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ID PMID Title PublicationDate abstract
31556983 2019 Mar 26 Rheumatoid arthritis (RA) is an inflammatory, chronic disease of the joint that is characterized by activation of autoantibodies against immunoglobulin G and anticitrullinated protein antibodies. Activated immune cells cause synovial accumulation that leads to cartilage and bone erosion. The prevalence of RA in urban Quebec between 1992 and 2008 was estimated to be as high as 995 per 100,000 females aged 45 years and older and 994 per 100,000 males in the same age group. The prevalence was estimated to be 205 per 100,000 females younger than 45 years, and 73 per 100,000 males younger than 45 years. The prevalence values were lower in age-matched rural populations except for females aged 45 years and older. In Ontario, the prevalence in 2010 was estimated to be 784 (with a 95% confidence interval of 779 to 789) per 100,000 people. Patients with RA have a shorter life expectancy than the general population and are at higher risk of experiencing cardiovascular events. Methotrexate (MTX), a conventional synthetic disease modifying anti-rheumatic drug (csDMARD), is a folic acid antagonist and is the drug that is most commonly used to treat RA. Some patients may be intolerant of or may not respond adequately to MTX monotherapy, therefore alternate forms of therapy have emerged. Other csDMARDs such as sulfasalazine (SSZ), leflunomide (LEF), and hydroxychloroquine (HCQ) are available and are offered as monotherapy or in combination with other csDMARDs or biologics. For patients who are intolerant of specific csDMARDs or whose RA is inadequately controlled with one or more csDMARDs, biologic therapies such as tumor necrosis inhibitors, T-cell stimulation inhibitors, CD20 inhibitors, IL-6 inhibitors, or JAK inhibitors, are increasingly being recommended. However, given that biologics are significantly more costly than csDMARDs, there are renewed efforts to determine whether combinations of csDMARDs may be more cost-effective. The aim of this report is to summarize the cost-effectiveness evidence on triple csDMARDs therapy (specifically, methotrexate, sulfasalazine, hydroxychloroquine) relative to other pharmacologic options for the management of RA in North America.
30888759 Whipple's disease in a man of North African descent : case report and brief review of the 2019 Jan A 62-year-old man of North African descent presented with weight loss in the past year and diarrhea for three weeks. His medical history included erosive rheumatoid arthritis, treated with methotrexate and adalimumab. Histological examination of a duodenal biopsy showed foamy macrophages in the lamina propria, with PAS-positive cytoplasmatic inclusions. These findings are compatible with Whipple's disease, a rare chronic infectious disease caused by Tropheryma whipplei, an opportunistic bacterium. It is typically seen in middle-aged Caucasian men and the immunocompromised host. The classical presentation of Whipple's disease consists of intermittent migratory arthralgia, followed by intestinal symptoms which typically occur six to seven years later. The clinical image can be very variable, and this complicates the diagnostic process. PAS-staining and PCR are the diagnostic cornerstones. In our case, treatment consisted of a prolonged cure of antibiotics: intravenous ceftriaxone for two weeks, followed by an oral maintenance therapy of doxycycline and hydroxychloroquine for at least one year. A therapeutic dilemma arose as continued anti-TNF blockade was necessary to maintain remission of the rheumatoid arthritis. Lifelong follow-up is necessary because relapse is possible.
31137815 Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis? 2019 May 27 The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like synoviocytes (FLS), and the synovial tissue macrophages (STM), toward an overproduction of enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration. Recent studies have shown metabolic changes in stromal and immune cells from RA patients. Metabolic disruption in the synovium provide the opportunity to use in vivo metabolism-based imaging techniques for patient stratification and to monitor treatment response. In addition, these metabolic changes may be therapeutically targetable. Thus, resetting metabolism of the synovial membrane offers additional opportunities for disease modulation and restoration of homeostasis in RA. In fact, rheumatologists already use the antimetabolite methotrexate, a chemotherapy agent, for the treatment of patients with inflammatory arthritis. Metabolic targets that do not compromise systemic homeostasis or corresponding metabolic functions in normal cells could increase the drug armamentarium in rheumatic diseases for combination therapy independent of systemic immunosuppression. This article summarizes what is known about metabolism in synovial tissue cells and highlights chemotherapies that target metabolism as potential future therapeutic strategies for RA.
