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PURPOSE OF REVIEW: This review will attempt to summarize the most potentially impactful new data on the way ANCA-associated vasculitis (AAV) is diagnosed, treated, and monitored. RECENT FINDINGS: The newly developed classification criteria for AAV have serious methodological issues that need to be addressed before they are widely adopted. The newly approved drugs and studies into both achieving remission and maintaining it have added to our overall knowledge of managing AAV and should hopefully contribute to improving outcomes in AAV. SUMMARY: The diagnosis, treatment and monitoring of AAV have seen major improvements in the last two years. The remaining issues outlined in this review still need to be addressed to best serve AAV patients.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Indução de RemissãoRESUMO
INTRODUCTION: Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. METHODS: Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. RESULTS: A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. CONCLUSION: No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04598542.
Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern.
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Behçet's syndrome is a systemic vasculitis affecting arteries and veins of all sizes as well as recurrent oral, genital, and intestinal ulcers, skin lesions, predominantly posterior uveitis, and parenchymal brain lesions. These can be present in various combinations and sequences over time and diagnosis is made by recognizing the manifestations, as there are no diagnostic biomarkers or genetic tests. Treatment modalities include immunomodulatory agents, immunosuppressives and biologics, tailored according to prognostic factors, disease activity, severity, and patients' preferences.
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Síndrome de Behçet , Vasculite , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapiaRESUMO
Disease assessment has been challenging in Behçet syndrome due to the heterogeneous disease course and multiorgan involvement with variable treatment response. There have been several recent improvements regarding outcome measures including development of a Core Set of Domains for Behçet syndrome and novel instruments for assessing specific organs and overall damage. This review focuses on the current state of outcome measures in Behçet syndrome, unmet needs, and a research agenda towards the development of standardized and validated outcome measure instruments.
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Síndrome de Behçet , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Avaliação de Resultados em Cuidados de Saúde , Progressão da DoençaRESUMO
Behcet syndrome is a systemic vasculitis which can involve many different organ systems. As such, treatment decisions need to be based on organ system involved. In addition, specific patient characteristics potentially predict milder or more severe course, and all these factors need to be taken into consideration when making treatment decisions. In this paper, we review the current approaches to treating Behcet syndrome patients.
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Síndrome de Behçet , Humanos , Síndrome de Behçet/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: A critique of the recently published classification criteria for three main types of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. RECENT FINDINGS: An ACR and EULAR joint task force recently published classification criteria for three main types of ANCA-associated vasculitis. The criteria were based on patient histories and findings in nearly 7000 patients from 136 sites in 32 countries. As such the study represented hitherto the most intensive attempt to prepare classification criteria vasculitis. We propose, this truly intensive effort was, unfortunately, unsuccessful. There were two main mishaps. The first one was that the proposed criteria were not validated in an independent cohort. This is curious in that the sponsors, ACR and EULAR, require such independent cohorts for validation. The second mishap is that the concept that disease classification criteria need to be 100% sensitive and specific for a diagnosis is unrealistic. Moreover, all-purpose disease classification criteria are not respectful to scientific research and to the probabilistic nature of the art and the science of medicine. SUMMARY: The new ACR/EULAR ANCA-associated vasculitis guidelines have not been validated in independent cohorts. We propose replacing the term disease criteria with disease guidelines.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Reumatologia , Humanos , Estados Unidos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnósticoRESUMO
OBJECTIVE: To assess apremilast's impact on patient quality of life (QoL) in active Behçet's syndrome and correlations between improvement in patients' QoL and efficacy measures in the phase 3 RELIEF study. METHODS: QoL measures included Behçet's Disease QoL (BDQoL), 36-Item Short-Form Health Survey V.2 (SF-36v2) Physical/Mental Component Summary (PCS/MCS) and eight subscale scores, focusing on Physical Functioning (PF). Pearson's correlation coefficients assessed relationships between efficacy endpoints (oral ulcer count, oral ulcer pain, Behçet's Syndrome Activity Scale (BSAS), Behçet's Disease Current Activity Form (BDCAF)) and QoL endpoints for apremilast at Week 12. RESULTS: Apremilast (n=104) demonstrated significantly greater improvements versus placebo (n=103) in SF-36v2 PCS (3.1 vs 0.9), MCS (4.6 vs â0.7) and PF (2.9 vs 0.14), respectively (all p<0.05). Mild correlations were observed in improvements of SF-36v2 measures (PCS, MCS, PF) with oral ulcer count (r=-0.11, PCS), and change in oral ulcer pain from baseline (r=-0.28, PCS; r=-0.10, PF) and BSAS (r=-0.38, PCS; r=-0.20, PF; r=-0.16, MCS). Correlations among BDCAF and SF-36v2 components and BDQoL were variable. BDQoL showed mild/moderate correlations with SF-36v2 components (r=-0.18, PCS; r=-0.13, PF; r=-0.45, MCS). CONCLUSIONS: Apremilast was associated with significant improvements in QoL measures of SF-36v2 PCS, MCS and PF and BDQoL in patients with Behçet's syndrome. Correlations of improvement among QoL endpoints support the beneficial clinical effects of apremilast in Behçet's syndrome. TRIAL REGISTRATION NUMBER: NCT02307513.
