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ID PMID Title PublicationDate abstract
33744307 Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patien 2021 Jul BACKGROUND & AIMS: We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. METHODS: Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n = 461), methotrexate (n = 171), tumor necrosis factor (TNF) α antagonists (n = 1082), or non-TNF-targeting biologic agents (n = 132) vs fathers not exposed to any of these medications (n = 5607). RESULTS: As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. CONCLUSIONS: In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.
33596941 Tibia stress injury and the imaging appearance of stress fracture in juvenile dermatomyosi 2021 Feb 17 BACKGROUND: Tibial stress injuries are frequent injuries of the lower extremity and the most common causes of exercise-induced leg pain among athletes and military recruits. They sometimes occur in patients with pathological conditions of bone metabolism such as osteoporosis or rheumatoid arthritis, but there are previously no cases reported in juvenile dermatomyositis (JDM). Here we report 6 JDM patients who presented with shin pain, and the imaging appearance of tibial stress fractures or stress reactions. CASE PRESENTATION: All 6 patients with JDM presented with shin pain or tenderness in the anterior tibia without any evidence of excessive exercise or traumatic episode. They were diagnosed with tibial stress injuries based on a combination of radiographs, three-phase bone scans, and magnetic resonance imaging (MRI), and 5 out of 6 patients had been treated with prednisone and/or methotrexate at onset of tibial stress injuries. In one patient, we could not find any abnormalities in his radiograph, but the subsequent MRI showed tibial stress reaction. In all 6 patients, the tibial stress injuries improved with only rest and/or analgesics. CONCLUSION: We experienced 6 children with JDM who presented with shin pain, and who were diagnosed with tibial stress fractures or stress reactions. Their underlying disease and weakness, treatment with glucocorticoid and methotrexate, or inactivity may have resulted in these tibial injuries, and made these patients more predisposed than other children. In addition to preventing JDM patients from getting osteoporosis, we need to consider stress reactions when children with JDM complain of sudden shin pain.
33515067 Does methotrexate cause progressive fibrotic interstitial lung disease? A systematic revie 2021 Jun The aim is to evaluate the published evidence on whether methotrexate (MTX) use causes progressive fibrotic interstitial lung disease (fILD). This PRISMA-compliant systematic review has been registered electronically with PROSPERO 2018 ID CRD42018087838, Centre of review and dissemination at the University of York. A total of 29 articles met the inclusion criteria. Thirteen articles were found to support the claim that MTX causes fILD. They all had a low Downs and Black quality score (< 6/27). Their 'risk of bias' assessment scores indicated serious to critical risk of bias. The 16 articles rejecting the claim that MTX causes fILD were of higher quality as indicated by their Downs and Black score. Their 'risk of bias' assessment scores suggested only a low to moderate risk of bias. This systematic literature review supports the finding that MTX does not cause fILD in humans. Three studies suggest that MTX treatment may actually improve outcomes in patients with rheumatoid arthritis (RA) associated fILD by slowing down ILD progression.
32519348 Clinical outcomes in T-cell large granular lymphocytic leukaemia: prognostic factors and t 2021 Feb T-cell large granular lymphocytic leukaemia (T-LGLL) is an incurable leukaemia characterised by clonal proliferation of abnormal cytotoxic T cells that can result in severe neutropenia, transfusion-dependent anaemia and pancytopenia requiring treatment. The most commonly used agents, methotrexate (MTX), cyclophosphamide (Cy) and cyclosporine primarily produce partial remissions (PRs), with few complete responses (CRs). We evaluated the clinical course and treatment response of 60 consecutive patients with T-LGLL to evaluate clinical outcomes and future potential treatment directions. Impaired overall survival was noted among male patients, patients with elevated lactate dehydrogenase, and those without rheumatoid arthritis. Cy was the most efficacious second-line agent, with a 70% overall response rate (ORR; three CR, four PR). All patients who failed frontline MTX responded to second-line Cy. In the relapsed or Cy-refractory setting, alemtuzumab (n = 4) and pentostatin (n = 3) had an ORR of 50% and 66%, respectively, while duvelisib induced a long-term response in one patient. In this large, retrospective analysis, our results suggest Cy is a highly effective therapy for second-line treatment in T-LGLL and should be considered a strong candidate for up-front therapy in select high-risk patients. Prospective studies evaluating pentostatin, alemtuzumab and novel agents, such as duvelisib, are needed for patients with relapsed/refractory T-LGLL.
