Prevention of Vascular Contributions to Cognitive Impairment and Dementia: The Role of Physical Activity and Exercise.

Vascular contributions to cognitive impairment and dementia, specifically cerebral small vessel disease (CSVD), are the second most common cause of dementia. Currently, there are no specific pharmacological treatments for CSVD, and the use of conventional antidementia drugs is not recommended. Exercise has the potential to prevent and mitigate CSVD-related brain damage and improve cognitive function. Mechanistic pathways underlying the neurocognitive benefits of exercise include the control of vascular risk factors, improving endothelial function, and upregulating exerkines. Notably, the therapeutic efficacy of exercise may vary by exercise type (ie, aerobic versus resistance training) and biological sex; thus, studies designed specifically to examine these moderating factors within a CSVD context are needed. Furthermore, future research should prioritize resistance training interventions, given their tremendous therapeutic potential. Addressing these knowledge gaps will help us refine exercise recommendations to maximize their therapeutic impact in the prevention and mitigation of CSVD.

A Cadaveric Study for the Improvement of Thread Carpal Tunnel Release.

PURPOSE: The thread carpal tunnel release (TCTR) technique has been improved and offers more precise control in dissecting thread placement. The purpose of this cadaveric study was to test the procedure operationally and verify the modified TCTR anatomically. METHODS: Eleven unembalmed cadaver wrists underwent the transverse carpal ligament (TCL) release by using the modified TCTR technique. An experienced observer dissected each specimen and assessed for completeness of release under direct visual assessment. Injury to the superficial palmar aponeurosis (SupPA), the Berrettini and common digital nerve branches were also recorded as a secondary outcome. RESULTS: Eleven out of 11 wrists (100%) underwent the modified TCTR with complete release of the TCL. All 11 wrists were released without damage to any vital neurovascular structure including the Berrettini branch and the common digital nerves. The SupPA remained intact in all 5 wrists performed with the preservation steps. CONCLUSIONS: The modified TCTR technique demonstrated complete division of the TCL while protecting the SupPA as well as the Berrettini and common digital nerve branches. CLINICAL RELEVANCE: The modified TCTR has the potential to offer a clinically safe and effective minimally invasive procedure for complete carpal tunnel release.

Intra-articular hylastan versus steroid for knee osteoarthritis.

PURPOSE: To assess the efficacy and safety of one and two intra-articular (IA) injections of the new viscosupplement, hylastan, compared with a single IA corticosteroid injection for pain due to knee osteoarthritis (OA). Hylastan is a high-molecular-weight hyaluronan derivative prepared from bacterial fermented sodium hyaluronate that was developed to remain in the joint for longer than most other viscosupplements. METHODS: This 6-month, double-blind, randomized, parallel group, multicenter trial enrolled patients aged ≥40 years who met American College of Rheumatology criteria for knee OA and had continued pain despite conservative treatment. Patients were randomized 1:1:1 to one of three arms: 2 × 4 mL hylastan (n = 129; arthrocentesis then IA hylastan Day 0, same treatment Week 2); 1 × 4 mL hylastan (n = 130; arthrocentesis then IA hylastan Day 0, arthrocentesis only Week 2); steroid (n = 132; arthrocentesis then IA methylprednisolone acetate 40 mg Day 0, arthrocentesis only Week 2). Participants and evaluators were blinded to treatment. The primary clinical outcome measure was change from baseline in WOMAC A pain score over all postbaseline visits to Week 26. RESULTS: Statistically significant pain reduction was observed in all three arms, with similar mean (95 % CI) changes in WOMAC A: 2 × 4 mL hylastan -0.9 (-1.0, -0.7); 1 × 4 mL hylastan -0.8 (-0.9, -0.7); steroid -0.9 (-1.0, -0.8); all P < 0.0001 versus baseline. Changes in secondary outcomes (OMERACT-OARSI and WOMAC A responder rates, patient/clinical observer global assessments, and WOMAC A1 walking pain) were similar in all three arms. Target knee adverse events were comparable for all treatments. CONCLUSIONS: Both IA hylastan injection regimens were effective in relieving pain with an acceptable safety profile. IA hylastan did not show a difference versus IA corticosteroid; therefore, the hypothesis of superior pain relief was not met. Further research is needed to compare the efficacy and safety of hylastan with other viscosupplements.

Targeting integrins in drug-resistant acute myeloid leukaemia.

