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ID PMID Title PublicationDate abstract
20402341 Beta2-microglobuline plasma level and painful shoulder in haemodialysed patients. 2010 Mar Painful shoulder in patients on chronic haemodialyis is most often associated with dialysis arthropathy or accumulation of deposits containing modified fibrils of beta2- microglobuline especially in bones and joints due to insufficient elimination during the therapy. The aim of this study is to investigate whether there is connection between painful shoulder and plasma level of beta2-microglobuline and to corroborate that with morphologic parameters found in proved amyloidosis. It has to be emphasized that even other causes may contribute the development of painful shoulder. Real time sonography and conventional plain radiographs of the 108 shoulders were performed in 54 patients receiving chronic haemodialysis as a treatment of terminal renal failure (without previous history of rheumatoid arthritis), 27 symptomatic with persistent pain and stiffness in both shoulders and lasting for more than 6 weeks and restriction of movements in various degree and 27 asymptomatic. Plasma level of beta2-microglobuline, CRP and uric acid were taken periodically as routine procedure during a one year prospective trial, as well as plasma level of calcium, phosphor and alkaline phosphatase. Plasmatic level of beta2-microglobuline is strongly connected with painful shoulder in dialyzed patients, as well as CRP as sign of acute inflammation. That is proved by morphologic parameters associated with histological proved amyloidosis in patients on long term dialysis, more then 10 years.
19232067 Transcription profiling of rheumatic diseases. 2009 Rheumatic diseases are a diverse group of disorders. Most of these diseases are heterogeneous in nature and show varying responsiveness to treatment. Because our understanding of the molecular complexity of rheumatic diseases is incomplete and criteria for categorization are limited, we mainly refer to them in terms of group averages. The advent of DNA microarray technology has provided a powerful tool to gain insight into the molecular complexity of these diseases; this technology facilitates open-ended survey to identify comprehensively the genes and biological pathways that are associated with clinically defined conditions. During the past decade, encouraging results have been generated in the molecular description of complex rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome and systemic sclerosis. Here, we describe developments in genomics research during the past decade that have contributed to our knowledge of pathogenesis, and to the identification of biomarkers for diagnosis, patient stratification and prognostication.
19655230 Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti 2010 Jan OBJECTIVE: The aim of this study is to verify the crucial role of cytosolic phospholipase A2 alpha (cPLA2 alpha) in the pathogenesis of collagen-induced arthritis in mice and to determine the anti-arthritic effects of pyrroxyphene, a cPLA2 alpha inhibitor. METHODS: Pyrroxyphene was administered (p.o.) twice a day for 18 days at 30 and 100 mg/kg. Its effects on arthritic symptoms, bone destruction, cPLA2 alpha activity, levels of prostaglandin E(2) and leukotriene B(4), and mRNA expression of matrix metalloproteinase (MMP)-3, -8, -9, -13 and cyclooxygenase-2 (COX-2) were tested. RESULTS: cPLA2 alpha activity gradually increased and showed a correlation with the severity of arthritis. Pyrroxyphene strongly inhibited the incidence of arthritis and bone destruction. Moreover, it significantly inhibited both the increase in levels of cPLA2 alpha and eicosanoids as well as the mRNA expression of MMP-3, -8, -9, -13, and COX-2. CONCLUSION: These results demonstrate that cPLA2 alpha plays an important role in the pathogenesis of collagen-induced arthritis. Oral administration of pyrroxyphene achieved anti-arthritic activity through inhibition of cPLA2 alpha activity, which led to a reduction in eicosanoid levels and suppression of MMP and COX-2 mRNA expression. These results support a potential therapeutic role for cPLA2 alpha inhibitors in the treatment of human rheumatoid arthritis.
20223838 The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, doub 2010 Mar BACKGROUND: Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). OBJECTIVE: To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. METHODS: Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfillment of remission criteria at weeks 2, 12 or 52, time course of 'core set variables' and proportion of patients starting DMARDs. RESULTS: 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). CONCLUSIONS: Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.