34875493 Simultaneous measurement of upadacitinib and methotrexate by UPLC-MS/MS and its pharmacoki 2022 Jan 1 Upadacitinib, as a selective and reversible Janus kinase (JAK) inhibitor, has been widely used in the treatment of atopic dermatitis, ulcerative colitis and other inflammatory bowel diseases and other immune-mediated diseases. The combination of methotrexate and upadacitinib is a common clinical treatment strategy for rheumatoid arthritis (RA) in recent years. In this study, we established an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for quantitative measurement of upadacitinib and methotrexate, by which we successfully determined pharmacokinetic parameters of them in rat plasma. In order to pretreat the samples, we used acetonitrile as the precipitant, and for the internal standard (IS), we chose tofacitinib. The Acquity BEHC18 (2.1 mm × 50 mm, 1.7 μm) column, with acetonitrile and 0.1% formic acid aqueous solution composed mobile phases, was used to separate upadacitinib, methotrexate and tofacitinib. A Xevo TQ-S triple quadrupole tandem mass spectrometer was used as the detecting instrument in the positive ion mode. For upadacitinib, excellent linearity was shown of this assay in the calibration range with 0.1-200 ng/mL, and as for methotrexate, the range was 0.05-100 ng/mL. As the results indicated, the lower limit of quantification (LLOQ) was respectively 0.1 and 0.05 ng/mL for upadacitinib and methotrexate, the intra- and inter-day precision were ≤ 13.3%, and the accuracy of all the analytes ranged from -4.1% to 12.7%. The recovery of each analyte was > 80.2% in this experiment, and matrix effects we observed were unobvious. The establishment of this method and its successful application in rat plasma can provide a theoretical and technical support for the deeper study of pharmacodynamics and the clinical medication strategies.
33388058 Cessation of methotrexate and a small intestinal resection provide a good clinical course 2021 Jan 2 BACKGROUND: Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported. CASE PRESENTATION: We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels. CONCLUSION: We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
33691801 Association of homocysteine with ankylosing spondylitis: a systematic review and meta-anal 2021 Mar 10 BACKGROUND: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. METHODS: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. RESULTS: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = - 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. CONCLUSION: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. TRIAL REGISTRATION: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426 .
34427158 Enhancement of anti-TNFα monoclonal antibody production in CHO cells through the use of U 2022 Recently, there has been a high demand for anti-tumor necrosis factor-α monoclonal antibodies (mAbTNFα) in the treatment of rheumatoid arthritis and other autoimmune diseases. Thus, efficient strategies and stable high-producing cell lines need to be established to increase antibody production. In this study, we describe an efficient approach to establish a mAbTNFα high-producing clone through the optimization of expression vectors and cell culture media. The ubiquitous chromatin opening element (UCOE) and dihydrofolate reductase (DHFR)-based vectors encoding mAbTNFα were introduced into the CHO-DG44 cells using lipofection. Clones were obtained by selecting transfected cells with G418, amplifying them by treatment with methotrexate, and isolating them by limiting dilution. Different media formulated with commercial feeds and media were also screened to develop an improved medium. The antibody produced by the selected clone was purified, characterized, and compared to standard adalimumab. Using our established protocol, a cell clone obtained from stable mAbTNFα-expressing cell pools showed a 3.8-fold higher antibody titer compared to stable cell pools. Furthermore, the highest antibody yield of selected clones cultured in fed-batch mode using improved medium was 2450 ± 30 µg/mL, which was 13.2-fold higher than that of stable cell pool cultivated in batch mode using a basal medium. The purified antibody had primary chemical and biological characteristics similar to those of adalimumab. Therefore, the use of UCOE and DHFR vectors in combination with the optimization of cell culture media may help in establishing stable and high-producing CHO cell lines for therapeutic antibody production.
