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ID PMID Title PublicationDate abstract
25936224 Evolution of undifferentiated arthritis: a ten-year experience from the early arthritis cl 2015 May OBJECTIVES: Undifferentiated arthritis (UA) is an inflammatory oligo/polyarthritis where no definite diagnosis can be reached. Patients with UA may progress towards a chronic inflammatory disease, however, in some cases arthritis may completely resolve. To date, a universally accepted diagnostic and therapeutic algorithm for UA is not available. METHODS: We retrospectively studied 192 patients with UA followed by us over the last 10 years in the early arthritis clinic of our institution. RESULTS: A total of 192 patients, 91 men (47.4%) and 101 women (52.6%), with mean age 57.9±17.8 years, were included in the study. Eighty-four patients (43.7%) presented with acute/subacute mono-/pauci-arthritis, 56 patients (29.2%) with chronic mono-/pauci arthritis, 42 patients (21.9%) with acute polyarthritis and 10 (5.2%) with chronic polyarthritis. From the total of 192 patients, 102 are currently followed. Current diagnosis at the time of this report included: rheumatoid arthritis in 18 (17.6%) patients, self-limiting arthritis in 35 (34.4%), undifferentiated/unclassified arthritis in 45 (44.1%), spondyloarthropathy in 3 (2.9%), and crystal-induced arthritis in one (1%). The time between the initial evaluation and the definitive diagnosis of RA ranged between 6 and 15 months. Seropositivity (RF and/or ACPA) and disease duration were strong predictors of developing RA in our cohort. CONCLUSIONS: Our data indicate that seropositive patients with chronic symptoms carry an increased risk of developing RA, and that these patients may be candidates for a more aggressive treatment.
27606481 An unusual case report of gingival overgrowth associated with the use of leflunomide. 2016 Apr Leflunomide is an immunomodulatory agent with antiproliferative activity that is used for the treatment of rheumatoid arthritis. Leflunomide induced side effects are hepatotoxicity, immunosuppression, skin reactions, peripheral neuropathy, hypertension, diarrhea, interstitial lung disease, and rarely oral mucosal lesions. Here, we presented an unusual case of gingival overgrowth associated with the use of leflunomide, which improved after ceasing the drug.
27354682 Resveratrol lowers synovial hyperplasia, inflammatory markers and oxidative damage in an a 2016 Oct OBJECTIVE: The present study aimed to determine the protective effects of dietary supplementation with resveratrol (RSV) in an acute antigen-induced arthritis (AIA) model. METHODS: Rats were randomly divided into three groups: control, AIA and RSV-treated AIA group. RSV (12.5 mg/kg/day) was given orally for 8 weeks before induction of AIA and until the end of the experiment (48 h after intra-articular injection). The control and AIA animals were administered 100 μl of water. Results were evaluated by macroscopic observation, histopathology and immunohistochemistry for anti-PCNA, macrophages (CD68), T lymphocytes (CD3), monocyte chemoattractant protein-1 and 8-oxo-7,8-dihydro-2'-deoxyguanine (a marker of DNA damage). Cytokine-induced neutrophil chemoattractant-1 in serum and peroxidase activity in synovial tissue were measured using commercial kits. RESULTS: At the end of the study, RSV significantly reduced knee swelling. Likewise, the histological score of synovial tissue also reduced significantly. The arthritis-protective effects were associated with a significant decrease in PCNA, CD68, CD3 and monocyte chemoattractant protein-1 staining, as well as a reduction in serum concentrations of cytokine-induced neutrophil chemoattractant-1. RSV treatment also decreased the level of the marker of DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanine. Accordingly, peroxidase activity in the synovial tissue was up-regulated. CONCLUSION: Dietary supplementation with RSV lowers the main pathological hallmarks of RA disease in an acute model of AIA. RSV may represent a promising strategy in controlling the severity of RA.
