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ID PMID Title PublicationDate abstract
31601292 Methotrexate Central Nervous System Toxicity Identified in a Pharmacogenomics Pharmacist C 2019 Oct 1 OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.
30886720 The potential usefulness of sputum cytology in the conclusive diagnosis of methotrexate-as 2019 BACKGROUND: Methotrexate has been used as an anchor drug for the treatment of rheumatoid arthritis and is considered to be a cause of methotrexate-associated lymphoproliferative disorder. Spontaneous regression can occur after withdrawal of methotrexate and may be associated with Epstein-Barr virus positivity and non-diffuse large B cell lymphoma histological type. Methotrexate-associated lymphoproliferative disorders are often diagnosed pathologically by lung biopsy. To the best of our knowledge, there have been no studies on the cytological diagnosis of methotrexate-associated lymphoproliferative disorder using sputum smears. CASE: A 70-year-old man, who was diagnosed with rheumatoid arthritis 13 years previously and who had been treated with methotrexate, presented shortness of breath and productive cough. Methotrexate-associated lymphoproliferative disorder was suspected as the sputum cytology showed many atypical lymphoid cells with hyperchromatic enlarged nuclei, foamy cytoplasm and distinct nucleoli. Chest computed tomography revealed multiple nodular shadows with interstitial pneumonia in the bilateral lower lung field. A lung biopsy specimen contained atypical lymphoid cells that were immunohistochemically positive for CD20 and MUM-1, and weakly positive for bcl-6, but negative for CD3 and CD10. There were no Epstein-Barr virus-infectious lymphoid cells by ISH-EBER. He was finally diagnosed with methotrexate-associated lymphoproliferative disorder (non-germinal center B-cell-like diffuse large B cell lymphoma histological type). Most of the nodules disappeared spontaneously following the withdrawal of methotrexate. DISCUSSION AND CONCLUSION: A cytologically conclusive diagnosis of methotrexate-associated lymphoproliferative disorder may be reached using sputum smears and clinical information.
31495827 A Novel Chinese Medicine, Xinfeng Capsule, Modulates Proinflammatory Cytokines via Regulat 2019 Sep 9 BACKGROUND Rheumatoid arthritis (RA) is a chronic autoimmune disease targeting joints. This research aimed to explore the effects of Xinfeng capsules (XFC) on cardiac injury in adjuvant arthritis (AA) model rats and assessed the associated mechanism. MATERIAL AND METHODS An adjuvant arthritis (AA) rat model was established by intracutaneously injection with Freund's complete adjuvant (FCA). Model rats were divided into 4 groups: an AA model group, an astragalus polysaccharides (APS) group, a methotrexate (MTX) group, and an XFC and triptolide (TPT) group. Hematoxylin-eosin (HE) staining was used to observe histopathologic changes. TUNEL assay was utilized to evaluate the apoptosis of cardiomyocytes. ELISA was utilized to evaluate levels of tumor necrosis factor alpha (TNF-alpha), interleukin 17 (IL-17), and interleukin 6 (IL-6) in myocardial tissues. Quantitative RT-PCR (qRT-PCR) was used to detect microRNA-21 (miRNA21) levels. Mitogen-activated protein kinase (MAPK)/p38, Toll-like receptor 4 (TLR4), and nuclear kappa B (NF-kappaB)/p65 levels were evaluated using Western blot. RESULTS XFC significantly improved proinflammatory response compared to the AA model group (p<0.05). XFC treatment significantly decreased the number of cells staining TUNEL-positive compared with the model group (p<0.05). XFC treatment significantly reduced TNF-alpha, IL-17, and IL-6 levels in myocardial tissues compared to the model group (p<0.05). Levels of miRNA21 were significantly lower in the XFC group compared to the AA model group (p<0.05). TLR4, MAPK/p38, and NF-kappaB/p65 expression levels were significantly lower in the XFC group than in the model group (p<0.05). CONCLUSIONS Xinfeng capsule, a traditional Chinese medicine preparation, protects against cardiac injury in AA rats by modulating proinflammatory cytokines expression via the TLR4/MAPK/NF-kappaB signaling pathway.
