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ID PMID Title PublicationDate abstract
19486063 Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric 2010 Jan A patient with a 25-year history of rheumatoid arthritis and a 3-year history of methotrexate treatment developed a generalized papular rash. The papules rapidly became necrotic and then resolved, leaving a depressed scar. The rapid course of lesion development and regression was reminiscent of pityriasis lichenoides. Histology revealed a nodular infiltrate composed of a mixture of pleomorphic large B cells positive for CD20, CD30 and CD79a, and of small T cells positive for CD3 and CD4. The T cells had a striking angiocentric distribution, with some of the vessels exhibiting fibrinoid necrosis of the vessel wall reminiscent of lymphomatoid granulomatosis. However, B cells were consistently negative for Epstein-Barr virus (EBV) antigen expression. A thorough examination excluded involvement of organs other than the skin. Thus, this patient was classified as having a rare form of an EBV-negative primary cutaneous T-cell-rich B-cell lymphoma in association with methotrexate treatment.
19301791 Protrusio of a ceramic femoral head through the acetabular metallic shell, extensive metal 2009 Feb A 24-year-old patient with a history of juvenile rheumatoid arthritis underwent a primary cementless left total hip arthroplasty (THA). The original THA consisted of an Optifix 54 cup with a 3-mm thick polyethylene liner, an Optifix size 4 stem (Smith & Nephew Richards, Memphis, Tennessee) and a Biolox aluminum 32-mm femoral head. Fourteen years later, radiographs demonstrated extensive wear of the polyethylene liner resulting in direct articulation and abrasion wear of the ceramic femoral head on the cup and a bubble sign. This article presents a case of a catastrophic failure of a ceramic/polyethylene bearing with destruction of the polyethylene liner and the metallic shell and protrusio of the nonfractured ceramic head through the metallic shell. To our knowledge this is the first description of extensive metallosis and subsequent radiograph bubble sign not presenting as a result of wear of a metal-on-metal articulation. At the time of revision surgery-Hydrocel TNT Monoblock 58 cup (Zimmer, Warsaw, Indiana), Wagner 265/14 stem (Zimmer), and a Co/Cr 28-mm head-copious metallic debris was seen both macroscopically and histologically, with the ceramic head protruding behind the metallic shell. Multiple factors may have been responsible for this failure including a thin polyethylene shell, a suboptimal locking mechanism, gamma in air sterilization for polyethylene, multiple screw-holes that reduce the contact surface between shell and polyethylene, the rough surface on the inside of the shell and non-articular wear at the metal polyethylene interface within the acetabular component and the high demands of this active young patient.
19280915 [Historical review of rheumatology and future directions]. 2009 Mar Rheumatic diseases are suggested to be recognized 2400 years ago, but little progress had been made in distinguishing specific diseases until the 17th century. After the two decades, the concept of rheumatic diseases was established and followed by the new concept of autoimmune diseases in the 20th century. Many key drugs for rheumatic diseases, such as glucocorticoids and immunosuppressants, were developed in the 1940s and 1950s. Their effect, toxicity and limitations have been investigated for fifty years. On the other hand, new treatment strategy was developed. Advances in genetics and molecular cell biology in the 1980s brought us the discovery of many cytokines and chemokines and elucidated the role of these molecules in autoimmune diseases. These progresses have led to the development of a number of biological agents for the rheumatic diseases during past decade. Among these drugs, TNF blockade showed the remarkable effectiveness in rheumatoid arthritis and this success indicated the new treatment era. However, compared to the simplicity of target molecules in monoclonal antibody therapy, biological effects are more complex. Therefore, we must keep in mind the possibility of the appearance of unexpected adverse effects such as TGN1412. This review presents a history of rheumatology and discusses future directions of basic and clinical research for rheumatic diseases.
21136940 Immunoglobulin 1 (IgG1) Fc-glycosylation profiling of anti-citrullinated peptide antibodie 2009 Jan In several autoimmune disorders, including rheumatoid arthritis (RA), autoantibodies are thought to be the driving force of pathogenicity. Glycosylation of the Fc-part of human Igs is known to modulate biological activity. Hitherto, glycosylation of human IgG-Fc has been analyzed predominantly at the level of total serum IgG, revealing reduced galactosylation in RA. Given the pathogenic relevance of autoantibodies in RA, we wished, in the present study, to address the question whether distinct Fc-glycosylation features are observable at the level of antigen-specific IgG subpopulations. For this purpose, we have developed a method for the microscale purification and Fc-glycosylation analysis of anti-citrullinated peptide antibodies (ACPA). ACPA represent a group of autoantibodies that occur with unique specificity in RA patients. Their presence is associated with increased inflammatory disease activity and rapid joint destruction. Results indicate that ACPA of the IgG1 subclass vary considerably from total serum IgG1 with respect to Fc-galactosylation, with galactosylation being higher on ACPA than on serum IgG1 for some patients, while other patients show higher galactosylation on serum IgG1 than on ACPA. Using this method, studies can be performed on the biological and clinical relevance of ACPA glycosylation within RA patient cohorts.
