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29302803 Update on the prevalence and incidence of rheumatoid arthritis in Korea and an analysis of 2018 Apr The objectives of this study are to identify the prevalence and incidence of rheumatoid arthritis (RA) and to investigate the patterns of medical care and drug utilization by RA patients in Korea. Korean National Health Insurance claims data were used for analysis. RA patients were defined as those having an RA code from 2009 to 2012 and using disease-modifying anti-rheumatic drugs (DMARDs) within 1 year after the code. RA patients identified in 2010 with a disease-free period for 12 months before the index date, and those who received continuous treatment in 2011-2013 were defined as incident cases. Patterns of medical care and drug utilization were compared among subgroups. The prevalence of RA increased yearly from 0.28% in 2009 to 0.32% in 2012. The incidence of RA in 2010 was 28.5 per 100,000 person-years. The use of biologic DMARDs (bDMARDs) increased from 2.31% in 2009 to 4.05% in 2012. Hydroxychloroquine (57.53-62.45%) was the most commonly used the conventional DMARDs, followed by methotrexate (49.99-51.87%). The use of bDMARDs (1.39 vs. 2.43%) was less frequent in EORA patients than YORA patients. Hydroxychloroquine (74.96 vs. 72.11%) was more frequently used, but methotrexate (55.24 vs. 59.25%) and sulfasalazine (27.96 vs. 32.72%) were used less frequently in EORA patients than in YORA patients. The prevalence of RA has increased in Korea. EORA patients used fewer bDMARDs, methotrexate, and sulfasalazine but more hydroxychloroquine than YORA patients.
29780157 Targeting Acquired Hemophilia A with Rheumatoid Arthritis by a Rituximab Shot: A Case Repo 2018 May 21 BACKGROUND Acquired hemophilia A (AH) is a rare hemorrhagic diathesis, characterized by the presence of autoantibodies directed against the pro-coagulant activity of factor VIII. It is associated with rheumatoid arthritis (RA) in 4% to 8% of cases and its prognosis remains severe. CASE REPORT A 66-year-old patient has been followed up for 20 years for deforming and severe RA, which was in low-disease activity. However, the patient presented a polyarticular flare involving the metacarpophalangeal and the proximal interphalangeal joints, the left elbow, and the right knee, which was warm and swollen. Articular puncture of this knee yielded a hematic fluid that did not coagulate. Its cytological analysis showed significant presence of red blood cells, which were also abundantly present in the other cell lines. Activated partial thromboplastin time was lengthened and not corrected by the addition of control plasma. Prothrombin time (Quick's test), fibrinogen level, and vitamin K-dependent factors were without abnormalities. In contrast, factor VIII was collapsed at 7% and the anti-factor VIII antibody was positive. The diagnosis of AH with anti-factor VIII inhibitor was thus retained. With regard to RA, the Disease Activity Score was 6.32 and exhibited a very active RA. Rituximab with methotrexate was begun and the evolution was favorable. After 6 months, the reappearance of the anti-factor VIII inhibitor was found, thus justifying a second cycle of rituximab. CONCLUSIONS AH is not exceptional in RA. Rituximab remains a relevant alternative for managing simultaneous AH with inhibitor and RA.