31777827 Joint Estimation of Remission and Response for Methotrexate-Based DMARD Options in Rheumat 2019 Oct OBJECTIVE: To jointly estimate American College of Rheumatology (ACR50) response (a more commonly reported outcome) and remission (a more clinically relevant outcome) for methotrexate (MTX)-based treatment options in rheumatoid arthritis (RA). METHODS: We conducted a bivariate network meta-analysis (NMA) to compare MTX monotherapy and MTX-based conventional and biologic disease-modifying antirheumatic drug (DMARD) combinations for RA. The correlation between the outcomes was derived from an incident RA cohort study, whereas the treatment effects were derived from randomized trials in the network of evidence. The analyses were conducted separately for MTX-naïve and MTX-inadequate response (IR) populations in a Bayesian framework with uninformative priors. RESULTS: From the cohort study, the correlation between ACR50 response and Disease Activity Score 28 remission at 6 months was moderate (Pearson correlation coefficient = 0.58). In the bivariate NMA for MTX-naïve populations, most combinations of MTX with either biologic or tofacitinib were statistically superior to MTX alone for both ACR50 response and remission. Triple therapy (MTX + sulfasalazine + hydroxychloroquine) was the only nonbiologic DMARD statistically superior to MTX for either ACR50 response (odds ratio [OR] 95% credible interval: 2.1 [1.0, 4.3]) or remission (OR: 2.5 [1.0, 5.8]). In the MTX-IR analysis, all treatments except MTX + sulfasalazine were statistically superior to MTX alone. Compared to analyzing the outcomes separately, the bivariate model often resulted in more precise estimates and allowed remission to be estimated for all treatments. CONCLUSION: Borrowing the strength of correlation between outcomes allowed us to demonstrate a statistically significant benefit for remission across most MTX-based DMARD combinations, including triple therapy.
31762886 Adult Still's disease and squamous cell carcinoma in a 69-year-old woman. 2019 Adult-onset Still's disease (AOSD) has been recognized as a cause of fevers of unknown origin. Malignancies are the most important differential diagnoses of AOSD which has been rarely reported in association with cancer. The present paper undertakes the study of a 69-year-old Tunisian woman with AOSD according to the diagnostic criteria of Yamaguchi. She was treated by prednisone, then associated with methotrexate. 18 months later, she developed a squamous cell carcinoma treated with chemotherapy and radiotherapy.
31391399 Acquired Amegakaryocytic Thrombocytopenia in Adult-onset Still's Disease: Successful Combi 2019 Dec 1 Adult-onset Still's disease (AOSD) sometimes demonstrates hematologic disorder, whereas acquired amegakaryocytic thrombocytopenia (AAT) involvement is extremely rare. We herein report a 67-year-old woman with relapse of AOSD who concomitantly developed AAT. Thrombocytopenia along with high disease activity of AOSD was resistant to high-dose prednisolone, even in combination with methotrexate and tacrolimus. However, alternative treatment with cyclosporine after administering tocilizumab resulted in the improvement of thrombocytopenia, ultimately demonstrating that combination therapy based on suppressing the intractable disease activity of AOSD and subsequently adding a reliable immunosuppressant was required to achieve remission.
31745741 Myocarditis in Adult-Onset Still's Disease: Case-Based Review. 2020 Mar Cardiac involvement in adult-onset Still's disease (AOSD) usually manifests as a pericardial disease. Myocarditis is uncommon (prevalence of 7%). However, the cardiocirculatory failure is the second cause of life-threatening AOSD. Herein, we report the case of a 38-year-old man who was diagnosed with myocarditis caused by AOSD. He was treated medically with steroids and methotrexate, and his course was favorable. A literature search in PubMed/MEDLINE and Scopus databases from 1971 to 2019 identified 47 additional cases of myocarditis and AOSD. The main features found in these reports were reviewed and are the following: (i) myocarditis is a rare complication of AOSD manifested by fever, chest pain, dyspnea, and tachycardia; (ii) cardiac biomarkers, electrocardiogram (ECG), transthroracic echocardiography (ECHO), and cardiac magnetic resonance imaging (MRI) are useful noninvasive diagnostic tools; and (iii) myocarditis is a potentially life-threatening complication of AOSD but responds positively to steroids and other immunomodulatory drugs. This review suggests that this entity should be suspected in cases of acute febrile myocarditis after ruling out other causes since a prompt treatment results in a good prognosis.