26726041 The longitudinal relation between patterns of goal management and psychological health in 2016 May OBJECTIVES: Due to their disease, patients with polyarthritis face the task of reconciling their threatened personal goals with their capabilities. Previous cross-sectional research on patients with chronic disease related higher levels of goal management strategies to lower levels of distress and higher levels of well-being. This study was the first to focus longitudinally on goal management patterns that combined strategies originating from different goal management theories. Our first study objective was to identify patterns that consisted of various strategies of goal management among patients with polyarthritis. Subsequently, the cross-sectional and longitudinal relationships between these patterns and the psychological health of the patients were studied. METHODS: A longitudinal questionnaire study with three measurements of goal management and psychological health was conducted among 331 patients with polyarthritis. Stability of goal management over time was analysed with ANOVAs. Patterns were identified using cluster analysis at baseline, based on the following strategies: Goal maintenance, goal adjustment, goal disengagement, and goal reengagement. Longitudinal relationships between the patterns and psychological health (specifically: Depression, anxiety, purpose in life, positive affect, and social participation) were analysed using a generalized estimating equations analysis. RESULTS: Three goal management patterns were found: 'Moderate engagement', 'Broad goal management repertoire', and 'Holding on'. Patients with the 'Broad goal management repertoire' pattern had the highest level of psychological health. The 'Holding on' pattern was identified as the most unfavourable in terms of psychological health. Over time, stable differences in levels of psychological health between the patterns were found. CONCLUSIONS: This study was the first to reveal patterns of several goal management strategies and their longitudinal relationship to psychological health. Psychosocial support for arthritis patients with lower psychological health should focus on helping patients to become familiar with a broad range of goal management strategies when dealing with threatened goals. STATEMENT OF CONTRIBUTION: What is already known on this subject? Polyarthritis is a collective term for a variety of disorders associated with autoimmune pathologies that may affect all aspects of a person's physical, psychological, and social functioning. Patients often experience difficulties in maintaining and achieving goals in several domains of life due to disease symptoms. The process of emotional adaptation to polyarthritis is characterized by searching equilibrium between desires and constraints and reacting constructive to stressors. Goal management strategies are ways to minimize the perceived disparity between the actual and the preferred situation with regard to personal goals and are applied both consciously and unconsciously. Cross-sectional, higher levels of goal management strategies have been related to lower levels of distress and higher levels of well-being both in patients with polyarthritis and in other patient groups. What does this study add? Contributes to our understanding of how combinations of goal management strategies relate to psychological health. Identifies patterns of goal management that are longitudinally related to psychological health. Provides clear guidance for improving psychological health of people with polyarthritis.
28217620 Human immunodeficiency virus polyarthropathy. 2016 Jul Articular manifestations are a frequent but often underdiagnosed manifestation in patients infected with the human immunodeficiency virus (HIV). We present a 7-year-old HIV-infected malnourished girl who presented with recurrent joint pain and effusion in the left knee joint. Her antistreptolysin O, dsDNA, antinuclear antibody and rheumatoid arthritis factor were negative. She responded to antiretroviral therapy.
26591580 [MELATONIN TREATMENT OF AUTOIMMUNE AND ALLERGIC PATHOLOGY]. 2015 Some autoimmune and allergic diseases (systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, atopic dermatitis, etc.) are accompanied with disturbances of the natural production of hormone melatonin by pineal gland and peripheral tissues. The administration of melatonin to animals and humans with such pathologies demonstrated showed a protective effect. It is proposed to carry out additional investigations of the possibility of using melatonin for the treatment of autoimmune disorders, after which it can be introduced into clinical practice.
26388237 Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoi 2016 May Recent studies have identified olfactory ecto-mesenchymal stem cells (OE-MSCs) as a new type of resident stem cell in the olfactory lamina propria. However, it remains unclear whether OE-MSCs possess any immunoregulatory functions. In this study, we found that mouse OE-MSCs expressed higher transforming growth factor-beta and interleukin-10 levels than bone marrow-derived MSCs. In culture, OE-MSCs exerted their immunosuppressive capacity via directly suppressing effector T-cell proliferation and increasing regulatory T (Treg) cell expansion. In mice with collagen-induced arthritis, adoptive transfer of OE-MSCs markedly suppressed arthritis onset and disease severity, which was accompanied by increased Treg cells and reduced Th1/Th17 cell responses in vivo. Taken together, our findings identified a novel function of OE-MSCs in regulating T-cell responses, indicating that OE-MSCs may represent a new cell therapy for the treatment of rheumatoid arthritis and other autoimmune diseases.