21180427 Adalimumab (humira™) in ophthalmology: a review of the literature. 2010 Oct Tumor Necrosis Factor alpha (TNF-α) is a pleiotropic cytokine which plays a primary role in the induction of inflammation in autoimmune diseases. The newest anti-TNF-α agent is adalimumab (Humira, Abbott Pharmaceutical Inc.), a human-derived antibody. This review summarizes the characteristics of adalimumab, highlighting its clinical use in systemic and ocular inflammatory disorders, and the possible therapeutic strategies. Adalimumab has been successfully used for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriasis arthritis. More recently, adalimumab has shown promising qualities in controlling intraocular inflammations, even though this has been used prevalently as a rescue therapy for unresponsive cases. This biologic agent was also used in pediatric cases, showing a good safety and efficacy profile. Albeit no direct comparison with other biologics has been done, and adalimumab seems to be equivalent to the other anti-TNF-α, the switching to adalimumab can offer a better uveitic control. Adalimumab is a promising drug for the treatment of uveitis, even though further studies are needed on its application as a primary therapy in uveitis.
20065636 Canakinumab. 2010 Jan Canakinumab (ACZ885, Ilaris) is a human anti-IL-1beta monoclonal antibody developed by Novartis. Its mode of action is based on the neutralization of IL-1beta signaling, resulting in suppression of inflammation in patients with disorders of autoimmune origin. In June 2009 the drug was approved by the US Food and Drug Administration for the treatment of familial cold auto-inflammatory syndrome and Muckle-Wells syndrome, which are inflammatory diseases related to cryopyrin-associated periodic syndromes. The drug is currently being evaluated for its potential in the treatment of rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, chronic obstructive pulmonary disease, type 1 and 2 diabetes and ocular diseases. Reports from clinical trials suggest that canakinumab is well-tolerated in most patients, and no serious adverse effects have been reported. The drug provides significant advantages over existing competitive therapies, including bimonthly administration and approved use in children.
27579057 Arthritis in pregnancy: the role and safety of biological agents. 2009 Dec As the average age of mothers is increasing there is a greater likelihood that they will have intercurrent medical problems at the time of their pregnancy. As a group, autoimmune diseases are relatively common with an estimated population prevalence of 5-8%. At least 75% of autoimmune diseases occur in women, most frequently during the child-bearing years. Rheumatoid arthritis (RA) is the most common chronic inflammatory disease of joints and occurs in approximately 1% of the population with women being affected two or three times more than men and many of the women being of child-bearing age. The pathogenesis of RA is multifactorial with a role for T-lymphocytes, B-lymphocytes, macrophages and other pro-inflammatory cells producing a plethora of cytokines including interleukin-1 and tumour necrosis factor-α in the synovial cavity resulting in irreversible damage to cartilage, soft tissues and bone.(1) The drug treatment of RA involves the use of disease-modifying agents to reduce or prevent permanent tissue damage. There is a new class of drugs that can be used to target specific cells and cytokines that have been called 'biological agents'. These drugs have been shown to significantly reduce inflammation and to retard the progression of joint damage in RA thereby reducing symptoms and improving function.(2).
19455385 Osteoclasts and the immune system. 2009 Investigation into arthritis as well as the numerous bone phenotypes found in mice lacking immune-related genes has highlighted the importance of the dynamic interplay between the bone and immune systems. It has recently led to both the emergence and subsequent rapid evolution of the field of osteoimmunology. Receptor activator of nuclear factor-kappaB ligand (RANKL) stimulates osteoclastogenesis through the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is well known as a crucial regulator of immunity. Studies on RANKL signaling revealed various immune-related genes which are involved in the regulation of osteoclastogenesis. Bone destruction in rheumatoid arthritis is caused by the enhanced activity of osteoclasts resulting from the activation of T cells. Here we describe our efforts to address the challenging question as to how abnormal T-cell activation mechanistically induces bone destruction. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to both the bone and immune systems.