Acute myeloid leukaemia (AML) continues to have a poor prognosis, warranting new therapeutic strategies. The bone marrow (BM) microenvironment consists of niches that interact with not only normal haematopoietic stem cells (HSC) but also leukaemia cells like AML. There are many adhesion molecules in the BM microenvironment; therein, integrins have been of central interest. AML cells express integrins that bind to ligands in the microenvironment, enabling adhesion of leukaemia cells in the microenvironment, thereby initiating intracellular signalling pathways that are associated with cell migration, cell proliferation, survival, and drug resistance that has been described to mediate cell adhesion-mediated drug resistance (CAM-DR). Identifying and targeting integrins in AML to interrupt interactions with the microenvironment have been pursued as a strategy to overcome CAM-DR. Here, we focus on the BM microenvironment and review the role of integrins in CAM-DR of AML and discuss integrin-targeting strategies. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

Supporting physical activity for mobility in older adults with mobility limitations (SuPA Mobility): study protocol for a randomized controlled trial.

BACKGROUND: Limited mobility in older adults consistently predicts both morbidity and mortality. As individuals age, the rates of mobility disability increase from 1.0% in people aged 15-24 to 20.6% in adults over 65 years of age. Physical activity can effectively improve mobility in older adults, yet many older adults do not engage in sufficient physical activity. Evidence shows that increasing physical activity by 50 min of moderate intensity physical activity in sedentary older adults with mobility limitations can improve mobility and reduce the incidence of mobility disability. To maximize the healthy life span of older adults, it is necessary to find effective and efficient interventions that can be delivered widely to prevent mobility limitations, increase physical activity participation, and improve quality of life in older adults. We propose a randomized controlled trial to assess the effect of a physical activity health coaching intervention on mobility in older adults with mobility limitations. METHODS: This randomized controlled trial among 290 (145 per group) community-dwelling older adults with mobility limitations, aged 70-89 years old, will compare the effect of a physical activity health coaching intervention versus a general healthy aging education program on mobility, as assessed with the Short Physical Performance Battery. The physical activity health coaching intervention will be delivered by exercise individuals who are trained in Brief Action Planning. The coaches will use evidence-based behavior change techniques including goal-setting, action planning, self-monitoring, and feedback to improve participation in physical activity by a known dose of 50 min per week. There will be a total of 9 health coaching or education sessions delivered over 26 weeks with a subsequent 26-week follow-up period, wherein both groups will receive the same duration and frequency of study visits and activities. DISCUSSION: The consequences of limited mobility pose a significant burden on the quality of life of older adults. Our trial is novel in that it investigates implementing a dose of physical activity that is known to improve mobility in older adults utilizing a health coaching intervention. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT05978336; registered on 28 July 2023.

Medical Management of Infants With Supraventricular Tachycardia: Results From a Registry and Review of the Literature.

Background: Several medication choices are available for acute and prophylactic treatment of refractory supraventricular tachycardia (SVT) in infants. There are almost no controlled trials, and medication choices are not necessarily evidence based. Our objective was to report the effectiveness of management strategies for infant SVT. Methods: A registry of infants admitted to hospital with re-entrant SVT and no haemodynamically significant heart disease were prospectively followed at 11 international tertiary care centres. In addition, a systematic review of studies on infant re-entrant SVT in MEDLINE and EMBASE was conducted. Data on demographics, symptoms, acute and maintenance treatments, and outcomes were collected. Results: A total of 2534 infants were included: n = 108 from the registry (median age, 9 days [0-324 days], 70.8% male) and n = 2426 from the literature review (median age, 14 days; 62.3% male). Propranolol was the most prevalent acute (61.4%) and maintenance treatment (53.8%) in the Registry, whereas digoxin was used sparingly (4.0% and 3.8%, respectively). Propranolol and digoxin were used frequently in the literature acutely (31% and 33.2%) and for maintenance (17.8% and 10.1%) (P < 0.001). No differences in acute or prophylactic effectiveness between medications were observed. Recurrence was higher in the Registry (25.0%) vs literature (13.4%) (P < 0.001), and 22 (0.9%) deaths were reported in the literature vs none in the Registry. Conclusion: This was the largest cohort of infants with SVT analysed to date. Digoxin monotherapy use was rare amongst contemporary paediatric cardiologists. There was limited evidence to support one medication over another. Overall, recurrence and mortality rates on antiarrhythmic treatment were low.

