Efficacy of guselkumab, a selective IL-23 inhibitor, in Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA): protocol of a randomised, double-blind, placebo controlled multicentre trial
INTRODUCTION:Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS:The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION:Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER:NCT05004727.
Postoperative Flares and Peri-arthroscopic Management of Immunosuppressive Medications in Patients with Rheumatic Disease [Meeting Abstract]
Background/Purpose: To determine the rate and characteristics of postoperative flares in rheumatic disease patients undergoing arthroscopic surgery, and the role of perioperative immunosuppression (IS) management in preventing or provoking these exacerbations. We conducted a retrospective review of arthroscopic surgeries in patients with rheumatologic disease over 11 years. Patients taking IS at baseline and those without were matched 1:1 using propensity scores on age, sex, rheumatic disease type, and procedure complexity. Patients taking IS at baseline were sub-divided into those remaining on IS perioperatively versus those who held IS before surgery. Multivariable logistic regression identified risk factors for postoperative flares for the three IS groups, and survival analysis was used to compare the probability of remaining flare-free up to 12 weeks postoperatively.
Method(s): We conducted a retrospective review of arthroscopic surgeries in patients with rheumatologic disease over 11 years. Patients taking IS at baseline and those without were matched 1:1 using propensity scores on age, sex, rheumatic disease type, and procedure complexity. Patients taking IS at baseline were sub-divided into those remaining on IS perioperatively versus those who held IS before surgery. Multivariable logistic regression identified risk factors for postoperative flares for the three IS groups, and survival analysis was used to compare the probability of remaining flare-free up to 12 weeks postoperatively.
Result(s): After matching,428 patients (214 on baseline IS, 214 not on baseline IS) were included, with 110 on baseline IS remaining on it perioperatively. Rates of postoperative flares were similar for those staying on vs holding their baseline IS (9.1% vs 9.6%) but flares were less frequent in patients not on baseline IS (1.9%). Patients who remained on perioperative IS did not have significantly less flares compared to patients taken off perioperative IS (OR 0.764 [0.267, 2.181]; p = 0.61). Patients not on baseline IS had a significantly higher probability of remaining flare-free up to 12 weeks (p = 0.004).
Conclusion(s): Rheumatic disease patients who hold IS medication before undergoing arthroscopy do not increase their risk of flaring their autoimmune disease. Those not taking any IS at baseline have amuch lower risk of post-arthroscopic flaring, though as a group they might harbor less of an autoimmune burden. Given the overall low observed rates of postoperative infection and complications among our cohort, the feared trade-off between infection risk and flare risk may not hold true in arthroscopy
Postoperative Risk of Immunosuppression in Rheumatic Disease Patients Undergoing Arthroscopy [Meeting Abstract]
Background/Purpose: Recent literature suggests that rheumatic disease patients hold most immunosuppressive (IS) medications before and after joint replacement surgery, to prevent infections and other complications. But there are currently no guidelines on peri-arthroscopic management of IS treatment in this population. The purpose of this study is to characterize the rheumatic disease patient population undergoing arthroscopy, compare the incidence of postoperative complications among patients who either remained on IS perioperatively, held IS perioperatively or were not on IS at baseline, and compare the incidence of postoperative complication by rheumatic disease type, medication type, and procedure.
Method(s): We conducted a retrospective review of all arthroscopic sports medicine surgeries in patients with a rheumatic disease diagnosis at our institution over an 11-year period. Patients on IS at baseline were grouped into those who remained on IS perioperatively or held all IS before the date of their surgery. These two groups were compared to rheumatic disease patients who were not on IS at baseline. Incidence of postoperative complications was calculated for the three cohorts and by medication class, rheumatic disease type, and procedure risk. Analysis of variance (ANOVA), Chi-squared, and Fisher's exact tests were used to determine the statistical significance of between-group differences in postoperative complication incidence.
Result(s): We identified 1,316 rheumatic disease patients undergoing arthroscopy, with 214 of them taking IS medications at baseline. Overall, 8.4% (n=110) remained on IS perioperatively, 7.9% (n=104) held IS perioperatively, and 83.7% (n=1102) were not on IS at baseline. In all cohorts, 7 patients experienced postoperative complications, with 6 of the 7 due to infections. There were two cases (1.82%) of infections among patients remaining on IS perioperatively, zero cases (0%) of infection in patients who held all IS, and four cases (0.36%) of postoperative infection in patients who were not on any IS at baseline. There was no statistically significant difference in postoperative infections or complication rates among the three cohorts or further subgroups.