19298770 Occurrence of plantar pustular psoriasis during treatment with infliximab. 2009 Jan BACKGROUND: Pustular psoriasis is an uncommon form of psoriasis that often affects areas of the hands and feet. It typically manifests as small pustules that develop within erythematous areas of the palms and soles. Infliximab, a tumor necrosis factor inhibitor, can be used to treat pustular psoriasis. Infliximab can also be effective in the treatment of various other disorders, including plaque-type psoriasis, psoriatic arthritis, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis. OBJECTIVE: We present a case of a young woman developing pustular psoriasis for the first time despite being on infliximab treatment for Crohn disease. RESULTS: Infliximab has been successful in the treatment of pustular psoriasis. In rare cases, plaque psoriasis appears for the first time during infliximab treatment for other disorders, such as Crohn disease. CONCLUSION: Plantar pustular psoriasis occurring for the first time during infliximab treatment is an uncommon occurrence.
19144181 Egr-1 inhibits the expression of extracellular matrix genes in chondrocytes by TNFalpha-in 2009 INTRODUCTION: TNFalpha is increased in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. TNFalpha activates mitogen-activated kinase kinase (MEK)/extracellular regulated kinase (ERK) in chondrocytes; however, the overall functional relevance of MEK/ERK to TNFalpha-regulated gene expression in chondrocytes is unknown. METHODS: Chondrocytes were treated with TNFalpha with or without the MEK1/2 inhibitor U0126 for 24 hours. Microarray analysis and real-time PCR analyses were used to identify genes regulated by TNFalpha in a MEK1/2-dependent fashion. Promoter/reporter, immunoblot, and electrophoretic mobility shift assays were used to identify transcription factors whose activity in response to TNFalpha was MEK1/2 dependent. Decoy oligodeoxynucleotides bearing consensus transcription factor binding sites were introduced into chondrocytes to determine the functionality of our results. RESULTS: Approximately 20% of the genes regulated by TNFalpha in chondrocytes were sensitive to U0126. Transcript regulation of the cartilage-selective matrix genes Col2a1, Agc1 and Hapln1, and of the matrix metalloproteinase genes Mmp-12 and Mmp-9, were U0126 sensitive--whereas regulation of the inflammatory gene macrophage Csf-1 was U0126 insensitive. TNFalpha-induced regulation of Sox9 and NFkappaB activity was also U0126 insensitive. Conversely, TNFalpha-increased early growth response 1 (Egr-1) DNA binding was U0126 sensitive. Transfection of chondrocytes with cognate Egr-1 oligodeoxynucleotides attenuated the ability of TNFalpha to suppress Col2a1, Agc1 or Hapln1 mRNA expression. CONCLUSIONS: Our results suggest that MEK/ERK and Egr1 are required for TNFalpha-regulated catabolic and anabolic genes of the cartilage extracellular matrix, and hence may represent potential targets for drug intervention in osteoarthritis or rheumatoid arthritis.
19278880 Profile of autoantibodies in Jaccoud's arthropathy. 2009 Jul OBJECTIVE: To compare the frequency of different autoantibodies in a group of patients with Jaccoud's arthropathy (JA) secondary to systemic lupus erythematosus (SLE) with those without JA. METHODS: A group of SLE patients with JA was compared with another group of SLE patients without this complication, matched by age and gender, regarding the presence of autoantibodies. Antibodies to cyclical citrullinated peptides (anti-CCP) and to mutated citrullinated vimentin (anti-MCV) as well as anti-SSA/Ro, anti-SSB/La, anti-Sm and anti-RNP and anticardiolipin (aCL) antibodies were searched by ELISA, using commercial kits. Rheumatoid factor was determined by nephelometry and antinuclear and anti-dsDNA antibodies by IIF. RESULTS: Forty-eight individuals were included in the study, being 24 patients with JA and 24 without JA, matched by gender and age. The frequency of anti-CCP antibodies in the whole population was 12.5% (6 cases), with no difference between the 2 groups. Anti-MCV antibodies were detected in 10.4% (5 cases), being found only in those with JA (p=0.05). There was no association between the presence of JA and aCL, anti-Sm, anti-RNP and anti-SSB/La antibodies. On the other hand, a statistically significant association between the presence of anti-dsDNA antibodies and JA was observed (p=0.04) as well as a marginal association with a decrease in serum levels of C3 (p=0.06). CONCLUSION: In the present study, there was an association between the presence of JA and anti-dsDNA antibodies, and anti-MCV antibodies were found only in those SLE patients with JA. Whether these antibodies have an etiopathogenic role in JA is entirely unknown.
