ABSTRACT
Background: Blockade of JAK, preferably JAK1, by upadacitinib is a feasible approach to achieve erosion repair as it (1) is approved for the treatment of rheumatoid arthritis (RA), (2) effectively controls the inflammation and (3) targets pathogenic pathways that influence local bone homeostasis in the joint. To address the question whether inhibition of JAK1 could lead to erosion repair in patients with active RA, we performed a pilot non-randomized study comparing the changes in bone erosions on high-resolution peripheral quantitative computer tomography (HR-pQCT) before and after upadacitinib. Method(s): This is a 24-week, single-centered, prospective, non-randomized pilot study. We enrolled 20 adult patients with active RA (Disease activity score 28-C- reactive protein [DAS28-CRP] > 3.2) and >=1 bone erosion on HR-pQCT. They were given upadacitinib 15mg once daily for 6 months. HR-pQCT of the 2-4 metacarpophalangeal (MCP) head was done at baseline and 6 months. The primary outcome was the change of erosion volume on HR-pQCT. Secondary outcomes included change in RA disease activity and predictors of response to treatment. Erosion regression was defined as decrease in volume exceeding the smallest detectable change. Result(s): The baseline clinical characteristics of the recruited patients were shown in Table 1. Of the 20 patients, 11 (55%) patients failed to respond to 3 or more csDMARDs. At 24-week, there was significant improvement in mean DAS28 (-1.75, P < 0.001). Erosion regression was seen in 8 (40%) patients on HR-pQCT (Figure 1). Although no significant change in overall median erosion volume before and after upadacintinib (0.07 [-0.90 to 0.76 mm3] mm3, P = 0.904) was noted, the deterioration was less obvious compared to a historic cohort of 20 patients with similar age and disease activity on csDMARDs (median erosion volume change in 6 months: 0.67 mm3). When patients were stratified according to whether or not they had failed multiple csDMARDs, significantly high proportion of patients in the non-multiple- DMARDs failure group had volume regression in at least one erosion compared to those in the failure group (75% vs 25%, P = 0.04). There was improvement in mean total erosion volume in the non-failure group (-0.33 +/- 1.33 mm3), whereas mean erosion volume in the failure group worsened (2.09 +/- 7.62 mm3). One patient developed chest infection requiring hospitalization and withdrew from the study. No other serious adverse event was noted. Conclusion(s): The results of the study suggest upadacitinib is clinically efficacious in refractory RA disease and can retard erosion progression. Regression of erosion is possible, particularly in those with limited csDMARDs exposure. Whether early JAK1 inhibition could lead to better structural outcome warrants further investigations. (Figure Presented).
ABSTRACT
Background: RA has been associated with poor COVID-19 outcomes, but few studies have investigated outcomes in RA features such as interstitial lung disease. Objectives: To assess COVID-19 outcomes in patients with RA overall, and those with and without ILD, compared to general population comparators. Methods: A multicenter, retrospective cohort study was conducted at Mayo Clinic (19 hospitals and affiliated outpatient centers in 4 states) and Mass General Brigham (14 hospitals and affiliated outpatient centers in New England). Consecutive patients with RA meeting ACR/EULAR criteria and a positive COVID-19 test from March 1, 2020 through June 6, 2021 were matched 1:5 on age, sex, race, and COVID-19 test date with general population comparators without RA. RA features assessed included: RA-ILD per Bongartz criteria [1], duration, rheumatoid factor (RF), cyclic citrullinated peptide antibody (CCP), bone erosions, and treatments. The primary outcome was a composite of hospitalization or death following COVID-19 diagnosis. We used multivariable Cox regression to investigate the association of RA, and features such as ILD, with COVID-19 outcomes compared to matched comparators. Results: We analyzed 582 patients with RA and 2892 comparators without RA, all with COVID-19. Mean age was 62 years, 51% were female, and 79% were White. Mean RA duration was 11 years, 67% were seropositive (52% RF+ and 54% CCP+), 27% had bone erosions, 28% were on steroids, and 79% were on DMARDs. 50/582 (9%) patients with RA had ILD. The COVID-19 hospitalization or death rate for RA patients was higher than comparators (3.0 per 1,000 days [95% CI 2.5-3.6] vs. 1.9 per 1,000 days [95% CI 1.7-2.1], respectively). Overall, RA patients had a 53% higher risk of hospitalization or death than comparators after adjustment (95% CI 1.20-1.94). Among those with RA-ILD, the hospitalization or death rate was signifcantly higher than comparators (10.9 [95% CI 6.7-15.2] vs. 2.5 per 1,000 days [1.8-3.2], respectively). RA-ILD was associated with nearly 3-fold higher risk for hospitalization or death than comparators (multivariable HR 2.84 [95% CI 1.64-4.91], Table 1). There was a signifcant interaction between RA/comparator status and presence/absence of ILD for risk of severe COVID-19 (p<0.001, Figure 1). The elevated risk for severe COVID-19 was similar for RA subgroups defned by serostatus or bone erosions. Conclusion: We confrmed that RA was associated with severe COVID-19 outcomes compared to the general population. We found evidence that ILD may be an effect modifer for the relationship between RA and severe COVID-19 outcomes, but RA subgroups defned by serostatus and bone erosions had similarly elevated risk. These fndings suggest that ILD or its treatment may be a major contributor to severe COVID-19 outcomes in RA.
