Conventional Disease-modifying Antirheumatic Drugs Research Articles

Treatment of rheumatoid arthritis with conventional, targeted and biological disease-modifying antirheumatic drugs in the setting of liver injury and non-alcoholic fatty liver disease.

Increased incidence of liver diseases emphasizes greater caution in prescribing antirheumatic drugs due to their hepatotoxicity. A transient elevation of transaminases to autoimmune hepatitis and acute liver failure has been described. For every 10 cases of alanine aminotransferase (ALT) elevation in a clinical trial, it is estimated that one case of more severe liver injury will develop once the investigated drug is widely available. Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (tsDMARDs) are less likely to cause liver damage. However, various manifestations, from a transient elevation of transaminases to autoimmune hepatitis and acute liver failure, have been described. Research on non-alcoholic fatty liver disease (NAFLD) has provided insight into a pre-existing liver disease that may be worsen by medication. Diabetes and obesity could be an additional burden in drug-induced liver injury (DILI). In the intertwining of the inflammatory and metabolic pathways, the most important cytokines are IL-6 and TNF alpha, which are also the cornerstone of biological treatment for rheumatoid arthritis. This narrative review evaluates the complexity and prevention of DILI in RA and treatment options involving biological therapy and tsDMARDs.

Extracellular vesicle-guided in situ reprogramming of synovial macrophages for the treatment of rheumatoid arthritis

Activation state of synovial macrophages is significantly correlated with disease activity and severity of rheumatoid arthritis (RA) and provides valuable clues for RA treatment. Classically activated M1 macrophages in inflamed synovial joints secrete high levels of pro-inflammatory cytokines and chemokines, resulting in bone erosion and cartilage degradation. Herein, we propose extracellular vesicle (EV)-guided in situ macrophage reprogramming toward anti-inflammatory M2 macrophages as a novel RA treatment modality based on the immunotherapeutic concept of reestablishing M1-M2 macrophage equilibrium in synovial tissue. M2 macrophage-derived EVs (M2-EVs) were able to convert activated M1 into reprogrammed M2 (RM2) macrophages with extremely high efficiency (>90%), producing a distinct protein expression pattern characteristic of anti-inflammatory M2 macrophages. In particular, M2-EVs were enriched for proteins known to be involved in the generation and migration of M2 macrophages as well as macrophage reprogramming factors, allowing for rapid and efficient driving of macrophage polarization toward M2 phenotype. After administration of M2-EVs into the joint of a collagen-induced arthritis mouse model, the synovial macrophage polarization was significantly shifted from M1 to M2 phenotype, a process that benefited greatly from the long residence time (>3 days) of M2-EVs in the joint. This superb in situ macrophage-reprogramming ability of EVs resulted in decreased joint swelling, arthritic index score and synovial inflammation, with corresponding reductions in bone erosion and articular cartilage damage and no systemic toxicity. The anti-RA effects of M2-EVs were comparable to those of the conventional disease-modifying antirheumatic drug, Methotrexate, which causes a range of toxic adverse effects, including gastrointestinal mucosal injury. Overall, our EV-guided reprogramming strategy for in situ tuning of macrophage responses holds great promise for the development of anti-inflammatory therapeutics for the treatment of various inflammatory diseases in addition to RA.

Positive impact on 10-year outcome of the window of opportunity for conventional synthetic DMARDs in rheumatoid arthritis: results from the ESPOIR cohort.

ObjectiveThis study aimed to assess the impact of disease-modifying antirheumatic drugs (DMARDs) on 10-year outcomes in rheumatoid arthritis (RA).MethodsPatients with RA from the ESPOIR cohort with complete data on Disease Activity Score in 28 Joints (DAS28) and Health Assessment Questionnaire (HAQ) at 10 years (n=418) and complete radiographic data at baseline and 10 years (n=343) were included in this study. Outcomes were favourable outcome (FavOut) at 10 years, defined as DAS28 of <2.6 and HAQ score of <0.5 at 10 years, and absence of structural damage progression (AbsSDP) at 10 years, defined as change in Sharp-van der Heijde Score less than the smallest detectable change at 10 years (11.5 points). Three multivariate logistic regression models predicting 10-year outcome were built, considering (1) baseline variables only, (2) baseline variables and DMARD exposure (ever exposed, yes/no) and (3) baseline variables and DMARD exposure as weighted cumulative exposure (WCE) variables.ResultsOverall, 196/418 (46.9%) patients showed FavOut and 252/343 (73.5%) AbsSDP. WCE models had the best predictive performance, with area under the curve=0.80 (95% CI 0.74 to 0.87) for FavOut and 0.87 (95% CI 0.83 to 0.92) for AbsSDP. In the WCE model, the odds of FavOut and AbsSDP were reduced with conventional synthetic disease-modifying antirheumatic drug (csDMARD) initiation at 12 months versus at baseline (OR 0.78, 95% CI 0.65 to 0.94, and OR 0.89, 95% CI 0.76 to 0.98, respectively). Early biologics initiation was not significantly associated with either outcome.ConclusionsWCE models can identify and quantify the long-term benefit of early csDMARD initiation on 10-year functional and structural outcomes in patients with RA.