33461449 Preparation and Formulation Optimization of Methotrexate-loaded Human Serum Albumin Nanopa 2021 BACKGROUND: Methotrexate (MTX) is the representative drug among the disease- modifying anti-rheumatic drugs. However, the conventional treatment with MTX showed many limitations and side effects. OBJECTIVE: To strengthen the targeting ability and circulation time of MTX in the treatment of rheumatoid arthritis, the present study focused on developing a novel drug delivery system of methotrexate-loaded human serum albumin nanoparticles (MTX-NPs) modified by mannose, which are referred to as MTX-M-NPs. METHODS: Firstly, mannose-derived carboxylic acid was synthesized and further modified on the surface of MTX-NPs to prepare MTX-M-NPs. The formulation of nanoparticles was optimized by the method of central composite design (CCD), with the drug lipid ratio, oil-aqueous ratio, and cholesterol or lecithin weight as the independent variables. The average particle size and encapsulation efficiency were the response variables. The response of different formulations was calculated, and the response surface diagram, contour diagram, and mathematical equation were used to relate the dependent and independent variables to predict the optimal formula ratio. The uptake of MTX-M-NPs by neutrophils was studied through confocal laser detection. Further, MTX-M-NPs were subjected to assessment of the pharmacokinetics profile after intravenous injection with Sprague-Dawley rats. RESULTS: This targeting drug delivery system was successfully developed. Results from Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy analysis can verify the successful preparation of this drug delivery system. Based on the optimized formula, MTX-M-NPs were prepared with a particle size of 188.17 ± 1.71 nm and an encapsulation rate of 95.55 ± 0.33%. MTX-M-NPs displayed significantly higher cellular uptake than MTX-NPs. The pharmacokinetic results showed that MTX-M-NPs could prolong the in vivo circulation time of MTX. CONCLUSION: This targeting drug delivery system laid a promising foundation for the treatment of RA.
34670840 TNFi is associated with positive outcome, but JAKi and rituximab are associated with negat 2021 Oct INTRODUCTION: Several risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor. METHODS: Data from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model. RESULTS: 2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome. CONCLUSION: General risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity-even without glucocorticoids-have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.
33169195 Nodal EBV-positive polymorphic B cell lymphoproliferative disorder with plasma cell differ 2021 May Plasma cell differentiation (PCD) is frequently observed in some entities of non-Hodgkin B cell lymphoma, including both low-grade and high-grade lymphomas. However, except for plasmablastic lymphoma and primary effusion lymphoma, EBV(+) B cell lymphoproliferative disorder (LPD) with PCD has not been well addressed due to its rarity. We clinicopathologically examined five cases of nodal EBV(+) polymorphic B cell LPD with PCD (PBLPD-PCD) initially diagnosed as polymorphic EBV(+) diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) with PCD (n = 3) and methotrexate-associated B cell LPD (MTX-associated B-LPD) (n = 2). One case had a concomitant brain lesion which was clinically diagnosed as EBV-related encephalitis. This patient received therapy with vidarabine, and both the brain lesion and the nodal EBV(+) PBLPD-PCD lesions disappeared. Another case was characterized by Mott cell differentiation. This case was the first reported case of EBV(+) B cell lymphoma or LPD with Mott cell differentiation. The two cases of MTX-associated B cell LPD which arose in patients with rheumatoid arthritis spontaneously regressed after MTX cessation. TCRγ and IGH PCR analysis was performed in four cases. Two cases had TCRγ rearrangements, but no IGH rearrangements. The other two cases had no rearrangements in these genes. We concluded that nodal EBV(+) PBLPD-PCD is rare, with heterogeneous characteristics. PCR analysis revealed that nodal EBV(+) PBLPD-PCD may have only TCR clonality and no IGH clonality. Considering the partial or complete loss of CD20 expression on the tumor cells, this result may be confusing for accurate diagnosis of EBV(+) PBLPD-PCD, and pathologists need to be aware of this phenomenon to avoid misdiagnosis.