19061425 Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications fo 2009 Jul Human adipose-derived stem cells (hASCs) are mesenchymal stem cells with reduced immunogenicity and the capability to modulate immune responses. These properties make hASCs of special interest as therapeutic agents in the settings of chronic inflammatory and autoimmune diseases. Exogenous and endogenous toll-like receptor (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis because of the permanent exposure of the immune system to TLR-specific stimuli. Therefore, hASCs employed in therapy are potentially exposed to TLR ligands, which may result in the modulation of hASC activity and therapeutic potency. In this study, we demonstrate that hASCs possess active TLR2, TLR3, and TLR4, because activation with specific ligands resulted in induction of nuclear factor kappa B-dependent genes, such as manganese superoxide dismutase and the release of interleukin (IL)-6 and IL-8. TLR3 and TLR4 ligands increased osteogenic differentiation, but no effect on adipogenic differentiation or proliferation was observed. Moreover, we show that TLR activation does not impair the immunogenic and immunosuppressive properties of hASCs. These results may have important implications with respect to the safety and efficacy of hASC-based cell therapies.
18946713 Relapsing polychondritis--case series from South India. 2009 Jun Relapsing polychondritis (RP) is a rare recurring inflammatory disorder with variable clinical course. It has been described mainly in Caucasian population. Reports from other ethnic groups are few. We report seven cases of relapsing polychondritis in south Indian population. In between 1995 and 2008, seven patients fulfilling the McAdam-Damiani-Levine criteria for diagnosis of relapsing polychondritis were identified. Records pertaining to these patients were studied and clinical presentation, course, and treatment offered were analyzed retrospectively. The female-to-male ratio in our series was 2.5:1. The age of onset of symptoms ranged from 28 to 54 years, with a mean of 40.2 years. An average of 20 months, ranging from 3 months to 6 years, elapsed before the patient presented to us seeking a diagnosis. Various structural involvement in our series were as follows: pinna in four (57%), nasal cartilage in five (71%), joints in three (43%), eyes in three (43%), laryngotracheal tree in three (43%), inner ear in one (14.3%), skin in one (14.3%), and heart in one (14.3%). Associated autoimmune diseases were present in four (57%) patients in the form of one of the following in each: vasculitis, autoimmune hemolytic anemia, hypothyroidism, and rheumatoid arthritis. All seven patients received prednisolone with three of them requiring additional immunosuppressants. There was no mortality amongst the four patients who had remained on follow-up at the time of this report. Although RP is an uncommon disorder, clinicians should be aware of the manifestations so as to initiate prompt treatment and prevent complications. Our series reports less frequent auricular cartilage and skin involvement and an exceptional case of basal cell carcinoma, although the other manifestations were similar to that seen in Caucasian and other Asian populations.
21386778 A review: the use of rituximab in neuromuscular diseases. 2010 Dec Autoimmunity plays a major role in the pathogenesis of many neuromuscular disorders such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, polymyositis, dermatomyositis, myasthenia gravis, Lambert Eaton syndrome, and stiff person syndrome. Although most of these disorders respond favorably to the commonly used immunomodulatory agents such as steroids, intravenous gamma globulin, plasmapheresis, and chemotherapy, some are initially refractory, whereas others gradually lose responsiveness. Therefore, alternative, selective, and novel immunosuppressive agents are used to treat these cases. Among these agents, rituximab has shown promise in some of the neuromuscular disorders with minimal side effects. Rituximab is a genetically engineered antibody that depletes CD20+ B-cells and is Food and Drug Administration- approved for treatment of non-Hodgkin lymphoma, CD20+ CLL, and rheumatoid arthritis. It carries a favorable side effects profile. However, evidence of efficacy is limited to case series and large prospective randomized controlled trials are lacking. In this article, we review and discuss the available literature on rituximab in treatment of various autoimmune neuromuscular diseases.