Tuberculin skin test before biologic and targeted therapies: does the same rule apply for all?

This study aimed to compare Tuberculin Skin Test (TST) and QuantiFERON®-TB Gold In-Tube (QFT-GIT) test in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients scheduled for biological and targeted synthetic disease modifying anti-rheumatic drugs (DMARDs) in a Bacillus Calmette-Guérin-vaccinated population. Adult RA (n = 206) and SpA (n = 392) patients from the TReasure database who had both TST and QFT-GIT prior to initiation of biological and targeted synthetic DMARDs were included in the study. Demographic and disease characteristics along with pre-biologic DMARD and steroid use were recorded. The distribution of TST and performance with respect to QFT-GIT were compared between RA and SpA groups. Pre-biologic conventional DMARD and steroid use was higher in the RA group. TST positivity rates were 44.2% in RA and 69.1% in SpA for a 5mm cutoff (p < 0.001). Only 8.9% and 15% of the patients with RA and SpA, respectively, tested positive by QFT-GIT. The two tests poorly agreed in both groups at a TST cutoff of 5mm and increasing the TST cutoff only slightly increased the agreement. Among age, sex, education and smoking status, pre-biologic steroid and conventional DMARD use, disease group, and QFT-GIT positivity, which were associated with a 5mm or higher TST, only disease group (SpA) and QFT-GIT positivity remained significant in multiple logistic regression. TST positivity was more pronounced in SpA compared to that in RA and this was not explainable by pre-biologic DMARD and steroid use. The agreement of TST with QFT-GIT was poor in both groups. Using a 5mm TST cutoff for both diseases could result in overestimating LTBI in SpA.

How well are biologic and conventional DMARDs tolerated in psoriatic arthritis: A real world study.

Even though disease-modifying antirheumatic drugs (DMARDs) are well established in rou- tine clinical practice, longitudinal real-world data for their retention and tolerability are sparse, espe- cially in psoriatic arthritis (PsA) patients. Our objective was to describe the characteristics of our large PsA cohort including the comorbidities and evaluate real-world DMARD tolerability and discontinua- tion rates with reasons for stopping treatment. We retrospectively interrogated the electronic, multipurpose, live setting database at our uni- versity hospital to identify 335 patients diagnosed with PsA who had received conventional DMARDs (cDMARDs) and/or biologic DMARDs (bDMARDs) between 1994 up to and including April 2019. In total, 170 (50.7%) patients had discontinued one or more cDMARDs prior with a mean dura- tion before discontinuation of 9.9 months. In contrast, only 28 (24.8%) patients had stopped a course of bDMARDs at some point. The mean duration before biologic therapy was discontinued was 18.2 months. To our knowledge, this is the first dedicated retrospective review of a large real-world PsA cohort addressing drug survival and tolerability of DMARDs over a 20-year period. Our study shows that in reality, cDMARDs are not well tolerated. This should encourage review of international guid- ance allowing earlier employment of biologics in the treatment paradigm.

Dermatomyositis and juvenile dermatomyositis

Dermatomyositis (DM) is an inflammatory multisystem disease of unknown etiology, which can already occur in children but first onset can also be in older adulthood. Myalgia and muscle weakness can occur later in the course of the disease or even be completely absent in some forms. Classical signs on the skin include heliotrope rash, facial erythema, Gottron's papules and nailfold capillary abnormalities. For the diagnosis, screening for the presence of myositis-specific autoantibodies has become increasingly more relevant. Muscle enzymes may be elevated but not in approximately one third of patients. In the absence of typical clinical or serologic findings, additional examination methods such as nailfold capillaroscopy, magnetic resonance imaging, electromyography, skin or muscle biopsies may help to establish the diagnosis. Depending on the clinical and serological subtype, additional screening for gastrointestinal or cardiopulmonary involvement should be considered. In adults, an age-appropriate tumor screening should also be performed. Apart from corticosteroids as induction therapy, biologics and small molecule inhibitors are gaining in importance in addition to conventional disease-modifying anti-rheumatic drugs and intravenous immunoglobulins. The prognosis for DM and juvenile DM (JDM) has improved. Most patients recover at least to some extent; however, afew patients die and a minority develop persisting muscle atrophy or severe calcinosis.