29205926 A retrospective review of the persistence on bDMARDs prescribed for the treatment of rheum 2018 Aug AIM: To describe the persistence of biologic disease modifying anti-rheumatic drugs (bDMARDs) in Australian rheumatoid arthritis (RA) patients, and assess the influence of methotrexate and other conventional DMARD (cDMARD) concomitant medications, and treatment line on bDMARD persistence and glucocorticoids usage. METHOD: RA patients, from the 10% Australian Medicare random sample, aged ≥18 for whom bDMARDs were dispensed were included. Individual sub-cutaneous (SC) anti-tumor necrosis factor-α (anti-TNFα) agents were combined as they were equivalent. RESULTS: Data from 1230 patients were analyzed. For all patients the 12-month persistence rates (based on Kaplan-Meier estimates) were 76% for intravenous (IV) tocilizumab, 63% abatacept (SC/IV), 61% SC-anti-TNFs and 36% IV-infliximab. Persistence rates on first-line bDMARDs were 79% (tocilizumab and abatacept), 64% (SC-anti-TNFs) and 13% (infliximab); rates were sustained for tocilizumab but dropped to 49% for abatacept and 51% for SC-anti-TNFs in the second-line setting. Median treatment persistence was 40 months tocilizumab (95% CI: 30-ND), 33 months abatacept (95% CI: 20-ND); 22 months SC-anti-TNF (95% Cl: 18-27), and 4 months infliximab (95% CI: 2-13). Longer persistence was observed for SC-anti-TNFs and abatacept combined with methotrexate or other cDMARDs. For tocilizumab, persistence was robust with or without concomitant medications. The median oral glucocorticoid doses decreased from 4.1 mg/day (min 0, max 21) to 2.0 mg/day (min 0, max 17.3) over 2 years. CONCLUSIONS: Treatment persistence was longer on tocilizumab followed by abatacept then SC-anti-TNF therapy and was influenced by co-therapy. Glucocorticoid dosage decreased with bDMARD use. This real-world data highlights that persistence on bDMARDs differs according to biologics mode of action and co-therapy.
29671942 Comparative efficacy and safety of biosimilar-infliximab and originator-infliximab in comb 2018 May OBJECTIVE: We aimed to assess the relative efficacy and safety of biosimilar-infliximab and originator-infliximab in combination with methotrexate (MTX) compared to placebo plus MTX in active rheumatoid arthritis (RA). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of biosimilar + MTX and infliximab + MTX and placebo + MTX (MTX group) in patients with active RA despite treatment with MTX. RESULTS: Seven RCts involving 2606 patients met the inclusion criteria. The American College of Rheumatology (ACR)20 response rate was significantly higher in the biosimilar + MTX group than in the MTX group (odds ratio [OR] 3.31, 95% credible interval [CrI] 1.74-6.06). Similarly, the ACR20 response rate was significantly higher in the infliximab + MTX group than in the MTX group (OR 3.15, 95% CrI 1.99-4.70). There was no difference in the ACR20 response rate between the biosimilar+ MTX and infliximab + MTX groups. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that treatment with biosimilar + MTX had the highest probability of achieving the ACR20 response rate (SUCRA = 0.7964), followed by infliximab + MTX (SUCRA = 0.7018) and MTX alone (SUCRA = 0.0018). The ACR50 and ACR70 response rates showed a similar distribution pattern to the ACR20 response rate. By contrast, the safety based on the number of serious adverse events (SAEs) did not differ significantly among the three interventions. CONCLUSIONS: Biosimilar- and originator-infliximab, in combination with MTX, represent effective interventions for active RA, with a low risk of SAEs. No significant difference between biosimilar- and originator-infliximab was found in terms of efficacy and safety.
30341453 On-drug and drug-free remission by baseline symptom duration: abatacept with methotrexate 2018 Dec Clinical outcomes in patients with early rheumatoid arthritis (RA) were assessed by baseline symptom duration in the Assessing Very Early Rheumatoid arthritis Treatment trial (ClinicalTrials.gov; NCT01142726). Patients with early, active RA were randomized to subcutaneous (SC) abatacept 125 mg/week plus methotrexate (MTX), SC abatacept alone, or MTX monotherapy for 12 months. All RA treatments were withdrawn after 12 months in patients with Disease Activity Score in 28 joints (C-reactive protein; DAS28-CRP) < 3.2. In this post hoc analysis, the proportion of patients achieving protocol-defined remission (DAS28-CRP < 2.6) or improvement in physical function at 12 and at both 12 and 18 months was assessed according to symptom duration (≤ 3 months, > 3 to ≤ 6 months, or > 6 months) and treatment group. No clinically significant differences were seen in baseline demographics or characteristics across symptom duration groups. Irrespective of baseline symptom duration, a numerically higher proportion of abatacept plus MTX-treated patients achieved DAS-defined remission at month 12 and sustained remission at month 18 compared with MTX monotherapy. A numerically higher proportion of abatacept plus MTX-treated patients with symptom duration ≤ 3 months maintained DAS-defined remission after complete treatment withdrawal from 12 to 18 months compared with longer symptom duration groups. This subgroup also had the fastest onset of clinical response (DAS28-CRP < 2.6) after initiation of treatment. Health Assessment Questionnaire-Disability Index response was similar regardless of baseline symptom duration. Overall, symptom duration of ≤ 3 months was associated with a faster onset of clinical response and higher rates of drug-free remission following treatment with abatacept plus MTX.