Contexte: De nombreux choix de médicaments existent pour le traitement aigu et prophylactique de la tachycardie supraventriculaire (TSV) réfractaire chez les nourrissons. Or, il n'y a presque pas d'essais contrôlés à ce sujet, et les choix de médicaments ne sont pas nécessairement fondés sur des données probantes. Notre objectif était de faire état de l'efficacité des stratégies de prise en charge de la TSV chez les nourrissons. Méthodologie: Un registre des nourrissons admis à l'hôpital pour une TSV par réentrée, sans cardiopathie d'importance hémodynamique, a été tenu de façon prospective dans 11 centres de soins tertiaires à l'échelle mondiale. De plus, une revue systématique des études sur la TSV par réentrée chez le nourrisson a été effectuée dans MEDLINE et EMBASE. Des données sur les caractéristiques démographiques, les symptômes, les traitements aigus et d'entretien, et les résultats ont été recueillis. Résultats: Un total de 2 534 nourrissons ont été inclus : n = 108 du registre (âge médian de 9 jours [0-324 jours], 70,8 % de sexe masculin) et n = 2 426 de la revue de la littérature (âge médian de 14 jours; 62,3 % de sexe masculin). Le propranolol était le traitement de soins aigus (61,4 %) et d'entretien (53,8 %) le plus fréquent dans le registre, alors que la digoxine a été utilisée occasionnellement (respectivement dans 4,0 % et 3,8 % des cas). Dans la littérature, le propranolol et la digoxine étaient fréquemment utilisés en soins aigus (31 % et 33,2 %) et en traitement d'entretien (17,8 % et 10,1 %) (p < 0,001). Aucune différence n'a été observée entre les médicaments au chapitre de l'efficacité du traitement de soins aigus ou du traitement prophylactique. Le taux de récurrence était plus élevé dans le registre (25,0 %) que dans la littérature (13,4 %) (p < 0,001), et 22 (0,9 %) décès ont été signalés dans la littérature, mais aucun dans le registre. Conclusion: Il s'agit de la plus grande cohorte de nourrissons atteints de TSV analysée à ce jour. De nos jours, les cardiologues pédiatriques prescrivent rarement la digoxine en monothérapie. Peu de données probantes favorisent l'utilisation d'un médicament par rapport à l'autre. Dans l'ensemble, les taux de récurrence et de mortalité sous traitement antiarythmique étaient faibles.

CXCL13: a novel biomarker of B-cell return following rituximab treatment and synovitis in patients with rheumatoid arthritis.

OBJECTIVES: The B-cell chemokine, CXCL13, is a proposed serum biomarker of synovitis in RA. Its behaviour in the context of B-cell depletion therapy and reconstitution was studied during treatment of RA with rituximab. METHODS: Serum samples from 20 RA patients were analysed for CXCL13, RF-IgM and anti-CCP by ELISA before and 2 and 6 months following rituximab treatment. B cells were monitored by flow cytometry. Gene expression in blood and synovial biopsies was determined by qPCR. RESULTS: Patients with detectable B cells at 6 months had significantly higher levels of CXCL13 and RF-IgM and slightly higher levels of anti-CCP throughout the study, including at baseline, compared with patients with undetectable B cells at 6 months. Conversely, 10 of 12 patients with high baseline CXCL13 had detectable circulating B cells at 6 months, whereas no B cells could be detected at 6 months in patients with low baseline CXCL13. Synovial CXCL13 expression at baseline correlated significantly with serum CXCL13 levels, and the synovium of patients with high serum CXCL13 expressed elevated levels of IL-1ß, IL-8, MMP1 and MMP3. In addition, synovial CXCL13 expression correlated significantly with several synovial inflammatory markers. CONCLUSIONS: Serum CXCL13 is predictive of the rate of B-cell repopulation following a course of rituximab in RA. Serum CXCL13 correlates with synovial CXCL13 measured at a single joint, suggesting synovitis as an important source of circulating CXCL13. Within the synovium, CXCL13 expression is highly correlated with markers of synovitis. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00147966.

Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis.

Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.

Psoriatic Arthritis: What is Happening at the Joint?

Psoriatic arthritis (PsA) is a heterogeneous and inflammatory disease with diverse clinical manifestations, including psoriasis, nail psoriasis, peripheral joint disease, axial joint disease, enthesitis, and dactylitis. Typically, this varied clinical presentation complicates the clinician's ability to distinguish PsA from other forms of arthritis. In the synovium of individuals with PsA, upregulation of the genes WNT3A, BMPR2, and TGFBR1 results in bone erosion and new bone formation, a pattern unique to the disease. Additionally, genes associated with angiogenesis and vascularization such as VEGF and TGFB1 facilitate inflammation and joint damage. Gross pathogenesis of PsA is driven by proinflammatory cytokines, and key cytokines affecting joint structures include tumor necrosis factor-α, interleukin (IL)-6, IL-17A, IL-21, IL-22, and IL-23. Early diagnosis is critical for providing treatment that prevents irreversible disease progression and function loss. This narrative review discusses differentiation of PsA from other forms of arthritis. Additionally, we detail the role of cytokines at the joint in mediating PsA pathogenesis.Funding: Novartis Pharmaceuticals Corporation.

Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action.