P174 HLA B27 status and disease phenotype: a cohort study of 223 patients with enthesitis-related arthritis

Abstract Background/Aims Enthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis (JIA) accounting for 10-20% of patients with JIA. ERA is associated with a poor prognosis compared to other JIA subtypes. Whilst a high proportion of patients with ERA are HLA-B27 positive, the correlation between HLA-B27 status and disease phenotype is not well described. The aim of our study was to investigate the influence of HLA-B27 status on ERA phenotype. Methods Demographic and clinical data were collected and HLA-B27 positive and negative patients were compared. All subjects included met ILAR classification criteria. The data were analysed using R software (R version 4.0.4). Median and interquartile range (IQR) were calculated for continuous variables and frequency and percentage for categorical variables. Subgroup comparison was performed using the chi-squared test for qualitative variables, and Wilcoxon rank-sum for quantitative variables. P values less than 0.05 were considered significant. Results 223 patients were included in this study. The median age of symptom onset was 12 years (IQR: 9-14). The median disease duration was 11 years (IQR: 7-14). 18% of patients had family history of HLA-B27-related disease and 67% had positive HLA-B27. 54% of patients were on conventional disease modifying anti-rheumatic drugs (cDMARDs). 80% were on biologic DMARDs (bDMARD). HLA-B27 positive patients (n = 148) and negative patients (n = 68) were compared. Our analysis revealed a higher proportion of male patients in the HLA-B27 positive cohort (74% [n = 111] versus 59% [n = 39], p = 0.02). HLA-B27 positive subjects developed ERA at an older age compared to the HLA-B27 negative group at 12 versus 11 years, respectively (p = 0.02). HLA-B27 positive patients also had a higher probability of an axial phenotype within 12 months of disease onset 51% (n = 75) in the HLA-B27 positive group versus 32% (n = 22) in the HLA-B27 negative group (p = 0.01). At any point of disease course, sacroiliitis was also more common in the HLA-B27 positive group (78% [n = 116] versus 63% [n = 43], p = 0.01), who also had a higher usage of bDMARDS (74% [n = 110] versus 56% [n = 38], p = 0.006). There was no significant difference between the two groups in terms of ethnicity, family history of HLA-B27 disease or the prevalence of extra-articular manifestations, including uveitis. Conclusion Our study revealed that patients with ERA who were HLA-B27 positive, were more likely to be male, developed disease at an older age and had a higher probability of axial phenotype at onset and later in disease. They also had an increased bDMARD requirement. These data suggest that HLA-B27 confers a worse prognosis clinically which is consistent with findings from other studies. Disclosure A. Bouraoui: None. C. Fisher: None. J. Glanville: None. D. Sen: None.

P104 Comparative risk of infection for first-line csDMARD therapy in rheumatoid arthritis: a multinational cohort analysis of real world data