27895095 Calprotectin in rheumatic diseases. 2017 Apr Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker. Impact statement Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.
27750439 Liposomal nano-drugs based on amphipathic weak acid steroid prodrugs for treatment of infl 2016 Nov BACKGROUND: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. OBJECTIVES: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. METHODS: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs. Their remote loading results in high, efficient and stable loading to the level that enables human clinical use. We characterized them for their physical chemistry and stability. We demonstrated their therapeutic efficacy in relevant animal models and studied their pharmacokinetics (PK), biodistribution (BD) and pharmacodynamics advantages over the free pro-drugs. RESULTS: Our steroidal nano-drugs demonstrate much superior PK, BD, tolerability and therapeutic efficacies compared to the free pro-drugs and to most drugs currently used to treat these diseases. These nano-drugs act as robust immune-suppressors, affecting cytokines secretion and diminishing hemorrhage and edema. CONCLUSIONS: The combination of improved physical-chemistry, PK, BD, tolerability and therapeutic efficacy of these steroidal nano-drugs over the pro-drugs "as-is" support their further clinical development as potential therapeutic agents for treating inflammatory diseases.
27767950 Systematic Review of Educational Interventions for Rheumatoid Arthritis. 2016 Nov/Dec OBJECTIVE: In this study, we systematically reviewed the effectiveness of educational interventions falling within the scope of occupational therapy practice for people with rheumatoid arthritis (RA). These interventions included disease education, joint protection and energy conservation, psychosocial techniques, pain management, and a combination category. METHOD: Two databases, MEDLINE and CINAHL, and select journals were searched for randomized controlled trials published between January 2002 and June 2015. Qualitative synthesis was used for between-study comparisons. RESULTS: Twenty-two studies, with approximately 2,600 participants, were included. The interventions were found to have strong evidence for constructs that dealt with increasing coping with pain and fatigue as well as maintaining positive affect. There was limited or no evidence supporting the effectiveness of these interventions on most other measured constructs. CONCLUSION: Interventions in which a combination of educational techniques is used may complement pharmacological therapies in the care of people with RA. Future research is needed to identify specific mechanisms of change.
27335685 Methotrexate-associated primary cutaneous CD30-positive cutaneous T-cell lymphoproliferati 2016 Methotrexate (MTX) is a commonly used anti-metabolite agent. Increased risk of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) has been documented with the prolonged use of immunosuppressive medications such as MTX. This is thought to be the result of immune dysregulation and/or chronic immune stimulation. Most cases of LPDs regress following withdrawal of the offending immunosuppressive agent. We present an interesting and rare case of CD30 and EBV positive CD8 primary cutaneous anaplastic large cell lymphoma (PC-ALCL) in a 66-year-old African American woman. Patient had been on MTX for rheumatoid arthritis (RA) which was stopped after the patient was evaluated at our institution. Patient had an incredible response to stopping immunosuppression with spontaneous regression of skin lesions and disappearance of clonal malignant cell population as evidenced on serial biopsy specimens. Primary cutaneous CD30+ LPDs constitute about 30% of the primary cutaneous T-cell lymphomas (CTLs) and includes entities such as lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and other CD30+ borderline LPDs. Histopathological criteria in addition to CD30 positivity is important for identification of these conditions. Treatment options include "wait and see", phototherapy, radiotherapy, topical agents, systemic therapy and surgical resection. Prognosis is excellent and most cases resolve spontaneously on withdrawal of immunosuppression. Refractory cases may require aggressive local treatment or systemic therapy. Brentuximab Vedontin, an anti-CD30 antibody drug conjugate (ADC), may provide additional therapeutic option in refractory cases.
