DMARD Treatment Research Articles

Biologic DMARD Treatment and Bone Strength and Structure in Psoriatic Arthritis

Biologic DMARD Treatment and Bone Strength and Structure in Psoriatic Arthritis

Should ultrasound be used routinely in the diagnosis of rheumatoid arthritis?

A growing body of evidence indicates the benefits of early diagnosis of rheumatoid arthritis (RA) and prompt treatment with disease-modifying anti-rheumatic drugs (DMARDS) in terms of relieving symptoms, improving prognosis, and reducing long-term complications. There is however some controversy over the most beneficial method of imaging in providing accurate early diagnosis. Though current practice favours clinical and radiological assessment, this is increasingly supplemented by ultrasound techniques (and, to a lesser extent, CT and MRI scanning). While EULAR and ESSR favour the use of ultrasonography (US) as the first-line investigation in cases of suspected RA, a recent NICE review upholds the traditional place of plain film radiographs of hands and feet to detect erosions as early signs of synovitis. This review considers the evidence for US in the early diagnosis of RA and the case for it becoming the primary assessment modality in rheumatology clinics. This paper aims to assess the current literature on the efficacy of ultrasonography in diagnosing early RA, by comparing US with alternative imaging modalities. The goal is to propose the most appropriate method of diagnosis to improve early initiation of DMARD treatment for optimum disease outcomes. Searches for related studies and review articles were carried out using electronic databases and hand searches. Additional references were gleaned from the bibliographies of included papers. Related articles and pop-outs from PubMed were also used. The search was refined in PubMed, by only using reviews which were written in English and published in past 10 years and had full free text available. This review confirms that US has a high level of sensitivity in diagnosing RA (and hence a low risk of missing cases of RA which might benefit from early treatment with DMARDs). It also has a high level of specificity (and hence a low risk of falsely diagnosing somebody with RA who may suffer adverse effects of DMARD therapy). US is already widely available and well accepted by clinicians and patients. It does not involve exposure to radiation and can be readily delivered by appropriately trained staff. This review of relevant studies indicates that US should become accepted as the investigation with the most favourable balance of benefits to risks in the early diagnosis of RA. Given the continuing controversy surrounding studies of different imaging techniques in RA, further research into the diagnostic role of US in RA is indicated.

Interleukin-36 family dysregulation drives joint inflammation and therapy response in psoriatic arthritis.

ObjectivesIL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy.MethodsSynovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes.ResultsPsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts.ConclusionThe impaired balance between IL-36 agonists–antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.

Factors associated with commencing and ceasing opioid therapy in patients with rheumatoid arthritis

ObjectiveTo determine factors associated with opioid use in rheumatoid arthritis (RA) patients. MethodsAdult RA patients (n = 3225, 73% female, mean age 57 years, median follow-up 54 months) were recruited into the Australian Rheumatology Association Database (ARAD) between 2001–2015. A logistic regression examining both within- and between-patient effect sizes for time-varying covariates, and transition-state analysis for covariates associated with opioid commencement or cessation were used to examine determinants of current opioid use. ResultsThe population-averaged prevalence of any opioid use was 33% (95%CI 32–34), 9% (95% CI 8, 10) for high potency opioid use, and 62% (95% 60, 64) of patients reported opioid ever-use after five years of follow-up. Opioid use was higher in females and decreased with older baseline age. Within-patients opioid use was associated with higher self-reported pain and HAQ scores (p < 0.001), and NSAID (OR 1.88; 1.67–2.10), oral glucocorticoid (2.23;1.93–2.58), csDMARD (2.08;1.78–2.44) and bDMARD (1.22;1.06–1.40) treatment. Younger baseline age, higher pain scores, HAQ scores and oral GC use were important determinants of change in opioid use, associated with both a higher probability of commencing opioid use, and a lower probability of cessation. Paradoxically, NSAID and DMARD treatments were associated with both a lower probability of commencing opioids, and a lower probability of cessation. ConclusionsThere was a high prevalence of opioid use among RA patients, which was associated with pain, function and GC treatment. NSAID, and DMARD treatments obviate the need for opioids in some, but not all, patients.