29745884 Type IV collagen metabolism is associated with disease activity, radiographic progression 2018 Sep OBJECTIVES: The expanding spectrum of targeted therapies for rheumatoid arthritis (RA) implies a need for development of precision tools for disease assessment reflecting pathobiologic processes. Type IV collagen is an abundant protein of basement membranes, but is also present in the intercellular matrix of the synovial lining layer. We aimed to investigate the association of type IV collagen turnover with RA disease activity, response to IL-6 inhibition and radiographic progression. METHODS: C4M, a serologic marker of type IV collagen metabolism, was measured at baseline and at follow-up in serum samples of RA patients participating in the phase III studies LITHE (n=687) and RADIATE (n=217). Both were double-blinded, placebo-controlled clinical trials testing the safety and efficacy of 4 and 8 mg/kg tocilizumab (TCZ) in combination with methotrexate (MTX) vs. MTX plus placebo. Associations with disease activity, radiographic severity and ACR response were investigated. RESULTS: Baseline C4M correlated significantly with clinical disease parameters in both study populations, including DAS28, HAQ score and VASpain (all p<0.00001). C4M at baseline correlated significantly with change in JSN (p=0.001) and Sharp score (p=0.00002) at 52 weeks. TCZ lowered C4M by 11-40% in a dose dependent manner. The likelihood of achieving an ACR20 response by week 16 was associated with C4M suppression exceeding the median decrease at week 4 (p<0.0001). CONCLUSIONS: Type IV collagen remodelling was associated with disease activity and radiographic progression in RA and was persistently and dose-dependently suppressed by TCZ. These findings indicate that C4M may serve as a plausible biologic marker of destructive synovitis growth in RA.
29532212 Predicting methotrexate resistance in rheumatoid arthritis patients. 2018 Jun Rheumatoid arthritis (RA) is an incurable, systemic autoimmune disease that decreases quality of life and can lead to severe disability. While there are many medications available to treat RA, the first-line of therapy is low-dose methotrexate (MTX), a small molecule disease-modifying anti-rheumatic drug (DMARD). MTX is the recommended therapy due to its affordability and efficacy in reducing symptoms in most RA patients. Unfortunately, there is great person-to-person variability in the physiological response to MTX, with up to 50% of patients showing little response to the medication. Thus, many RA patients initially placed on MTX do not experience an adequate reduction of symptoms, and could have benefited more in both the short and long terms if initially prescribed a different drug that was more effective for them. To combat this problem and better guide treatment decisions, many research groups have attempted to develop predictive tools for MTX response. Currently, there is no reliable, clinical-grade method to predict an individual's response to MTX treatment. In this review, we describe progress made in the area of MTX non-response/resistance in RA patients. We specifically focus on application of the following elements as predictive markers: proteins related to MTX transport and function, intracellular MTX concentration, immune cell frequencies, cytokines, and clinical factors.
30142184 Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patient 2018 OBJECTIVE: The mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA). METHODS: Between October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined. RESULTS: We followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity. CONCLUSION: Risk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.
30394138 Upadacitinib for the treatment of rheumatoid arthritis. 2019 Jan 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.