OBJECTIVE: Many types of treatment are available for patients with rheumatoid arthritis (RA), however, some patients fail to achieve remission. This report aims to determine the safety and efficacy of using repository corticotropin injection (RCI) as an adjunctive therapy in patients with RA refractory to at least three therapeutics with different mechanisms of action. METHOD: In this open-label, interventional, single-group study, patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie-Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. RESULTS: Eight patients were enrolled and consisted of seven females and one male with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 and the physician and patient visual analog scale scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in disease activity score 28, physician and patient visual analog scale, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. CONCLUSION: While larger clinical trials are necessary to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggests that RCI can be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggests that RCI has an alternative mode of action, compared to other available antirheumatic drugs.

Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis.

OBJECTIVE: To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA. METHODS: We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence. RESULTS: Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR. CONCLUSION: This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA.

A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee.

OBJECTIVE: The Low Molecular Weight Fraction of 5% human serum Albumin (LMWF-5A) is being investigated as a treatment for knee pain from osteoarthritis. METHODS: This was a multicenter randomized, vehicle-controlled, double-blind, parallel study designed to evaluate the safety and efficacy of two doses of an intra-articular injection of LMWF-5A. Patients with symptomatic knee osteoarthritis were randomized 1∶1∶1∶1 to receive a single 4 mL or 10 mL intra-articular knee injection of either LMWF-5A or vehicle control (saline). The primary efficacy endpoint was the difference between treatment groups in the Western Ontario and McMaster Universities (WOMAC) pain change from baseline over 12 weeks. Safety was examined as the incidence and severity of adverse events (AEs). RESULTS: A total of 329 patients were randomized and received treatment. LMWF-5A resulted in a significant decrease in pain at 12 weeks compared to vehicle control (-0.93 vs -0.72; estimated difference from control: -0.25, p = 0.004); an injection volume effect was not observed (p = 0.64). The effect of LMWF-5A on pain was even more pronounced in patients with severe knee OA (Kellgren Lawrence Grade IV): the estimated difference from control was -0.42 (p = 0.02). Adverse events were generally mild and were similar in patients who received vehicle control (47%) and LMWF-5A (41%). CONCLUSIONS: This clinical trial demonstrated that LMWF-5A is safe and effective at providing relief for the pain of moderate to severe OA of the knee over 12 weeks when administered by intra-articular injection into the knee. TRIAL REGISTRATION: ClinicalTrials.gov NCT01839331.

Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate.

OBJECTIVE: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX. RESULTS: The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related. CONCLUSION: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

Evaluation of heterophilic antibody blocking agents in reducing false positive interference in immunoassays for IL-17AA, IL-17FF, and IL-17AF.

IL-17AA, IL-17FF, and IL-17AF are proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). In order to measure the levels of these cytokines in synovial fluid and serum samples from RA patients, immunoassays specific for IL-17AA, FF, and AF were developed. Although these assays could tolerate up to 50% pooled normal human serum, false positive reactivity was problematic in patient samples suggesting interference from heterophilic antibodies. We therefore evaluated the ability of several commercially available heterophilic antibody blocking agents to reduce false positive reactivity by testing them against samples that were confirmed as false positives in the IL-17AA, FF, and AF assays. Several of the blockers performed well, including HBR-1, HBR-9, HBR-11, HBR-Plus, Serum Cytokine Assay Diluent, and IIR. We chose to move forward using IIR blocker for sample analysis and verified that IIR had no effect on the assay standard curves and did not affect IL-17 quantitation in plasma from ex vivo stimulated human whole blood. IL-17FF and IL-17AF were below the limits of quantitation of the assays (12.3 and 10.5pg/ml, respectively) in synovial fluid and serum samples from patients with RA and osteoarthritis (OA). For the more sensitive IL-17AA assay (1.6pg/ml limit of quantitation), low levels of IL-17AA were measurable in 48% of RA synovial fluid samples (mean, 7.9pg/ml; median, <1.6pg/ml; range, <1.6-29.7pg/ml; n=23) but not in synovial fluid from patients with OA (n=33). For serum samples, however, IL-17AA was below the limit of detection for both RA and OA patients. When these same serum samples were analyzed in the absence of a heterophilic antibody blocker, false positive reactivity yielded apparent mean IL-17AA levels of 43.3pg/ml (28% positive; n=50) and 14.8pg/ml (12% positive; n=50) for RA and OA patients, respectively, results that could potentially be interpreted as consistent with disease biology. These studies demonstrate the importance of ensuring that HAb interference is well controlled, particularly when measuring low concentrations of cytokines in samples from patients with autoimmune disease.

Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study.

OBJECTIVE: To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. METHODS: In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection. RESULTS: 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14). CONCLUSION: IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.