21219793 [Application of dual-energy computed tomography for detecting uric acid deposition in pati 2010 Dec OBJECTIVE: To assess the value of dual energy computed tomography (DECT) for the detection of uric acid (UA) deposition in patients with gout. METHODS: A total of 37 patients with tophaceous gout (including 8 crystal-proven cases) and 10 control patients (5 with unknown arthropathy, 3 with rheumatoid arthritis, and 2 with osteoarthritis) were included. DECT was performed for all peripheral joints (wrists, hands, elbows, knees, ankles and feet) . Color coding was used to display the localization of UA deposition. Images were reviewed independently by two trained radiologists. RESULTS: With DECT, patients with gout were found to have UA deposits in hands and wrists 46% (17/37) , elbows 16% (6/37) , knees 27% (10/37) , ankles and feet 89% (33/37) . No UA deposit was observed in all 10 control patients (P=0.000) . Among the 37 patients with gout, the number of UA deposition sites detected by DECT (n=297) was 2.25 times of that detected by physical examinations (n=132) (P=0.000) . CONCLUSIONS: DECT allows the visualization of UA deposition in gouty arthropathy. Even subclinical disease can be delineated with this technique. However, the accuracy of DECT requires further investigations.
24527153 Calciphylaxis: a review. 2010 Dec Human calciphylaxis reflects a form of severe tissue compromise attributable to a unique microangiopathy that combines features of vascular thrombotic occlusion with endoluminal calcification. While most frequently described in patients with renal failure, it is seen in other settings, such as multiple myeloma; polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome; cirrhosis; and rheumatoid arthritis. Although most commonly involving the skin, calciphylaxis can affect other organs including the heart and gastrointestinal tract, in which cases it falls under the appellation of systemic calciphylaxis. There are cases in which the main pathology is one of endovascular thrombosis of the vessels of the fat without discernible calcification or one manifesting a pseudoangiosarcomatous pattern, hence adding to the histomorphologic spectrum of calciphylaxis. A variety of factors contribute to this severe occlusive microangiopathy, including an underlying procoagulant state and ectopic neo-osteogenesis of the microvasculature through varied mechanisms, including increased osteopontin production by vascular smooth muscle or reduced synthesis of fetuin and GLA matrix protein, important inhibitors of ectopic neo-osteogenesis. Certain factors adversely affect outcome, including truncal and genital involvement and systemic forms of calciphylaxis. With a better understanding of its pathophysiology, more-effective therapies, such as sodium thiosulfate and biphosphanates to reduce reactive oxygen species and receptor activator of nuclear factor κβ-mediated nuclear factor κβ activity, respectively, are being developed.
20834190 Dihydrofolate reductase gene intronic 19-bp deletion polymorphisms in a Japanese populatio 2010 Dihydrofolate reductase gene (DHFR) 19-bp deletion polymorphisms result in varied DHFR enzymatic activity affecting the risk for preterm delivery, spina bifida, and the efficacy of methotrexate (MTX). Ethnic differences in DHFR 19-bp polymorphisms may be responsible for the divergent findings in previous genetic studies. We compared genotype and allele frequency of DHFR intronic 19-bp deletion polymorphisms in ethnically homogenous East Asians (from Japan) and others by polymerase chain reaction assay conducted on 277 healthy Japanese individuals. The genotype distribution was as follows: wild/wild, 11.9% (n=33); wild/deletion, 40.1% (n=111); deletion/deletion, 48.0% (n=133). The frequencies of wild type and deletion alleles were 0.32 and 0.68, respectively. The obtained genotype distribution was consistent with those calculated by Hardy-Weinberg equilibrium. The genotype distribution and allele frequencies in the Japanese population were significantly different from those previously reported for other ethnic populations. Determination of intronic 19-bp deletion polymorphisms of DHFR may be useful for monitoring the efficacy and side effects of MTX for the treatment of diseases such as rheumatoid arthritis and childhood acute leukemia in the Japanese population because the frequency of the deletion allele is higher.
21426088 Concise asymmetric synthesis of configurationally stable 4-trifluoromethyl thalidomide. 2009 Aug BACKGROUND: Thalidomide is one of the promising multidimensional drugs that possess high activity against serious diseases such as rheumatoid arthritis, Crohn's disease, leprosy, AIDS and various cancers. However, its medicinal applications are plagued by its configurational instability, as it easily undergoes racemization under the physiological conditions (t(1/2) = 8 h at pH 7.1, 37°C in water). Consequently, the design and synthesis of configurationally stable analogs of thalidomide continue to be an important area of research in bioorganic and medicinal chemistry. DISCUSSION: 4-trifuoromethyl thalidomide-3c was identified as an important synthetic target, which was expected to be a configurationally stable analog of thalidomide. Synthetic challenges in preparation of compound 3c were truly multipronged, considering the unique steric, electronic as well as electrostatic characteristics of trifluoromethyl group, significantly affecting properties of parent amino acids. After numerous experiments and unsuccessful attempts, both (3S,4R) and (3R, 4S) enantiomers of 4-trifluoromethyl-substituted thalidomide were effectively synthesized in six steps starting from enantio- and diastereomerically pure 3-(trifluoromethyl)pyroglutamates, prepared by highly diastereoselective Michael addition reactions between achiral glycine equivalents and chiral 3-(trifluoromethyl)acrylate. CONCLUSION: We have developed a reliable asymmetric approach for preparation of hitherto unknown 4-trifluoromethyl-substituted thalidomide in (3S,4R) and (3R,4S) enantiomerically pure forms. These thalidomide derivatives were shown to be configurationally stable and therefore may serve as useful lead compounds for the development of a new generation of thalidomide-based pharmaceuticals.