31316856 A Case of Severe Symptomatic Central Nervous System Sarcoidosis Secondary to Treatment wit 2019 Antitumor necrosis factor-α therapy has been used effectively in treatment of many inflammatory diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease. There are increasing number of paradoxical reactions associated with this therapy that are being reported. We present the case of a 63-year-old male with psoriatic arthritis maintained on adalimumab and methotrexate (previous treatment trials of prednisone and leflunomide) who developed severe symptomatic sarcoidosis in the brain, liver, and lung. Upon discontinuation of adalimumab, the symptoms resolved but the imaging findings persisted. Although the development of sarcoidosis (usually in the lung, skin, and eyes) while on antitumor necrosis factor-α therapy is increasingly reported, the brain and liver are less commonly involved but should be borne in mind by physicians when extensive granulomatous lesions develop.
31492040 Effect of Baricitinib and Adalimumab in Reducing Pain and Improving Function in Patients w 2019 Sep 5 Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks' treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation.
30547379 Use of Auto-Injector for Methotrexate Subcutaneous Self-Injections: High Satisfaction Leve 2019 Mar INTRODUCTION: The objective of the study was to compare compliance and acceptability of a new auto-injector (AI) versus syringe for administration of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: We conducted a randomized, open-label, parallel group study comparing AI to pre-filled syringe (PFS). Adult patients with RA (ACR/EULAR 2010) receiving MTX (orally or by injection) for at least 3 months were allocated to AI or PFS for 6 months and then were allocated to AI for 6 further months. Two co-primary endpoints were defined at M6: percentage of patients with compliance at least 80%; change in functional capacity assessed by Health Assessment Questionnaire (HAQ). Secondary endpoints included quality of life (RaQoL), RA activity (DAS28), and acceptability. Local safety at injection site was assessed at each visit. RESULTS: Two-hundred and sixty-five patients were randomized. The main analysis was conducted on per protocol set (99 AI and 98 PFS). Compliance was 96.2% in AI and 98.9% in PFS. Good complier rates were 89.9% and 94.9%, thus a difference of - 5.0% (- 18.9%; 8.9%). HAQ remained stable in both groups. No difference was found on RaQoL, change in RA activity, and safety profile. Autonomy, acceptability, and patient satisfaction were better with AI, and patients having had the experience of both AI and PFS preferred AI (p < 0.001). CONCLUSIONS: Although this study did not demonstrate non-inferiority of AI versus PFS, compliance was excellent in the two groups, and AI, which was preferred by patients, is a valuable alternative to PFS for administration of MTX. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02553018. FUNDING: Nordic Pharma SAS.
31610524 Methotrexate-associated lymphoproliferative disorder with hypopituitarism and central diab 2019 Oct 12 SUMMARY: Patients treated with immunosuppressive drugs, especially methotrexate (MTX), rarely develop lymphoproliferative disorders (LPDs), known as MTX-related LPD (MTX-LPD). The primary site of MTX-LPD is often extranodal. This is the first reported case of MTX-LPD in the pituitary. A 65-year-old woman was admitted to our hospital with symptoms of oculomotor nerve palsy and multiple subcutaneous nodules. She had been treated with MTX for 11 years for rheumatoid arthritis. Computed tomography showed multiple masses in the orbit, sinuses, lung fields, anterior mediastinum, kidney, and subcutaneous tissue. Brain magnetic resonance imaging revealed a sellar mass. She was diagnosed with hypopituitarism and central diabetes insipidus based on endocrine examination. Although pituitary biopsy could not be performed, we concluded that the pituitary lesion was from MTX-LPD, similar to the lesions in the sinuses, anterior mediastinum, and subcutaneous tissue, which showed polymorphic LPD on biopsy. MTX was discontinued, and methylprednisolone was administered to improve the neurologic symptoms. After several weeks, there was marked improvement of all lesions, including the pituitary lesion, but the pituitary function did not improve. When pituitary lesions are caused by MTX-LPD, the possibility of anterior hypopituitarism and central diabetes insipidus needs to be considered. Further studies are needed to investigate the effectiveness of early diagnosis and treatment of MTX-LPD in restoring pituitary dysfunction. LEARNING POINTS: Pituitary lesions from MTX-LPD may cause hypopituitarism and central diabetes insipidus. Pituitary metastasis of malignant lymphoma and primary pituitary lymphoma, which have the same tissue types with MTX-LPD, have poor prognosis, but the lesions of MTX-LPD can regress only after MTX discontinuation. In cases of pituitary lesions alone, a diagnosis of MTX-LPD may be difficult, unless pituitary biopsy is performed. This possibility should be considered in patients treated with immunosuppressive drugs. Pituitary hypofunction and diabetes insipidus may persist, even after regression of the lesions on imaging due to MTX discontinuation.
