Upadacitinib for the treatment of rheumatoid arthritis

Introduction: Tofacitinib and baricitinib have recently been approved as second-line treatments for Rheumatoid arthritis (RA) though their maximum expected efficacy may be limited by dose-related toxicities. Upadacitinib selectively inhibits Janus Kinase 1 (JAK1) which could potentially reduce JAK2 and JAK3-related side effects.

Areas covered: In this paper, we review a newly developed oral selective JAK inhibitor, upadacitinib for the treatment of RA. The doses of upadacitinib extended-release 15 and 30 mg daily selected in phase III RA studies have shown a near-maximum efficacy in phase II studies. Upadacitinib inhibited radiographic progression and displayed rapid and sustained clinical and functional efficacy in RA when in combination with methotrexate (MTX), upadacitinib was superior to placebo in MTX-Inadequate Responders (IRs) and biologic disease modifying antirheumatic drugs-IRs while as monotherapy, it was superior to MTX in MTX-IRs and MTX-naïve patients. Upadacitinib was superior to adalimumab using ACR70, reduction of pain-VAS and improvement of HAQ-DI. The comparison with abatacept is still ongoing.

Expert commentary: Upadacitinib has displayed a rapid and favorable efficacy profile in RA but despite being a selective JAK1 inhibitor appears to have a similar safety profile to less-selective Jakinibs. Longer term safety data are awaited.     

Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic

Background/aim To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.Materials and methods A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).Results A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients. Conclusion Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.     

Psychosocial predictors of outcome in subjects with untreated depressive disorder

Untreated community volunteers (n = 66) with a significant reactive or neurotic depressive disorder were assessed at interview to determine predictors of improvement at 6 and at 20 weeks. The degree to which subjects improved by 6 weeks could be predicted by their pattern of improvement one week after initial interview and more definitely at the third week. Key baseline predictors of improvement both at 6 and at 20 week were the break-up of an intimate relationship in the preceding 12 months and weight loss, replicating findings in a study of depressive patients receiving psychiatric assessment and psychotherapy. Other isolated variables appeared to be predictors more of response to the non-specific therapeutic effects of the assessment process.     

Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature

Adherence to medication in patients with rheumatoid arthritis is low, varying from 30 to 80%. Improving adherence to therapy could therefore dramatically improve the efficacy of drug therapy. Although indicators for suboptimal adherence can be useful to identify nonadherent patients, and could function as targets for adherence-improving interventions, no indicators are yet found to be consistently and strongly related to nonadherence. Despite this, nonadherence behavior could conceptually be categorized into two subtypes: unintentional (due to forgetfulness, regimen complexity or physical problems) and intentional (based on the patient’s decision to take no/less medication). In case of intentional nonadherence, patients seem to make a benefit–risk analysis weighing the perceived risks of the treatment against the perceived benefits. This weighing process may be influenced by the patient’s beliefs about medication, the patient’s self-efficacy and the patient’s knowledge of the disease. This implicates that besides tackling practical barriers, clinicians should be sensitive to patient’s personal beliefs that may impact medication adherence.     

Diagnostic value of antibodies to modified citrullinated vimentin in early rheumatoid arthritis

The aim of this study was to evaluate the usefulness of antibodies to modified citrullinated vimentin (anti-MCV) for diagnosing early rheumatoid arthritis (RA) and to examine the correlations between anti-MCV and clinical parameters as well as radiographic and ultrasound data. Our results suggest that anti-MCV has a sensitivity and specificity of 53.3 and 83.3%, respectively, and a positive prognostic value of 96% in patients with early RA. Anti-MCV antibodies were observed in 48.5% of rheumatoid factor (RF)-negative RA patients in data from a latex test and in 35.7% of patients with negative results for immunoglobulin (Ig)-M-RF. The positive result for both anti-MCV and IgM-RF has a sensitivity of 42.2% and a specificity of 100%. No significant correlation was observed between anti-MCV and disease activity score using 28 joint counts, radiographic RA stage, number of erosions on ultrasonography of joints, and quality-of-life scores at disease onset. The Spearman correlation was significant in early RA patients with positive results of anti-MCV between the titers of this marker and arthritis duration, level of erythrocyte sedimentation rate, and IgM-RF. The best diagnostic strategy in early RA may be to assay both anti-MCV and IgM-RF. Thus, a question arises regarding the possible inclusion of anti-MCV in future revisions of the classification criteria of RA.     