31661133 CP-25 exerts anti-angiogenic effects on a rat model of adjuvant-induced arthritis by promo 2019 Dec Angiogenesis can produce an invasive and destructive front, also named a pannus, comprised of inflammatory vascular tissue that covers and erodes articular cartilage, subchondral bone and peri‑articular soft tissues in rheumatoid arthritis (RA). Paeoniflorin‑6'‑O‑benzene sulfonate (CP‑25) is a novel ester derivative of paeoniflorin. We previously demonstrated that CP‑25 exerts anti‑inflammatory and immunoregulatory effects. CP‑25 also exhibits a marked therapeutic effect on adjuvant‑induced arthritis (AA), and is able to inhibit synovial and immune cell function, according to our previous study. However, the effect of CP‑25 on angiogenesis remains unclear. In the present study, AA was initiated in Sprague‑Dawley rats via intradermal immunization in the right hind metatarsal footpad with heat‑killed Mycobacterium butyricum in liquid paraffin, and rats were divided into four groups: Normal, AA rat model, CP‑25 (50 mg/kg) and methotrexate (0.5 mg/kg) groups (n=10 rats/group). Subsequently, joint synovium in AA rats was pathologically evaluated by hematoxylin and eosin staining, synovial vascular proliferation was evaluated by immunofluorescence, the synovial expression levels of C‑X‑C motif chemokine ligand 12 (CXCL12) were detected by immunohistochemistry and ELISA, and synovial C‑X‑C chemokine receptor type 4 (CXCR4) was detected by western blotting. The results demonstrated that CP‑25 ameliorated clinical signs and pannus formation in the ankle joint in rats with AA. Furthermore, there was a positive correlation between pannus score and CXCL12 and CXCR4 expression. In addition, the effects of CP‑25 on endothelial cell function and CXCL12/CXCR4 signaling were studied in vitro using human umbilical vein endothelial cells (HUVECs). The results demonstrated that CXCL12 significantly promoted HUVEC proliferation, migration and tube formation, and that CP‑25 could reverse these abnormalities by inhibiting plasma membrane localization of G protein‑coupled receptor kinase 2 (GRK2) in HUVECs. These findings suggested that CP‑25 may markedly inhibit pannus formation in AA. This effect may be associated with a reduction in the plasma membrane localization of GRK2 in endothelial cells, an enhancement of the inhibitory effect of GRK2 on ERK1/2 in the cytoplasm, a reduction in the phosphorylation of ERK1/2 and in the function of HUVECs.
31685753 Reactions of Methotrexate with Hypobromous Acid and Hypochlorous Acid. 2019 Methotrexate is a folate antagonist cytotoxic drug employed in the therapy of cancers and rheumatoid arthritis. Hypobromous acid (HOBr) and hypochlorous acid (HOCl) are generated by eosinophils and neutrophils at inflammation sites. The administered methotrexate may encounter HOBr and HOCl, and react with them to generate products. When methotrexate was incubated with HOBr or HOCl at pH 7.4 and 37°C for 30 min, a single product was generated almost exclusively in each case, identified as 3'-bromomethotrexate for HOBr and 3'-chloromethotrexate for HOCl. When methotrexate was incubated with HOCl in the presence of NaBr, the concentration of 3'-bromomethotrexate increased with decreasing concentration of 3'-chloromethotrexate in a dose-dependent manner with NaBr, probably due to the formation of HOBr. Free amino acids suppressed the reactions of methotrexate with HOBr and HOCl. Taurine suppressed the HOCl reaction but not the HOBr reaction. These results suggest that 3'-bromomethotrexate and 3'-chloromethotrexate may be generated from methotrexate at inflammation sites in humans, although their formation will be suppressed by coexistent amino acids.
31777840 Real-World Adherence to Oral Methotrexate Measured Electronically in Patients With Establi 2019 Nov OBJECTIVE: To assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA). METHODS: Eligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression. RESULTS: Overall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease-modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD-experienced versus biologic DMARD-naïve patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89). CONCLUSION: Even in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.