30992058 Correction to: Sarilumab plus methotrexate in patients with active rheumatoid arthritis an 2019 Apr 16 Following publication of the original article [1], the authors reported an error in Table 2.
31684171 Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arth 2019 Nov 3 OBJECTIVES: Th1.17 are highly polyfunctional, potentially harmful CD4(+) effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. METHODS: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. RESULTS: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73(+) Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. CONCLUSION: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.
30824460 Hydroxychloroquine-induced inverse psoriasis. 2019 Feb 28 A 65-year-old woman presented to our rheumatology clinic with pain and swelling of multiple joints of her hands. After a thorough evaluation, she was diagnosed with rheumatoid arthritis and was started on hydroxychloroquine therapy. A week later, she presented to our clinic with an acute condition and reported that after taking hydroxychloroquine for a few days she developed multiple rashes, most prominent at skin folds around her breasts, neck, axillae and buttocks. The rashes were characteristic of inverse psoriasis. Hydroxychloroquine was discontinued and the patient was started on methotrexate therapy that resulted in resolution of her rashes in a week.
30832414 Superiority of a Treat-to-Target Strategy over Conventional Treatment with Fixed csDMARD a 2019 Mar 3 BACKGROUND: Treatment of rheumatoid arthritis (RA) includes the use of conventional (cs), biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) and oral, intramuscularly, intravenous, or intraarticular (IA) glucocorticoids (GCs). In this paper, we analysed whether a treat-to-target (T2T) strategy optimizing csDMARD, oral, and IA-GC treatment as an adjunct new therapy to a new certolizumab pegol (CZP) therapy improves the effectivity in RA patients. METHODS: 43 patients with active RA (≥6 tender, ≥6 swollen joints, ESR ≥ 20 mm/h or CRP ≥ 7mg/L) despite csDMARD treatment for ≥ 3 months and naïve to bDMARDs were randomized to CZP (200 mg/2 weeks after loading with 400 mg at weeks 0⁻2⁻4) plus a treat-to-target strategy (T2T, n = 21), or to CZP added to the established csDMARD therapy (fixed regimen, n = 22). The T2T strategy consisted of changing the baseline csDMARD therapy (1) SC-methotrexate (dose: 15 ≥ 20 ≥ 25 mg/week, depending on the initial dose) ≥ leflunomide (20 mg/d) ≥ sulphasalazine (2 × 1000 mg/d) plus (2) oral GCs (prednisolone 20⁻15⁻12.5⁻10⁻7.5⁻5⁻2.5⁻0 mg/d tapered every five days) and (3) injections of ≤5 affected joints with triamcinolone. DMARD modification and an addition of oral GCs were initiated, depending on the achievement of low disease activity (DAS 28 < 3.2). The primary objective was defined as the ACR 50 response at week 24. RESULTS: ACR 50 was achieved in 76.2% of the T2T, as compared to 36.4% of the fixed regimen patients (p = 0.020). ACR 20 and 70 responses were achieved in 90.5% and 71.4% of the T2T patients and 59.1% and 27.3% of the fixed regimen patients, respectively (p = 0.045 and p = 0.010, respectively). The adverse event rate was similar for both groups (T2T n = 51; fixed regimen n = 55). CONCLUSION: Treat-to-target management with the optimization of csDMARDs, oral, and IA-GCs of RA patients in parallel to a newly established CZP treatment was safe and efficacious in comparison to a fixed regimen of csDMARDs background therapy.
31890833 The Masquelet technique for septic arthritis of the small joint in the hands: Case reports 2020 Feb Septic arthritis in distal interphalangeal (DIP) joints sometimes occurs in association with mucous cysts or after the surgical treatment of mallet fingers. Recently, several studies have demonstrated the effectiveness of the Masquelet technique in the treatment of bone defects caused by trauma or infection. However, only few studies have reported the use of this technique for septic arthritis in small joints of the hand, and its effectiveness in treating septic arthritis in DIP joints remains unclear. We report the clinical and radiological outcomes of three patients who were treated with the Masquelet technique for septic arthritis in DIP joints. One patient had uncontrolled diabetes and another had rheumatoid arthritis treated with methotrexate and prednisolone. The first surgical stage involved thorough debridement of the infection site, including the middle and distal phalanx. We placed an external fixator from the middle to the distal phalanx and then packed the cavity of the DIP joint with antibiotic cement bead of polymethylmethacrylate (40 g) including 2 g of vancomycin and 200 mg of minocycline. At 4-6 weeks after the first surgical stage, the infection had cleared, and the second surgical stage was performed. The external fixator and cement bead were carefully removed while carefully preserving the surrounding osteo-induced membrane. The membrane was smooth and nonadherent to the cement block. In the second surgical stage, an autogenous bone graft was harvested from the iliac bone and inserted into the joint space, within the membrane. The bone graft, distal phalanx, and middle phalanx were fixed with Kirschner wires and/or a soft wire. Despite the high risk of infection, bone union was achieved in all patients without recurrence of infection. Although the Masquelet technique requires two surgeries, it can lead to favorable clinical and radiological outcomes for infected small joints of the hand.