27165981 Ultrasound imaging of the distal radioulnar joint: a new method to assess ulnar radial tra 2017 May A cross-sectional reliability study was conducted with 23 normal participants to establish normal values, and the repeatability and validity of distal radioulnar joint translation measurements using ultrasound imaging. Static transverse images of maximal supination, neutral and maximal pronation were examined to assess translation, using a method consistent with the rheumatoid arthritis subluxation ratio. Translation while gripping a 1 kg weight in supinated and pronated positions was then compared with non-gripping translation. There was significantly more ulnar radial translation found with pronation than supination, when compared with neutral. Gripping in pronation did not produce statistically significant changes in translation, whereas the changes produced by gripping in supination were significant. Internal consistency was deemed very high and the rheumatoid arthritis subluxation ratio values measured using ultrasound imaging were consistent with previously documented values measured by computerized tomography. This study demonstrated that translational movement of the distal radioulnar joint can be reliably detected in healthy participants using ultrasound imaging. This may reduce dependency on other imaging modalities to diagnose distal radioulnar joint instability. LEVEL OF EVIDENCE: 2.
26800167 Prevalence of Peri-implantitis in Medically Compromised Patients and Smokers: A Systematic 2016 Jan PURPOSE: To verify whether the diversity of systemic medical conditions and smoking act as biologic associated factors for peri-implantitis. MATERIALS AND METHODS: The PICO question was: "In patients with osseointegrated dental implants, does the presence of smoking habits or a compromised medical status influence the occurrence of peri-implantitis compared with the presence of good general health?" Smoking and systemic conditions such as type 2 diabetes mellitus, cardiovascular diseases, rheumatoid arthritis, lung diseases, obesity, cancer, deep depression, and osteoporosis were screened. Selection criteria included at least 10 patients per condition, 1 year of follow-up after implant loading, and strict cutoff levels (probing pocket depth [PPD], bleeding on probing [BOP] and/or pus, marginal bone loss) to define peri-implantitis. RESULTS: From the 1,136 records initially retrieved, 57 were selected after title and abstract analyses. However, only six papers were considered for qualitative evaluation. No randomized controlled clinical trial was found. Smoking was associated with peri-implantitis in only one out of four studies. Poorly controlled type 2 diabetes accentuated only PPD and radiographic marginal bone level prevalence rates in peri-implant patients (one study). Cardiovascular disease was considered a risk (one out of two studies). The chance of peri-implant patients harboring the Epstein-Barr virus was threefold in one report. No associations were found for rheumatoid arthritis. CONCLUSION: Data from existing studies point to smoking and diabetes as biologic associated factors for peri-implantitis. However, the body of evidence is still immature, and the specific contribution of general health problems to peri-implantitis requires additional robust epidemiologic and clinical investigations.
26379753 Systemic Review and Meta-Analysis of the Clinical Efficacy and Adverse Effects of Zhengqin 2015 Chinese medicines are gaining wider acceptance. They have been used for treating rheumatoid arthritis (RA) for thousands of years, and the need to investigate the interaction between Chinese medicines and western medicines is widely recognized. In this study, a large number of RCTs and CCTs were analyzed to systematically assess the effects and adverse events of Zhengqing Fengtongning (ZQFTN) for RA. Eleven studies that contained 956 participants (508 in the treatment group; 448 in the control group) were included. The results showed that although ZQFTN combined with methotrexate MTX could not decrease the swollen joint count and tender joint count of RA patients better than MTX alone, the combination therapy might relieve the duration of morning stiffness (SMD: -16.06; 95% CI: -28.77 to -3.34), reduce laboratory indexes (RF: SMD: -10.84; 95% CI: -19.39 to -2.29; ESR: SMD: -7.26; 95% CI: -11.54 to -2.99; CRP: SMD: -3.66; 95% CI: -5.94 to -1.38), and improve the overall effect (RR: 1.08; CI: 1.01 to 1.16) better than monotherapy. The combination therapy was significantly better in controlling adverse drug reactions (RR: 0.60; 95% CI: 0.46 to 0.79). Through this systematic review, we found that ZQFTN combined with MTX for the treatment of RA might have better clinical efficacy than MTX only and might be superior in terms of controlling adverse drug reactions.