30985672 Managing Adult-onset Still's disease: The effectiveness of high-dosage of corticosteroids 2019 Apr To assess the effectiveness of the treatment with high dosage of corticosteroids (CCSs), as first-line therapy, in inducing remission in naïve Adult-onset Still's disease (AOSD) patients compared with low dosage of CCSs, after 6 months. To further evaluate the rate of patients maintaining the remission and the rate of CCSs discontinuation, after additional 12 months of follow-up.A retrospective evaluation of patients prospectively followed was designed to compare the rate of clinical remission in naïve AOSD patients treated with high dosages of CCSs (0.8-1 mg/kg/day of prednisone-equivalent) or low dosage of CCSs (0.2-0.3 mg/kg/day of prednisone-equivalent), after 6 months. An additional analysis was performed to compare the rate of monocyclic pattern between these groups, after further 12 months of follow-up.The clinical remission was achieved in a higher percentage of patients treated with the first-line treatment with high dosage of CCSs than treated the first-line treatment with low dosage of CCSs. At the end of 18 months of follow-up, a larger percentage of patients treated the first-line treatment with high dosage of CCSs was classified as monocyclic pattern and discontinued CCSs when compared with patients treated the first-line treatment with low dosage of CCSs. Patients defined as CCSs non-responder were treated with methotrexate (MTX)+CCSs or with combination therapy CCSs+MTX+biologic drug. The clinical remission was observed in a percentage of these patients.We showed the effectiveness of the first-line treatment with high dosage of CCSs in inducing clinical remission in naïve AOSD patients when compared with the first-line treatment with low dosage of CCSs. The first-line treatment with high dosage of CCSs was also associated with the achievement of monocyclic pattern and CCSs discontinuation, after 18 months of follow-up.
31462834 Mixed-etiology leg ulcers in a patient on long-term glucocorticoid therapy. 2019 Chronic leg ulceration is a frequent condition in elderly patients. Chronic wounds that are nonresponsive to 3-month therapy affect approximately 6.5 million people in the United States with a prevalence of 1% and costs estimated at 25 billion dollars per year. Although the main causes are venous insufficiency, lower extremity arterial disease and diabetes, in many cases the etiology is multi-factorial. Approximately 20-23% of non-healing wounds that are refractory to vascular intervention have other etiologies including vasculitis, rheumatoid arthritis and Sjögren syndrome. Adverse drug interactions are the least commonly considered, especially those which involve disease-modifying anti-rheumatic drugs. The authors present a report on a female patient with reported Sjögren syndrome, multiple morbidities and non-healing lower limb ulceration that developed during treatment with methotrexate, and no significant improvement after discontinuation of the drug and after vascular surgery. Microvascular deterioration caused by beta-blockers was considered decisive. Calcium-blocker replacement brought complete healing in the follow-up.
31872183 The Impact of Exercise, Lifestyle, and Clinical Factors on Perceived Cognitive Function in 2019 Dec OBJECTIVE: Lifestyle factors, such as inactivity and obesity, contribute to cognitive decline in the general population, but little is known about how these factors may affect individuals with a chronic inflammatory condition such as rheumatoid arthritis (RA). We studied the clinical and functional risk factors related to a worsening of perceived cognitive function in patients with RA. METHODS: We collected clinical and functional questionnaire data over 10 years in a prospective RA cohort including yearly self-reported memory, concentration, and word-finding difficulties graded from "never" to "often." Generalized estimating equation models examined the role of exercise (defined as those meeting the Department of Health and Human Services physical activity guidelines of 75 minutes of vigorous or 150 minutes of moderate aerobic activity per week), body mass index (BMI), sleep, depression (Mental Health Index-Depression), Disease Activity Score (DAS)28-c-reactive protein (CRP)3 score, disease-modifying antirheumatic drug, and corticosteroid use from the previous year as predictors of cognitive complaints that progressed to "often" compared with the previous year (the first year (T (i) ) progressed to "often" 1 year later (T (i+1))). RESULTS: Of 1219 RA subjects, 127 (10.4%) described either poor memory, concentration, or word-finding difficulties as affecting them "often" at study entry. RA patients (n = 1092, mean age = 56.5 years, 82% female, 58% college educated) were less likely to report word-finding difficulties, poor memory, and concentration as "often" if they were physically active (p = 0.0001, P = 0.01, P < 0.0001, respectively). Female RA patients developed more concentration complaints compared with males (P = 0.03); patients taking an anti-tumor necrosis factor therapy were less likely to complain of poor memory (P = 0.01). Sleep, BMI, fatigue, depression, DAS28-CRP3, methotrexate, and corticosteroid use were not independently associated with a worsening of any cognitive complaints. CONCLUSION: RA patients who are physically active are less likely to report cognitive difficulties. Our study suggests potential modifiable risk factors for the prevention of cognitive dysfunction in RA.