21426149 Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor deve 2010 Oct Several 'classical' protein tyrosine phosphatases are attractive therapeutic targets, including PTP1B for obesity and Type II diabetes; SHP2 for cancer and Lyp for rheumatoid arthritis. Progress has been made in identifying a broad range of chemically distinct inhibitors; however, developing selective and cell-permeable clinically useful compounds has proved challenging. Here the ongoing challenges and recent significant advances in the field are reviewed. Key novel compounds are highlighted and a perspective on the future of phosphatase inhibitor development is presented.
21245821 Amyloidosis secondary to rheumatic diseases - 16 cases. 2010 Oct INTRODUCTION: Secondary amyloidosis (SA) results of tissue deposition of an acute phase reactant protein produced by chronic inflammation. Its incidence appears to be declining, following the improvement of medical care to primary diseases. Our aim is to assess a group of Portuguese patients with amyloidosis secondary to inflammatory rheumatic diseases, and their evolution over the past 10 years. METHODS: The study comprised 16 patients with SA confirmed by tissue biopsy, hospitalized in the Rheumatology Department of Hospital São João in Oporto in the last 10 years. We made a protocol on epidemiological, clinical and analytical data focusing the rheumatic disease and SA, and possible elements of connection between them. RESULTS: Of the 16 patients, mainly women (81,2%), with mean age at entry of 56 years, 68,8% had rheumatoid arthritis. Amyloidosis was diagnosed in average at 13,5 years of primary rheumatic disease, and its main manifestation was kidney involvement, which together with infection and orthopaedic surgery or its complications, were the leading causes of hospitalization. In this time interval, 6 patients died. They were older, with longer duration and lower rate of treatment of the primary rheumatic disease, and had SA diagnosed 1,5 years before death (different of the 5 years of those that still alive). They had higher rate of gastrointestinal, neurological and serious kidney involvement, and hospitalizations. CONCLUSIONS: Improving medical care in rheumatic inflammatory diseases has reduced the incidence of SA. Also, biotherapy appears to be achieving positive results in established amyloidosis, whatever the mechanisms involved. Our data, on Portuguese patients, seems to follow this trend.
21186199 Right coronary artery fistula to the coronary sinus and right atrium associated with giant 2011 Mar We present the case of a 54-year-old female with a previous history of lung fibrosis secondary to methotrexate used for rheumatoid arthritis who was referred to cardiology evaluation due to precordial pain. Echocardiography showed biatrial enlargement with an enlarged coronary sinus and tubular image posterior to the heart. On the coronary angiogram, the right coronary artery was enlarged, and a distal fistula was identified. The patient underwent a contrast enhanced cardiac computed tomography which demonstrated an aneurysmatic right coronary artery with a distal fistula to the right atrium and coronary sinus. As the chest pain did not recur and there was a high risk of the intervention to correct coronary fistula, the patient remained on conservative treatment.
21131699 Autoimmune diseases co-existing with hepatitis C virus infection. 2010 Dec Autoimmunity and viral infections are closely associated fields, and viruses have been proposed as a likely aetiological, contributory or triggering factors of systemic autoimmune diseases. Hepatitis C virus seems to be the virus usually associated with the appearance of autoimmune diseases, and the relationship between chronic hepatitis C virus infection and some autoimmune disease has been studied. For some of these disorders their association with hepatitis C virus infection is well recognized while for others it remains probable or weak. Examples of autoimmune phenomena observed in chronic hepatitis C virus infection include rheumatoid arthritis, thyroid disease, cryoglobulinaemia, immune thrombocytopenic purpura, systemic lupus erythematosus and sjogren syndrome. To date, the etiological role and the pathogenetic involvement of the hepatitis C infection remains unknown.The aim of this study is to assess the presence of different autoimmune manifestations of hepatitis C virus infection reported in literature.