Health status, adherence with health recommendations, self-efficacy and social support in patients with rheumatoid arthritis

A study was performed in 86 patients with rheumatoid arthritis (RA) to assess their health problems, the problems they experience in adhering to health recommendations and the relationships of these problems with self-efficacy and social support. Feeling dependent, disability and pain were the most important health related problems. The results showed self-efficacy to be related to the subjective experience of health status as measured by DUTCH-AIMS. Social emotional support was not related to health status and contrary to what we expected social instrumental support was positively related to health status. The majority of the patients (55%) experienced adherence problems with health recommendations. These problems were not related to functional incapacity, pain or other aspects of health status but to the patient's self-efficacy expectations about coping with arthritis. Our conclusion is that to improve the self-management of disability and pain and adherence to health recommendations, patient education should be aimed at strengthening self-efficacy expectations in which social emotional support might be a motivating factor.     

Exploring the impact of depressive symptoms and medication beliefs on medication adherence in hypertension--a primary care study

Objective

This study aimed to assess the levels of adherence in a sample of hypertensive patients being cared for in primary care in Northern Ireland and to explore the impact of depressive symptoms and medication beliefs on medication adherence.

Methods

The study was conducted in 97 community pharmacies across Northern Ireland. A questionnaire containing measures of medication adherence, depressive symptoms and beliefs about medicines was completed by 327 patients receiving antihypertensive medications.

Results

Analysis found that 9.3% of participants were non-adherent with their antihypertensive medication (self-report adherence scale) and 37.9% had scores indicative of depressive symptoms as determined by the Center for Epidemiological Studies Depression Scale (CES-D). In the univariate analysis, concerns about medications had negative effects on both adherence and depressive symptomatology. However, logistic regression analysis revealed that patients over the age of 50 were more likely to be adherent with their medication than those younger than 50. Depressive symptomatology and medication beliefs (concerns) were not significantly related to adherence in the regression analysis.

Conclusion

Depressive symptomatology was high in the sample as measured by the CES-D. Age was the only significant predictor of medication adherence in this population.

Practice implications

Health care professionals should consider the beliefs of the patient about their hypertensive medications and counsel younger patients on adherence.     

影响哮喘患者生活质量的心理和社会因素分析

目的探讨影响哮喘患者生活质量的心理社会因素,为制定心理干预和教育管理方案提供依据。方法对近10年来影响哮喘患者生活质量的心理社会因素的研究成果等进行综述。结果影响哮喘患者生活质量的心理社会因素主要包括:人格、应对、社会支持、情绪等。结论应该从改变患者的应对方式,提高其社会支持、改善情绪等方面入手,提高哮喘患者的生活质量。     

新婚夫妻婚前暴力社会心理因素探讨

目的了解新婚登记夫妻婚前暴力的社会心理因素,为制定防止家庭暴力有关政策及心理干预提供科学的理论依据。方法采取横断面调查。于2005年11月—2006年2月在长沙市5个市辖区中抽取2个市辖区,再在每个市辖区对新婚登记夫妻进行自编的新婚夫妻婚前暴力调查问卷评估,仅限于初婚的夫妻。根据新婚夫妻报告在婚前1年至少有1次暴力的发生作为暴力家庭组(Spouse v iolence,SV组),有122对(244人);婚前1年双方都无暴力的发生作为非暴力家庭组(非SV组),195对(390人)。结果婚前暴力的前3位诱发因素是夫妻的个性与应对方式问题、沟通与交流不足、经济问题或工作问题。SV组同居、饮酒史、赌博高于非SV组(P<0.01)。SV组职业与非SV组比较,差异有显著性(P<0.05),其中干部或职员的比例(54.9%)明显高于非SV组(46.9%)(P<0.05)。结论新婚夫妻在婚前出现暴力的主要诱发因素是个性和/或应对方式问题、沟通与交流问题、经济问题或工作问题。婚前暴力与职业、同居、赌博、饮酒史均有一定的相关性。     

A randomized clinical trial for the assessment of the efficacy and safety of guluronic acid (G2013) in patients with rheumatoid arthritis

Objective: To evaluate the safety, efficacy and tolerability of guluronic acid (G2013) in order to treat the rheumatoid arthritis patients who had inadequate response to conventional drugs.

