Diet affects inflammatory arthritis: a Mendelian randomization study of 30 dietary patterns causally associated with inflammatory arthritis.

Background: The causal associations between dietary intake and the risk and severity of Inflammatory Arthritis (IA) are currently unknown. Objective: In this study, we aimed to investigate the causal relationship between nine dietary categories (30 types of diet) and IA using Mendelian randomization (MR). Methods: We analyzed data from 30 diets and IA in a genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) that could influence the results of MR analyses were screened out through the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. SNPs were analyzed through two-sample bidirectional MR using inverse variance weighting, MR-Egger regression, and weighted median method. The multiplicity and heterogeneity of SNPs were assessed using MR-Egger intercept term tests and Cochran's Q tests. FDR correction was used to correct the p-values. Results: IVW results showed that Beef intake [Odds ratio (OR) = 2.862; 95% confidence interval (CI), 1.360-6.021, p = 0.006, p_fdr < 0.05] was positively associated with rheumatoid arthritis(RA); Dried fruit intake (OR = 0.522; 95% CI, 0.349-0.781, p = 0.002, p_fdr < 0.05), and Iron intake (OR = 0.864; 95%CI, 0.777-0.960, p = 0.007, p_fdr < 0.05) were negatively associated with RA, all of which were evidence of significance. Fresh fruit intake (OR = 2.528. 95% CI, 1.063-6.011, p = 0.036, p_fdr > 0.05) was positively associated with psoriatic arthritis (PsA); Cheese intake (OR = 0.579; 95% CI, 0.367-0.914, p = 0.019, p_fdr > 0.05) was negatively associated with PsA; both were suggestive evidence. Processed meat intake (OR = 0.238; 95% CI, 0.100-0.565, p = 0.001, p_fdr < 0.05) was negatively associated with reactive arthritis (ReA), a protective factor, and significant evidence. All exposure data passed the heterogeneity check (Cochrane's Q test p > 0.05) and no directional pleiotropy was detected. Leave-one-out analyses demonstrated the robustness of the causal relationship in the positive results. Conclusion: Our study presents genetic evidence supporting a causal relationship between diet and an increased risk of IA. It also identifies a causal relationship between various dietary modalities and different types of IA. These findings have significant implications for the prevention and management of IA through dietary modifications.

Post-traumatic Total Hip Arthroplasty After Acetabular Fractures: Benefits of the Hardinge Approach.

Post-traumatic arthritis is a common sequelae after undergoing open reduction and internal fixation (ORIF) of acetabular fractures. This often necessitates conversion to total hip arthroplasty (THA) to help alleviate pain and improve function for these patients. Unfortunately, dislocation rates for post-traumatic THA have been alarmingly high especially when the posterior approach has been used. In the setting of prior soft tissue disruption, the theoretical risk of dislocation is even greater. Conversely, the lateral or the abductor-split approach (Hardinge) is associated with decreased dislocation rates. In this retrospective case series, we evaluated the dislocation rate of the Hardinge approach on patients who underwent THA after developing post-traumatic arthritis after acetabulum ORIF. All patients who matched CPT code 27132 (Repair, Revision, and/or Reconstruction Procedures on the Pelvis and Hip Joint), from January 2009 to December 2019, and treated by the senior author, were pulled from the electronic medical record at the University of Pittsburgh Medical Center. Thirty-one of the resultant 110 were treated with THA for post-traumatic arthrosis through a lateral, abductor-splitting Hardinge approach and met the inclusion criteria for further study. Our case series involves 31 patients who underwent post-traumatic THA through a Hardinge approach: the mean age at the time of index acetabular ORIF is 48.5 years, the mean age at the time of THA is 53.5 years, and the mean interval between ORIF and ultimate THA was five years. The mean length of follow-up after THA was 22.4 months. Overall, patients did well with an all-cause revision rate of 9.7%, with no revision performed for loosening of either the acetabular or femoral component. One patient developed an infection. No patient in our group sustained a dislocation, and all implants were stable without evidence of radiographic loosening at the final follow-up. This study found satisfactory results with patients undergoing THA via lateral or abductor split approach (Hardinge) for post-traumatic arthritis after acetabular ORIF. The use of a Hardinge approach for post-traumatic reconstruction of the hip may be protective against dislocation without increasing baseline risks in this difficult patient population.

Isolated Acromioclavicular Joint Septic Arthritis: A Case Report and Review of Literature.