Comorbidities-Their role in the treat to target concept for rheumatoid arthritis

Treat to target (T2T) strategies and comorbidities are closely related. Strong evidence exists for reducing the risk and extent of comorbidities, such as cardiovascular (CV) diseases, depression and infections by implementing T2T concepts and inducing good disease control of rheumatoid arthritis (RA) in this way. On the other hand existing comorbidities may hinder implementation of T2T concepts by aggravating RA or influencing rheumatologists to overcautiously use DMARD treatment. Among along list of potentially relevant comorbidities with RA, in this review two particularly relevant accompanying diseases with respect to T2T, CV diseases and infections, are selected for discussion in detail. The CV comorbidities are the main cause of death for RA patients and are triggered by RA-associated inflammatory mechanisms. Their negative influence on implementation of T2T strategies can be stopped or at least reduced by optimal control of RA activity with the help of selecting drugs with cardioprotective properties (such as biologicals, methotrexate and hydroxychloroquine) as well as assessing and treating traditional CV risk factors. Infections are among most important adverse events of DMARD treatment and can disturb the optimal use of these drugs and so hinder the success of the T2T strategy. Optimal infection prophylaxis and identification of high risk patients are particularly important and minimization of glucocorticoid use is critical to reduce the risk of infections. In summary, comorbidities are important potential risk factors for the success of T2T strategies.

PBI17 BUDGETARY IMPACT OF INFLIXIMAB BIOSIMILAR IN THE TREATMENT OF PSORIASIS AND ULCERATIVE COLITIS IN THE PERSPECTIVE OF BRAZILIAN PUBLIC HEALTHCARE SYSTEM

After failure or intolerance to treatment with synthetic DMARDs, patients diagnosed with psoriasis (PSO) or ulcerative colitis (UC) are candidates for treatment with biological DMARDs, however currently this treatment is not covered by Brazilian Healthcare System, generating unmet medical needs. This analysis proposes to estimate the potential budget impact on providing infliximab and its biosimilar for PSO and UC patients in a 5 years time horizon in Brazilian Public Healthcare System. Were analyzed DATASUS database on reported outpatients that utilize synthetic DMARDs to treat those clinical conditions in the year of 2017. Thus, were considered the percentage of no-response to synthetic DMARs for both diseases to obtain the number of patients to be treated with biologic DMARDs. It was also considered: the participation percentage of infliximab in biologic DMARDs market, the maximum government sale price for reference and biosimilar infliximab, the recommended medicine dosage, and the average of total population growth ratio for the next 5 years was used to determine the treated population for the following years. Were found 7,905 patients that would not respond to synthetic DMARDs, and will be eligible for biologic DMARDs treatment, which results in a total potential of 85,848 units of infliximab in the first year to 88,807 in year 5. The corresponding budget impact was BRL 216 million and BRL 204.3 million in the first year, to BRL 223.5 and BRL 195.2 in the fifth year for reference infliximab and its biosimilar respectively. The results presented indicate a potential saving of BRL 99.5 million in five years. The inclusion of biosimilar infliximab in the treatment of PSO and UC may contribute to broadening access to treatment for patients with those clinical conditions while representing important savings for the public healthcare system in Brazil.

Time of Disease-Modifying Antirheumatic Drug Start in Juvenile Idiopathic Arthritis and the Likelihood of a Drug-Free Remission in Young Adulthood.

