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ID PMID Title PublicationDate abstract
28589069 Looks Can Be Deceiving: A Case Report on Multicentric Reticulohistiocytosis Successfully T 2017 May 3 Multicentric reticulohistiocytosis (MRH) is an idiopathic multisystemic inflammatory disease characterized by symmetric erosive polyarthritis and typical papulonodular skin lesions. MRH can be associated with autoimmune diseases, malignancy, mycobacterial infections, and hyperlipidemia, and it is important to consider appropriate screening in this population. There is no specific diagnostic laboratory test for MRH. The gold standard for diagnosis is skin or synovial biopsy, which shows characteristic multinucleated non-Langerhans giant cells and ground glass eosinophilic cytoplasm. Although the disease spontaneously remits in approximately 10 years, MRH can rapidly progress to arthritis mutilans in the majority of cases. The diagnosis and treatment are challenging due to its low prevalence and lack of robust guidelines from major rheumatological societies. Corticosteroids and methotrexate are generally first-line treatment options. However, more recently, biologic agents have been increasingly used in refractory cases with some success. Early diagnosis is crucial in preventing disease progression. We report a case of MRH in a patient whose clinical presentation mimicked rheumatoid arthritis and was subsequently treated successfully with rituximab.
28421999 Use and withdrawal of immunosuppressors in primary Sjögren's syndrome. 2018 May OBJECTIVES: To assess the use and causes of withdrawal of glucocorticoids and immunosuppressors among patients with primary Sjögren's syndrome (pSS) in the clinical setting. METHODS: We retrospectively reviewed the medical records of 155 pSS patients and registered demographics, glandular/extraglandular features, serological data, cumulative ESSDAI and SSDDI. A single rheumatologist attributed the indication and cause of withdrawal of glucocorticoids and immunosuppressors. RESULTS: 92.2% of the patients were female, mean age 57.4±14.7 years and median follow-up 11 years. One hundred and four (67%) patients received glucocorticoids and/or immunosuppressors: 3.8% only glucocorticoids, 43.9% only immunosuppressors and 56.5% their combination. The most used drugs were antimalarials (46.4%), prednisone (36.7%), azathioprine (AZA) (23.8%) and methotrexate (MTX) (18%). At the multivariate analysis, the presence of non-erosive arthritis OR 5.02 (95% CI 1.74-14.47, p=0.003) and the median cumulative ESSDAI score OR 1.10 (95% CI 1.03-1.17, p=0.002) were associated with the use of these drugs. The causes of withdrawal were: 39% improvement, 35.2% patient's own decision, 18.1% toxicity and 11% lack of efficacy. We found toxicity in 14.2% MTX users, 9.7% for AZA, 9.7% for antimalarials and 7.6% for cyclophosphamide. CONCLUSIONS: More than half the patients received glucocorticoids and/or immunosuppressors and a not negligible number decided on their own to suspend them, alerting physicians of secondary adverse events and tolerability.
30064602 Subcutaneous Granuloma Annulare. 2017 Dec Dear Editor, Subcutaneous granuloma annulare (SGA) is considered a rare clinical variant of granuloma annulare, a common self-healing chronic inflammatory disorder that may appear in childhood as well as in adult age (1-3). A 29-year-old female patient reported the onset of several small subcutaneous nodules on the dorsal aspect of the second interphalangeal joint of the left medius finger and the left elbow, accompanied by vague joint pain, had occurred 13 years ago. Specific markers for rheumatoid arthritis were negative, leading to a diagnosis of sero-negative rheumatoid arthritis, for which treatment with methotrexate was initiated. No clinical benefit was obtained and the treatment was abandoned. New nodules continued to appear on several distal joints of the fingers of both hands and, in the last 6 months, on the second right toe. The course of the disease included spontaneous remission of some of the nodules. Personal medical history was significant for a thyroid nodule, surgically removed at the age of 22. A general physical exam did not reveal pathological changes. A clinical dermatological exam at the time of presentation revealed several round to oval, deep subcutaneous, indurated, asymptomatic, discreetly pigmented lesions with a diameter of 4-6 mm, located on the dorsal aspect of the interphalangeal joints of the fingers of both hands (Figure 1) and the second right toe. Hematologic and biochemical tests were within normal limits, as well as the serological tests for rheumatoid factor, ANCA, ANA, and anti-CCP antibody. Hand radiographs did not show geodes, marginal erosions, or narrow joint spaces. A pathological exam of a subcutaneous nodule showed focally altered collagen surrounded by fibroblasts, phagocytes, rare lymphocytes, and neutrophils, as well as small capillaries (Figures 2-5), compatible with the diagnosis of a pseudorheumatoid nodule or benign rheumatoid