20615964 Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. 2010 Jul 20 Osteoclasts are bone-eroding cells that develop from monocytic precursor cells in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclasts are essential for physiological bone remodeling, but localized excessive osteoclast activity is responsible for the periarticular bone destruction that characteristically occurs in patients with rheumatoid arthritis (RA). The origin of osteoclasts at sites of bone erosion in RA is unknown. Natural killer (NK) cells, as well as monocytes, are abundant in the inflamed joints of patients with RA. We show here that such NK cells express both RANKL and M-CSF and are frequently associated with CD14(+) monocytes in the RA synovium. Moreover, when synovial NK cells are cocultured with monocytes in vitro, they trigger their differentiation into osteoclasts, a process dependent on RANKL and M-CSF. As in RA, NK cells in the joints of mice with collagen-induced arthritis (CIA) express RANKL. Depletion of NK cells from mice before the induction of CIA reduces the severity of subsequent arthritis and almost completely prevents bone erosion. These results suggest that NK cells may play an important role in the destruction of bone associated with inflammatory arthritis.
18276740 Stress, coping strategies and social support in patients with primary Sjögren's syndrome 2009 Jan OBJECTIVES: Previous evidence suggests the role of psychological stress in triggering the onset of autoimmunity. We aimed to investigate whether stress following major and minor life events could precede the onset of primary Sjögren's syndrome (pSS). The role of coping strategies and social support, as compensating buffering mechanisms, was also explored. METHODS: 47 patients with pSS were compared with two control groups: 35 patients with lymphoma (disease controls, DC) and 120 healthy controls (HC) with disease onset within the previous year. All subjects completed questionnaires assessing the occurrence of major and minor stressful events, coping strategies and social support prior to disease onset. Data analysis was performed by univariate and multivariate logistic regression models. RESULTS: A higher number of patients with pSS reported the occurrence of negative stressful life events prior to disease onset compared with patients with lymphoma and HC, while the number and impact of daily hassles did not differ between the three groups. Coping strategies were defective and the overall social support was lower in patients with pSS compared with DC and HC groups. In the multivariate model, pSS status was associated with maladaptive coping and lower overall social support relative to DC and HC, as well as with an increased number of negative stressful life events compared with HC but not DC. CONCLUSIONS: Prior to disease onset, patients with pSS experience high psychological stress following major negative life events, without developing satisfactory adaptive coping strategies to confront their stressful life changes. Lack of social support may contribute to the relative risk of disease development.
21120495 Nephrocalcinosis and hypokalemia in a patient with primary Sjögren's syndrome. 2013 Mar Clinically significant renal involvement is uncommon in primary Sjögren's syndrome, amid which tubulointerstitial disorders, distal renal tubular acidosis (dRTA) particularly, account for the majority. Conversely, Sjögren's syndrome comprises at least half the patients presenting with renal tubular acidosis. While underlying dRTA itself is an important cause of nephrocalcinosis and urolithiasis, nephrocalcinosis is rarely a presenting feature of primary Sjögren's syndrome. I report a 41-year-old female contracting nephrocalcinosis and hypokalemia as complications of primary Sjögren's syndrome with dRTA, hereby to emphasize the importance of alkali therapy.