To study juvenile idiopathic arthritis (JIA) long-term outcomes in relation to the time of initiation of biologic disease-modifying antirheumatic drug (bDMARD). Outcomes of JIA patients prospectively followed by the Biologika in der Kinderrheumatologie (BiKeR) and Juvenile Arthritis Methotrexate/Biologics Long-Term Observation (JuMBO) registers were analyzed with regard to drug-free remission and inactive disease, functional status and quality of life, and surgery. To analyze the influence of early bDMARD therapy on outcomes, patients were assigned to 3 groups based on the time from symptom onset to bDMARD start (G1: ≤2 years, G2: >2 to ≤5 years, and G3: >5 years). Propensity score-adjusted outcome differences were analyzed by multinomial logistic regression analyses among the groups. A total of 701 JIA patients were observed for mean ± SD 9.1 ± 3.7 years. At the last follow-up (disease duration mean ± SD 14.3 ± 6.1 years), 11.7% of patients were in drug-free remission, and 40.0% had inactive disease. More than half of the patients reported no functional limitation, while 5% had undergone arthroplasty, and 3% had eye surgery. At the 10-year time point, patients in G1 (n = 108) were significantly more likely to be in drug-free remission than those patients who began treatment later (G2, n = 199; G3, n = 259), with 18.5%, 10.1%, and 4.9%, respectively. Patients in G1 had significantly lower disease activity (clinical Juvenile Arthritis Disease Activity Score in 10 joints = 4.9), a better overall well-being (18.2% patient global assessment score = 0), and higher functional status (59.2% Health Assessment Questionnaire score = 0), compared to patients in G3 (7.1, 8.4%, and 43.7%, respectively). G1 patients required arthroplasty significantly less frequently than G3 patients and had significantly lower disease activity over time than patients in both G2 and G3. Early DMARD treatment is associated with better disease control and outcomes, which supports the concept of a "window of opportunity" for JIA.

Assessments of the unmet need in the management of patients with rheumatoid arthritis: analyses from the NOR-DMARD registry.

ObjectiveTo describe the outcomes of MTX and biologic DMARD (bDMARD) treatment in patients with RA and assess unmet needs in patients who fail treatment, using real-world data from the Norwegian DMARD (NOR-DMARD) registry.MethodsData included RA treatment courses from January 2007 until July 2016. Patients received MTX monotherapy (in MTX-naïve patients), bDMARD monotherapy, bDMARDs + MTX, or bDMARDs + other conventional synthetic DMARDs (csDMARDs). DAS28-4(ESR) was used to measure remission (<2.6) and inadequate response (>3.2) across all groups at Months 6 and 12. Estimated ACR20/50/70 and EULAR good and good/moderate response rates (based on DAS28-4[ESR] score) for bDMARDs were modelled at Months 6 and 12 using logistic mixed regression. DAS28-4(ESR) scores and changes from baseline, and rates and reasons for discontinuation, were evaluated for all groups over 24 months.ResultsThe 2778 treatment courses in this analysis included 714 MTX monotherapy, 396 bDMARD monotherapy, 1460 bDMARDs + MTX and 208 bDMARDs + other csDMARDs. Of patients with DAS28-4(ESR) data at Months 6 and 12 (25.0–34.1%), 33.9–47.2% did not switch treatment and were inadequate-responders at Month 12. There were no significant differences in efficacy between bDMARD groups (bDMARD monotherapy, or bDMARDs + MTX or other csDMARDs). Lack of efficacy was the most common reason for stopping treatment across all groups (13.7–22.1% over 24 months).ConclusionAn unmet treatment need exists for patients still experiencing inadequate response to MTX monotherapy and bDMARDs as monotherapy or in combination with MTX/other csDMARDs after 12 months.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01581294.

The current standard of care and the unmet needs for axial spondyloarthritis.

The aim of this article is to explore the benefits and limitations of the established treatments for axial SpA (axSpA), including physiotherapy, NSAIDs, conventional synthetic DMARDs and biologic DMARDs such as TNF inhibitors (TNFis). It also briefly discusses the emerging role of anti-IL-17 therapy, which could be used as a valuable alternative to first-line biologic DMARD treatment or as a second-line treatment for patients who are inadequate responders to TNFi therapy, as evidenced by various studies. Exercise programmes improve health-related quality of life and hydrotherapy improves disease activity and functional parameters in AS. NSAIDs have been proven to substantially relieve symptoms in 70–80% of patients and enhance physiotherapy by reducing pain and stiffness. The role of NSAIDs in preventing radiographic progression remains unclear. The use of conventional synthetic DMARDs (csDMARDs) is limited to peripheral arthritis; there is insufficient evidence to support the use of csDMARDs for axial disease. TNFi therapy reduces the disease activity of axSpA, however, as not all patients respond to treatment in the same way, it is good to have other therapeutic options available. Finally, this article explores the potential for IL-17 inhibition in AS and introduces clinical data for secukinumab, a fully human monoclonal antibody targeting IL-17A.