Methods: A randomized, 12-week clinical trial with two treatment arms: guluronic acid (G2013) and conventional treatment was performed. The diagnosed RA patients according to the ACR/European League against Rheumatism 2010 classification criteria, with an active disease at baseline that had inadequate response to conventional therapy were considered for the study. G2013 was administered orally twice a day with capsules of 500 mg during a period of 12 weeks and the patients were followed up for the safety and efficacy.

Results: Our data showed that, the mean changes in the G2013 and control groups were ?7.54 and ?2.5 for tender joint count; ?7.59 and ?3.59 for swollen joint count; ?30 and ?0.9 for physician global assessment; ?23.18 and ?1.81 for patient global assessment; ?14.45 and ?1.45 for erythrocyte sedimentation rate, respectively. Improvements seen with G2013 were significantly greater than those with conventional drugs. In total, in 15.3% of G2013-treated patients and 69.2% of conventional-treated patients adverse events (AEs) occurred in this study.

Conclusion: These data from routine rheumatology clinical practice highlight the effectivenessof G2013 in combination with conventional therapy with more desirable safety profile compared to the conventional-treated patients. Therefore, G2013 therapy could be an appropriate choice in order to manage the RA disease. (Clinical trial identifier: IRCT2016092813739N5).     

Development and content of a group-based intervention to improve medication adherence in non-adherent patients with rheumatoid arthritis

Objective

To describe the systematic development and content of a short intervention to improve medication adherence to disease-modifying anti-rheumatic drugs in non-adherent patients with rheumatoid arthritis (RA).

Methods

The intervention mapping (IM) framework was used to develop the intervention. The following IM steps were conducted: (1) a needs assessment; (2) formulation of specific intervention objectives; (3) inventory of methods and techniques needed to design the intervention and (4) production and piloting of the intervention.

Results

The intervention (consisting of two group sessions led by a pharmacist, a homework assignment, and a follow-up call) aims to improve the balance between necessity and concern beliefs about medication, and to resolve practical barriers in medication taking. The central communication method used is motivational interviewing.

Conclusion

By applying the IM framework, we were able to create a feasible, time-efficient and promising intervention to improve medication adherence in non-adherent RA patients. Intervention effects are currently being assessed in a randomized controlled trial.

Practice implications

This paper could serve as a guideline for other health care professionals when developing similar interventions. If the RCT demonstrates sufficient effectiveness of this intervention in reducing medication non-adherence in RA patients, the intervention could be embedded in clinical practice.     

潜艇官兵社交回避及苦恼的心理社会因素研究

目的探讨导致潜艇官兵社交回避及苦恼的心理社会因素。方法对568名潜艇官兵进行量表测评,包括社交回避及苦恼量表、卡特尔16种人格因素问卷、生活事件量表、特质应对问卷、领悟社会支持量表、症状自评量表。数据采用SPSS15.0软件包进行统计分析。结果潜艇官兵社交回避(SA)和社交苦恼(SD)分值均显著低于国内大学生常模(SA:t=-3.28,P<0.01;SD:t=-2.24,P<0.05);不同衔级(SA:F=13.02,P<0.01;SD:F=5.58,P<0.01)、文化程度(SA:F=3.94,P<0.05;SD:F=3.77,P<0.05)、婚姻状况(SA:t=-5.22,P<0.01;SD:t=-2.63,P<0.01)潜艇官兵的社交焦虑状况比较存在显著差异;潜艇官兵社交回避及苦恼与个性、生活事件、特质应对、社会支持、心理健康水平有显著相关性;多元回归分析显示,人际关系敏感、敢为性、消极应对方式和兴奋性对社交回避行为的影响较大(标准回归系数依次为-0.274-、0.246、0.230-、0.227);敢为性、强迫症状、积极应对方式和敌对对社交苦恼情感的影响较大(标准回归系数依次为-0.332-、0.305-、0.300-、0.258)。结论个性、生活事件、特质应对、社会支持和心理健康水平等心理社会因素影响潜艇官兵社交回避及苦恼。     

Leflunomide in the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic and highly morbid disease affecting approximately 1% of the world’s population. With the advent of disease-modifying antirheumatic drugs, patients are increasingly able to maintain control of their arthritis and prevent joint destruction. However, not all patients respond adequately to any single disease-modifying antirheumatic drug, and many newer parenteral therapies are cost prohibitive. Leflunomide, an inhibitor of pyrimidine biosynthesis, is the first oral disease-modifying antirheumatic drug to have been approved for rheumatoid arthritis in the USA in the last 15 years, and is now widely used in over 70 countries around the world. Leflunomide is efficacious when used as monotherapy or in combination with methotrexate to treat patients with rheumatoid arthritis, and is generally well tolerated. As clinical use increases, new ways to use leflunomide in order to minimize toxicity and maximize efficacy are being explored.     