A 60-year-old diabetic patient presented with acute pain and swelling localized to the left acromioclavicular joint. Laboratory and radiological investigations revealed the presence of pus in the left acromioclavicular joint along with bony erosion of the lateral end of the left clavicle. She was treated with open arthrotomy, debridement, and appropriate antibiotics for the causative methicillin-resistant Staphylococcus aureus (MRSA) infection. Prompt diagnosis and timely intervention can reduce the morbidity and mortality due to septic arthritis. We conducted a review of the literature on patients treated for isolated septic arthritis of the acromioclavicular joint.

IGJ depletion suppresses proliferation, inflammation, and motility of rheumatoid arthritis fibroblast-like synoviocytes via targeting NF-κB pathway.

OBJECTIVE: To investigate the impact of IGJ on the proliferation, inflammation, and motility of rheumatoid arthritis (RA) fibroblast-like synoviocytes and elucidate the underlying mechanism. METHODS: The expression of IGJ RA fibroblast-like synoviocytes was assessed using immunoblot and qPCR. Cell growth was evaluated using CCK-8 and FCM assays. The effects on inflammatory response were determined by ELISA and immunoblot assays. Cell motility was assessed using transwell and immunoblot assays. The mechanism was further confirmed using immunoblot assays. RESULTS: IGJ expression was found to be elevated in fibroid synovial cells of RA. IGJ ablation inhibited the growth of MH7A cells and suppressed the inflammatory response. Knockdown of IGJ also blocked cell motility. Mechanically, the knockdown of IGJ suppressed the NF-κB axis in MH7A cells. CONCLUSION: IGJ suppresses RA in fibroblast-like synoviocytes via NF-κB pathway.

Air Pollution and Rheumatoid Arthritis Risk and Progression: Implications for the Mucosal Origins Hypothesis and Climate Change for RA Pathogenesis.

PURPOSE OF REVIEW: The goal of this review paper is to summarize the main research and findings regarding air pollution and its association with the risk and progression of rheumatoid arthritis (RA). RECENT FINDINGS: The most studied components of air pollution included particulate matter of ≤ 2.5 microns in diameter (PM2.5), PM10, carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOx), sulfur dioxide (SO2), and ozone (O3). In addition, specific occupations and occupational inhalants have been investigated for RA risk. Several studies showed that increased exposure to air pollutants increased the risk of developing RA, particularly seropositive RA. There was evidence of gene-inhalant interactions for seropositive RA risk. Fewer studies have been conducted on RA disease activity and bone erosions. Some studies suggest that patients with RA-associated interstitial lung disease may have worse outcomes if exposed to air pollution. We summarized associations between air pollution and increased RA risk, including RA-associated interstitial lung disease. Relatively few studies investigated air pollution and RA disease activity or other outcomes. These results suggest an important role of air pollution for seropositive RA development and suggest that climate change could be a driver in increasing RA incidence as air pollution increases.

ANA-arthritis: clinical and biomarker characterization of a population for basket trials.

OBJECTIVES: ANA-associated RMDs (ANA-RMDs-SLE, pSS, scleroderma, inflammatory myositis, mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease) are a disease spectrum with overlapping clinical and immunological features. Musculoskeletal inflammation is common and impactful across ANA-RMDs. We evaluated musculoskeletal inflammation (ANA-arthritis) prevalence in a multi-disease ANA-RMD study, assessed its clinical impact across ANA-RMD diagnoses, proposed new basket groupings of patients and evaluated immunological profiles in legacy and new basket contexts. METHODS: An observational study enrolled ANA-RMD patients. Demographic variables, comorbidities, therapies, disease activity instruments (BILAG, SLEDAI, ESSDAI, physician-VAS), patient-reported outcomes (SF36, FACIT-Fatigue, EQ5D, ICECAP-A, WPAI, patient-VAS) and biomarker profile (6 gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian Mixture Modelling (GMM). Clinical and immune features of new and legacy clusters were compared. RESULTS: Inflammatory MSK symptoms were prevalent across ANA-RMDs, in 213/294 patients. In ANA-arthritis patients, most variables did not differ between diagnoses, excluding EQ5D-5L index and mobility domains (lower in MCTD/pSS, both p< 0.05). Fibromyalgia and osteoarthritis prevalence were similar across diagnoses. Therapy use differed significantly, biologic use being greatest in SLE (p< 0.05).GMM yielded two multi-disease clusters; High-MSK disease activity (n = 89) and Low-MSK disease activity (n = 124). High-MSK disease activity contained all patients with active joint swelling and had significantly higher prednisolone usage, PGA and Sm/RNP/SmRNP/Chromatin positivity, Tetherin-MFI and Interferon Score-A activity; with numerically lower fibromyalgia and osteoarthritis prevalence. CONCLUSION: We define ANA-Arthritis, a more clinically and immunologically homogeneous population than existing RMDs for trials, and a more prevalent population for therapies in the clinic.