The effects of methotrexate and hydroxychloroquine combination therapyvsmethotrexate monotherapy in early rheumatoid arthritis patients

To investigate the added value of MTX-HCQ combination therapy (CTG) in early RA in a controlled cohort study. MTX monotherapy (MTG) is recommended as (part of) first choice treatment but no head-to-head comparisons are available comparing MTX-HCQ CTG with MTG. RA patients from the Sint Maartenskliniek and Radboudumc Nijmegen who started MTX with or without concomitant HCQ from April 2010 to October 2015 were included. The primary outcome was the between-group ΔDAS28-CRP at 6 months, and secondary outcomes were ΔDAS28-CRP at 12 months, EULAR response at 6 and 12 months, and treatment intensification. Regression modelling was used to correct for confounding. We included 325 patients, with only small between-group differences at baseline. The DAS28-CRP improvement at 6 months was larger in the CTG (Δ = 0.38 (CI: 0.01, 0.76)), and the difference between groups in DAS28-CRP improvement was smaller at 12 months (Δ = 0.22 points (CI:-0.19, -0.62)). At 6 months, a higher percentage of patients had a good EULAR response in the CTG (Δ = 15% (CI: 2.7%, 27%)). This difference was reduced at 12 months (Δ = 6% (CI -6.4%, 19%)). Treatment intensification with conventional synthetic DMARDs was more likely in the MTG (Δ = 31% (CI: -43%, 19%)). The proportion of patients starting biologic DMARD treatment during the observation period was comparable (Δ = 2% (CI: -8%, 12%)). In contrast to indirect comparison review data, MTX-HCQ seems somewhat more effective after 6 months than MTX monotherapy in early RA patients. After 12 months, we observed no significant differences between the two strategies, probably due to treat-to-target efforts.

The Use of Tocilizumab in Combination with Methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

Background Aim of this research is to assess the efficacy and safety of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response to non-biologic DMARDs.Methods This was a interventional, prospective, single arm, multicenter, study in  Indonesian male or female patients aged ≥ 18 years old, with a diagnosis of RA for &gt; 6 months based on ACR 1987 revised criteria with moderate to severe disease activity (DAS28 score &gt; 3.2) after ≥ 12 weeks of non-biologic DMARDs treatment. The treatment consisted of tocilizumab, 8 mg/kg, intravenous (IV), every 4 weeks for a total of 6 infusion in combination with oral MTX (10−25 mg) every week. Efficacy was assessed based on the percentage of patients achieving low disease activity state (DAS28 &lt; 3.2), percentage of patients achieving reduction &gt; 1.2 point of DAS28, percentage of patients achieving remission (DAS28 &lt; 2.6), and percentage of patients with ACR20, ACR50, and ACR70 responses. Descriptive statistics will be used for presentation of results.Results 100% patients reached low disease activity (DAS28 ≤ 3.2) at last study visit (week 24) and clinically significant improvement (reduction at least 1.2 units) at every visit in DAS28, both for ITT or PP patients. Remission (DAS28 &lt; 2.6) was observed in 82.1% (ITT patients) and 93.1 % (PP patients) on last study visit. ACR20, ACR50, and ACR70 were achieved in 20%, 34%, and 34% (ITT patients), and 7%, 24%, and 62% (PP patients) on week 24. There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis. Most common adverse events were hepatic dysfunction (30.7%), hypercholesterolemia (23.1%), followed by arthralgia (20.5%) Twelve percent of patients needed dose modification due to elevated liver enzyme (elevated ALT/SGPT level).Conclusion Tocilizumab seems to be efficacious and likely to have good safety profile in non- biologic DMARD nonresponsive RA patients of PICTURE INA study.   Keywords: Rheumatoid Arthritis, Tocilizumab, DMARD, DAS28

The Use of Tocilizumab in Combination with Methotrexate in Indonesian Rheumatoid Arthritis Patients (PICTURE INA Study)

