIONS: Curcumin treatment may help establish a microenvironment in which the effects of pro-inflammatory cytokines are antagonized, thus facilitating chondrogenesis of MSC-like progenitor cells in vivo. This strategy may support the regeneration of articular cartilage.
20056598 In situ D-periodic molecular structure of type II collagen. 2010 Mar 5 Collagens are essential components of extracellular matrices in multicellular animals. Fibrillar type II collagen is the most prominent component of articular cartilage and other cartilage-like tissues such as notochord. Its in situ macromolecular and packing structures have not been fully characterized, but an understanding of these attributes may help reveal mechanisms of tissue assembly and degradation (as in osteo- and rheumatoid arthritis). In some tissues such as lamprey notochord, the collagen fibrillar organization is naturally crystalline and may be studied by x-ray diffraction. We used diffraction data from native and derivative notochord tissue samples to solve the axial, D-periodic structure of type II collagen via multiple isomorphous replacement. The electron density maps and heavy atom data revealed the conformation of the nonhelical telopeptides and the overall D-periodic structure of collagen type II in native tissues, data that were further supported by structure prediction and transmission electron microscopy. These results help to explain the observed differences in collagen type I and type II fibrillar architecture and indicate the collagen type II cross-link organization, which is crucial for fibrillogenesis. Transmission electron microscopy data show the close relationship between lamprey and mammalian collagen fibrils, even though the respective larger scale tissue architecture differs.
19664287 The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properti 2009 INTRODUCTION: The Fibromyalgia Impact Questionnaire (FIQ) is a commonly used instrument in the evaluation of fibromyalgia (FM) patients. Over the last 18 years, since the publication of the original FIQ, several deficiencies have become apparent and the cumbersome scoring algorithm has been a barrier to widespread clinical use. The aim of this paper is to describe and validate a revised version of the FIQ: the FIQR. METHODS: The FIQR was developed in response to known deficiencies of the FIQ with the help of a patient focus group. The FIQR has the same 3 domains as the FIQ (that is, function, overall impact and symptoms). It differs from the FIQ in having modified function questions and the inclusion of questions on memory, tenderness, balance and environmental sensitivity. All questions are graded on a 0-10 numeric scale. The FIQR was administered online and the results were compared to the same patient's online responses to the 36-Item Short Form Health Survey (SF-36) and the original FIQ. RESULTS: The FIQR was completed online by 202 FM patients, 51 rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients (31 RA and 20 SLE), 11 patients with major depressive disorder (MDD) and 213 healthy controls (HC). The mean total FIQR score was 56.6 +/- 19.9 compared to a total FIQ score of 60.6 +/- 17.8 (P < 0.03). The total scores of the FIQR and FIQ were closely correlated (r = 0.88, P < 0.001). Each of the 3 domains of the FIQR correlated well with the 3 related FIQ domains (r = 0.69 to 0.88, P < 0.01). The FIQR showed good correlation with comparable domains in the SF-36, with a multiple regression analysis showing that the three FIQR domain scores predicted the 8 SF-36 subscale scores. The FIQR had good discriminant ability between FM and the 3 other groups; total FIQR scores were HC (12.1 +/- 11.6), RA/SLE (28.6 +/- 21.2) and MDD (17.3 +/- 11.8). The patient completion time was 1.3 minutes; scoring took about 1 minute. CONCLUSIONS: The FIQR is an updated version of the FIQ that has good psychometric properties, can be completed in less than 2 minutes and is easy to score. It has scoring characteristics comparable to the original FIQ, making it possible to compare past FIQ results with future FIQR results.