Abstract Background/Aims Infections on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are an important concern for rheumatoid arthritis (RA) patients, especially during the COVID-19 pandemic. However comparative safety data between csDMARDs have been conflicting and limited in power. The objective was to assess the comparative safety of serious, opportunistic and all infections (including non-serious) of first-line csDMARDs in RA through a large multinational observational study. Methods We evaluated first-line new users of methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SZ) and leflunomide (LEF) monotherapy. Data was obtained from four US databases (IQVIA US Ambulatory EMR (AMBER), Optum® De-identified Clinformatics® Datamart (Optum), IBM MarketScan® Medicare Supplemental Database (MDCR), and IBM MarketScan Commercial Database (CCAE)), one from Germany (IQVIA Disease Analyser Germany EMR (Germany)), and another from the UK (IQVIA UK The Health Improvement Network). Patients included were ≥18 years with a RA diagnosis between 2005-2019, without prior inflammatory arthritis, cancer or infection (in the preceding 30 days). Serious infections were defined as those requiring hospitalisation or resulting in death within 30 days; opportunistic infections were defined as per published EULAR consensus. Patients were followed from 1-day following treatment initiation to the earliest of treatment discontinuation, switching, or add-on plus 14 days, or loss to follow-up. Cox proportional-hazards models for MTX against each csDMARD with large-scale propensity score stratification were performed. A large set of negative control outcomes were used to calibrate hazard ratios (cHR) to account for potential residual confounding. Estimates were pooled where homogeneity across sources was adequate (I2&amp;lt;0.4). Results A total of 247,511 patients were included (MTX: 141,647; HCQ: 73,286, SSZ: 16,521, LEF: 16,057), with pooled incidence rates of serious, opportunistic and all infections across sources for MTX users of 33.7, 20.1 and 311.8 per 1,000 pyrs, respectively. With MTX as the referent, for all infections, the pooled cHR (with 95% Confidence Intervals) for SSZ was 0.73 (0.62, 0.86); HCQ, 0.96 (0.89, 1.04); and LEF, 0.74 (0.50, 1.08). The serious infection pooled cHR for SSZ was 0.75 (0.58, 0.97) and for LEF, 0.93 (0.61, 1.40). For opportunistic infections, pooled cHR for HCQ was 1.04 (0.92, 1.19). Conclusion SSZ, LEF and less consistently HCQ had a lower risk of all (including non-serious) infections, compared to MTX. SSZ and LEF were associated with a 25% reduction in the expected risk of all infections. SSZ was associated with a 25% lower risk of serious infections relative to MTX. In the first large scale observational network study assessing comparative risk of infection with csDMARDs there were differences between drugs in risk for all infections, with potential implications for clinical care. Disclosure M. Jani: None. E. Burn: None. J. Weaver: Corporate appointments; Janssen. L. Carmona: None. K. Chatzidionysiou: None. B. Illigen: None. D. Vizcaya: Corporate appointments; Bayer. T. Duarte-Salles: None. P. Ryan: Corporate appointments; Janssen. D. Prieto-Alhambra: None.

P274 The effect of ixekizumab versus adalimumab on individual components of the ACR composite score, with and without concomitant methotrexate or other conventional synthetic DMARDs, at 52 weeks in patients with psoriatic arthritis

Abstract Background/Aims It is useful to evaluate individual American College of Rheumatology (ACR) components in large trials for active psoriatic arthritis (PsA) because individual patient domains may influence treatment choice. SPIRIT-H2H showed superiority of ixekizumab (IXE) over adalimumab (ADA) in patients with PsA and inadequate response (IR) to conventional synthetic disease modifying antirheumatic drugs (csDMARDs). This analysis describes the effect of IXE and ADA on individual ACR components at week (Wk) 52, with and without concomitant methotrexate (MTX) and csDMARDs. Methods Patients from SPIRIT-H2H (NCT03151551, 52 Wk randomized multicenter study) who met Classification Criteria for Psoriatic Arthritis (CASPAR) (N = 566), were randomized (1:1, stratified by baseline concomitant csDMARDs and moderate-to-severe PsO) to IXE or ADA on-label PsA or PsO dosing. Patients were bDMARD-naïve with IR to csDMARDs, active PsA (≥3 tender joints [TJC] and ≥3 swollen joints [SJC]) and had psoriasis (PsO) ≥3% BSA (body surface area). Patient’s Global Assessment (PtGA) and Physicians Global Assessment (PGA), Health Assessment Questionnaire-Disability Index (HAQ-DI), and joint pain were assessed by visual analog scale, and TJC and SJC as well as C-reactive protein (CRP) were analyzed. All post-hoc analyses were performed on the intent-to-treat (ITT) population. Change from baseline (CFB) in individual ACR components was analyzed using an Analysis of Covariance (ANCOVA) model, for overall as well as with and without concomitant therapies (e.g., MTX or csDMARD). Least square mean (LSM) and standard error (SE) are presented. Missing data were imputed using modified baseline observation carried forward (mBOCF). Nine patients with active PsO and BSA≥3% were assessed as Psoriasis Area and Severity Index (PASI)=0 at baseline, a medical inconsistency that was resolved using medical judgment. These patients were considered PASI100 responders if PASI=0 and BSA=0 at post baseline visits. Results A total of 566 patients received either IXE (N = 283) or ADA (N = 283). Baseline values for individual ACR components were balanced between IXE and ADA. At Wk 52, IXE demonstrated efficacy across all individual ACR components in the ITT population, specifically in PGA, PtGA and Joint Pain; ADA also demonstrated numerical efficacy. Improvements from baseline for IXE were observed across ACR components, with or without MTX or csDMARD. The effect of MTX (with or without) was notably different between IXE and ADA in TJC68, PGA, Joint Pain, and PtGA. Conclusion In this analysis, there was improvement with IXE in all components of the ACR composite score at Wk 52, irrespective of MTX or csDMARD use (with or without). In the ITT population, IXE showed comparable efficacy to ADA at Wk 52 in all components of ACR, demonstrating improvement across musculoskeletal domains. These results may provide further confidence of the clinical benefits of ixekizumab across musculoskeletal domains in patients with PsA, regardless of MTX or csDMARD use. Disclosure A. Kiprianos: None. E. Husni: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, and UCB Pharma. S. Kamat: Member of speakers’ bureau; AbbVie, Amgen, Eli Lilly and Company, and Exogen. K. Stenger: Shareholder/stock ownership; Eli Lilly and Company. R. Bolce: Shareholder/stock ownership; Eli Lilly and Company. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly and Company. C.C. Helt: Shareholder/stock ownership; Eli Lilly and Company. S. Park: Shareholder/stock ownership; Eli Lilly and Company. J.R. Lisse: Shareholder/stock ownership; Eli Lilly and Company. L. Idolazzi: Member of speakers’ bureau; AbbVie, Amgen, Eli Lilly and Company, and Janssen.