21122509 Methotrexate-induced pneumonitis in a patient with Crohn's disease. 2010 Jun Pulmonary toxicity is a well recognised but infrequent adverse event of treatment with methotrexate. The vast majority of cases have occurred in patients with rheumatoid arthritis; here we present the case of a 44-year old woman with ileo-colonic Crohn's disease who developed methotrexate pneumonitis. The patient had a 10 year history of Crohn's disease and, in the last 18 months, she was treated with oral methotrexate because of steroid-dependency and intolerance to thiopurines. She was admitted to the hospital because of acute dyspnoea, non-productive cough and fever. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity, and pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity. Blood cultures for pathogenic bacteria or fungi were negative as well as serologic tests against major pneumotropic agents. Methotrexate-induced lung injury was considered: the drug was discontinued and the patient received a steroid course with rapid symptomatic improvement. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal. To our knowledge this is the second reported case of methotrexate-induced pneumonitis occurring in a patient with Crohn's disease. A definite diagnosis has been made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings.
21107711 Interleukin-21 as a potential therapeutic target for systemic lupus erythematosus. 2011 Aug Interleukin-21(IL-21) is the most recently discovered member of the type-I cytokine family. Structurally, IL-21 shows homology to IL-2, 4, and 15 proteins. It has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. Many previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, recent work has explored the role of IL-21 in systemic lupus erythematosus (SLE). Elevated expression of IL-21 was found in the sera of patients and mice with SLE. Moreover, association of IL-21 and IL-21R polymorphisms with susceptibility to SLE have been reported. All these findings suggest that IL-21 may have promise as a potential therapeutic target for SLE. In this review, we will discuss the biological features of IL-21, the IL-21 signaling and its potential role in SLE.
21079906 Hematopoietic colony-stimulating factors: new players in tumor-nerve interactions. 2011 Apr A variety of cancers are accompanied by debilitating pain, which constitutes the primary reason for poor quality of life in cancer patients. There is an urgent demand for the development of specific mechanism-based therapies against cancer pain. Recently, important advances have been made in mechanisms contributing to cancer pain. A notable finding was that the tumor-derived hematopoietic growth factors, granulocyte- and granulocyte-macrophage-colony-stimulating factors (G-CSF/GM-CSF), subserve important functions in the generation of pain hypersensitivity in tumor-affected regions. In this context, their receptors were unexpectedly found on pain-sensing nerves and were observed to be functionally linked to nociceptive sensitization and tumor-induced pain. Here, we review evidence supporting a role for G-/GM-CSF in sensitization of pain-sensing nerves, the underlying signaling pathways and the cross-talk with other pronociceptive cytokines, peptides and modulators derived from immune cells, osteoclasts and tumor cells. These findings hold implications in the therapy of pain in disease states, such as cancer and rheumatoid arthritis.
21030559 Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers 2011 Jan 20 Levels of regulatory T cells (Tregs) are increased in different cancer types as well as in inflammatory diseases, such as rheumatoid arthritis. Treg accumulation may result from aberrant proliferation and trafficking as well as greater resilience to oxidative stress compared with conventional T cells. This enhanced antioxidative capacity of Tregs possibly serves as feedback inhibition during inflammation and prevents uncontrolled immune reactions by favoring survival of suppressor rather than effector cells. In this study, we demonstrate that human Tregs express and secrete higher levels of thioredoxin-1, a major antioxidative molecule. Thioredoxin-1 has an essential role in maintaining their surface thiol density as the first line of antioxidative defense mechanisms and is sensitive to proinflammatory stimuli, mainly tumor necrosis factor-α, in a nuclear factor-κB-dependent fashion. The antiapoptotic and oncogenic potential of (secreted) Trx-1 suggests that it may exert effects in Tregs beyond redox regulation.
20872282 Interleukin-27: biological properties and clinical application. 2010 Dec Interleukin (IL)-27 is a novel cytokine secreted by stimulated antigen-presenting cells. Initial studies on the biology of IL-27 provided evidence for its role in the initiation of T(H)1 responses; however, subsequent work has indicated that IL-27 has broad inhibitory effects on T(H)1, T(H)2, and T(H)17 subsets of T cells as well as the expansion of inducible regulatory T cells. The involvement of IL-27 in the regulation of angiogenesis and antiviral response has also recently been reported. The aim of this review is to highlight the potential areas of IL-27 clinical application, especially the management of neoplastic and viral diseases as well as autoimmune disorders, including rheumatoid arthritis and multiple sclerosis. The review will also serve to elaborate on the molecular mechanisms involved in the expression of this cytokine and signaling from the IL-27 receptor.