Interpreting the pharmacological mechanisms of Juanbi recipe on rheumatoid arthritis through network pharmacology, molecular docking.

Background: Traditional Chinese medicine (TCM) offers the advantage of effectively relieving rheumatoid arthritis (RA) with minimal side effects. The Juanbi recipe is a commonly utilized TCM treatment for RA, yet its pharmacological mechanism remains unclear. Network pharmacology serves as an effective tool for identifying pharmaceutical ingredients and potential therapeutic targets of TCM, thereby uncovering its mechanisms. This study aimed to identify the core target genes and explore the mechanisms underlying the treatment of RA with the Juanbi recipe. Methods: This study adopted the method of network pharmacology to filter key gene targets of Juanbi recipe in RA treatment. Single-cell ribonucleic acid (RNA) sequencing data was used to screen the key genes to form the core genes of Juanbi recipe in RA treatment. The molecular docking technique was used to verify the core target genes and explore the mechanisms of Juanbi recipe in RA treatment. The RA model of mice was induced by the collagen-induced arthritis and the effect of Juanbi recipe was evaluated by intragastric administrating of extraction of Juanbi recipe. Enzyme linked immunosorbent assay was used to analysis serum inflammatory factors. Hematoxylin and eosin staining was used to evaluate inflammation and immunohistochemical (IHC) staining was used to evaluate core target genes and pathways in synovium of ankle. Results: This study screened out 281 active molecules in Juanbi recipe, found 105 key target genes of Juanbi recipe in RA treatment, and drew an "ingredient - molecule - gene" diagram. Juanbi recipe reduced the levels of serum interleukin (IL)-1 and IL-6, the inflammatory infiltration in synovium, demonstration that Juanbi recipe reduced both systemic and synovial inflammatory response. Single cell RNA sequencing data were used to select six core target genes and six core active molecules of Juanbi recipe in RA treatment. The pathways of Juanbi recipe in RA treatment involved in activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) pathway. Results of western blot and IHC staining showed that Juanbi recipe decreased the expressions of c-jun and p65, which demonstrated that Juanbi recipe inhibited the expression of AP-1 and NF-κB pathway in RA. Conclusions: The core active molecules of Juanbi recipe could inhibit key factors of AP-1 and NF-κB pathway to inhibit the inflammation, which played a protective role in RA.

Causal association of juvenile idiopathic arthritis or JIA-associated uveitis and gut microbiota: a bidirectional two-sample Mendelian randomisation study.

Background: The gut microbiota significantly influences the onset and progression of juvenile idiopathic arthritis (JIA) and associated uveitis (JIAU); however, the causality remains unclear. This study aims to establish a causal link between gut microbiota and JIA or JIAU. Methods: Using publicly available genome-wide association studies (GAWS) summary data, we conducted a two-sample Mendelian randomisation (MR) analysis employing various methods, namely inverse variance weighted (IVW), simple mode, weighted mode, weighted median and MR-Egger regression methods, to assess the causal association between JIA or JIAU and gut microbiota. Sensitivity analyses, including Cochrane's Q test, MR-Egger intercept test, leave-one-out analysis and MR-PRESSO, were performed to evaluate the robustness of the MR results. Subsequently, reverse MR analysis was conducted to determine causality between gene-predicted gut microbiota abundance and JIA or JIAU. Results: The MR analysis revealed a causal association between gut microbiota abundance variations and JIA or JIAU risk. Specifically, the increased abundance of genus Ruminococcaceae UCG013 (OR: 0.055, 95%CI: 0.006-0.103, p = 0.026) and genus Ruminococcaceae UCG003 (ß: 0.06, 95%CI: 0.003-0.117, p = 0.041) correlated with an increased risk of JIA, while genus Lachnospiraceae UCG001 (OR: 0.833, 95%CI: 0.699~0.993, p = 0.042) was associated with a reduced risk of JIA, among others. Sensitivity analysis confirmed MR analysis robustness. Conclusions: This study provides substantial evidence supporting a causal association between genetically predicted gut microbiota and JIA or JIAU. It highlights the significant role of intestinal flora in JIA or JIAU development, suggesting their potential as novel biomarkers for diagnosis and prevention. These findings offer valuable insights to mitigate the impact of JIA or JIAU.