Background Aim of this research is to assess the efficacy and safety of tocilizumab (TCZ) in combination with methotrexate (MTX) in Indonesian patients with moderate to severe active rheumatoid arthritis (RA) who have an inadequate response to non-biologic DMARDs.Methods This was a interventional, prospective, single arm, multicenter, study in Indonesian male or female patients aged ≥ 18 years old, with a diagnosis of RA for &gt; 6 months based on ACR 1987 revised criteria with moderate to severe disease activity (DAS28 score &gt; 3.2) after ≥ 12 weeks of non-biologic DMARDs treatment. The treatment consisted of tocilizumab, 8 mg/kg, intravenous (IV), every 4 weeks for a total of 6 infusion in combination with oral MTX (10−25 mg) every week. Efficacy was assessed based on the percentage of patients achieving low disease activity state (DAS28 &lt; 3.2), percentage of patients achieving reduction &gt; 1.2 point of DAS28, percentage of patients achieving remission (DAS28 &lt; 2.6), and percentage of patients with ACR20, ACR50, and ACR70 responses. Descriptive statistics will be used for presentation of results.Results 100% patients reached low disease activity (DAS28 ≤ 3.2) at last study visit (week 24) and clinically significant improvement (reduction at least 1.2 units) at every visit in DAS28, both for ITT or PP patients. Remission (DAS28 &lt; 2.6) was observed in 82.1% (ITT patients) and 93.1 % (PP patients) on last study visit. ACR20, ACR50, and ACR70 were achieved in 20%, 34%, and 34% (ITT patients), and 7%, 24%, and 62% (PP patients) on week 24. There were 3 out of 39 patients (7.69%) with adverse events (AE) and serious adverse events (SAE) that resulted in discontinuation of TCZ treatment, consisting of 1 patient with SAE of sepsis ec acquired community pneumonia, 1 patient with SAE of pneumonia tuberculosis, and 1 patient with AE of candidiasis. Most common adverse events were hepatic dysfunction (30.7%), hypercholesterolemia (23.1%), followed by arthralgia (20.5%) Twelve percent of patients needed dose modification due to elevated liver enzyme (elevated ALT/SGPT level).Conclusion Tocilizumab seems to be efficacious and likely to have good safety profile in non- biologic DMARD nonresponsive RA patients of PICTURE INA study. Keywords: Rheumatoid Arthritis, Tocilizumab, DMARD, DAS28

Spironolactone (an adjuvant therapy) in rheumatoid arthritis: a case control study.

ObjectivesDisease-modifying anti-rheumatic drugs (DMARDs) are conventionally used in rheumatoid arthritis (RA). The role of spironolactone as add on therapy to DMARDs in RA patients was evaluated.Material and methodsA total of 100 patients with rheumatoid arthritis diagnosed as per 1987 criteria having evidence of active disease despite ongoing DMARD therapy were enrolled in this study. Patients were assigned randomly to two groups. Group I (n = 50) patients were treated with 50 mg/day of spironolactone along with their maintenance DMARD and NSAID therapy. Group II (n = 50) patients continued their maintenance DMARD therapy without spironolactone. Disease activity was assessed using the Disease Activity Score-28 (DAS28) and the Clinical Disease Activity Index (CDAI) in each patient of each group was evaluated monthly for the next three months.ResultsAll patients completed the study. Mean age of group I was 46.44 ±11.67 and of group II 44.52 ±11.82. DAS28 assessed in time according to the schedule was for group I 6.78 ±0.74, 5.34 ±0.74, 3.98 ±0.7, 3.00 ±0.75, while in group II it was 6.61 ±0.82, 5.49 ±0.90, 4.58 ±0.81, 3.55 ±0.93 at baseline, 4, 8, and 12 weeks respectively. CDAI in group I was 41.68 ±11.14, 24.36 ±8.13, 12.34 ±5.73, 6.42 ±4.4 and in group II 37.84 ±11.12, 24.54 ±9.4, 16.38 ±6.81, 9.62 ±6.1 at baseline, 4, 8, and 12 weeks respectively. Group I showed significant improvement in disease activity in the form of tender joint count (p = 0.001), swollen joint count (p = 0.023), patient global assessment (p = 0.001), physician global health (p = 0.001), DAS28 (p < 0.001) and CDAI (p = 0.001) but other parameters showed non-significant improvement compared to group II. No serious adverse events were observed in either group during the course of the study.ConclusionsSpironolactone as an adjuvant therapy can improve the effect of conventional DMARD treatment of patients with RA.