26962613 2015 Aug Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature mortality. The prevalence of RA in Canada is about 1%. The pharmacological therapy of RA aims to achieve remission and, if remission is not possible, to minimize disease activity while controlling symptoms, halting damage, preventing disability, and improving quality of life. Non-biologic synthetic disease-modifying antirheumatic drugs (DMARDs) have been shown to alter the clinical course of RA and slow or halt radiographic progression when used early and aggressively in the treatment of RA. Methotrexate is the preferred DMARD with respect to efficacy and safety and is recommended as first-line DMARD treatment in patients with RA unless contraindicated or not tolerated. Based on Canadian Rheumatology Association guidelines, if patients do not attain the desired target within three to six months of non-biologic DMARD therapy, treatment with a biologic therapy should be initiated. Tocilizumab (TCZ) is a recombinant humanized anti-human interleukin (IL)-6 receptor monoclonal antibody. It blocks the pleiotropic cytokine IL-6, which is found at high levels in the joints affected by RA. In Canada, TCZ is available as 162 mg/0.9 mL solution in single-use pre-filled syringes for subcutaneous (SC) injection, and in single-use vials containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL for intravenous (IV) infusion. The IV formulation of TCZ was previously reviewed by the Canadian Drug Expert Committee for the treatment of RA and received a recommendation to be listed for adults with moderate to severely active RA who have failed to respond to an adequate trial of both DMARDs and a tumour necrosis factor (TNF) alpha inhibitor. The objective of this review was to evaluate the beneficial and harmful effects of the SC formulation of TCZ at recommended doses alone or in combination with methotrexate (MTX) or other DMARDs in adult patients with moderately to severely active RA with an inadequate response to one or more DMARDs and/or TNF alpha inhibitor therapies.
25551802 Apolipoprotein M in lipid metabolism and cardiometabolic diseases. 2015 Feb PURPOSE: This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases. RECENT FINDINGS: ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P. SUMMARY: The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also, the importance in regulating endothelial function is being investigated. Furthermore, both apoM and S1P have been linked to diabetes and glucose and insulin metabolism. Finally, genetic variations in the apoM gene are associated with lipid disturbances, diabetes and rheumatoid arthritis. These findings suggest not only diverse effects of apoM, but also the important question of whether apoM mainly acts as a S1P carrier, if apoM carries other substances with biological effects as well, or whether the apoM protein has effects on its own.
27981248 Absence of a positive correlation between CRP and leptin in rheumatoid arthritis. 2016 Dec AIMS: Rheumatoid Arthritis (RA) is a model of chronic inflammatory disease. In this study we evaluated the correlation of leptin and CRP in patients with RA and normal controls. MAIN METHODS: A total of 75 patients with RA and 40 healthy adults were recruited in this case-control study. RA patients were categorized into high (DAS-28 > 3.2) and low activity (DAS ≤ 3.2) group according to their DAS-28 score. KEY FINDINGS: Leptin level was significantly correlated with CRP in healthy controls (r = 0.365; p < 0.05), but this correlation was lost in RA patients (r = 0.095, p = 0.41). Patients with RA had higher serum leptin levels compared to healthy controls (P < 0.01). No difference in serum leptin level was observed between patients with high and low activity disease. Also leptin was correlated with BMI in healthy controls (r = 0.326, p = 0.037). This correlation was not present in RA patients (r = 0.039, p = 0.756). SIGNIFICANCE: We observed that the physiologic correlation between leptin and CRP and BMI and CRP was not present RA patients. This is a new study reporting the lost correlation between leptin and CRP in RA patients.