19248097 Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchym 2009 Mar OBJECTIVE: Stromal cell-derived factor 1 (SDF-1; CXCL12/pre-B cell growth-stimulating factor) is a dominant chemokine in bone marrow and is known to be involved in inflammatory diseases, including rheumatoid arthritis. However, its role in bone repair remains unknown. The purpose of this study was to investigate the role of SDF-1 and its receptor, CXCR4, in bone healing. METHODS: The expression of SDF-1 during the repair of a murine structural femoral bone graft was examined by real-time polymerase chain reaction and immunohistochemical analysis. The bone graft model was treated with anti-SDF-1 neutralizing antibody or TF14016, an antagonist for CXCR4, and evaluated by histomorphometry. The functional effect of SDF-1 on primary mesenchymal stem cells was determined by in vitro and in vivo migration assays. New bone formation in an exchanging-graft model was compared with that in the autograft models, using mice partially lacking SDF-1 (SDF-1(+/-)) or CXCR4 (CXCR4(+/-)). RESULTS: The expression of SDF1 messenger RNA was increased during the healing of live bone grafts but was not increased in dead grafts. High expression of SDF-1 protein was observed in the periosteum of the live graft. New bone formation was inhibited by the administration of anti-SDF-1 antibody or TF14016. SDF-1 increased mesenchymal stem cell chemotaxis in vitro in a dose-dependent manner. The in vivo migration study demonstrated that mesenchymal stem cells recruited by SDF-1 participate in endochondral bone repair. Bone formation was decreased in SDF-1(+/-) and CXCR4(+/-) mice and was restored by the graft bones from CXCR4(+/-) mice transplanted into the SDF-1(+/-) femur, but not vice versa. CONCLUSION: SDF-1 is induced in the periosteum of injured bone and promotes endochondral bone repair by recruiting mesenchymal stem cells to the site of injury.
19706351 Older adults' pain descriptions. 2009 Sep The purpose of this study was to describe the types of pain information described by older adults with chronic osteoarthritis pain. Pain descriptions were obtained from older adults' who participated in a post-test-only double-blind study testing how the phrasing of health care practitioners' pain questions affected the amount of communicated pain information. The 207 community-dwelling older adults were randomized to respond to either the open-ended or the closed-ended pain question. They viewed and orally responded to a computer-displayed videotape of a practitioner asking them the respective pain question. All of them then viewed and responded to the general follow-up questions, "What else can you tell me?" and lastly, "What else can you tell me about your pain, aches, soreness or discomfort?" Audiotaped responses were transcribed and their content analyzed by trained independent raters using 16 a priori criteria from the American Pain Society's Guidelines for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. Older adults described important but limited types of information primarily about pain location, timing, and intensity. Pain treatment information was elicited after repeated questioning. Therefore, practitioners need to follow up older adults' initial pain descriptions with pain questions that promote a more complete pain management discussion. Routine use of a multidimensional pain assessment instrument that measures information such as functional interference, current pain treatments, treatment effects, and side effects would be one way of ensuring a more complete pain management discussion with older adults.
20797507 Skin diseases associated with hepatitis C virus: facts and controversies. 2010 Sep Hepatitis C virus (HCV) is a common infectious agent and may induce several systemic disorders like mixed cryoglobulinemia. In the geographic areas where HCV infection is hyperendemic, HCV is the predominant etiologic factor for porphyria cutanea tarda and lichen planus. Vasculitides and autoimmune disorders, such as sicca syndrome, are probably often related to the virus. Interferon-a2b, which is largely used in the treatment of HCV-positive patients, may induce cell-mediated autoimmune side effects. Dermatologists may help to identify those patients timely.
20546191 Pulmonary amyloidosis in Sjogren's syndrome: a case report and systematic review of the li 2010 Jul Amyloidosis is a heterogeneous group of disorders characterized by misfolding of extracellular proteins. The two most common forms are light-chain (AL) and reactive (AA) amyloidosis. Pulmonary amyloidosis secondary to Sjogren's syndrome (SS) is rare, and there is a paucity of data on its clinical and radiological features. We describe the case of a 41-year-old woman with diffuse septal pulmonary AL (lambda) amyloidosis related to SS, in the absence of systemic amyloidosis. A systematic search for pulmonary amyloidosis in SS yielded 37 cases. Amyloidosis occurred almost exclusively in women (96.5%). Cough and dyspnoea (56%) were the most common symptoms. The diagnosis of pulmonary amyloidosis was made subsequent to that of SS, with a median delay of 7 years. Radiologically, diffuse nodules with (45.5%) or without (33.3%) multiple cysts were the most common pattern. Most cases were related to nodular AL amyloidosis (both kappa and lambda). Diffuse septal AA amyloidosis has been reported in SS. The index patient is the first documented case of diffuse septal pulmonary AL amyloidosis in SS, without systemic amyloidosis. Surgical lung biopsy (78%) is usually required to establish the diagnosis and rule out lymphoma. There is no data to support any definitive therapeutic intervention for SS-related pulmonary amyloidosis. Observation is sufficient for nodular amyloidosis. Further studies are necessary to assess the efficacy of current therapies in diffuse septal amyloidosis secondary to SS.