Anti-IL23for nail psoriasis in real life: Results of efficacy and safety during a 52-week period.

Nail psoriasis (NP) is often considered disfiguring for patients with a relevant impact on quality of life (QoL). It is also difficult to treat for dermatologists who are often frustrated by the scarcity of effective therapeutic alternatives in this particular location. Topical therapies are often used as the first-line treatment for mild NP, but efficacy is the modest. Conventional disease-modifying antirheumatic drugs (cDMARDs) (e.g., cyclosporine, methotrexate, acitretin, and dimethyl fumarate) are generally avoided in NP without general cutaneous involvement. Biologics represent, to date, a concrete possibility for the management of these patients. The data from the clinical trials are encouraging, although there are still few data in real-life. Here, we report a study conducted at Siena University Hospital on 20 patients with NP on both hands and feet treated with anti-IL23 for 52 weeks. No differences were evaluated from baseline to week 4 of anti-IL-23 treatment. NAPSI greatly improved at week 24 with almost 60% of patients reaching NAPSI75 and 40% NAPSI50. At week 52, almost 75% of patients reached NAPSI90. No adverse effects were reported in the patients in the study. The clinical response observed in these patients suggests that treatments that target interleukin-23 may be an effective option for NP, especially when refractory to conventional therapies.

The Impact of Traditional Chinese Medicine QingreHuoxue Treatment and the Combination of Methotrexate and Hydroxychloroquine on the Radiological Progression of Active Rheumatoid Arthritis: A 52-Week Follow-Up of a Randomized Controlled Clinical Study.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). QingreHuoxue treatment (QingreHuoxue decoction [QRHXD]/QingreHuoxue external preparation [QRHXEP]) is a Chinese medicine treatment for RA. To date, very few studies have compared the long-term effects of QRHXD with those of conventional disease-modifying antirheumatic drugs on RA disease activity and radiological progression. QRHXD delayed the radiological progression and showed long-term clinical efficacy of RA. In clinical experiments, the clinical evidence of delaying the radiological progression of RA patients was obtained. A portion of the patients who participated in the “Traditional Chinese Medicine QingreHuoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis” study were followed up for 52 weeks, and intention-to-treat (ITT) and compliance protocol (PP) analyses were used to collect and compare the clinical indicators and imaging data between baseline and week 52. Two radiologists who were blind to treatment scored the images independently. Of the 468 subjects, 141 completed the 52-week follow-up. There were no significant differences among the three groups: the traditional Chinese medicine comprehensive treatment group, the Western medicine treatment group, and the integrated traditional Chinese and Western medicine treatment group. There were no differences in the total Sharp score, joint space stenosis score, and joint erosion score at baseline or 52 weeks. In the comparison of the estimated annual radiographic progression (EARP) and the actual annual Sharp total score changes among the three groups, the actual changes were much lower than the EARP at baseline. The radiological progress in all three groups was well controlled. Results of the ITT and PP data sets showed that the disease activity score 28 level of the three groups at 52 weeks was significantly lower than that at baseline. During the 52-week treatment period, the clearance of heat and promotion of blood circulation controlled disease activity and delayed the radiological progress of active RA.