30713571 Water Extract of Acori Graminei Rhizoma Attenuates Features of Rheumatoid Arthritis in DBA 2019 The dry rhizome of Acorus gramineus Solander, known as Acori Graminei Rhizoma, is used to treat dementia, stroke, eczema, and indigestion in traditional Chinese medicine, traditional Korean medicine, and traditional Japanese Kampo medicine. Previous studies have reported that Acori Graminei Rhizoma extract ameliorated cognitive impairment in Aβ1-42 injected mice. However, the effect of Acori Graminei Rhizoma on type II collagen induced arthritis (CIA) has not been elucidated. Thus, we evaluated the water extract of Acori Graminei Rhizoma (WAG) in CIA mice models. Male DBA/1 mice were separated into five groups (NOR; n=10, CON; n=10, CIA + methotrexate (MTX); n=10, CIA + 100 mg/kg WAG; n=10, CIA + 500 mg/kg WAG; n=10). CIA was induced by injecting the mice with bovine type II collagen, after which the mice were treated with WAG and/or MTX. Hematological parameters and liver and kidney serum toxicity markers were analyzed. Further, serum levels of interleukin (IL)-6, TNF-α, and type II collagen IgG were analyzed via enzyme-linked immunosorbent assay (ELISA). Treatment with 500 mg/kg WAG decreased serum levels of IL-6, TNF-α, and collagen IgG in a CIA model. Moreover, WAG treatment decreased CIA-induced swelling of mouse hind legs, infiltration of inflammatory cells into the synovial membrane, and blood neutrophil levels. WAG administration did not influence hematological parameters or kidneys and liver toxicity markers. WAG may be used to treat arthritis by reducing the inflammation indicators. However, further experiments are required to determine how WAG affects inflammation mechanisms in vitro and in vivo.
31521892 Regulation of CP-25 on P-glycoprotein in synoviocytes of rats with adjuvant arthritis. 2019 Nov OBJECTIVE: Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA) and it has been studied in RA resistance recently. P-glycoprotein (P-gp) is one of the important transporters that mediate MTX resistance. This study investigated the effect of Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) in the resistance of P-gp-mediated MTX to RA. METHODS: Adjuvant arthritis (AA) was induced in rats via complete Freund's adjuvant. The experimental groups were divided into normal group; AA model group; monotherapy groups, including CP-25, MTX and dexamethasone; and CP-25 combined with MTX group. The expression of P-gp in synovial tissue was measured by western blot and histochemistry. Besides, P-gp high expression of human hepatoma cell line Bel7402/5-FU and Bel7402 were chose to study in MTX resistance and the function of P-gp was detected by Flow cytometry. RESULTS: CP-25 had a good therapeutic effect on AA rats, significantly improved manifestations and reduced the expression of P-gp in synovial tissue, spleen medulla and small intestinal epithelial cells in the apical tissues of AA rats. In addition, CP-25 significantly inhibited the up-regulation of P-gp induced by TNF-α stimulation in synoviocytes. Furthermore, according to the accumulation and efflux of rhodamine 123 in Bel7402/5-FU resistant cells and Bel7402 sensitive cells, CP-25 could reverse the resistance of MTX in Bel7402/5-FU cells compared with Bel7402 cells, which was reflected by the reduced IC50 values of MTX. Further study indicated that CP-25 could decrease P-gp expression and inhibit P-gp function in Bel7402/5-FU cells. CONCLUSION: CP-25 regulates the expression of P-gp and inhibits the function of P-gp, thereby improving the resistance of MTX.