nodule in the clinical and paraclinical context. SGA is considered a rare clinical and histological variant of granuloma annulare that predominantly affects children and occasionally young adults (1-6). In 1941, Ziegler first described a case of subcutaneous nodules that appeared concomitantly with classical cutaneous lesions of granuloma annulare, as well as the histological aspect of these nodules similar to that of rheumatoid nodules (RN) (7). Since then, several case reports in the literature refer to the subcutaneous lesions of GA as "pseudorheumatoid nodules", "deep granuloma annulare" or "palisading granuloma" (3,4,8). Most reported cases of SGA occur in the first three decades of life: 98% according to Muhlemann, 79% according to Andersen and Verdich, 62% according to Studer; most cases occur in children between 2 and 6 years of age (9). Lesions often regress spontaneously, but recurrences are common in 19%-75% of the patients, often on the same anatomical areas (9,10). Reported SGA cases in adult patients predominantly affected women, and typically involved multiple lesions located on the hands, feet, ankles, and inferior pretibial area (4-6). The etiology and pathogenesis of SGA are not completely understood. Precipitating factors such as insect bites, infections with Borellia spp., herpetic virus, EBV, Streptococcus spp., PUVA-therapy, several drugs, physical trauma, acute phlebitis, and post-surgery sepsis have been considered (8). There is evidence for the pathogenic involvement of an immunological mechanism, possibly a delayed type hypersensitivity reaction mediated by T-cells that triggers a panniculitis-type inflammatory response (8,10). Correlations between SGA and systemic diseases such as diabetes mellitus, sarcoidosis, HIV infection, or autoimmune diseases have not been found (8). A positive diagnosis of pseudorheumatoid nodules relies on clinical and anamnestic data. Differential diagnosis includes rheumatoid nodules, benign rheumatoid nodules, foreign body reactions, hematomas, abscesses, and infectious granulomas (3,5). Pseudorheumatoid nodules and SGA have a low risk of progression to a systemic connective tissue disorder. In the presence of subcutaneous nodular lesions with an uncertain clinical diagnosis, cutaneous biopsy, hematological and immunological tests, and imaging may be performed to establish a positive diagnosis. Skin biopsy is the most useful test for the diagnostic approach because, even though it is sometimes difficult to interpret, a pathological exam may offer important data to distinguish between rheumatoid and pseudorheumatoid nodules. Necrobiosis may be identified in the deep dermis and subcutaneous tissue, and rarely in the deep soft tissues. Necrobiosis is less important and less deep than in rheumatoid nodules, as well as less extensive and less diffuse than in lipoidic necrobiosis (6). Anomalies in the morphology of the deep cutaneous structures may coexist with typical changes in classical granuloma annulare. Immunohistochemical studies using specific histiocyte markers such as CD68/PGM1 proved to be occasionally useful in differentiating SGA from other granulomatous conditions (11). Several tests are necessary to exclude an association with a systemic disease: hemoleucogram (absence of leucocytosis), ESR (normal values), acute phase reactants (negative fibrinogen, RCP), autoantibodies (negative ANA), and rheumatoid factor (negative). SGA is a benign disorder with esthetic implications and sometimes functional impairment. Surgical excision is only required for juxta-articular nodules causing functional impairment. Partial therapeutic benefit was reported after the administration of dapsone, clorambucil, isotretinoin, potassium iodide, or intralesional/topical steroids. Even though the risk of systemic involvement is low, periodical follow-up of these patients is required given the reported cases of associated systemic connective tissue disorders (8,12).
29208331 Autoimmune and medication-induced lymphadenopathies. 2018 Jan This article will provide a discussion of some common autoimmune disorders that could affect the lymph nodes and potentially mimic B and T-cell lymphomas. Some of these disorders are more characteristic of individuals in the pediatric age group (autoimmune lymphoproliferative syndrome, Kawasaki disease), while others present in older individuals (rheumatoid arthritis, lupus erythematosus, sarcoidosis). A common finding that groups all of these disorders together is the overall relative preservation of the architecture, a feature that can be particularly helpful to distinguish them from many B and T-cell lymphomas. Another area of interest, that will be discussed in this review, is the pathologic manifestations that can be present in lymph nodes secondary to medications. Such alterations range from 'reactive' forms of follicular, interfollicular or paracortical hyperplasia, to specific B and T-cell lymphoproliferative disorders (particularly documented in association with methotrexate and TNF-inhibitors).