29228799 Calprotectin in patients with chronic rheumatoid arthritis correlates with disease activit 2018 Feb OBJECTIVE: Calprotectin (myeloid-related protein 8/14) is elevated in inflammatory diseases and a correlation of serum calprotectin and disease activity in rheumatoid arthritis (RA) has been shown. In this study, we investigated plasma calprotectin as a disease marker in patients with chronic RA treated with methotrexate (MTX) monotherapy and compared plasma calprotectin with C-reactive protein (CRP) in this matter. METHODS: Seventy-six patients with chronic RA were included in this open prospective study and of these 40 were included prior to initiation of MTX therapy. The patients were followed with laboratory and clinical parameters for 52-56 weeks. Plasma calprotectin was analyzed at the start of study and at various intervals. Radiographic evaluation was performed at baseline and after 17.2 months and progression in joint destruction was measured with Larsen score. The response to MTX was evaluated according to the American College of Rheumatology criteria. RESULTS: Patients starting MTX treatment had significantly higher levels of plasma calprotectin compared to patients well established on MTX therapy (p = .008). Among the 40 patients naive to MTX, 25 responded to MTX therapy and serum calprotectin decreased significantly in these patients (p = .0007). The radiographic damage showed no relation to calprotectin. CONCLUSIONS: Plasma calprotectin is associated with disease activity in patients with chronic RA and is more strongly correlated to MTX response compared to CRP. The role of calprotectin as a disease marker is promising and the advantages compared to CRP needs to be further investigated.
30076156 Predictors of disease activity and structural progression after treatment with adalimumab 2018 Nov OBJECTIVES: Methotrexate is considered to be first-line therapy for rheumatoid arthritis (RA). However, a substantial proportion of treated patients do not achieve the desired goals of therapy. This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA. METHODS: The Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for <1 and <3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients. This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months. Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval. In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year. RESULTS: Baseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP. Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy. CONCLUSIONS: In patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months. The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes. These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA. TRIAL REGISTRATION NUMBER: NCT00420927, NCT00195663; Post-results.
30168781 Methotrexate-related lymphoproliferative disorder of the lumbar spine origin presenting wi 2018 Nov 1 The use of methotrexate (MTX) to treat rheumatoid arthritis (RA) is increasing. Recently, MTX-associated lymphoproliferative disorder (MTX-LPD) has been frequently reported as lymphoma occurring during MTX therapy. The authors report their experience with a relatively rare case of MTX-LPD presenting in the lumbar spine. The patient, a 73-year-old woman who experienced low-back pain while receiving MTX therapy for RA, was suspected of having developed MTX-LPD based on her medical history, images of the L1 vertebra, and transpedicular biopsy results. One week after discontinuing MTX, the patient's low-back pain reportedly improved. The woman was diagnosed with MTX-LPD based on histopathological findings. MTX discontinuation alone coincided with spontaneous tumor regression. Because MTX-LPD can occur in tissues other than lymph nodes, such as in bones and joints, it is a disease that should be considered when diagnosing spinal tumors in patients receiving MTX therapy.
28388816 Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators 2018 Feb OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.
29886354 Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the A 2018 Aug BACKGROUND AND AIMS: To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study. METHODS: Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time. RESULTS: In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept. CONCLUSIONS: Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism.
30078086 Structural damage progression in patients with early rheumatoid arthritis treated with met 2018 Sep The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.
30587928 Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient 2019 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and systemic manifestations, such as anemia, fatigue, osteoporosis, and increased risk for cardiovascular diseases. The pathogenesis of RA is driven by a complex network of proinflammatory cytokines, with a pivotal role of IL-6 and tumor necrosis factor (TNF). The management of RA has been dramatically changed during the last years by the introduction of a treat-to-target approach aiming to achieve an acceptable disease control. Nowadays, TNF inhibitors (TNFis) are the most frequently prescribed class of biologic therapies, but the significant proportion of patients experiencing the failure of a TNFi led to the development of alternative therapeutic options targeted on different pathways. Considering the increasing number of targeted therapeutic options for RA, there is a growing interest in the identification of potential predictors of clinical response to each available mechanism of action, with the aim to drive the management of the disease toward a personalized approach according to the concept of precision medicine. Tocilizumab (TCZ) is the first humanized anti-IL-6 receptor subunit alpha (anti-IL-6R) monoclonal antibody approved for the treatment of RA refractory to methotrexate or TNFis. TCZ inhibits both the cis- and trans-signaling cascades involving the Janus kinase-signal transducer and the activator of transcription pathway, playing a crucial role in modulating not only joint inflammation but also the previously mentioned extra-articular manifestations and comorbidities of RA, such as fatigue, anemia, bone loss, depression, type 2 diabetes, and increased cardiovascular risk. In this review, moving from pathogenetic insights and evidence-based clinical data from randomized controlled trials and real-life observational studies, we will discuss the drivers for the selection of patient candidates to receive TCZ, in order to clarify the current positioning of this drug in the treatment algorithm of RA.