19644378 B cell depletion in lupus and Sjögren's syndrome: an update. 2009 Sep PURPOSE OF REVIEW: The critical role of B cells in the pathogenesis of systemic lupus erythematosus and Sjogren's syndrome has provided a strong rationale to specifically target B cells. This review summarizes recent advances in the field of B cell depletion in systemic lupus erythematosus and Sjögren's syndrome. RECENT FINDINGS: Reports of successful B cell depletion therapy in refractory SLE have continued to surface over the last year. The accumulation of positive results therefore stands in stark contrast to the recent reports that two phase III randomized placebo controlled trials employing B cell depletion with rituximab in nonlupus and lupus nephritis (Explorer and Lunar, respectively) did not achieve. Multiple reasons, including trial design, limitations of outcome instruments and sort follow-up have been invoked to explain these disconcerting results. In the representative studies addressing B cell depletion in lupus in the last year, complete and partial remission in lupus nephritis has been achieved in 60-89% of cases. Improvements in the British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were associated with decrease in anti-dsDNA and increase in complement levels. B cell depletion seemed quite efficacious also in pediatric SLE. While more definitive studies are still lacking for primary Sjogren's syndrome, incidental reports indicating potential efficacy have also been recently published. SUMMARY: Despite the disappointing results of Explorer and Lunar trials, other evidence continues to be published in support of the notion that B cell depletion could be useful for patients with refractory disease, including lupus nephritis, and antibody-mediated cytopenias, possibly in combination with other immunosuppressant medication.
19330707 An expanded phenotype of maternal SSA/SSB antibody-associated fetal cardiac disease. 2009 Mar OBJECTIVES: Conventional manifestations of fetal Sjogren's antibodies (SSA/SSB) associated cardiac disease include atrioventricular block (AVB), transient sinus bradycardia, endocardial fibroelastosis (EFE) and dilated cardiomyopathy. We describe other manifestations of cardiac disease. METHODS: We describe three fetuses with unique myocardial and conduction system disease. RESULTS: One had isolated EFE with subsequent mitral and tricuspid valve chordal avulsion, the second had sinoatrial and infrahissian conduction system disease, and in both, neonatal progression to life threatening disease occurred. The third had sinus node dysfunction and atrial flutter. CONCLUSION: These findings expand the clinical phenotype of maternal SSA/SSB antibody associated fetal cardiac disease.
19323907 Effects of Ganoderma lucidum spores on sialoadenitis of nonobese diabetic mice. 2009 Mar 5 BACKGROUND: Sjögren syndrome (SS) is a systematic autoimmune disease, on which traditional therapeutic agents show limited effect. More effective agents with longer-lasting and fewer side effects are needed in the clinic. The aim of this study was to investigate the effects of Ganoderma lucindum spores (GLS) on sialoadenitis of nonobese diabetic (NOD) mice. METHODS: Thirty-two female NOD mice were assigned randomly into 4 groups: low-dose GLS-treated (L-GLS) group and high-dose GLS-treated (H-GLS) group, a dexamethasone group, and a normal saline (NS) control group. Stimulated total saliva flow rate (STFR), area of lymphocytic infiltration in submandibular glands and ratios of CD4(+) and CD8(+) T lymphocytes and B lymphocytes in peripheral blood as well as apoptosis of these subsets and serum IgG level were tested after 10 weeks of treatments. Differences among the groups were analyzed by one-way analysis of variance (ANOVA), Student-Newman-Keuls Test (SNK) was used between each two groups and a P < 0.05 was considered statistically significant. RESULTS: STFR of the high-dose GLS group increased significantly after a 10-week treatment compared with those of the NS control group (P < 0.05). The incidence of sialoadenitis in GLS-treated NOD mice groups showed no significant difference compared with the control group (P > 0.05), but the area of lymphocytic foci in both the H-GLS and L-GLS groups decreased significantly to 50% of the NS control group (P < 0.05); the ratio of CD4(+)/CD8(+) T lymphocytes and apoptosis of B lymphocytes of NOD mice with sialoadenitis were less and apoptosis of CD4(+) and CD8(+) T lymphocytes were significantly increased compared with the control group (P < 0.05). After pretreatment with H-GLS before sialoadenitis onset, the ratio of CD4(+)/CD8(+) T lymphocyte and the serum IgG levels of NOD mice decreased significantly (P < 0.05). CONCLUSIONS: Pretreatment with H-GLS can relieve symptoms of sialoadenitis in NOD mice. GLS has some protective effects on sialoadenitis in NOD mice through increasing STFR and decreasing the area of lymphocytic foci by regulating the ratio of CD4(+)/CD8(+) T and apoptosis of B lymphocytes.