29222448 Effect of Qianghuo Erhuang Decoction on T Regulatory and T Helper 17 Cells in Treatment of 2017 Dec 8 QianghuoErhuang Decoction (QED) is an effective recipe in treating rheumatoid arthritis. The present study aimed to explore the effects of QED on Treg and Th17 in adjuvant arthritis (AA) model. The study included 6 group rats: normal control group, AA group, AA + methotrexate (MTX) group, AA + high, moderate, and low dose QED groups. The arthritis score was significantly decreased in the MTX and high-dose QED groups compared with the AA group on days 24 and 28 (P < 0.01), respectively. The synovial tissue inflammation was attenuated by histological observation, and the proliferation of splenocytes was significantly inhibited in MTX and high-dose QED groups (P < 0.01). High-dose QED can up-regulated the percentage of Treg cells (P < 0.01) and down-regulated the percentage of Th17 cells (P < 0.05). Notably, the serum levels of IL-6, IL-17 and TNF-α were significantly decreased, while TGF-β levels were apparently elevated compared with AA group (P < 0.05, P < 0.01). Interestingly, moderate and low-dose QED had no such similar effects. In summary, high-dose QED had a therapeutic effect against adjuvant arthritis and regulated the related cytokine levels in serum. The underlying mechanism might be mediated via restoration of the imbalance in CD4(+) T lymphocyte subsets, Treg/Th17.
29181029 Incidence and Risk Factors for Infections Requiring Hospitalization, Including Pneumocysti 2017 OBJECTIVE: Rheumatoid arthritis (RA) may be complicated by different infections, but risk factors for these are not fully elucidated. Here, we assessed the incidence of and risk factors for infections requiring hospitalization (IRH) including pneumocystis pneumonia (PCP) in patients with RA. METHODS: We retrospectively surveyed all RA patients treated at our hospital from 2009 to 2013, for whom data were available on demographic features, medications, comorbidities, and severity of RA. Multivariate logistic regression analysis was applied to calculate adjusted odds ratios (ORs) for factors associated with the occurrence of IRH. RESULTS: In a total of 9210 patient-years (2688 patients), there were 373 IRH (3.7/100 patient-years). Respiratory tract infections were most frequent (n = 154, and additionally 16 PCP), followed by urinary tract infections (n = 50). Significant factors for PCP included higher age (≥70 years; OR 3.5), male sex (6.6), underlying lung disease (3.0), use of corticosteroids (4.8), and use of biologics (5.4). Use of methotrexate (5.7) was positively associated with PCP but negatively with total infections (0.7). Additionally, functional disorders and higher RA disease activity were also related to total infections. CONCLUSIONS: Risk factors for infection should be taken into account when deciding treatment for the individual RA patient.
28418334 Juvenile Idiopathic Arthritis. 2017 Apr 5 Juvenile idiopathic arthritis is the most common chronic rheumatic disease of unknown aetiology in childhood and predominantly presents with peripheral arthritis. The disease is divided into several subgroups, according to demographic characteristics, clinical features, treatment modalities and disease prognosis. Systemic juvenile idiopathic arthritis, which is one of the most frequent disease subtypes, is characterized by recurrent fever and rash. Oligoarticular juvenile idiopathic arthritis, common among young female patients, is usually accompanied by anti-nuclear antibodie positivity and anterior uveitis. Seropositive polyarticular juvenile idiopathic arthritis, an analogue of adult rheumatoid arthritis, is seen in less than 10% of paediatric patients. Seronegative polyarticular juvenile idiopathic arthritis, an entity more specific for childhood, appears with widespread large- and small-joint involvement. Enthesitis-related arthritis is a separate disease subtype, characterized by enthesitis and asymmetric lower-extremity arthritis. This disease subtype represents the childhood form of adult spondyloarthropathies, with human leukocyte antigen-B27 positivity and uveitis but commonly without axial skeleton involvement. Juvenile psoriatic arthritis is characterized by a psoriatic rash, accompanied by arthritis, nail pitting and dactylitis. Disease complications can vary from growth retardation and osteoporosis secondary to treatment and disease activity, to life-threatening macrophage activation syndrome with multi-organ insufficiency. With the advent of new therapeutics over the past 15 years, there has been a marked improvement in juvenile idiopathic arthritis treatment and long-term outcome, without any sequelae. The treatment of juvenile idiopathic arthritis patients involves teamwork, including an experienced paediatric rheumatologist, an ophthalmologist, an orthopaedist, a paediatric psychiatrist and a physiotherapist. The primary goals of treatment are to eliminate active disease, to normalize joint function, to preserve normal growth and to prevent long-term joint damage. Timely and aggressive treatment is important to provide early disease control. The first-line treatment includes disease-modifying anti-rheumatic drugs (methotrexate, sulphasalazine, leflunomide) in combination with corticosteroids, used in different dosages and routes (oral, intravenous, intra-articular). Intra-articular application of steroids seems to be an effective treatment modality, especially in monoarthritis. Biological agents should be added in the treatment of unresponsive patients. Anti-tumour necrosis factor agents (etanercept, infliximab, adalimumab), anti-interleukin-1 agents (anakinra, canakinumab), anti- interleukin-6 agents (tocilizumab) and T-cell regulatory agents (abatacept) have been shown to be safe and effective in childhood patients. Recent studies reported sustained reduction in joint damage with even complete clinical improvement in paediatric patients, compared to previous data.