31181879 Diagnostic utility of PET/CT in a patient with miliary tuberculosis. 2019 Jun 11 A 63-year-old male presented with loss of appetite, subfebrile fever, swelling of the right hand and dyspnea on exertion for three months. Past medical history revealed methotrexate treatment of six months for rheumatoid arthritis. Chest radiography and computed tomography (CT) revealed diffuse miliary nodules. PET/CT scan demonstrated diffuse FDG uptake in both lungs, in the spleen, in the right hand, the mediastinal and the axillary lymph nodes. MR of the right hand showed inflammatory arthritis. Histopathology of the right hand tru-cut biopsy revealed degenerative changes. Culture of the hand biopsy tissue was positive for mycobacterium tuberculosis. PET/CT may determine the biopsy and the sampling sites for the early diagnosis of patients with suspected miliary tuberculosis where lesion identification on other modalities may be difficult or unfeasible. High sensitivity for inflammatory diseases makes PET/CT a useful diagnostic utility for enabling early diagnosis in miliary tuberculosis which is a diagnostic predicament.
31165299 The use of leukocytes' secretome to individually target biological therapy in autoimmune a 2019 Jun 5 BACKGROUND: Biological agents have allowed remarkable improvement in controlling autoimmune arthropathies, although none of the numerous biologics readily available represent a universal treatment standard. Moreover, classical and genetic predictors are currently unsatisfactory to predict individual response to a biologic, and the best treatment selection is still based on a trial-and-error approach. Here, we report a clinical case demonstrating the usefulness of examining the leukocytes' secretome of patients. We set up and standardized a protocol that examines a patient's immune responses to establish the secretome of the blood mononuclear leukocytes and personalize the biotherapy. CASE PRESENTATION: A 24-year-old woman was diagnosed with active early rheumatoid arthritis. The initial treatment regimen (prednisone, methotrexate, hydroxychloroquine, naproxen) was inefficient, as well as the anti-TNF adalimumab. The diagnosis was revised as possible rheumatoid arthritis-like psoriatic arthritis and adalimumab was replaced by abatacept (IgG1 Fc-CTLA-4) to no avail. Five years later, abatacept was replaced by the anti-IL-12/IL-23 ustekinumab with no objective control over the symptoms. The patient was thus enrolled in a prospective study based on the quantification of cytokines secreted by peripheral blood leukocytes stimulated with well-known immune activators of pattern recognition receptors and cytokine signalling. The results of this study revealed that plasma concentrations of cytokines were similar between the patient and healthy donors. In comparison to leukocytes from healthy donors, the patient's secretome showed a unique overproduction of IL-6. The anti-IL-6 receptor tocilizumab was, therefore, administered with a rapid improvement of her active psoriatic arthritis that remained dependent on low prednisone dosage. Clinical parameters progressively returned to normal levels and her quality of life was greatly improved, despite the major delay to begin the present personalized treatment. CONCLUSIONS: An efficient way to effectively treat patients with complex autoimmune arthropathies, and avoid irreversible disability, is to know their leukocytes' secretome to identify abnormally secreted cytokines and personalize their biotherapy, as exemplified by this case report.