31228100 Relative Impact of Pain and Fatigue on Work Productivity in Patients with Rheumatoid Arthr 2019 Sep INTRODUCTION: To explore the relationship of pain and fatigue with daily activity and work productivity in rheumatoid arthritis (RA) patients from the baricitinib clinical trial, RA-BEAM. METHODS: In RA-BEAM, a double-blind phase 3 study, patients were randomized 3:3:2 to placebo (n = 488), baricitinib 4 mg once daily (n = 487), or adalimumab 40 mg biweekly (n = 330) with background methotrexate. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) measured fatigue and the pain visual analog scale (0-100 mm) assessed pain. Work Productivity and Activity Impairment Questionnaire-RA measured daily activity and work productivity. At weeks 12 and 24, pain was assessed using pain reduction (< 30%, 30% to < 50%, ≥ 50%) and overall pain score; clinically relevant FACIT-F changes were assessed by values < 3.56 and ≥ 3.56 and the FACIT-F normative value score (< 40.1, ≥ 40.1). Pairwise comparisons between pain/fatigue reduction groups were assessed using ANCOVA with pooled data on daily activity and work productivity. A mediator analysis with pain, fatigue, and disease activity measured their contribution to daily activity and work productivity. Data were pooled from all patients for most analyses, and baricitinib-treated patients were assessed as a sensitivity analysis. RESULTS: Reductions in pain (≥ 50%) and fatigue (≥ 3.56) had significant (p ≤ 0.001) effects on daily activity and work productivity improvement at weeks 12 and 24. Reductions in pain, fatigue, and disease activity accounted for most of the improvements in daily activity and work productivity. At the lowest levels of remaining pain (≤ 10 mm) at weeks 12 and 24, however, fatigue did not appear to impact work productivity. Similar trends were observed with baricitinib-treated patients. CONCLUSIONS: Reductions in pain and fatigue were associated with improved daily activity and work productivity for all RA patients and for baricitinib-treated patients in RA-BEAM. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01710358. FUNDING: Incyte Corporation and Eli Lilly and Company.
31804172 Characteristics of coexisting localized scleroderma and inflammatory arthritis. 2019 Dec 3 OBJECTIVE: Localized scleroderma (LS), including morphea and linear scleroderma, is an autoimmune disease where excessive subcutaneous collagen deposits lead to thickening, scarring, and fibrosis of the tissues. LS coexisting with inflammatory arthritis is less well-described but has been reported in as many as 20% of 53 LS patients in a recent cohort. Herein, we describe a cohort of 8 children with both LS and inflammatory arthritis. The objective of this study is to determine the characteristics of inflammatory arthritis in children with LS and their response to treatment regimens. MATERIALS AND METHODS: A retrospective chart review was completed on patients less than 19 years of age who were diagnosed with either morphea or linear scleroderma at the Children of Alabama center from 2004-2018. Patients were identified using ICD-9 and ICD-10 diagnostic codes. Records were reviewed for additional diagnostic codes, exams, and laboratory findings confirming coexisting inflammatory arthritis and LS. RESULTS: A total of 87 patients with a diagnosis of either morphea or linear scleroderma were identified. Eight (9%) had coexisting inflammatory arthritis according to the diagnostic codes with documented active arthritis. Median age of initial rheumatic disease diagnosis was 7.5 years. A majority of patients with both LS and inflammatory arthritis were female (62.5%). Half of the patients (n=4, 50%) had LS lesions over arthritic joints. All of the identified patients were diagnosed with a form of juvenile idiopathic arthritis (JIA). The JIA diagnoses varied widely in 3 (37.5%) patients with rheumatoid factor (RF) negative polyarticular JIA, 2 (25%) with oligoarticular JIA, 2 (25%) with psoriatic JIA, and 1 (12.5%) with enthesitis-related JIA. The timing of onset of LS and inflammatory arthritis varied widely. Three (37.5%) patients had LS lesions preceding clinical arthritis, and three (37.5%) had arthritis before the appearance of LS. Two (25%) patients had both LS and arthritis at the time of diagnosis. All patients received methotrexate (MTX) during their disease course with only 3 (37.5%) receiving systemic steroids during treatment. All 8 patients showed resolution of LS lesions. However, 6 of the 8 patients demonstrated active arthritis on combination MTX and TNFi therapy. CONCLUSION: In this cohort of pediatric LS, 9% of patients had coexisting inflammatory arthritis. The characteristics of this cohort varied widely. All patients received MTX initially and showed a resolution of LS lesions. However, in the majority of patients, the arthritis failed to respond to MTX and TNFi combination therapy. These results suggest that inflammatory arthritis coexisting with LS may be less likely to respond to traditional inflammatory arthritis or JIA therapies.