28349925 Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induc 2017 Mar 28 T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4(+) helper T (Th) cell and CD8(+) cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1β, TNF-α and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway.
28708978 Methotrexate, combined with cyclophosphamide attenuates murine collagen induced arthritis 2017 Oct To explore the mechanism of methotrexate (MTX) and its combination with cyclophosphamide (CTX) in collagen-induced arthritis (CIA), we investigated the levels of several immune cells and cytokines in mice with different treatments. CIA was induced in DBA/1 mice at the age of 7 weeks by primary immunization with 100μl emulsion containing 2mg/ml bovine type II collagen which was mixed with complete Freund's adjuvant (CFA). The booster immunization was performed with 50-100μl emulsion containing 2mg/ml bovine type II collagen (CII) mixed with incomplete Freund's adjuvant (IFA). MTX, CTX or both were administrated after the booster immunization. Therapeutic effect was evaluated by arthritic scores, X-rays and assessment of histopathological joint destruction. The expression of TNF-α, IL-6, IL-23, IL-10 were also measured. The frequencies of different immune cell subsets in the lymph node, spleen and bone marrow were determined by flow cytometry analysis. Our results showed that CTX and MTX treatment attenuated the severity of arthritis of CIA mice and reduced the levels of several cytokines. CTX and MTX treated mice showed a lower frequency of B cells in bone marrow. Also, when treated the CIA mice with MTX, alone or together with CTX, the lymph nodes and spleen exhibited a decrease in regulatory B cells (Breg) and dendritic cells (DCs). Notably, the combination of MTX and CTX had a more pronounced effect. By measuring the levels of different immune cells those participated in the development of rheumatoid arthritis (RA), our experiment may help to evaluate the therapeutic effects and prognosis of arthritic diseases.
28877615 Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, wit 2018 May Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.
27307501 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. 2017 Jan OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. RESULTS: We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
28913747 Primary Sjögren's syndrome: Extraglandular manifestations and hydroxychloroquine therapy. 2017 Nov The use of hydroxychloroquine (HCQ) in Primary Sjögren's Syndrome (pSS) has been assessed in different studies over the last years, with conflicting results regarding its efficacy in sicca syndrome and extraglandular manifestations (EGM). The goal of this study was to compare the incidence rate of EGM in pSS patients with and without HCQ therapy.We performed a multicenter retrospective study, including patients with pSS (European classification criteria) with at least 1 year of follow-up. Subjects with concomitant fibromyalgia, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis were excluded. Demographics and pSS characteristics were recorded. The EGM were defined by EULAR-SS disease activity index (ESSDAI). Patients were divided into two groups according to their use or not of HCQ therapy. We evaluated the use of HCQ and its relationship to EGM. HCQ therapy was defined as the continuous use of the drug for at least 3 months. A descriptive analysis of demographics and pSS characteristics was performed. We compared the incidence of EGM between groups defined by HCQ therapy using chi(2) test or Fisher's exact test. A total of 221 patients were included (97.3% women), mean age, 55.7 years (SD 14). Mean age at diagnosis, 48.8 years (SD 15); median disease duration, 60 months (IQR 35-84). One hundred and seventy patients (77%) received HCQ. About half of the patients had at least one EGM during the course of the disease, 20% of them developed an EGM before the onset of the sicca syndrome and 26% simultaneously with dryness symptom. Overall, EGM were less frequent in those on HCQ therapy (36.5% vs 63.5%, p < 0.001). Considering each EGM individually, the following manifestations were more frequent in the non-treated group: arthritis (p < 0.001), fatigue (p < 0.001), purpura (p = 0.01), Raynaud phenomenon (p = 0.003), and hypergammaglobulinemia (p = 0.006). Immunosuppressive treatment was indicated on 28 patients (12.7%), 13 of which were receiving also HCQ. The first reason for those treatments was the presence of arthritis in 12/28 patients (42.8%), and the drug used in all the cases was methotrexate. Only three patients required immunosuppressive therapy with cyclophosphamide, due to the presence of glomerulonephritis, vasculitis, and interstitial lung disease. None of the patients received biologic therapy. The lower incidence of EGM was observed in patients on HCQ therapy supports its efficacy in pSS. However, further large scale prospective studies are needed to confirm these findings.