34136195 Antioxidant vitamins promote anticancer effects on low-concentration methotrexate-treated 2021 Jun Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.
30000400 Methotrexate. 2006 Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy with methotrexate. An abstinence period of at least 1 week after chemotherapy doses of methotrexate has been suggested.[1] Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[2] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.[3] Maternal doses of methotrexate up to 92 mg (1.12 mg/kg) produce low levels in milk, leading some authors to state that low single or weekly doses, such as those used for ectopic pregnancy or rheumatoid arthritis, are of low risk to the breastfed infant,[4-8] although some expert opinion warns against this use.[9-13] Withholding breastfeeding for 24 hours after a weekly low dose of methotrexate may decrease the infant's dose by 40%.[14-16] If breastfeeding during long-term, low-dose methotrexate use is undertaken, monitoring of the infant's complete blood count and differential could be considered.
33957974 Identification of neutrophil β2-integrin LFA-1 as a potential mechanistic biomarker in AN 2021 May 6 BACKGROUND: Leukocyte activation by anti-neutrophil cytoplasmic antibody (ANCA) and the subsequent leukocyte-endothelium interaction play a key role in the development of endothelial damage in ANCA-associated vasculitis (AAV). In contrast to that of leukocyte activation, the exact role of the leukocyte-endothelium interaction via integrin remains unclear. Here, we performed microarray and validation analyses to explore association between the expression levels of lymphocyte function-associated antigen-1 (LFA-1) and the clinical characteristics of patients with AAV. METHODS: We performed gene set enrichment analysis (GSEA) to identify the functional gene sets differentially expressed between patients with AAV and other types of vasculitis and the healthy controls (HCs). Flow cytometry was performed to validate the GSEA results. Treatment-naïve patients were monitored until 24 weeks of treatment. To examine the role of LFA-1 in the neutrophil-endothelium interaction, we performed a leukocyte adhesion and transmigration assay using peripheral blood and human umbilical vein endothelial cells (HUVECs). RESULTS: GSEA revealed that the molecular pathways involving integrin-related genes were significantly upregulated in patients with AAV compared to that in patients with other types of vasculitis and the HCs. Flow cytometry revealed that the percentage of neutrophils expressing LFA-1 was significantly higher in patients with AAV than in those with large-vessel vasculitis or polyarteritis nodosa and the HCs. LFA-1 levels in the neutrophils were higher in patients with MPO-ANCA-positive expression than in those with a positive PR3-ANCA expression and correlated with the peripheral eosinophil count, serum rheumatoid factor titre, serum C-reactive protein levels, and the vasculitis activity score of systemic and chest components. After 24 weeks of treatment, including prednisolone, cyclophosphamide, rituximab, azathioprine, methotrexate, and/or tacrolimus, neutrophil LFA-1 expression remained high in the non-responder patients, but decreased in the responder patients. The in vitro assay showed that leukocyte migration toward HUVECs was dependent on the interaction between LFA-1 and intercellular adhesion molecule-1 (ICAM1); the migration of leukocytes was inhibited by blocking the adhesion of LFA-1 to ICAM1. CONCLUSIONS: The expression of LFA-1 in neutrophils is increased in patients with AAV. Neutrophil LFA-1 levels correlate with the clinical features of AAV. Inhibiting the adhesion of LFA-1 and ICAM1 impedes the neutrophil-endothelium interaction and may have a therapeutic role in AAV.
34016483 Triggers of Cardiovascular Diseases in Rheumatoid Arthritis. 2022 Jun The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is higher than that in patients without RA, and it is even higher than that in patients with diabetes. Autoimmune-mediated inflammation is observed in patients with RA, resulting in endothelial dysfunction, oxidative stress and activation, and vascular migration of white blood cells. Traditionally, RA-associated CVD was assumed to be mediated by disease-related inflammation, resulting in atherosclerosis (AS). However, this concept has been challenged because treatment with anti-rheumatic drugs, such as methotrexate or proinflammatory cytokine antagonists, such as tumor necrosis factor-alpha (TNF-α) inhibitors, did not reduce the risk of CVD in patients with RA. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in patients with RA but without clear biomarkers and treatment goals. There is no scientific basis for establishing therapeutic targets for cardiovascular risk factors in RA. Numerous studies have shown that the mechanism of early cardiac dysfunction in patients with RA may occur prior to AS. Therefore, it is crucial to explore the related mechanisms to prevent early cardiac dysfunction in patients with RA.