Conclusion(s): Physicians and surgeons will increasingly be faced with challenging perioperative management decisions regarding IS in their rheumatic disease patients undergoing arthroscopic surgery. The present study is the first to suggest a low and acceptable risk of postoperative infections and other complications in these patients on IS at the time of arthroscopy
CoLchicine for Treatment of OsteoArthritis of the Knee (CLOAK)-A Double-blind, Placebo-controlled Trial [Meeting Abstract]
Background/Purpose: Knee osteoarthritis (OA) is an inflammatory disease, with a probable role for IL-1b. Calcium and urate crystals may promote OA by activating the NLRP3 inflammasome to produce IL-1b. Colchicine is a well-tolerated anti-inflammatory agent that inhibits the inflammasome and suppresses IL-1b. Studies examining the impact of colchicine on knee OA have yielded varying results, with some reporting pain relief, others improvement of inflammatory markers, and none assessing synovial effusions. We report the interim, blinded results of our ongoing colchicine trial for knee OA.
Method(s): CLOAK is a randomized, double-blind, placebo-controlled trial of colchicine (once daily for 3 months) (Figure 1). We are enrolling subjects >= 40 years of age, with symptomatic knee OA, Kellgren-Lawrence grade 2 or 3 radiographs, and willingness to forego other anti-inflammatory therapy during the trial. The primary outcome is the change in knee pain by visual analog scale (VAS) after 3 months of treatment, comparing the colchicine and placebo groups. Secondary outcomes include pre to post treatment Knee Injury and Osteoarthritis Outcome Score (KOOS), mean doses of analgesics used, and changes in plasma and peripheral blood leukocyte inflammatory markers. Patients undergo knee ultrasound (US) pre-and post-treatment to assess synovitis and effusion. We aspirate synovial fluid when appropriate, and will analyze all available blood and synovial samples after study completion.
Result(s): To date, 715 potential subjects have been contacted, 82 screened, and 71 enrolled. Among 60 who have completed the study, 51.6% are male, 60% White, 30% Black, 3.3% Asian and 6.7% other, with mean BMI of 27.6 kg/m2 and age of 66.8 years. The mean VAS pain score among all completing participants (subjects and controls combined) improved Figure 1. Flow diagram of study plan. Figure 2. Subject improvement in KOOS score from beginning to end of study, according to high or low baseline severity as measured by VAS and KOOS scores and presence of synovial effusion. by 0.98 units in the index knee, and mean KOOS scores improved for symptoms, pain, activities of daily living (ADL), sports activity, and quality of life (QOL). Overall 36 (60%) demonstrated VAS improvement (mean improvement 2.3) whereas 24 (40%) demonstrated no change or worsening. Overall, subjects whose VAS improved showed concordant improvement in the KOOS: mean symptoms by 10.5, pain by 12.4, ADL by 14.8, sports activity by 5.8 and QOL by 11.4 units. The subsets of patients with baseline VAS >=6 and baseline KOOS <=60 (i.e., more severe) showed significantly more 3-month KOOS pain improvement, even with the blinded inclusion of placebo (Figure 2). All underwent US at baseline and 3 months. Among 36 patients with VAS improvement over 3 months, 6 had baseline synovial effusions >=4 mm (in longitudinal and transverse views) and 5 of these effusions were smaller on US post-treatment and one remained stable.
Conclusion(s): The results of this blinded analysis are consistent with a potential benefit of colchicine for pain, function and effusion in subjects not taking other anti-inflammatory agents. Enrollment is ongoing and the study will be unblinded and fully analyzed after completion
Methotrexate and TNF inhibitors affect long-term immunogenicity to COVID-19 vaccination in patients with immune-mediated inflammatory disease
Colchicine and clinical trials for hand osteoarthritis [Letter]
14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis
OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3Îµ) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3Îµ. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3Îµ was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3Îµ was downregulated in OA and its deficiency deteriorated OA. 14-3-3Îµ was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3Îµ largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3Îµ signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-ÎºB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3Îµ as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.