26271167 [Dutch-language patient-reported outcome measures for foot and ankle injuries; a systemati 2015 OBJECTIVE: To investigate which valid and reliable patient-reported outcome measures (PROMs) are available for foot and ankle disorders in the Dutch population, and which of these is the most suitable for uniform use. DESIGN: Systematic review. METHOD: PubMed, Embase and Google Scholar were systematically searched for relevant articles; subsequently two researchers screened first the title and the abstract, and then the full article within a selection of these articles. Studies that described a validation process for foot- and ankle-PROMs in a Dutch population were included. Data on measurement characteristics and translation procedure were extracted, and methodological quality of the studies was assessed using the COSMIN checklist. ('COSMIN' stands for 'Consensus-based standards for the selection of health status measurement instruments'.) RESULTS: Two general foot- and ankle-PROMs in the Dutch language were validated: the Foot and Ankle Outcome Score (FAOS) and the Foot and Ankle Ability Measurement (FAAM); two foot-PROMs: the Manchester Foot Pain and Disability Index (MFPDI) and the 5-point Foot Function Index (FFI-5pt) were also validated. There were also two disorder-specific PROMs available in Dutch: the Victorian Institute of Sports Assessment-Achilles (VISA-A) for Achilles tendinopathies and the Foot Impact Scale for Rheumatoid Arthritis (FIS-RA) for rheumatoid arthritis patients. CONCLUSION: The FAOS and the FFI-5pt showed the strongest evidence for having good measurement characteristics. Currently, we regard the FAOS as the most appropriate foot- and ankle-PROM for general foot and ankle problems. Further studies of higher methodological quality are, however, required to draw firmer conclusions.
25964853 Reversible methotrexate-associated lymphoma of the liver in rheumatoid arthritis: a unique 2015 Primary hepatic lymphoma (PHL) is an extremely rare disease, frequently associated with viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immune deficiency virus (HIV). On the other hand, an increased risk of lymphoproliferative disorders (LPD) has been demonstrated in patients treated with immunosuppressive drugs such as methotrexate (MTX) for rheumatoid arthritis (RA). The role of Epstein-Barr virus (EBV) has been discussed in the pathogenesis of the immunodeficiency-associated LPDs. We here describe a RA patient, who developed PHL during RA treatment. The patient was a 64 year-old Japanese male with a 2-year history of RA, who had been treated with MTX at weekly dose of 8-14 mg for 2 years and infliximab (IFX) for 7 months. He presented with a 2 month history of generalized malaise, right hypochondrium pain and fever. Contrast-enhanced computed tomography (CECT) of the abdomen showed multiple irregular and nodular liver masses with a maximum of 13 cm in diameter on the right liver. Biopsy specimens demonstrated CD20-positve diffuse large B-cell lymphoma (DLBCL), but EBV was not identified by EBV-encoded RNA in situ hybridization. Serology for HBV, HCV, human T-cell leukemia virus I (HTLV-I), and HIV was negative. His symptoms disappeared following discontinuation of RA treatment including MTX. A drastic regression of the tumor masses was further obtained without cytotoxic chemotherapy. In addition, although the patient had no past history of liver dysfunction before MTX therapy, persistent elevation of liver enzymes has been observed during MTX treatment. These findings show a causative role of MTX in the development of reversible PHL in the patient.
27471717 CD28 co-stimulation in T-cell homeostasis: a recent perspective. 2015 T-cells play a key role within the adaptive immune system mediating cellular immunity and orchestrating the immune response as a whole. Their activation requires not only recognition of antigen/major histocompatibility complexes by the T-cell receptor but in addition co-stimulation via the CD28 molecule through binding to CD80, CD86, or as recently discovered, inducible co-stimulator ligand expressed by antigen-presenting cells. Apart from tight control of the co-stimulatory signal by the T-cell receptor complex, expression of the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) sharing its ligands with CD28 is required to avoid inappropriate or prolonged T-cell activation. CD4(+) Foxp3(+) regulatory T (Treg) cells, which are crucial inhibitors of autoimmunity, add another level of complexity in that they differ from conventional non-regulatory CD4(+) T-cells by strongly depending on CD28 signaling for their generation and homeostasis. Moreover, CTLA-4 is constitutively expressed by Treg cells where it serves as a key mediator of suppression, while conventional CD4(+) T-cells express CTLA-4 only after activation. Here, we discuss recent insights into the molecular events underlying CD28-mediated co-stimulation, its impact on gene regulation, and the differential role of CD28 expression on Treg cells versus conventional CD4(+) and CD8(+) T-cells. Moreover, we summarize the exciting therapeutic options which have arisen from our current understanding of T-cell co-stimulation. Some of these have already been translated into the clinic, while others are expected to follow soon due to promising preclinical results. In particular, we discuss the failed 2006 trial of the CD28 superagonist TGN1412, and the return of this potent T-cell activator to clinical development.