34997270 [Innovative strategies for treatment of rheumatoid arthritis]. 2022 Mar Besides excellent guidelines and newly developed highly effective drugs, evidence-based strategic use of these new drugs has especially contributed to enormous advances in rheumatoid arthritis treatment, apparent especially since 2000. Currently, the treat-to-target (T2T) strategy has proven to be the most successful in several studies and systematic reviews. The target is to achieve remission, which should be reached and sustained for an optimal outcome (i.e. stable over a long time period). If the initial disease-modifying antirheumatic drug (DMARD) treatment fails, the best strategy for continuing treatment is controversial, with swap or switch being open to debate (change within a class of drugs or change in the mechanism of action). Recent studies seem to indicate that switching to another mechanism of action is the most successful approach. A hotly discussed topic is the question whether DMARD treatment can or should be tapered when sustained remission has been achieved? Many patients wish for a reduction of drugs in cases of stable remission; however, the stable disease control might become destabilized by tapering. The main priority is the reduction or tapering of glucocorticoid treatment. When the decision for reduction of DMARD treatment is made together with the patient, a complete cessation bears a high risk of a flare, therefore, a careful step by step reduction of DMARD treatment should be preferred. In the case of a running combination, the question whether the conventional DMARD (mostly methotrexate), the biological (b)DMARD or targeted synthetic (ts)DMARD should be reduced first, must be decided on an individual basis. Most patients prefer to first reduce methotrexate and transfer to a monotherapy.
35031874 Rheumatoid arthritis and myasthenia gravis: a case-based review of the therapeutic options 2022 Apr INTRODUCTION: Myasthenia gravis is an autoimmune disease affecting the neuromuscular junction, often associated with other autoimmune diseases, including rheumatoid arthritis. Patients with rheumatoid arthritis present an increased prevalence of myasthenia gravis compared to the general population. While these two diseases share some therapeutic options, such as glucocorticoids, methotrexate, and rituximab, there are no guidelines for treating concomitant disease. We aim to review the available evidence and to discuss the efficacy and safety of the therapeutic options in patients with rheumatoid arthritis associated with myasthenia gravis. METHOD: We described three patients with rheumatoid arthritis associated with myasthenia gravis and we performed a systematic review of the associated literature. RESULTS: A 48-year-old man and two women (48 and 55 years old) with concomitant diagnoses of active rheumatoid arthritis and well-controlled myasthenia gravis are described. They were treated with methotrexate, leflunomide, upadacitinib, and adalimumab. None of them experienced changes in their myasthenic symptoms. We found 9 additional cases from our literature review. Methotrexate, rituximab, upadacitinib, diphenyl sulfone, auranofin, and loxoprofen sodium did not show an impact on the seven patients with previously well-controlled myasthenia. Glucocorticoids, methotrexate, and rituximab proved effective in active myasthenia gravis and arthritis. Conflicting data emerged for Tumor-necrosis factor inhibitors. CONCLUSIONS: Although the available evidence remains scarce, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options. The role of tumor-necrosis factor inhibitors remains uncertain. Eventually, Janus Kinase inhibitors are a novel interesting option for these patients. Key Points • To date, the only evidence on the treatment of patients with rheumatoid arthritis and concomitant myasthenia gravis derives from case reports. • Based on the review of the available case reports and on the cases we described, we consider glucocorticoids, methotrexate, and rituximab as safe and effective options, while the role of Tumor-necrosis factor inhibitors remains uncertain. • Based on the cases we described, Janus Kinase inhibitors are a novel interesting option for patients with concomitant rheumatoid arthritis and myasthenia gravis.