20924723 Approach to a patient with connective tissue disease. 2010 Oct Connective tissue disease (CTDs), though rare in childhood, are an important cause of morbidity. Most of them involve multiple organ systems and are associated with presence of autoantibodies. Systemic lupus eryethematosus (SLE) is the most common CTD, the others being Juvenile dermatomyositis, systemic sclerosis, mixed connective disease and Sjogren syndrome. The clinical presentation of CTD in childhood can range from an acute severe illness mimicking a serious infection, to an insidious onset of disease with gradual accumulation of symptoms and signs over wks to months. The presence of multi-system involvement, evidence of inflammation and lack of any obvious cause should alert a clinician to the possibility of CTD. Diagnosis is usually clinical and features like malar rash, Raynaud's phenomenon, Gottron's rash, photosensitivity, oral ulcers suggest a possibility of CTD. Presence of autoantibodies like anti-nuclear antibodies, anti-dsDNA etc. provide supportive evidence to a diagnosis of CTD. Most CTDs are treated with immunosuppressive drugs with good success. Early recognition and prompt treatment results in excellent outcome.
20428907 May anakinra be used earlier in adult onset Still disease? 2010 Oct Interleukin-1 antagonist anakinra is increasingly used as third-line therapy in adult-onset Still disease (AoSD) after corticosteroids (CS) and immunosuppressive drugs have failed or have induced serious adverse effects. We recently had to use anakinra earlier in the course of AoSD in two patients. In both cases, the disease had a major social impact. One patient was a plane pilot, and he was forbidden to continue his job as long as he was on CS. He also had developed CS-induced central serous chorioretinopathy (CSC), and methotrexate did not allow a prompt reduction in the prednisone dosage. Anakinra had a dramatic effect and allowed the complete withdrawal of CS and methotrexate and the full remission of CSC, and the patient could pilot again. The doses of anakinra have been since then successfully reduced by two thirds. In the second case, AoSD occurred a few weeks before the patient's A-level exams. The disease was resistant to prednisone 1 mg/kg for 15 days. Anakinra controlled all symptoms in 3 days and was stopped 3 months later. She has not relapsed since then. No adverse drug reaction has occurred. These cases suggest that a treatment by anakinra of short duration could be used early in AoSD to induce a prompt remission, to avoid the adverse effects of high dose CS and/or immunosuppressive drugs and to reduce the social impact of the disease.
19655220 Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocy 2009 Nov Elevated levels of serum ferritin and a low percentage of glycosylated ferritin have been reported in adult-onset Still's disease (AOSD) as well as in hemophagocytic lymphohistiocytosis (HLH). The objective of the current study was to investigate total ferritin levels and the percentage of glycosylated ferritin in patients with secondary HLH. From October 2007 to October 2008, 29 patients with suspected HLH older than 14 years of age treated at Beijing Friendship Hospital were enrolled. Twenty-five healthy volunteers were recruited as controls. The suspected HLH patients were further divided into secondary HLH-confirmed (confirmed) (22 out of 29) and HLH-unconfirmed (unconfirmed) (7 out of 29) groups based on HLH-2004 diagnostic criteria. Total serum ferritin levels and the percentage of glycosylated ferritin were determined in subjects at the time of admission. Significantly higher levels of total serum ferritin were observed in confirmed (2,897.6 +/- 1,837.2 microg/L) compared with unconfirmed (653.1 +/- 249.1 microg/L) patients (P < 0.01) or controls (414.6 +/- 212.6 microg/L) (P < 0.01). A significantly lower percentage of glycosylated ferritin was observed in the confirmed (20.5 +/- 10.1%) compared with the unconfirmed (48.7 +/- 12.1%) group (P < 0.01) or the control group (53.6 +/- 13.3%) (P < 0.01). In addition, a low percentage of glycosylated ferritin was observed in HLH patients. Finally, regarding the diagnosis of HLH based on a low percentage of glycosylated ferritin, the sensitivity and specificity, as well as positive and negative predictive values were 0.86, 0.71, 0.91, and 0.63, respectively. For the diagnosis of HLH based on hyperferritinemia, the sensitivity, specificity, positive, and negative predictive values were 0.82, 0.43, 0.82, and 0.43, respectively. The results of this study suggest that a low percentage of glycosylated ferritin is associated with HLH. On comparison with hyperferritinemia, a low percentage of glycosylated ferritin appeared to be more specific, sensitive, and predictive of HLH. In conclusion, a low percentage of glycosylated ferritin may be a useful marker for the early diagnosis of secondary HLH.