30940693 Exposure-Effect Relationships in Established Rat Adjuvant-Induced and Collagen-Induced Art 2019 Jun The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis. A range of doses of indomethacin (a nonsteroidal anti-inflammatory drug), and three disease-modifying antirheumatic drugs (DMARDs), methotrexate, etanercept, and tofacitinib, were evaluated in AIA and CIA rats. Dexamethasone was included in this study as a positive control. The area under the ankle diameter-time profile (AUC(ankle)) and ankle histopathology summed scores (AHSS) were used as efficacy endpoints for activity against disease symptoms (joint inflammation) and disease progression (joint damage), respectively. Translational PK-PD analysis was performed to rank order preclinical efficacy endpoints at clinically relevant concentrations. For each drug tested, inhibition of AUC(ankle) and AHSS scores was generally comparable in both magnitude and rank order. Overall, based on both AUC(ankle) and the AHSS inhibition, the rank ordering of preclinical activity for the DMARDs evaluated was tofacitinib > etanercept ≥ methotrexate. This ranking of preclinical efficacy was consistent with reported clinical efficacy. Of interest, indomethacin showed equal or often better efficacy than the three DMARDs evaluated on inhibiting AHSS despite having limited ability to prevent joint damage clinically in patients. The translational value of performing PK-PD analysis of arthritis models in rats is discussed.
31118865 Casual effect of methotrexate+etanercept/infliximab on survival of patients with rheumat 2019 Background and objectives: Following the discovery of new drugs, physicians and pharmaceutical companies have become interested in examining patients' mortality and morbidity rates. In this respect, the effects of methotrexate (MTX)+etanercept/infliximab (ETA/INF) therapy on the survival of rheumatoid arthritis patients (RA) were evaluated in this study using marginal structural piecewise constant baseline hazard model. Patients and methods: According to the standard protocol, MTX is considered as the first-line treatment for RA patients. If there is no adequate response to MTX, biologic drugs will be added. To compare the survival rates of RA patients in MTX- and MTX+ETA/INF-treated groups, the piecewise constant baseline hazard model was fitted. Then, due to the existence of the time-dependent confounder (VAS) which was affected by previous treatment, the weight for each person-time was calculated via the inverse probability treatment weighting method. These weights were then used by marginal structural piecewise constant baseline hazard model. Finally, these models were compared. Results: The median (IQR) of the follow-up period in patients receiving MTX+ETN/INF and MTX was 11 (15.25) and 11 (31), respectively, and the 8-year survival rate was reported by 70% versus 68%, respectively. First, the piece-wise constant baseline hazard model was fitted. Fitting the given model showed that MTX+ETA/INF had a significant effect on patients' survival (HR=0.789, 95% CI [0.634, 0.983]). Second, marginal structural piecewise constant baseline hazard model was fitted. But, the results of this model revealed that MTX+ETA/INF did not have a significant impact on patients' survival (HR=0.968, 95% CI [0.860, 1.090]). Conclusion: Adjusting the pain score over time as a time-dependent confounder via marginal structural piecewise constant baseline hazard model, it has been demonstrated that MTX+ETA/INF does not have a significant effect on patients' survival rates. Therefore, a significant difference can be found between survival rates of these groups using longitudinal studies.
31782724 Does biologic survival depend on co-prescribed methotrexate dose in established rheumatoid 2020 Jan OBJECTIVE: Several seminal studies have suggested that a combination therapy of biologics with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) improve disease outcomes in rheumatoid arthritis (RA). Hence, most guidelines reflect this practice. It has also been shown that methotrexate (MTX) at a dose of 8-10 mg/week is perhaps sufficient to achieve better outcomes in early RA. However, it is not clear whether this strategy enhances biologic retention in the patients with established RA. We present a real-world retrospective study to investigate whether csDMARD co-prescription improves biologic retention and the optimal dose to preserve such response. MATERIALS AND METHODS: All patients prescribed biologic therapy for RA at our center between 2003 and 2017 were identified through the departmental database. They were split into five groups based on a weekly MTX dose (≤7.5 mg, 10-17.5 mg, ≥20 mg), other csDMARD prescription, or biologic monotherapy. The one-way analysis of variance model for independent values was utilized to ascertain the significance of data. The Mann-Whitney two-tailed U test was employed to determine the significance of relationship between the monotherapy group and other arms. The significance level was predefined at 0.05. RESULTS: A total of 168 patients with 198 biologic events were included. The mean age was 59.4 years (range, 24-90 years). 78% were women. The mean disease duration was 155.6 months (range, 15-491). There was a statistically significant difference (p=0.03) in biologic retention among the five arms. Compared to monotherapy, the data remained significant for ≥20 mg MTX and csDMARD groups; however, the biologic retention in the other two MTX arms was not significant. There was no significant relationship among groups for DAS28 improvement (p=0.24). CONCLUSION: Our results suggest that to improve biologic retention, the MTX dose should be increased to 20 mg a week or more, and, in people with MTX intolerance, csDMARDs co-presciption can be an alternative strategy. Maintenance with a low-to-moderate MTX dose can lead to poorer retention rates.