Apremilast for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.     

The influence of early life factors on the risk of developing rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that develops as a result of the interaction between genetic and environmental risk factors. Although increasing evidence shows the importance of genes in determining the risk of RA, it is clear that environmental factors also have a vital role. Studies to date have tended to concentrate on environmental influences around the time of disease onset. However, a number of pieces of evidence, including the fact that autoantibodies, such as rheumatoid factor (RF), can develop several years before the onset of clinical disease, suggest that environmental factors may influence disease susceptibility during early life. Several recent studies lend weight to this possibility, with an increased risk of RA in the offspring of mothers who smoked during pregnancy and in those with higher birth weight. There has also been a suggestion that the risk of RA is reduced in breast-fed infants. We describe the evidence surrounding the effect of early life factors on the risk of developing RA and possible mechanisms by which they may act.     

Iguratimod for the treatment of rheumatoid arthritis in Japan

Iguratimod (IGU), a small-molecule compound, was developed as a disease-modifying antirheumatic drug in Japan. The pharmacological studies showed that inhibition of the production of cytokines and immunoglobulins mainly contributes to its improvement effect on animal arthritis models. The first clinical study of IGU in Japanese patients with rheumatoid arthritis was started in 1992 and Phase III studies were started in 1998. From the results of Phase II studies, a dose-escalating regimen was recommended to relieve the side effects. In a double-blind study comparing the efficacy and safety of the drug with those of placebo and salazosulfapyridine, it was confirmed that IGU was superior to placebo and was not inferior to salazosulfapyridine. Furthermore, a double-blind controlled trial of IGU in combination with methotrexate revealed an efficacious and manageable safety profile. IGU would be widely used as a new option for rheumatoid arthritis treatment and combination drug with methotrexate.     

Immunohistology of the early course of lentivirus-induced arthritis

Caprine arthritis encephalitis (CAE) is a lentiviral infection of goats characterized by mononuclear cell infiltration of various tissues, most prominently the joints, mammary glands and, in young animals, the brain. We have investigated the early stages of arthritis induced by intracarpal and intravenous infection with molecularly cloned CAE virus. Analysis of the synovial membranes by immunohistological methods showed that the proportion of CD8⁺T cells peaked around day 12 post-infection. CD4⁺ T cells increased to a lesser degree. The relative proportion of B cells rose steadily post-infection. At 33 days post-infection, plasma cells accounted for over one third of all inflammatory cells in the inflamed synovium. Histopathologically, the arthritic lesions in the synovial membranes closely resembled those in membranes of animals with a 2-year history of chronic arthritis. Our observations indicate that this type of short-term experimental infection is particularly suitable for studying the pathogenesis of goat lentiviral infection. In addition, our observations support the view that a predominantly humoral (type 2) immune response may contribute to the pathogenesis of CAE.     

Adalimumab for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease occurring in 6–39% of patients with psoriasis. Standard therapy of PsA includes nonsteroidal anti-inflammatory drugs, intra-articular steroids and disease-modifying antirheumatic drugs. Failure of standard therapy is an indication for anti-TNF-α therapy. Adalimumab – a fully human monoclonal antibody against TNF-α – is an effective and generally reasonably well-tolerated drug for treating signs and symptoms of PsA. In placebo-controlled clinical trials, adalimumab showed American College of Rheumatology (ACR)20 response rates of 39–58% and ACR50 response rates of 25–39% in patients with active PsA who had failed previous standard therapy. Significant improvement of psoriatic skin changes and disease-related quality of life were also noted. The response of joints and skin and quality of life improvement was sustained over 2 years of therapy. In addition, adalimumab suppressed structural joint damage and retards radiographic progression of PsA.     

Abatacept for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that abatacept may play a role in the progression and/or even the initiation of RA.

Areas covered: a review of the different studies carried out during clinical development of abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors.

Expert commentary: abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.