ABSTRACT
Background: Current pharmacological treatments remain inadequate for a signifcant proportion of patients with rheumatoid arthritis (RA), and thus alternative treatment approaches are needed. Prior results from the frst 12 weeks of a proof-of-concept (POC) study showed that ATHENS, a non-invasive high-frequency vagus nerve therapy, was well-tolerated with meaningful reductions in RA disease severity as measured by the American College of Rheumatology response criteria (ACR) and the Disease Activity Score using 28 joints (DAS28)[1]. Objectives: The current analysis assessed long-term changes (52 weeks total follow-up) in disease activity as measured by ACR, DAS28, and the following MRI-assessed changes: synovitis, osteitis, bone erosion, and cartilage loss. Methods: Following the completion of the 12-week POC study, patients achieving a reduction in DAS28-CRP of ≥1.2 were given the option to enroll in the 9-month open-label extension (OLE) study. During the extension phase, patients were to use the wearable device for 15 minutes per day. Adjustment of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic disease-modifying antirheumatic drugs (bDMARDs) were allowed during the OLE. Changes from baseline were assessed at 12 weeks (end of initial POC) and 52 weeks (end of the OLE). Structural damage and disease progression were evaluated by standardized MRI of the wrist and hand, with and without intravenous gadolinium-based contrast. MRIs were evaluated by two independent, central readers, blinded to clinical information and visit-order of the images, and were scored for synovitis, osteitis and bone erosion using the OMERACT-RAM-RIS method. Cartilage loss was also determined using the 9-point cartilage loss scale (CARLOS). Results: Twenty-seven of 30 patients completed the initial 12-week study, of whom 19 consented and entered the OLE. Of those 19 patients, 4 (21%) discontinued due to lack of efficacy, while the remaining 15 completed the 9-month extension. Due to the COVID-19 pandemic, 7 patients were unable to complete a 52-week MRI scan;MRI evaluations at baseline, 12 weeks, and 52 weeks were available for 8 patients. DAS28-CRP mean (standard deviation [SD]) change from baseline was-1.78 (1.01) at 12 weeks (n=19;p<0.0001) and-2.30 (1.22) at 52 weeks (n=15;p<0.0001). ACR20, ACR50, and ACR70 response rates were 68%, 42%, and 21% at 52 weeks (n=19;discontinued participants were deemed non-responders). MRI analysis of synovitis, osteitis, bone erosion, and cartilage loss showed no evidence of disease progression through 52 weeks compared with baseline (Table 1). During the 9-month extension study, two new adverse events were reported (cornea transplant and right hand dysesthesia) in 2 (11%) patients;neither was treatment-related and both resolved without intervention. No serious adverse events were reported. Conclusion: In patients with an initial treatment response to the Nēsos ATHENS therapy in the 12-week POC study, reductions in DAS28-CRP were sustained through 52 weeks. Although results should be interpreted cautiously given the small sample size and lack of control arm, MRI evaluation of synovitis, osteitis, bone erosion, and cartilage loss suggested no disease progression.