28155935 Folate binding protein: therapeutic natural nanotechnology for folic acid, methotrexate, a 2017 Feb 16 Blood serum proteins play a critical role in the transport, biodistribution, and efficacy of systemically-delivered therapeutics. Here, we have investigated the concentration- and ligand-dependent aggregation of folate binding protein (FBP), focusing in particular on folic acid, an important vitamin and targeting agent; methotrexate, an antifolate drug used to treat cancer and rheumatoid arthritis; and leucovorin which is used to decrease methotrexate toxicity. We employed atomic force microscopy to characterize, on a particle-by-particle basis, the volumes of the FBP nanoparticles that form upon ligand binding. We measured the distribution of FBP nanoparticle volumes as a function of ligand concentration over physiologically- and therapeutically-relevant ranges. At physiologically-relevant concentrations, significant differences in particle volume distributions exist that we hypothesize are consistent with different trafficking mechanisms for folic acid and methotrexate. In addition, we hypothesize leucovorin is trafficked and delivered like folic acid at therapeutically-relevant concentrations. We propose that changes in dosing procedures could improve the delivery and therapeutic index for methotrexate and other folic acid-targeted drug conjugates and imaging agents. Specifically, we suggest pre-binding the drugs to FBP may provide a better formulation for drug delivery of methotrexate for both cancer and rheumatoid arthritis. This would be analogous to pre-binding paclitaxel to albumin, which is already used in the clinic.
27934678 Incidence of hepatitis B virus reactivation in patients with resolved infection on immunos 2017 Jun BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.
29103180 Safety of weekly adalimumab in the treatment of juvenile idiopathic arthritis and pediatri 2018 Feb Weekly adalimumab dosing is used to treat juvenile idiopathic arthritis (JIA), uveitis, and other pediatric rheumatic diseases, but the safety of such dosing has not previously been studied. A retrospective chart review was conducted to assess the safety of weekly adalimumab. Demographic and clinical data were collected. Basic descriptive analysis was performed to assess for adverse events from weekly adalimumab. Sixty-nine patients at the University of Minnesota or Gillette Children's Hospital were identified as treated with weekly adalimumab. Sixty (87%) were eligible for the chart review. Weekly adalimumab was used most commonly to treat uveitis (28%, 17/60) and rheumatoid factor-negative polyarticular JIA (25%, 15/60). Mean age at the start of weekly dosing was 13.9 years. The majority of patients were concurrently treated with a non-steroidal anti-inflammatory drug and methotrexate. Fifty-three (90%) patients continued weekly dosing for greater than 3 months. The mean duration of weekly adalimumab was 2 years. Throughout the duration of weekly dosing, 24/60 (40%) patients had documented minor infections not requiring antimicrobials and 24/60 (40%) had documented infections requiring antimicrobial treatment. Only three patients (5%) had an infection requiring hospitalization. Two patients (3%) developed autoimmune disease. Laboratory abnormalities and injection site reactions were rare. Weekly adalimumab was used most commonly to treat uveitis and rheumatoid factor-negative polyarticular JIA, and mean duration of weekly dosing was 2 years. Serious adverse events were rare.