Identification of new biomarkers to promote personalised treatment of patients with inflammatory rheumatic disease: protocol for an open cohort study

IntroductionThe introduction of biological disease-modifying antirheumatic drugs (bDMARDs) has improved the treatment of inflammatory rheumatic diseases dramatically. However, bDMARD treatment failure occurs in 30%–40% of patients due to lack of...

Immunogenicity and safety of pneumococcal vaccination in patients with systemic sclerosis.

Objective. To study the impact of disease and treatment with DMARDs on antibody response elicited by either pneumococcal conjugate vaccine (PCV13) or pneumococcal polysaccharide vaccine (PPV23) in patients with SSc. Methods. Forty-four SSc patients and 49 controls received a dose of either PCV13 or PPV23. Twelve patients were treated with DMARDs. Antibody levels to pneumococcal polysaccharides 6B and 23 F were measured before and 4-6 weeks after vaccination using ELISA. Antibody functionality was studied using opsonophagocytic assay performed on serotype 23 F. Results. Number of patients, percentage female and mean age (years) at vaccination were: 32, 94%, 57.5 years in SSc without DMARDs; 12, 100%, 55.5 years in SSc on DMARDs and 49, 63% and 50.6 years in controls. Post-vaccination antibody levels for both serotypes increased significantly in SSc without DMARDs and controls (P < 0.001), but in SSc on DMARDs only for 6B (P = 0.041). Compared with the other groups, patients with SSc receiving DMARDs had lower post-vaccination antibody levels for both serotypes. Opsonophagocytic assay increased significantly in all three groups. No significant difference in immunogenicity between PCV13 and PPV23 was seen. Conclusion. Pneumococcal vaccination using either PCV13 or PPV23 yielded satisfactory antibody response in SSc patients without DMARD treatment, but a lower response in patients treated with synthetic DMARDs. Type of pneumococcal vaccine (conjugate or polysaccharide) did not significantly influence antibody response. (Less)

Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways.

ObjectivesThis study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown.MethodsPaired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing.ResultsLarge differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function.ConclusionsWe have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.

Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia

ObjectiveTo compare DMARD use in patients with and without FM over time, including overtreatment and undertreatment rates in both groups. MethodsA prospective cohort study with patients attending an RA outpatient clinic was conducted. Participants were consecutively recruited between March 2006 and June 2007 and were followed through December 2013. Data on DMARD use (prevalences, doses and escalation rates), DAS28, HAQ and radiographic progression were compared among RA patients with FM and without FM. Mistreatment clinical scenarios were allegedly identified and compared between groups. Results256 RA patients (32 with FM) were followed for 6.2±2.0 (mean±SD) years comprising 2986 visits. At baseline, RA duration was 11.1±7.4 years. DAS28 and HAQ were greater in RA with FM group, and were closer to RA without FM group towards the end. RA patients with FM used higher doses of tricyclic antidepressants, leflunomide and prednisone, and lower doses of methotrexate. When compared to RA patients without FM, participants with RA and FM used more often tricyclic antidepressants, leflunomide, prednisone, continuous analgesics and less often methotrexate. Groups presented similar 7-year biologic-free survival, and radiographic progression-free survival in Cox regression. RA patients with FM had greater proportions of visits in mistreatment scenarios when compared to RA patients without FM (28.4 vs. 19.8%, p<0.001). ConclusionsRA patients with FM used more leflunomide and prednisone, and RA mistreatment was more frequent in FM patients. Certainly, RA patients with FM will benefit from a personalized T2T strategy, including ultrasound (when suitable) and proper FM treatment.

Adherence to combination DMARD therapy and treatment outcomes in rheumatoid arthritis: a longitudinal study of new and existing DMARD users.