35121639 Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid ar 2022 Feb OBJECTIVES: To assess the long-term safety and efficacy of the Janus kinase inhibitor upadacitinib versus adalimumab over 3 years in the ongoing long-term extension (LTE) of SELECT-COMPARE, a randomised controlled phase 3 trial of patients with active rheumatoid arthritis and inadequate response to methotrexate (MTX). METHODS: Patients on stable background MTX were randomised 2:2:1 to upadacitinib 15 mg, placebo or adalimumab 40 mg. Patients with an insufficient response were switched by week 26 from placebo to upadacitinib, upadacitinib to adalimumab or adalimumab to upadacitinib. Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years. Safety and efficacy results were analysed here through 3 years. Treatment-emergent adverse events (AEs) were summarised based on exposure to upadacitinib and adalimumab. Efficacy was analysed by original randomised groups (non-responder imputation), as well as separately by treatment sequence (as observed). RESULTS: Rates of several AEs were generally comparable between upadacitinib and adalimumab, including AEs leading to discontinuation, serious infections and serious AEs, malignancies, major adverse cardiac events, venous thromboembolism and deaths. Consistent with earlier results, herpes zoster, lymphopaenia, hepatic disorder and CPK elevation were reported at higher rates with upadacitinib versus adalimumab. In terms of efficacy, upadacitinib continued to show numerically better clinical responses than adalimumab over 3 years across all endpoints, including low disease activity and remission. CONCLUSION: The safety profile of UPA 15 mg was consistent with previous study-specific and integrated safety reports. Higher levels of clinical response continued to be observed with upadacitinib versus adalimumab through 3 years of treatment.
34526397 Radiographic Progression of Structural Joint Damage Over 5 Years of Baricitinib Treatment 2022 Feb OBJECTIVE: To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA). METHODS: Patients completed 1 of 3 phase III baricitinib trials (ClinicalTrials.gov: NCT01711359, NCT01710358, or NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab (ADA) switched to baricitinib 4 mg at Week 52. Patients initially receiving placebo (PBO) switched to baricitinib 4 mg at Week 24. Radiographs were scored at baseline and Years 2, 3, 4, and 5. Change from baseline in van der Heijde modified total Sharp score (ΔmTSS) was computed. RESULTS: Overall, 2125 of 2573 (82.6%) randomized patients entered RA-BEYOND; 1837 of 2125 (86.4%) entered this analysis. From Years 3 to 5, higher proportions of disease-modifying antirheumatic drug (DMARD)-naïve patients on initial baricitinib (monotherapy or with MTX) had no progression vs initial MTX (ΔmTSS ≤ 0 at Year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg + MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or ADA vs PBO had no progression (ΔmTSS ≤ 0 at Year 5: 54.8% baricitinib 4 mg; 55.0% ADA; 50.3% PBO). Higher proportions of patients with conventional synthetic DMARD-IR on initial baricitinib 4 mg had less progression vs initial PBO or baricitinib 2 mg (ΔmTSS ≤ 0 at Year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% PBO). CONCLUSION: Oral baricitinib maintained lower levels of radiographic progression than initial conventional synthetic DMARD or PBO through 5 years in patients with active RA.
35256364 Monarticular rheumatoid arthritis of the elbow. 2022 Mar 7 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by symmetric inflammatory polyarthritis. However, RA limited to a single joint is extremely rare. Here, we report a middle-aged woman who presented with insidious right elbow arthritis. She had no other peripheral joint pain, tenderness or swelling. She had high-positive anti-cyclic citrullinated peptide antibodies. An MRI of the right elbow showed capsular distension, joint effusion and bone marrow oedema. Synovial biopsy revealed hyperplasia with lymphoplasmacytic infiltrate consistent with RA. Therapy with methotrexate 7.5 mg orally weekly was effective to control her inflammatory arthritis. This case highlights the relevance of synovial tissue analysis for patients presenting with chronic inflammatory monarthritis when the cause is not clinically evident, and the importance of considering RA even in the absence of polyarticular involvement. Delayed diagnosis and treatment of inflammatory monarthritis can lead to joint destruction and disability.