Real-world data reveals the complexity of disease modifying anti-rheumatic drug treatment patterns in juvenile idiopathic arthritis: an observational study

ObjectivePharmacological treatment is a cornerstone of care for children with juvenile idiopathic arthritis (JIA). The objective of this study is to evaluate prescription patterns of conventional and biologic disease modifying anti-rheumatic drugs (c-DMARDs and b-DMARDs) for patients with JIA.MethodsWe conducted a retrospective cohort study of children diagnosed with JIA at a rheumatology pediatric clinic. Eligibility criteria were defined as children and youth newly diagnosed with enthesis-related arthritis, polyarticular, or oligoarticular JIA between 2011 and 2019, with at least one year of observation. Data on c-DMARDs and b-DMARDs prescriptions were obtained from electronic medical charts. We used descriptive statistics, Kaplan–Meier survival methods, and Sankey diagrams to describe treatment prescription patterns.ResultsA total of 325 patients with JIA were included, with a median observation time of 3.7 years. The most frequently prescribed c-DMARD and b-DMARD were methotrexate and etanercept, respectively. Within the first year of rheumatology care, 62% and 21% of patients had a c-DMARD and a b-DMARD prescribed, respectively. These proportions varied greatly by JIA subtype. Among the 147 (147/325, 45%) patients that had at least one b-DMARD prescribed, 24% were prescribed a second, and 7% a third-line of b-DMARD. A total of 112 unique treatment sequences were observed, with c-DMARD monotherapy followed by the addition of either a b-DMARD (56%) or another c-DMARD (30%) being the two most prevalent patterns in this cohort.ConclusionWe observed a variety of treatment trajectories, with many patients experiencing multiple treatment lines, illustrating the complexity of the overall JIA treatment path.

Oral Conventional Synthetic Disease-Modifying Antirheumatic Drugs with Antineoplastic Potential: a Review.

There is an increasing trend of malignancy worldwide. Disease-modifying antirheumatic drugs (DMARDs) are the cornerstones for the treatment of immune-mediated inflammatory diseases (IMIDs), but risk of malignancy is a major concern for patients receiving DMARDs. In addition, many IMIDs already carry higher background risks of neoplasms. Recently, the black box warning of malignancies has been added for Janus kinase inhibitors. Also, the use of biologic DMARDs in patients with established malignancies is usually discouraged owing to exclusion of such patients in pivotal studies and, hence, lack of evidence. In contrast, some conventional synthetic DMARDs (csDMARDs) have been reported to show antineoplastic properties and can be beneficial for patients with cancer. Among the csDMARDs, chloroquine and hydroxychloroquine have been the most extensively studied, and methotrexate is an established chemotherapeutic agent. Even cyclosporine A, a well-known drug associated with cancer risk, can potentiate the effect of some chemotherapeutic agents. We review the possible mechanisms behind and clinical evidence of the antineoplastic activities of csDMARDs, including chloroquine and hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, mycophenolic acid, methotrexate, sulfasalazine, and thiopurines. This knowledge may guide physicians in the choice of csDMARDs for patients with concurrent IMIDs and malignancies.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis (COMPLETE-PsA): a double-blind, placebo-controlled, randomised, trial.

Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the preferred first-line treatment in patients with psoriatic arthritis, although there is a paucity of evidence for the efficacy of conventional synthetic DMARDs and especially their combination. We aimed to investigate whether a combination of methotrexate plus leflunomide is superior to methotrexate monotherapy at improving disease activity in patients with psoriatic arthritis. This single centre, investigator-initiated, double-blind, randomised, placebo-controlled trial was conducted at Sint Maartenskliniek in the Netherlands (locations included Boxmeer, Geldrop, Woerden, and Nijmegen). Patients aged 16 years or older with a clinical diagnosis of psoriatic arthritis and active disease (defined as two or more swollen joints; dactylitis counting as one swollen joint) were included. Patients were randomly allocated (1:1) and stratified by high disease activity (psoriatic arthritis disease activity score [PASDAS] ≥5·4) to either methotrexate plus leflunomide (combination therapy) or methotrexate plus placebo (monotherapy), using computer-generated stratified variable block randomisation. In both groups, patients received oral methotrexate 15 mg per week for the first 4 weeks and 25 mg per week thereafter combined with two leflunomide 10 mg tablets once per day or two placebo tablets. During the study period, the patients, nurses, researchers, and treating physicians were all masked to treatment allocation. The primary outcome was the difference in mean PASDAS at week 16, adjusted for baseline PASDAS, between the combination and monotherapy groups, assessed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register (NL7404) on Dec 3, 2018. Between Feb 19, 2019, and March 11, 2021, 82 patients were screened for eligibility. Four patients were ineligible and 78 were enrolled and randomly assigned to either methotrexate plus leflunomide (n=39) or methotrexate plus placebo (n=39). 50 (64%) of 78 patients were male, 28 (36%) were female, and the median age of patients was 55·0 years (IQR 42·0-64·0). Methotrexate plus leflunomide combination therapy was superior to methotrexate monotherapy at week 16 (PASDAS 3·1 [SD 1·4] vs 3·7 [SD 1·3]; treatment difference -0·6, 90% CI -1·0 to -0·1; p=0·025). There were no study deaths. The most frequently occurring adverse events were nausea or vomiting (17 [44%] of 39 patients in the methotrexate plus leflunomide group vs 11 [28%] of 39 in the methotrexate plus placebo group), tiredness (9 [23%] vs 13 [33%]) and elevated alanine aminotransferase (12 [31%] vs 7 [18%]. Generally, the incidence of mostly mild adverse events was higher in the methotrexate plus leflunomide group than in the methotrexate plus placebo group. Methotrexate plus leflunomide combination therapy results in greater improvement in disease activity according to PASDAS in patients with psoriatic arthritis. However, methotrexate plus leflunomide combination therapy is less well tolerated than methotrexate monotherapy. Regional Junior Researcher Grant from the Sint Maartenskliniek.