Medication adherence is believed to be a major contributor to treatment outcomes yet studies quantifying this relationship as rare in rheumatoid arthritis (RA). To determine the association of adherence to DMARD therapy with treatment outcomes among new and existing DMARD users over 2years. Relevant clinical parameters were obtained from a longitudinal cohort of RA patients, most of who were treated with combination therapy. Patients were classified as adherent if the proportion of days covered for each DMARD was ≥80%. Outcome measures were the change in the disease activity score in 28 joints (DAS28), simplified disease activity index (SDAI), modified health assessment questionnaires (mHAQ) and proportion of patients who achieved response criteria. An inverse propensity-score weighting method was used to estimate the association of adherence with each outcome. Of 194 patients invited, a total of 111 patients (new = 45 and existing = 66 DMARD users) met study eligibility. DMARD-naive patients demonstrated relatively higher rates of adherence compared to existing users. After controlling for confounding variables, adherence was significantly associated with reduction in DAS28 (β = -1.5, 95% CI of β = - 2.17 to -0.83, p < 0.0001), SDAI (β = -9.44, 95% CI of β = -15.53 to -3.35, p = 0.002) and mHAQ (β = -0.269, 95% CI of β, -0.462 to -0.077, p = 0.017) over 2years among new patients and adherent patients were more likely to achieve most response criteria compared to non-adherent patients. Such associations were not replicated among existing DMARD users. Adherence to combination DMARD therapy was associated with improvements in disease activity and functional outcomes in the first 2years of therapy.

Clinical Characteristics of Rheumatoid Arthritis Patients Achieving Functional Remission with Six Months of Biological DMARDs Treatment.

Objective Although previous studies have reported the prognostic factors for functional remission, no reports have cited the predictive factors. Our aim was to study the predictive factors for functional remission, which is a treatment goal in rheumatoid arthritis (RA), after receiving biological disease-modifying antirheumatic drugs (bDMARDs) treatment for six months. Methods The study consisted of 333 RA patients treated with bDMARDs for six months. The following patient characteristics were investigated: age, gender, disease duration, type of bDMARDs, baseline steroid and methotrexate dosage, and levels of serum rheumatoid factor, matrix metalloprotease, anti-cyclic citrullinated peptides antibody, tumor necrosis factor-α, and interleukin-6. In our evaluation, we used the Simplified Disease Activity Index (SDAI) for RA disease activity, health assessment questionnaire disability index (HAQ-DI) for activity of daily living, Short Form (SF)-36 for quality of life, and Hamilton Depression Rating Scale (HAM-D) or Self-rating Depression Scale (SDS) to determine the patients' depression status. The subjects were divided into two groups: patients with HAQ-DI≤0.5 and HAQ-DI>0.5 at 6 months. Results A univariate analysis comparing a group of RA patients without functional remission (n=68) showed that the patients with functional remission (n=164) had the following in common compared with those without remission: younger age, shorter disease duration, lower baseline steroid dosage, lower SDAI, lower HAQ-DI, higher SF-36, and lower HAM-D. Only lower HAQ-DI scores and “mental health” score on the SF-36 were detected using a logistic regression analysis. Conclusion These findings suggested that RA patients with lower HAQ-DI and lower depression scores at baseline were more likely to achieve functional remission using bDMARDs treatment than those without these variables.

Differentially Methylated DNA Regions in Monozygotic Twin Pairs Discordant for Rheumatoid Arthritis: An Epigenome-Wide Study.

In an explorative epigenome-wide association study (EWAS) to search for gene independent, differentially methylated DNA positions and regions (DMRs) associated with rheumatoid arthritis (RA) by studying monozygotic (MZ) twin pairs discordant for RA. Genomic DNA was isolated from whole blood samples from 28 MZ twin pairs discordant for RA. DNA methylation was measured using the HumanMethylation450 BeadChips. Smoking, anti-cyclic citrullinated peptide antibodies, and immunosuppressive treatment were included as covariates. Pathway analysis was performed using GREAT. Smoking was significantly associated with hypomethylation of a DMR overlapping the promoter region of the RNF5 and the AGPAT1, which are implicated in inflammation and autoimmunity, whereas DMARD treatment induced hypermethylation of the same region. Additionally, the promotor region of both S100A6 and EFCAB4B were hypomethylated, and both genes have previously been associated with RA. We replicated several candidate genes identified in a previous EWAS in treatment-naïve RA singletons. Gene-set analysis indicated the involvement of immunologic signatures and cancer-related pathways in RA. We identified several differentially methylated regions associated with RA, which may represent environmental effects or consequences of the disease and plausible biological pathways pertinent to the pathogenesis of RA.