21182786 Pathogenic effect of interleukin-17A in induction of Sjögren's syndrome-like disease usin 2010 INTRODUCTION: Sjögren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding TH17 cell populations that secrete predominantly interleukin (IL)-17A have been shown to play an important role in an increasing number of autoimmune diseases, including SS. In the present study, we investigated the function of IL-17A on the development and onset of SS. METHODS: Adenovirus serotype 5 (Ad5) vectors expressing either IL-17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6 and 8 weeks of age or between 15 and 17 weeks of age. The mice were characterized for SS phenotypes. RESULTS: Disease profiling indicated that SS-non-susceptible C57BL/6J mice whose salivary glands received the Ad5-IL17A vector developed a SS-like disease profile, including the appearance of lymphocytic foci, increased cytokine levels, changes in antinuclear antibody profiles, and temporal loss of saliva flow. CONCLUSIONS: Induction of SS pathology by IL-17A in SS-non-susceptible mice strongly suggests that IL-17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti-IL17 therapy may be effective in preventing glandular dysfunction.
20002531 Salivary flow rate and clinical characteristics of patients with xerostomia according to i 2010 Mar The purpose of the present study was to investigate the differences in salivary flow rates and dry mouth-related subjective symptoms and behaviours in patients with xerostomia according to its aetiology. One hundred and forty patients (24 men and 116 women, mean age, 58.1 +/- 13.3 years) with a chief complaint of xerostomia were included. The patients were divided into five groups; Sjögren's syndrome (n = 34), post-radiation therapy in the head and neck region (n = 16), antipsychotic medications (n = 30), systemic diseases or medications affecting salivary flow (n = 35), and unknown aetiology (n = 25). The patients were asked a standardized series of questions concerning dry mouth, and their whole salivary flow rates were measured. Patients with a history of radiation therapy displayed the most decreased values of salivary flow rates and the most severe associated symptoms and behaviours while patients with unknown aetiology displayed the least decreased values of salivary flow rates and relatively favourable symptoms and behaviours. A burning sensation in the mouth was the most prevalent in patients with systemic diseases or those who were taking medications while altered taste perception was the most prevalent in patients taking antipsychotics. In conclusion, patients with xerostomia displayed various degrees of discomfort related to the quality of life according to the aetiology of their conditions.
20525449 Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune dis 2010 Jul OBJECTIVES: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents). RESULTS: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases). CONCLUSIONS: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.
20452465 What do we know about memory B cells in primary Sjögren's syndrome? 2010 Jul Abnormalities of memory B cells seem to be closely involved in the pathogenesis of primary Sjögrens Syndrome (pSS) and its malignant complication, B cell lymphoma. Recent studies on B cells in pSS add to our understanding of the distinct memory B cell subsets in pSS. Reduction of peripheral memory CD27(+) B cells, most strikingly of the CD27(+)IgM(+) subset, may indicate a lack of appropriate censoring mechanisms and incomplete differentiation processes within the ectopic lymphoid tissues in pSS. This ectopically formed lymphoid tissue might protect autoreactive memory B cells from deletion by physiological check-points and, thereby, may contribute to the perpetuation of the disease as well as to an enhanced lymphoma risk. Thus, B cells may be potential targets of direct or indirect treatment in pSS.
19882292 [Sjögren-associated MALT-type lymphoma of labial salivary glands: rare constellation with 2009 Nov We report a complex and rare combination of clinical and histological findings in a 59-year-old female patient: severe sicca-syndrome due to M. Sjögren, marginal zone B-cell lymphoma (MALT-type) in labial salivary glands with localized amyloid deposition, IgM-paraproteinemia, and Bence-Jones proteinuria. The causal association of these findings could only be elucidated by intense interdisciplinary correlation of all findings.
20581138 Non-length-dependent small fibre neuropathy. Confocal microscopy study of the corneal inne 2010 Jul BACKGROUND: It has been recently observed that small fibre neuropathy (SFN) may present as distal symmetrical polyneuropathy and with atypical non-length-dependent pattern. OBJECTIVE: To describe a small series of patients with non-length-dependent SFN, investigating corneal innervation with corneal confocal microscopy (CCM). METHODS: Evaluation of the corneal nerve fibre density using CCM in six women with non-length-dependent SFN. The patients were characterised by sensory disturbance involving proximal regions of the limbs, face and trunks, and the diagnosis was confirmed by the findings of decreased intraepidermal nerve fibre density on skin biopsy. RESULTS: Six women, aged 35-64, had non-length-dependent SFN, related to Crohn disease, impaired glucose tolerance and Sjögren's syndrome, or idiopathic (three cases). In all patients, CCM demonstrated decreased corneal nerve fibre density (12.5-23.4/mm(2); normal, >30.6/mm(2)). CONCLUSION: Non-length-dependent SFN may represent an intriguing diagnostic problem because of its puzzling presentation and the need for special investigations for its confirmation. In this perspective, CCM may provide a useful, non-invasive tool to complement the diagnostic workup.