Effect of combined Zhuang medicine treatment on tricuspid annular displacement and heart rate variability in rheumatoid arthritis patients.

Objectives To assess the benefits of Zhuang medicine in treating rheumatoid arthritis (RA), with a focus on cardiac tricuspid annulus displacement and heart rate variability (HRV), thereby providing evidence supporting Zhuang medicine theories. METHODS: This retrospective study analyzed echocardiographic data and HRV of 30 healthy subjects and 60 RA patients. RA patients were divided into two groups for a 6-month treatment: 30 received iguratimod (control group), and 30 underwent combined Zhuang medicine and needle-pricking therapy (test group). Echocardiographic assessments and HRV measures were recorded both before and after treatment. RESULTS: Compared to the healthy group, RA patients showed increased late diastolic tricuspid annular velocity. However, early diastolic tricuspid annular velocity to late diastolic tricuspid annular velocity ratios, tricuspid annular plane systolic excursion (TAPSE), and the standard deviation of average normal RR intervals (SDANN) were significantly lower (all P<0.05). After treatment, the test group exhibited higher clinical efficacy (90% vs. 56.67% in the control group). Significant improvements were observed in TAPSE and HRV indices [SDANN, standard deviation of the RR intervals (SDNN), root mean square of successive RR interval differences (RMSSD), and the percentage of adjacent RR interval differences greater than 50 milliseconds (PNN50)] in the test group (all P<0.05). Additionally, a positive correlation was noted among these measurments. CONCLUSION: Zhuang medicine significantly enhances right ventricular function and autonomic balance in RA patients, thus affirming its therapeutic potential.

Rheumatoid arthritis, cardiometabolic comorbidities, and related conditions: need to take action.

Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease and mortality, however, traditional cardiovascular risk factors do not fully explain this relationship. This high risk of cardiovascular morbidity and mortality in RA has been increasingly acknowledged in past decades, with accumulating evidence that RA is an independent cardiovascular risk factor; RA is also associated with metabolic syndrome, which correlates with disease activity, contributing to the increased prevalence of coronary heart disease in RA patients. Moreover, multimorbidity, including the presence of long-term conditions, impacts adverse clinical outcomes in RA patients, emphasizing the need for holistic management that requires an understanding of shared pathophysiological mechanisms, such as systemic inflammation and immune dysregulation. For all these reasons, the management of RA patients with cardiometabolic comorbidities is a complex endeavor that requires a patient-centered, multidisciplinary approach. In this sense, there is a need to re-evaluate the approach toward a proactive model of care, moving away from a reactive medical paradigm to a multidimensional integrated management model, including aggressive screening, preventive strategies, and tailored therapeutic interventions. The aim of this review was to thoroughly review the literature on cardiometabolic comorbidities and related conditions linked to RA to enable us to identify the necessary actions required to effectively tackle the increasing burden of illness from a fully comprehensive perspective.

Assessing disparities through missing race and ethnicity data: results from a juvenile arthritis registry.

Introduction: Ensuring high-quality race and ethnicity data within the electronic health record (EHR) and across linked systems, such as patient registries, is necessary to achieving the goal of inclusion of racial and ethnic minorities in scientific research and detecting disparities associated with race and ethnicity. The project goal was to improve race and ethnicity data completion within the Pediatric Rheumatology Care Outcomes Improvement Network and assess impact of improved data completion on conclusions drawn from the registry. Methods: This is a mixed-methods quality improvement study that consisted of five parts, as follows: (1) Identifying baseline missing race and ethnicity data, (2) Surveying current collection and entry, (3) Completing data through audit and feedback cycles, (4) Assessing the impact on outcome measures, and (5) Conducting participant interviews and thematic analysis. Results: Across six participating centers, 29% of the patients were missing data on race and 31% were missing data on ethnicity. Of patients missing data, most patients were missing both race and ethnicity. Rates of missingness varied by data entry method (electronic vs. manual). Recovered data had a higher percentage of patients with Other race or Hispanic/Latino ethnicity compared with patients with non-missing race and ethnicity data at baseline. Black patients had a significantly higher odds ratio of having a clinical juvenile arthritis disease activity score (cJADAS10) of ≥5 at first follow-up compared with White patients. There was no significant change in odds ratio of cJADAS10 ≥5 for race and ethnicity after data completion. Patients missing race and ethnicity were more likely to be missing cJADAS values, which may affect the ability to detect changes in odds ratio of cJADAS ≥5 after completion. Conclusions: About one-third of the patients in a pediatric rheumatology registry were missing race and ethnicity data. After three audit and feedback cycles, centers decreased missing data by 94%, primarily via data recovery from the EHR. In this sample, completion of missing data did not change the findings related to differential outcomes by race. Recovered data were not uniformly distributed compared with those with non-missing race and ethnicity data at baseline, suggesting that differences in outcomes after completing race and ethnicity data may be seen with larger sample sizes.