30886989 Malignancy risk in Australian rheumatoid arthritis patients treated with anti-tumour necro 2019 BACKGROUND: Tumour necrosis factor inhibitor (TNFi) therapy has been available for rheumatoid arthritis (RA) patients for several decades but data on the long-term risk of malignancy associated with its use is limited. Our aims were to assess malignancy risk in a cohort of Australian RA patients relative to the Australian population and to compare cancer risk for patients exposed to TNFi therapy versus a biologic-naïve group. METHODS: Demographic data for RA participants enrolled in the Australian Rheumatology Association Database (ARAD) before 31 Dec 2012 were matched to national cancer records in May 2016 (linkage complete to 2012). Standardised incidence ratios (SIRs) were used to compare malignancy incidence in TNFi-exposed and biologic-naïve ARAD participants with the Australian general population using site-, age- and sex-specific rates by calendar year. Malignancy incidence in TNFi-exposed participants and biologic-naïve RA patients, were compared using rate ratios (RRs), adjusted for age, sex, smoking, methotrexate use and prior malignancy. RESULTS: There were 107 malignancies reported after 10,120 person-years in the TNFi-exposed group (N = 2451) and 49 malignancies after 2232 person-years in the biologic-naïve group (N = 574). Compared with the general population, biologic-naïve RA patients showed an increased risk for overall malignancy (SIR 1.52 (95% confidence interval (CI) 1.16, 2.02) prostate cancer (SIR 2.10, 95% CI 1.18, 4.12). The risk of lung cancer was increased for both biologic naïve and TNFi-exposed patients compared with the general population (SIR 2.69 (95% CI 1.43 to 5.68) and SIR 1.69 (95% CI 1.05 to 2.90) respectively). For the TNFi-exposed patients there was an increased risk of lymphoid cancers (SIR 1.82, 95% CI 1.12, 3.18). There were no differences between the exposure groups in the risk of cancer for any of the specific sites examined. CONCLUSIONS: Overall malignancy incidence was elevated for biologic-naïve RA patients but not for those exposed to TNFi. TNFi exposure did not increase malignancy risk beyond that experienced by biologic-naïve patients. Lung cancer risk was increased for both TNFi-treated and biologic-naïve RA patients compared with the general population suggesting that RA status or RA treatments other than TNFi may be responsible in some way.
31212775 Achieving Pain Control in Rheumatoid Arthritis with Baricitinib or Adalimumab Plus Methotr 2019 Jun 12 The purpose of the study was to assess the proportion of patients who achieve pain relief thresholds, the time needed to reach the thresholds, and the relationship between pain and inflammation among patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate in RA-BEAM (NCT0170358). A randomized, double-blind trial was conducted, comparing baricitinib (N = 487), adalimumab (N = 330), and placebo (N = 488) plus methotrexate. Pain was evaluated by patient's assessment on a 0-100 mm visual analog scale (VAS). The following were assessed through a 24-week placebo-controlled period: the proportion of patients who achieved ≥30%, ≥50%, and ≥70% pain relief, the time to achieve these pain relief thresholds, remaining pain (VAS ≤ 10 mm, ≤20 mm, or ≤40 mm), and the relationship between inflammation markers and pain relief. Baricitinib-treated patients were more likely (p < 0.05) to achieve ≥30%, ≥50%, and ≥70% pain relief than placebo- and adalimumab-treated patients, as early as Week 1 vs. placebo and at Week 4 vs. adalimumab. A greater proportion of baricitinib-treated patients achieved ≤20 mm or ≤40 mm remaining pain vs. placebo- and adalimumab-treated patients. Baricitinib-treated patients tended to demonstrate consistent pain relief independent of levels of inflammation control. In RA patients with an inadequate response to methotrexate, baricitinib provided greater and more rapid pain relief than adalimumab and placebo. Analyses suggest the relationship between inflammation and pain may be different for baricitinib and adalimumab treatments.
30906325 Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotr 2019 We examined whether the cathepsin K inhibitor, ONO-5334, administered alone or in combination with methotrexate (MTX), could ameliorate joint destruction evoked by collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine type II collagen. ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of C-terminal telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) were measured. Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this collagen-induced arthritis monkey model. ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group. ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively. After treatment with ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion, ONO-5334 prevented joint destruction but not joint inflammation in this monkey CIA model. Concomitant use of ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore, ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of rheumatoid arthritis.