19130557 Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes 2009 Jan We examined the hypothesis that stromal fibroblasts modulate the ability of endothelial cells (EC) to recruit lymphocytes in a site-specific manner. PBL were perfused over HUVEC that had been cultured with fibroblasts isolated from the inflamed synovium or the skin of patients with rheumatoid arthritis or osteoarthritis, or from normal synovium, with or without exposure to the inflammatory cytokines TNF-alpha+IFN-gamma. Fibroblasts from inflamed synovium, but no others, caused unstimulated HUVEC to bind flowing lymphocytes. This adhesion was supported by alpha(4)beta(1)-VCAM-1 interaction and stabilised by activation of PBL through CXCR4-CXCL12. Antibody neutralisation of IL-6 during co-culture effectively abolished the ability of EC to bind lymphocytes. Cytokine-stimulated EC supported high levels of lymphocyte adhesion, through the presentation of VCAM-1, E-selectin and chemokine(s) acting through CXCR3. Interestingly, co-culture with dermal fibroblasts caused a marked reduction in cytokine-induced adhesion, while synovial fibroblasts had variable effects depending on their source. In the dermal co-cultures, neutralisation of IL-6 or TGF-beta caused partial recovery of cytokine-induced lymphocyte adhesion; this was complete when both were neutralised. Exogenous IL-6 was also found to inhibit response to TNF-alpha+IFN-gamma. Normal stromal fibroblasts appear to regulate the cytokine-sensitivity of vascular endothelium, while fibroblasts associated with chronic inflammation bypass this and develop a directly inflammatory phenotype. Actions of IL-6 might be pro-inflammatory or anti-inflammatory, depending on the local milieu.
20149306 Non-typhi Salmonella infection in patients with rheumatic diseases on TNF-alpha antagonist 2009 Nov OBJECTIVES: The morbidity and mortality of patients with rheumatic diseases has improved considerably following the use of biologic therapies. However, an increase in the frequency of bacterial infections has been observed in patients receiving these drugs. In the present study we aimed to establish the incidence and clinical manifestations of non-typhi Salmonella infection in a large cohort of patients with rheumatic diseases undergoing TNF-alpha antagonist therapy due to severe rheumatic diseases refractory to conventional therapies. METHODS: The rate of non-typhi Salmonella infection found in the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) was compared with that observed in a cohort of rheumatoid arthritis (RA) patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) Study, who were not treated with TNF-alpha antagonists. The rate found in the BIOBADASER registry was also compared with that available in a non-RA historic control cohort reported in a population from Huesca (Northern Spain). RESULTS: Seventeen cases of non-typhi Salmonella infection were observed in the series of patients exposed to anti-TNF-alpha therapies. The incidence rate of non-typhi Salmonella in BIOBADASER was 0.73 per 1000 patient-years (95% confidence interval [CI]: 0.45-1.17). The incidence rate in the EMECAR cohort was 0.44 per 1000 patient-years. The relative risk for non-typhi salmonellosis in RA patients exposed to TNF-alpha inhibitors compared to those not treated with biological therapies was 2.07 (95% CI: 0.27-15.73) (p=0.480) whereas the relative risk of non-typhi Salmonella infections in patients with rheumatic diseases undergoing TNF-alpha antagonist therapy compared with the non-RA Spanish control cohort was 0.63 (95% CI: 0.38-1.04) (p=0.07). Nine of the 17 patients with non-typhi salmonellosis presented a severe systemic infection. CONCLUSION: Incidence of non-typhi Salmonella infection is not increased significantly in rheumatic patients undergoing anti-TNF-alpha therapy when compared with RA patients undergoing conventional DMARD therapy or with the general population. Nevertheless, at least 50% of patients on TNF-alpha have severe complications once they develop non-typhi Salmonella infection. This fact suggests that anti-TNF-alpha therapies may predispose to salmonella dissemination rather than to infection.