31943973 Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune- 2020 Jan OBJECTIVE: Immune-mediated inflammatory arthritis (IMIA) is a heterogeneous group of diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). Disease-modifying antirheumatic drugs (DMARDs) target very different cellular components of the disease processes. Characterization of the pathobiological subtypes of IMIA could provide more specific treatment approaches for each disease. For example, RA has been proposed to consist of at least three synovial pathotypes (lymphoid, myeloid, and fibroid), and only a subgroup of RA patients have erosive disease. The objective of this study was to evaluate the effects of various DMARDs on different synovial cell subsets using human ex vivo models of IMIA. METHODS: Synovial fluid and blood samples were obtained from a study population consisting of patients with RA, PsA, or peripheral SpA with at least one swollen joint (n = 18). The DMARDs used in this study were methotrexate, adalimumab, etanercept, tocilizumab, anakinra, ustekinumab, secukinumab, tofacitinib, and baricitinib. Paired synovial fluid mononuclear cells (SFMCs), peripheral blood mononuclear cells (PBMCs), and fibroblast-like synovial cells (FLSs) were used in three different previously optimized ex vivo models. RESULTS: In SFMCs cultured for 48 hours, all DMARDs except anakinra decreased the production of monocyte chemoattractant protein (MCP)-1. In SFMCs cultured for 21 days, only the two tumor necrosis factor alpha (TNFα) inhibitors adalimumab and etanercept decreased the secretion of tartrate-resistant acid phosphatase (P < 0.01, P < 0.001). In the FLS and PBMC 48-hour co-cultures, only tocilizumab (P < 0.001) and the two Janus kinase inhibitors tofacitinib and baricitinib (both P < 0.05) decreased the production of MCP-1 by around 50%. CONCLUSION: TNFα inhibition was effective in preventing inflammatory osteoclastogenesis, whereas tocilizumab, tofacitinib, and baricitinib had superior efficacy in cultures dominated by FLSs. Taken together, this study reveals that responses to cytokine inhibitors associate with cellular composition in models of IMIA. In particular, this study provides new evidence on the differential effect of DMARDs on leukocytes compared with stromal cells.
30808625 Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double 2019 May OBJECTIVES: Early initiation of effective treatment favours remission in rheumatoid arthritis, but it remains unknown if the same concept applies to psoriatic arthritis (PsA). Therefore, this study investigated whether the combination of golimumab plus methotrexate (MTX) as a first-line treatment is superior to MTX alone in inducing remission in PsA. METHODS: This investigator-initiated, multicentre, double-blind, randomised, placebo-controlled trial included 51 MTX and bDMARD-naive patients with PsA fulfilling the CASPAR criteria and with active disease at baseline (≥3 swollen joint count/tender joint count). Patients were randomised to golimumab (50 mg SC monthly)+MTX (n=26) (TNFi arm) or matched placebo+MTX (n=25) (MTX arm). MTX was started 15 mg/week and increased to 25 mg/week over 8 weeks. The primary endpoint was percentage of patients achieving Disease Activity Score (DAS) remission (<1.6) at week 22. Safety was assessed throughout the study. RESULTS: The primary efficacy endpoint was achieved by 81% in the TNFi arm versus 42 % in the MTX arm (p=0.004). This difference in DAS remission was already observed at week 8. A significant difference in favour of the golimumab+MTX arm at week 22 was also observed for other response criteria such as MDA, ACR20/50/70, disease measures and patient-reported outcomes. The occurrence rates of adverse event and treatment-emergent adverse event were similar in both arms. CONCLUSIONS: In patients with early PsA, DAS remission at week 22 was almost doubled with golimumab+MTX versus MTX alone. This double-blind, randomised, placebo-controlled study supports the concept that early initiation of TNFi in patients with PsA favours remission. TRIAL REGISTRATION NUMBER: NCT01871649.
30455954 Transbronchial lung cryobiopsy: a novel confirmatory tool to diagnose asbestos-related pul 2019 Jan Asbestosis is diagnosed with a combination of historical, clinical and radiological findings in the absence of another cause. Histology is required when uncertainty exists, with lung biopsy via VATs being gold standard. Transbronchial cryobiopsy is becoming increasingly popular for diagnosing interstitial lung disease and may provide sufficient lung sample to demonstrate asbestosis. A 73 year old man presented with dyspnoea on a background of rheumatoid arthritis, previous methotrexate use and asbestos exposure. Examination revealed fine crackles in the mid and lower zones bilaterally without signs of pulmonary hypertension. The presence of pleural plaques and basal interstitial reticulation on HRCT was suggestive of asbestosis but histology was required to differentiate this from rheumatoid or methotrexate associated ILD. Samples of lung tissue were obtained via transbronchial cryobiopsy, demonstrating fibrosis and asbestos fibres consistent with asbestosis. Transbronchial cryobiopsy appears effective in obtaining sufficient parenchymal lung samples to diagnose asbestosis when clinical uncertainty exists.