Perioperative Management of Immunosuppressive Medications in Rheumatic Disease Patients Undergoing Arthroscopy
PURPOSE OF REVIEW/OBJECTIVE:This manuscript reviews relevant prior literature regarding management of immunosuppressants in patients with rheumatic diseases around the time of orthopedic surgery, highlighting important considerations specifically regarding arthroscopy. RECENT FINDINGS/RESULTS:Utilization rates of arthroscopic surgery in patients with rheumatic diseases are on the rise, as immunosuppressive treatment options enable them to lead more active lives and hence experience more injuries. Physicians regularly manage patients' glucocorticoids and conventional synthetic and biologic disease modifying antirheumatic drugs around the time of orthopedic surgery, aiming to minimize infection risk while optimizing disease control. However, there is a paucity of randomized controlled trial data for orthopedic surgery-and specifically nothing in the literature pertaining to arthroscopic surgery. Recent guidelines for rheumatic disease patients undergoing elective total hip and knee arthroplasty recommend that most immunosuppressive medications should be held perioperatively, citing the high-risk profile of arthroplasty cases and arthroplasty patients. While 2017 societal guidelines for perioperative immunosuppression during arthroplasty currently serve as a guide for physicians, they may not be applicable to arthroscopy. The less aggressive arthroscopic surgeries span a broader range of patient ages and risk profiles, indications for surgery, and procedural complexity and associated risks. Given these considerations, the majority of routine arthroscopic patients may not require holding of their immunosuppressive medications in the perioperative period.
Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease
Methotrexate hampers immunogenicity to BNT162B2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease [Meeting Abstract]
Background/Purpose: Patients with immune mediated inflammatory disorders (IMIDs) have an inherently heightened susceptibility to infection and may be considered high risk for developing COVID-19. While data regarding the COVID-19 vaccine's immunogenicity in an immunocompetent adult population is rapidly emerging, the ability of IMID patients to adequately respond to these vaccines is not known. Here, we investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with IMIDs on immunomodulatory treatment Methods: Patients with immune mediated inflammatory disorders (IMIDs) have an inherently heightened susceptibility to infection and may be considered high risk for developing COVID-19. While data regarding the COVID-19 vaccine's immunogenicity in an immunocompetent adult population is rapidly emerging, the ability of IMID patients to adequately respond to these vaccines is not known. Here, we investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with IMIDs on immunomodulatory treatment.
Result(s): The NY cohort baseline characteristics are found in Table 1. The Erlangen cohort consisted of 182 healthy subjects, 11 subjects with IMID receiving TNFi monotherapy, and 20 subjects with IMID on MTX monotherapy. In both cohorts, healthy individuals and those with IMID not on MTX were similar in age, while those IMID patients receiving MTX were generally older. In the NY cohort, of the healthy participants, 96.3% demonstrated adequate humoral immune response. Patients with IMID not on MTX achieved a similar rate of high antibody response rate (91.8%), while those on MTX had a lower rate of adequate humoral response (75.0%) (Figure 1A). This remains true even after the exclusion of patients who had evidence of prior COVID-19 infection (P= 0.014). Of note, 3 out of the 4 IMID patients receiving rituximab did not produce an adequate response. Similarly, in the Erlangen validation cohort, 98.3% of healthy controls, 90.9% of patients with IMID receiving TNFi monotherapy, and 50.0% receiving MTX monotherapy achieved adequate immunogenicity (Figure 1B). These differences remain significant when combining the cohorts, using a stricter definition of adequate response, and in a subgroup analysis by age. Cellular response was also analyzed in a subgroup of the NY cohort before and after second vaccination. Activated CD8+ T cells (CD8+ T cells expressing Ki67 and CD38) and the granzyme B-producing subset of these activated CD8+ T cells, were induced in immunocompetent adults and those with IMID not on MTX, but not induced in patients receiving MTX (Figure 2).
Conclusion(s): In two independent cohorts of IMID patients, MTX, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking MTX to increase the chances of immunization efficacy against SARS-CoV-2, as has been demonstrated for other viral vaccines