29510810 Structural joint damage and hand bone loss in patients with rheumatoid arthritis. 2018 Mar Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, swelling and progressive destruction of the joints leading to loss of function and invalidity. The bone destruction in RA is characterised by two distinct features: structural joint damage and hand bone loss, and their prevention is an important treatment goal. Inhibitors of tumour necrosis factor alpha (TNF-inhibitors) have markedly improved the treatment options in RA patients who fail treatment with conventional synthetic Disease Modifying Anti Rheumatic Drugs (sDMARDS), but their effectiveness with regards to structural joint damage and hand bone loss, predictors thereof and the association with disease activity during treatment have mainly been investigated in randomized controlled trials (RCTs) with limited generalizability due to strict in- and exclusion criteria.
 The main aim of the PhD thesis was to assess and predict structural joint damage and hand bone loss in patients with early and established RA treated with sDMARDs and TNF-inhibitors. This was investigated in two cohorts: A) The "DANBIO X-ray study": an observational, nationwide, longitudinal cohort study of established RA patients treated in clinical practice who initiated TNF-inhibitor treatment after failure of sDMARDs and B) The "OPERA study": a randomized controlled trial of sDMARD-naïve patients with early RA treated with methotrexate (MTX) and intraarticular glucocorticoid injections in combination with adalimumab or placebo-adalimumab. Structural joint damage progression was assessed with the Sharp/van der Heijde radiographic method and hand bone loss was assessed with Digital X-ray Radiogrammetry. 
From the studies presented in the PhD thesis the following was concluded:
 Structural joint damage progression and hand bone loss were significantly lower during two years of TNF-inhibitor treatment compared to the previous two years of sDMARD-treatment in the DANBIO X-ray Study. The majority of patients had no progression of structural joint damage during two years of TNF-inhibitor treatment, while hand bone loss remained increased compared to reference values from the general population in the majority of patients. Adalimumab had no impact on hand bone loss in the OPERA study.
 Existing structural joint damage, older age, IgM-rheumatoid factor positivity and concomitant treatment with prednisolone were independent predictors of progression in structural joint damage in the DANBIO X-ray cohort, while high hand bone loss in the first 6 months of treatment and placebo treatment were independently associated with increase in structural joint damage scores in the OPERA study. A high hand bone mass and disease activity were independent predictors of increased hand bone loss in the DANBIO X-ray study, while older age and high functional disability predicted hand bone loss in the OPERA study. High disease activity during treatment was associated with structural joint damage progression during TNF-inhibitor treatment in the DANBIO X-ray study and with hand bone loss in the DANBIO X-ray and OPERA studies.
29224127 Defining and characterizing sustained remission in patients with rheumatoid arthritis. 2018 Apr The objective of this study is to characterize stability and clinical features of patients with rheumatoid arthritis (RA) in sustained remission. Combination therapy with methotrexate and tumor necrosis factor inhibitors (TNFi) has increased remission rates in RA but optimal regimens to maintain remission are unknown. We describe Study of Etanercept And Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis (SEAM-RA) and data from a run-in period of longitudinal observation. Patients in Simplified Disease Activity Index (SDAI) remission (score ≤ 3.3) receiving etanercept and methotrexate were screened and had to maintain remission over 3 run-in visits/24 weeks before randomization to combination therapy or withdrawal of etanercept or methotrexate. Baseline characteristics were examined for predictive factors for maintaining remission. As of November 2016, 141 patients have enrolled; of these, 64 have been randomized, 34 were ineligible after run-in, and 43 are in run-in period; 70% have completed run-in. Enrolled and randomized patients, respectively, had mean (standard deviation [SD]) disease duration 11.0 (8.6) and 12.6 (9.7) years; mean (SD) duration of etanercept use 4.2 (3.8) and 4.9 (4.2) years; mean (SD) methotrexate dose 15.9 (4.8) and 15.5 (4.9) mg/week; and mean (SD) SDAI scores 1.5 (0.9) and 1.4 (0.8). At enrollment, 73% and 63% were in Boolean remission based on 28 joints and 66/68 joints, respectively. No enrollment characteristic predicted successful completion of run-in. Two-thirds of patients considered to be in remission at enrollment sustained remission through 24 weeks. Baseline characteristics of enrolled patients and those who completed run-in were comparable.