Unveiling the arthritis divide: Exploring treatment response and impact in late-onset vs. young-onset rheumatoid arthritis.

OBJECTIVES: Impact of osteoarthritis (OA) on the initial treatment response of rheumatoid arthritis (RA) by treat to target (T2T) practice was compared between the patients with an onset age ≥65 years old (late-onset RA [LORA]) and those with an onset age <65 years old (young-onset RA [YORA]). METHODS: A retrospective study was conducted on the patients with RA, who were referred to our clinic without treatment between January 2021 and July 2022. Patients with grade ≥3 OA according to the Kellgren-Lawrence (K-L) classification either in the knee or hand were classified in the OA(+) group and others were in the OA(-) group. The clinical data were compared at the diagnosis and one year after the initial treatment between the groups for 74 LORA and 59 YORA patients, respectively. RESULTS: One year after starting treatment in the LORA patients, the OA(+) group had poorer disease activity control and greater disability in the several activities of daily living (ADL) than the OA(-) group. In the YORA patients, there were no differences in ADL disability between the groups. CONCLUSIONS: In the initial treatment of the LORA patients, the prevalence of OA was high, and impact of OA on LORA was larger than on YORA.

MiR-204/-211 double knockout exacerbates rheumatoid arthritis progression by promoting splenic inflammation.

OBJECTIVE: Collagen-induced arthritis (CIA) model was induced in C57BL/6 wild-type (wt) and C57BL/6 miR-204/-211 double-knockout (dKO) mice to investigate the role of miR-204/-211 in suppressing splenic inflammation in rheumatoid arthritis (RA). METHODS: Differences of miR-204/-211 and structure-specific recognition protein 1 (SSRP1) in the spleen of DBA/1J wt and CIA mice were detected via PCR and immunohistochemistry. CIA was induced in both C57BL/6 wt and C57BL/6 miR-204/-211 dKO mice, and the onset of CIA and disease severity were statistically analyzed. Immunohistochemistry staining of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and SSRP1 in spleen or knee joints was performed and analyzed. In CIA miR-204/-211 dKO mice, AAV-shSSRP1 was intra-articularly injected, with both the AAV-shRNA Ctrl and AAV-shRNA Ctrl CIA groups receiving the same dose of AAV-shRNA. Spleen sections were stained with hematoxylin and eosin (H&E). RESULTS: Compared to wt mouse spleens, aberrant expression of miR-204/-211 and SSRP1 was observed in the spleens of CIA mice. Immunized dKO mice exhibited a higher incidence of CIA onset and a more exacerbated RA disease phenotype, characterized by increased spleen inflammation score and elevated levels of IL-1ß, TNF-α, and SSRP1 expression. AAV-shSSRP1 injection in CIA dKO mice significantly reduced spleen inflammation scores, IL-1ß and TNF-α expression levels, and down-regulated Ki-67 expression compared to CIA dKO mice. CONCLUSION: Knockout of miR-204/-211 exacerbated the onset of CIA in C57BL/6 mice, while miR-204/-211 played a protective role against the progression of splenic inflammatory and proliferative progression in RA by targeting SSRP1.

Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance.

The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. Tnfaip3, Ptpn6 and Irak3 were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of TNFAIP3, INPP5D, PTPN6, CD38 and SIGIRR in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of TNFAIP3 was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of TNFAIP3 and SLPI, compared to responders. Although the expression of TNFAIP3 was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy.

Impact of initiation of targeted therapy on the use of psoriatic arthritis-related treatments and healthcare consumption: a cohort study of 9793 patients from the French health insurance database (SNDS).