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Síndrome de Behçet , Úlceras Orais , Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Humanos , Úlceras Orais/complicações , Úlceras Orais/tratamento farmacológico , Dor , Qualidade de Vida , Talidomida/análogos & derivadosRESUMO
BACKGROUND: Durable, meaningful symptom responses to intra-articular saline placebo injections are observed in knee osteoarthritis (OA) trials, but it is unclear if these are due to physiological effects. PURPOSE: To perform a prospective comparison of patient-reported outcome responses among participants with knee OA who underwent intra-articular injection of saline-based placebo or sham (dry needle). STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: From a 24-week randomized double-blind trial, participants with moderate to severe knee OA received 2-mL intra-articular injections of saline-based placebo (PBO; 99.45% PBS) or sham (dry needle) to the target knee. Least squares mean differences of changes from baseline to week 24 were compared between the PBO and sham groups for the following: pain Numeric Rating Scale; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function; and patient global assessment. Bang Blinding Index was used to evaluate all-group blinding on day 1 and week 24. RESULTS: In total, 116 and 117 participants were randomized to the PBO and sham groups, respectively. Within the full trial population, the mean ± SD age and body mass index were 59.0 ± 8.5 years and 28.97 ± 4.01, respectively. An overall 406 (58.4%) were female, and 394 (57.3%) had Kellgren-Lawrence grade 3 target knee OA. The PBO and sham groups demonstrated clinically meaningful improvements (≥10%) from baseline in all patient-reported outcomes at all time points (ie, weeks 4-24). Mean differences (95% CI) at week 24 between the PBO and sham groups were as follows: pain Numeric Rating Scale, -0.10 (-0.79 to 0.59; P = .78); WOMAC pain, -2.89 (-9.70 to 3.92; P = .40); WOMAC stiffness, -2.37 (-9.37 to 4.63; P = .51); and WOMAC function, -1.39 (-8.06 to 5.29; P = .68). Bang Blinding Index indicated that blinding was maintained. CONCLUSION: PBO and sham groups demonstrated equivalent patient-reported outcomes at all time points through week 24, suggesting that responses attributed to saline were contextual (ie, to the procedure) and not physiological. REGISTRATION: NCT03122860 (ClinicalTrials.gov identifier).
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Osteoartrite do Joelho , Método Duplo-Cego , Feminino , Humanos , Imidazóis , Indazóis , Injeções Intra-Articulares , Osteoartrite do Joelho/tratamento farmacológico , Medição da Dor , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Piridinas , Resultado do TratamentoRESUMO
OBJECTIVE: An unmet need exists for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet's syndrome. The Outcome Measures in Rheumatology (OMERACT) Behçet's Syndrome Working Group, a large, multidisciplinary group of experts in Behçet's syndrome and patients with Behçet's syndrome, had an objective of developing a core set of data-driven outcome measures for use in all clinical trials of Behçet's syndrome. METHODS: The core domain set was developed through a comprehensive, iterative, multistage project that included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in Behçet's syndrome, a Delphi exercise involving both patients and physician experts in Behçet's syndrome, and use of the data, insight, and feedback generated by these processes to develop a final core domain set. RESULTS: All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in Behçet's syndrome often focus on specific manifestations and not on the disease in its entirety, the final proposed core set includes 5 domains mandatory for study in all trials in Behçet's syndrome (disease activity, new organ involvement, quality of life, adverse events, and death) with additional subdomains mandatory for study of specific organ-systems. The final core set was endorsed at the 2018 OMERACT meeting. CONCLUSION: The core set of domains in Behçet's syndrome provides the foundation through which the international research community, including clinical investigators, patients, the biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.
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Síndrome de Behçet , Reumatologia , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Grupos Focais , Humanos , Avaliação de Resultados em Cuidados de Saúde , Qualidade de VidaRESUMO
OBJECTIVES: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks. METHODS: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study. RESULTS: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure. CONCLUSIONS: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.
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Síndrome de Behçet , Úlceras Orais , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Humanos , Úlceras Orais/tratamento farmacológico , Úlceras Orais/etiologia , Qualidade de Vida , Talidomida/análogos & derivadosRESUMO
OBJECTIVES: Behçet's syndrome (BS) is a systemic vasculitis with heterogeneous clinical presentation and a relapsing disease course. The International Study Group (ISG) criteria are most often used for classification. A significant proportion of patients is classified as probable BS because they do not fulfil the criteria at initial presentation. The aim of this study is to explore clinical BS symptoms present at initial patient visit predictive of ISG criteria diagnosis during follow-up. METHODS: Patients classified as probable BS at initial visit were included. Follow-up ISG status (defined as meeting criteria ISG+ vs. not meeting criteria ISG-) was abstracted from last visit. Univariable logistic regression was used to screen initial visit clinical features and symptoms with follow-up ISG status. All variables that passed screening at p<0.10 were included in the final multivariable model, which was then used to create a probability risk score. RESULTS: 189 patients were included (169 from New York and 20 from Amsterdam). 71 (37.6%) patients were classified as ISG+ during follow-up. In the final model, presence of morning stiffness, genital ulcers, skin lesions, and eye disease were associated with increased odds of ISG+, adjusting for age, symptom duration and family history. This was used to create a probability risk score. CONCLUSIONS: Over a third of patients with suspected or probable BS developed new manifestations over time that led to classification as ISG+ BS. The presence of morning stiffness, genital ulcers, skin lesions and eye disease at initial visit were independently associated with significantly higher odds for developing ISG+ Behçet's during follow-up.