29667330 No increased risk of herpes zoster in TNF inhibitor and non-TNF inhibitor users with rheum 2018 Sep OBJECTIVE: It is controversial whether the use of biological disease-modifying antirheumatic drugs (DMARDs) increases the risk of herpes zoster (HZ). We aimed to evaluate the risks of HZ in tumor necrosis factor inhibitor (TNFI) and non-TNFI users with rheumatoid arthritis (RA) over 3 years in Japan. METHOD: Using the Japanese health insurance database, we assigned patients with at least one RA diagnostic code and one prescription for any DMARDs (RA cases) recorded between January 2005 and December 2013 to the RA group. We randomly selected five age-, sex-, calendar year- and observation length-matched non-RA cases for each RA case (non-RA group), and assessed associations between RA and HZ. To evaluate the risks of HZ in TNFI and non-TNFI users, we conducted a nested case-control study (NCC) in the RA group. RESULTS: The RA group (n = 6712) had a significantly higher crude incidence rate of HZ than the non-RA group (n = 33 560) (14.2 vs. 8.3/1000 patient-years), and the adjusted odds ratio (95% confidence interval) of the RA versus non-RA groups was 1.43 (1.17-1.75). The NCC demonstrated that use of TNFI, non-TNFI, methotrexate, or immunosuppressive DMARDs did not increase the risks of HZ. Use of corticosteroid ≥ 5 mg/day conveyed a significant risk of HZ in patients with RA. CONCLUSIONS: Rheumatoid arthritis was significantly associated with the development of HZ, and use of corticosteroids ≥ 5 mg/day was identified as a significant risk factor, whereas either TNFI or non-TNFI use were not.
29530998 Clinical Significance of Myeloid-Related Protein 8/14 as a Predictor for Biological Treatm 2018 Jan OBJECTIVES: To investigate the serum level of Myeloid-Related Protein 8/14 complex (MRP8/14) and to predict and monitor the response to biologic treatment in rheumatoid arthritis (RA) patients. METHODS: Each patient underwent clinical examination and blood sampling for assessment of serum high-sensitivity C-reactive protein (hs-CRP) levels, erythrocyte sedimentation rate (ESR), rheumatoid factors (RF), anti-cyclic citrullinated protein antibodies (anti-CCP), and serum concentrations of MRP8/14 protein complexes (myeloid-related proteins, MRP8/14) were measured at baseline, and weeks 4 and 12 (after initiation of treatment). RESULTS: Serum MRP8/14 protein complex levels correlated with DAS28 and anti-CCP antibody. MRP8/14 protein complex levels decreased significantly after 12 weeks treatment with biological therapy: mono-rhTNFR-Fc active group. rhTNFR-Fc plus methotrexate (MTX) decreased MRP8/14 protein complex levels from 11839±1849 ng/ml to 5423±1130 ng/ml (p<0.01) a reduction of 54.2% compared with 32.9% in the rhTNFR-Fc group. CONCLUSIONS: MRP8/14 protein complex levels were increased in active stage RA patients. MRP8/14 levels were decreased with rhTNFR-Fc treatment, suggesting serum concentrations of MRP8/14 protein complex might be a promising biomarker to predict responses to biological therapy in active RA patients at baseline and could be used to monitor responses to treatment across different mechanisms of action.