OBJECTIVES: To assess the potential impact of targeted therapies for psoriatic arthritis (PsA) on symptomatic treatments (non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, opioid analgesics), methotrexate and mood disorder treatments and on hospitalisation and sick leave. METHODS: Using the French health insurance database, this nationwide cohort study included adults with PsA who were new users (not in the year before the index date) of targeted therapies for ≥9 months during 2015-2021. Main endpoints were difference in proportion of users of associated treatments, hospitalisations and sick leaves between 3 and 9 months after and 6 months before targeted therapy initiation. Logistic regression models adjusted for sex, age, psoriasis, inflammatory bowel disease and Charlson Comorbidity Index compared the impact of biologics initiation (tumour necrosis factor inhibitor (TNFi)/interleukin 17 inhibitor (IL17i)/IL12/23i) on associated treatment discontinuation. RESULTS: Among 9793 patients initiating targeted therapy for PsA (mean age: 51±13 years, 47% men), 62% initiated TNFi, 14% IL17i, 10% IL12/23i, 1% Janus kinase inhibitor, 12% phosphodiesterase-4 inhibitor. After treatment initiation, the proportion of treatment users was significantly reduced for NSAIDs (-15%), opioid analgesics (-9%), prednisone (-9%), methotrexate (-15%) and mood disorder treatments (-2%), along with decreased hospitalisations (-12%) and sick leaves (-4%). TNFi had a greater sparing effect on NSAIDs and prednisone use than IL17i (ORa=1.04, 95% CI=1.01 to 1.07; 1.04, 1.02 to 1.06) and IL12/23i (1.07, 1.04 to 1.10; 1.06, 1.04 to 1.09). Odds of methotrexate discontinuation was reduced with TNFi versus IL17i (0.96, 0.94 to 0.98) and IL12/23i (0.94, 0.92 to 0.97). CONCLUSIONS: Targeted therapy initiation for PsA reduced the use of associated treatment and healthcare, with TNFi having a slightly greater effect than IL17i and IL12/23i, except for methotrexate discontinuation.

Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial.

OBJECTIVES: To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt. METHODS: CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups. RESULTS: Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%). CONCLUSION: Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104. TRIAL REGISTRATION NUMBER: NCT03649061. CTR PILOT APPROVAL BELGIUM: S59474, EudraCT number: 2017-004054-41.

Survival in patients with rheumatoid arthritis and early breast cancer treated with tumor necrosis factor inhibitors.

BACKGROUND: There have been concerns about the use of tumor necrosis factor inhibitors (TNFi) for autoimmune disease in patients with recently diagnosed cancer. We assessed the survival of patients with rheumatoid arthritis (RA) and newly diagnosed early breast cancer (BC) treated with TNFi in the first two years after BC diagnosis. METHODS: We identified patients in two datasets: (1) Optum's de-identified Clinformatics® Data Mart Database (CDM), (2) Surveillance, Epidemiology, and End Results program (SEER) and Texas Cancer Registry (TCR) Medicare-linked cohort. We grouped patients according to whether they received TNFi, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) only, or no DMARDs within 2 years after BC. Outcomes were overall survival (OS) and BC-specific survival (BCSS). We conducted landmark analyses at years 1 and 2, with multivariable Cox regressions using propensity scores for adjustment. RESULTS: In the first year after BC, 165/970 (17.0%) and 201/1246 (16.1%) patients received TNFi in CDM and SEER/TCR-Medicare respectively. In the 1 year landmark, no significant differences in OS were observed between patients treated with TNFi and patients treated with csDMARDs only in CDM (hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.42-1.40) or SEER/TCR-Medicare (HR = 0.84, 95% CI 0.54-1.31). BCSS (SEER/TCR-Medicare) was better in patients receiving TNFi than in those receiving csDMARDs only (HR = 0.28, 95% CI 0.08-0.98). In CDM, glucocorticoid therapy had worse OS than those without glucocorticoids (HR = 2.18, 95% CI 1.13-4.18). This was also observed in SEER/TCR-Medicare (not statistically significant). Similar results were observed for the 2 year landmark. CONCLUSIONS: TNFi treatment during the first two years after early BC was not associated with worse survival.

The History of Macrophage Activation Syndrome in Autoimmune Diseases.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.

Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far most common in systemic juvenile idiopathic arthritis (SJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure seen in MAS. Whole exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with SJIA-associated MAS demonstrated increased "burden" of rare protein-altering variants affecting the cytolytic pathway compared to healthy controls, suggesting that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state, their presence partially reduces cytolytic activity that may lead to increased cytokine production.