19474776 [Applicability of syalometry and other instruments to evaluate xerostomia and xerophtalmia 2009 Apr OBJECTIVES: To evaluate the applicability and utility of unstimulated syalometry and instruments of evaluation of sicca complaints in a Sjögren's syndrome outpatient clinic. MATERIAL AND METHODS: We performed unstimulated syalometry to 45 consecutive Primary Sjögren's Syndrome patients (PSS) and 21 healthy asymptomatic individuals age and sex-matched. PSS patients were further evaluated with Schirmer's test. We applied 3 published questionnaires to PSS patients: Xerostomia Inventory (XI), Oral Health Impact Profile-short form (OHIP) and Ocular Surface Disease Index (OSDI), and correlated the results with syalometry and Schirmer's test. Statistical analysis was performed with SPSS (Mann-Whitney U-test and Spearman's correlation). RESULTS: Salivary flux was significantly lower in PSS patients, as compared to controls (0.08+/-0.01 ml/min versus 0.38+/-0.25 ml/min, p=0.000), and decreased with age. Syalometry didn't correlate with Schirmer's test. OHIP scores (mean 26.8 points, ranging from 2 to 43 for a maximum of 56 points) didn't correlate with syalometry neither with Schirmer's test, but showed an association with the XI (p<0.0005) and OSDI (p<0.0005) tests. The XI questionnaire (mean 28.4 points, ranging from 11 to 41 for a maximum of 44 points) correlated with syalometry (p=0.018), with the OHIP questionary (p<0.0005) and with the OSDI scale (p=0.004), although it didn't correlate with Schirmer's test. OSDI scores (mean 56.5 points, ranging from 7 to 90 for a maximum of 100 points) didn't correlate with Schirmer's test neither with syalometry, but associated with the XI (p=0.004) and OHIP (p<0.0005) scales. CONCLUSIONS: Unstimulated syalometry is useful in the evaluation of patients suspected of suffering from Sjögren's syndrome, since it can confirm salivary hypofunction in a quick and cheap manner, allowing to differentiate between healthy individuals and patients. In a specialized clinic, the immediate availability of a salivary functional test is important in the classification of PSS or sicca syndrome. The xerostomia and xerophtalmia impact scales were mutually concordant, and since they evaluate the effects of the disease through time, could be helpful in our daily consultation.
20191581 Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic 2010 Jun OBJECTIVE: Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. METHODS: Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. RESULTS: Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). CONCLUSION: In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).
20427009 Mechanisms involved in injury and repair of the murine lacrimal gland: role of programmed 2010 Apr The non-keratinized epithelia of the ocular surface are constantly challenged by environmental insults, such as smoke, dust, and airborne pathogens. Tears are the sole physical protective barrier for the ocular surface. Production of tears in inadequate quantity or of inadequate quality results in constant irritation of the ocular surface, leading to dry eye disease, also referred to as keratoconjunctivitis sicca (KCS). Inflammation of the lacrimal gland, such as occurs in Sjogren syndrome, sarcoidosis, chronic graft-versus-host disease, and other pathological conditions, results in inadequate secretion of the aqueous layer of the tear film and is a leading cause of dry eye disease. The hallmarks of lacrimal gland inflammation are the presence of immune cell infiltrates, loss of acinar epithelial cells (the secreting cells), and increased production of proinflammatory cytokines. To date, the mechanisms leading to acinar cell loss and the associated decline in lacrimal gland secretion are still poorly understood. It is also not understood why the remaining lacrimal gland cells are unable to proliferate in order to regenerate a functioning lacrimal gland. This article reviews recent advances in exocrine tissue injury and repair, with emphasis on the roles of programmed cell death and stem/progenitor cells.