Management results of a cohort of rheumatoid arthritis patients in a specialized comprehensive healthcare institution in Colombia

ObjectiveTo determine the management results in a cohort of patients with rheumatoid arthritis in a specialized integral healthcare institution for this disease in Colombia. Materials and methodsDescriptive cross-sectional study based on a cohort of rheumatoid arthritis patients according to ACR/EULAR 2010 criteria. The information was analysed based on consolidated data from clinical records and national reports in the period 2015–2018. Administrative records related to medication authorizations and prescriptions were considered. Sociodemographic variables, outcome indicators related to disease activity status and medication use percentage were evaluated. ResultsAs of June 30th 2018, 698 patients were identified, of which the female sex represented 83.8%, the general average age was 55.47 years, and the highest number of cases were in the 60–64 year age group. Of the patients, 68.3% were between remission and low disease activity. Seventy-three point one percent were managed with conventional disease-modifying antirheumatic drugs and a reduction in the use of biological therapy was recorded from 27.2% in 2016 to 17.8% at the end of the period. ConclusionsThis study presents the management results of a comprehensive care model for patients with rheumatoid arthritis in Colombia, which managed to maintain the highest proportion of patients in low activity and remission as they had a longer follow-up time, to decrease the percentage of biological DMARDs use, and establish conventional DMARDs as the main therapeutic alternative.

2021 clinical practice guideline for the early detection, diagnosis, treatment, and monitoring of patients with axial spondyloarthritis. Colombian Association of Rheumatology

BackgroundAxial Spondyloarthritis is a rheumatic condition affecting young patients with social and occupational consequences. Diagnosis delay is associated with functional impairment and impact on quality of life, requiring a multidisciplinary approach. ObjectiveTo develop a set of recommendations based on the best available evidence for early detection, diagnosis, treatment and monitoring adult patients with axial spondyloarthritis. MethodsA working group was established, questions were developed, outcomes were graded, and a systematic search for evidence was conducted. A multidisciplinary panel of members was established (including patient representatives), minimizing bias in relation to conflicts of interest. The GRADE approach “Grading of Recommendations Assessment, Development and Evaluation” was used to assess the quality of the evidence as well as the direction and strength of recommendations. In total, 11 recommendations with regard to diagnosis (n = 2), pharmacological treatment (n = 6), non-pharmacological treatment (n = 2) and monitoring (n = 1) are presented. ResultsSacroiliac joint radiography as the first diagnostic method, and the use of disease activity scales for patient monitoring (ASDAS or BASDAI), are recommended. Nonsteroidal anti-inflammatory drugs are the first treatment option; in case of intolerance or residual pain, acetaminophen or opioids are recommended. In patients with axial involvement, it is recommended not to use conventional disease-modifying antirheumatic drugs or systemic or local glucocorticoids. In patients with failure to non-steroidal anti-inflammatory drugs, anti-TNF or anti-IL17A is recommended. In those patients presenting with anti-TNF failure, starting an anti-IL17A is recommended. Exercise, physical and occupational therapy are recommended as part of treatment. It is recommended not to use unconventional therapies as the only treatment option. ConclusionsThis set of recommendations provides an updated guide on the diagnosis, treatment and monitoring of patients with axial spondyloarthritis.