27751863 Impact of genetic variants of ATP binding cassette B1, AICAR transformylase/IMP cyclohydro 2017 Nov OBJECTIVE: To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolatereductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamatesynthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX). PATIENTS AND METHODS: We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient. RESULTS: When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0 U/L; P<.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (-0.67±0.32; 0.038), hemoglobin (-0.34±0.11g/dL; P=.002), and platelet (-11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX. DISCUSSION: Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity.
30489710 2017 May Sarilumab (Kevzara) for subcutaneous (SC) injection is a fully human immunoglobulin G1 monoclonal antibody that binds specifically to both soluble and membrane-bound interleukin-6 receptors inhibiting interleukin-6 mediated signalling. It is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more biologic or non-biologic disease-modifying antirheumatic drugs (DMARDs). Sarilumab is available in 150 mg and 200 mg single-use pre-filled syringes for SC injection. The recommended dose of sarilumab is 200 mg SC injection every two weeks, with a reduction to 150 mg every two weeks for management of neutropenia, thrombocytopenia, and elevated liver enzymes. Sarilumab should be given in combination with methotrexate or other conventional DMARD but may be used as monotherapy in cases of intolerance or contraindication to methotrexate or DMARDs. The manufacturer has submitted a price of $700 per pre-filled syringe (for both 150 mg and 200 mg doses) resulting in an annual cost of $18,200 per patient. [Table: see text]
28371797 Real-life effectiveness of Golimumab in biologic-naïve patients with rheumatoid arthritis 2017 Jun OBJECTIVES: To assess the effectiveness of subcutaneous Golimumab 50 mg/monthly combined with methotrexate (SC GLM + MTX) over 52 weeks of treatment, in biologic-naïve RA patients, in a multicentre nationwide cohort from the Rheumatic Diseases Portuguese Register (Reuma.pt). METHODS: Data for this observational study was collected from March 2011 to August 2015. Disease activity (DAS28), functional capacity (HAQ) and Patient Global Disease Assessment (PGDA) were measured at baseline and weeks 12, 24 and 52 of treatment. The primary objective was clinical remission over 52 weeks (1 year) and secondary objectives were: functional response and functional remission over 52 weeks, variation of individual components of DAS over time and treatment persistence at week 52. Comparison between baseline variables of subjects with and without clinical remission was performed. The SC GLM + MTX persistence rate was estimated by the Kaplan-Meier analysis. Cox proportional hazard model approach was used to evaluate predictive factors of persistence, response and remission. RESULTS: A total of 109 patients were enrolled in the study: 94 (86.2%) female, mean age 55.5±13.2 years, mean age at diagnosis 45.5±13.5 years, mean age at beginning of treatment with biologic agents 53.1±13.1 years; 78.1% positive for serum rheumatoid factor. All patients were biologic-naïve and had active disease, despite previous treatment with conventional DMARDs. At the time of this analysis, 93 patients had a follow-up time of at least 52 weeks (i.e. started treatment before August 2014). Of this group, 38.3% achieved clinical remission, 91.9% functional response and 35.2% functional remission, over 52 weeks. Treatment persistence was 75.3% at 1 year. Disease activity indices were all statistically significantly lower at 12, 24 and 52 weeks when compared to baseline. Older age at diagnosis was associated to a lower probability of clinical remission (HR= 0.96, p= 0.031) whereas higher C-reactive protein baseline levels were associated with a lower probability of functional response (HR= 0.54; p= 0.026). CONCLUSIONS: Golimumab 50 mg + MTX showed effectiveness in the treatment of patients with active RA, in accordance to what previously observed in clinical trials. A consistent and significant decrease in RA disease activity through 52 weeks of treatment and a significant functional improvement were observed, as well as a high persistence on treatment.
28396011 Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhi 2017 Apr Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis.
29158925 Splenic Infarct and Pulmonary Embolism as a Rare Manifestation of Cytomegalovirus Infectio 2017 Cytomegalovirus (CMV) is a type of herpes infection that has a characteristic feature of maintaining lifelong latency within the host cell. CMV manifestations can cover a broad spectrum from fever to as severe as pancytopenia, hepatitis, retinitis, meningoencephalitis, Guillain-Barre syndrome, pneumonia, and thrombosis. Multiple case reports of thrombosis associated with CMV have been reported. Deep vein thrombosis or pulmonary embolism is more common in immunocompetent patients while splenic infarct is more common in immunocompromised patients. However, here we report a female patient on low-dose methotrexate for rheumatoid arthritis who presented with both pulmonary embolism and splenic infarct.