Hepatitis B and C virus reactivations under biologic treatments in patients with rheumatic diseases: long-term results from a single-center

Objectives: To find out the effects and prevalence of disease-modifying antirheumatic drugs (DMARDs) and anti-TNF agents on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients with rheumatic diseases (RD). Methods: This retrospective study was conducted on 1,548 RD patients. Patients’ medical records regarding immunological profiles, clinical courses, and outcomes, were obtained. In this research, the patient used conventional DMARDs (cDMARDs) and biological DMARDs (bDMARDs). A drug exposure was considered when a patient was administered GC, cDMARDs, or bDMARDs for &amp;gt; 4 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin were measured. HBsAg, HBV DNA assay, anti-HCV and HIV were identified. Results: HBsAg was positive in 19 (37.3%) patients. Anti-HBs in 5 (9.8%) patients and anti-HBc IgG in 35 (68.6%) patients were positive. All patients with HBsAg positivity were receiving antiviral prophylaxis. Anti-HCV was positive in 25.5% (n = 13) of individuals . There was not any reactivation among the patients. No HBV reactivation was observed. Conclusions: Screening before treatment and give prophylaxis to patients who have occult hepatitis or hepatitis B, may be an important factor in the absence of reactivation. Hepatitis screening should be performed in all patients prior to biological treatment is initiated.

Predicting infection risk in iatrogenic immune deficiency

For many years, conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) such as methotrexate and salazopyrine have been standard therapy for treatment of inflammatory arthritis. The advent of biologic DMARDS, such as adalimumab and tocilizumab, have revolutionised therapy and improved patient outcomes. More recently, the increasing use of oral targeted synthetic DMARDS which inhibit Janus Kinases (JAKi), such as tofacitinib and upadacitinib, have further broadened therapeutic options.

Prospects for the use of monoclonal antibodies to interleukin 23 Gusеlkumab in psoriatic arthritis: New data

Among the pathophysiological mechanisms of immune-mediated inflammatory diseases (IMIDs), specific attention has been paid to the abnormal activation of Th17 type immune response related to the dysregulated synthesis of cytokines forming the interleukin (IL)-23 and IL-17 axis. IL-23 blockade is an innovative approach to the treatment of psoriasis and psoriatic arthritis (PsA). Much of the interest has focused on guselkumab (GUS) (TREMFYA, Janssen, Johnson &amp; Johnson, USA), a fully human IgG λ monoclonal antibody (mAb) targeting the p19 IL-23 subunit and the first-in-class treatment approved for patients with psoriasis and PsA. In patients with psoriasis, GUS is at least as effective as other biologic therapies for PsA and is superior to ustekinumab, an anti-IL-12/IL-23 mAb, and secukinumab, an anti-IL-17 mAb. Compared with TNF-α inhibitors, GUS therapy is less likely to cause infections and does not increase the risk of the reactivation of latent TB infection. The new GRAPPA guidelines (2021) recommend GUS (and other IL-23 inhibitors) for patients with PsA resistant to conventional disease-modifying antirheumatic drugs (DMARDs), who have peripheral arthritis, enthesitis, dactylitis, psoriatic skin and nail lesions. The paper discusses new data on the efficacy of GUS in patients resistant to TNF-α inhibitors, its benefits in patients with axial PsA, and safety during the COVID-19 pandemic.

Intra-articular injection of biologic anti-rheumatic drugs enhances local exposure to the joint-draining lymphatics

Recent reports have highlighted the role of the lymphatic system and its resident immune cells in the development of inflammatory arthritis. Directing therapeutics to the joint-draining lymphatics could improve access to lymphatic-resident pro-inflammatory immune cells, improve local treatment efficacy and enable the administration of lower drug doses to achieve the same or a better effect. Here, we assessed the delivery of disease modifying anti-rheumatic drugs (DMARDs) to the joint-draining lymphatics as a function of therapeutic size and route of administration (intravenous (IV), subcutaneous (SC) and intra-articular (IA) injection). The model drugs included the low molecular weight conventional DMARD methotrexate and the larger biologic DMARDs etanercept and rituximab. Plasma pharmacokinetics, thoracic lymph fluid concentrations and lymph node deposition of the DMARDS were assessed in male Sprague-Dawley rats after IV, IA or SC injection at or near the knee joint. Administration by IA injection resulted in rapid and higher absorption of all drugs into the systemic circulation, compared to SC administration. The large DMARDs etanercept and rituximab were preferentially transported from the IA and SC injection sites via the lymphatics, but a greater percentage of the absorbed dose was recovered in lymph after IA (49–58%) compared to SC administration (17–20%). Methotrexate was almost exclusively transported from the injection site via the blood after IA injection, consistent with its small size which presents minimal barriers to diffusion across the synovium into blood vessels. Importantly, IA but not SC administration resulted in biologic DMARD access to the knee joint-draining iliac lymph fluid and iliac lymph node that is dysfunctional in inflammatory knee arthritis. Overall, IA injection of biologic DMARDs may provide a simple strategy to improve lymph and lymph node access and thus the treatment of inflammatory arthritis.