The structure and expression of the pentraxins, serum amyloid P component (SAP), and C-reactive protein (CRP), have been investigated in the guinea pig. Northern blot analysis of hepatic RNA from animals in which acute inflammation had been induced by intraperitoneal injection of thioglycollate established that neither SAP or CRP is a major acute phase reactant in the guinea pig. Genomic clones of SAP and CRP were isolated and sequenced, and the gene and the derived protein sequences were compared with other mammalian homologues. Both genes have organizations typical of the pentraxin genes of other species, but some differences were defined in the regions that potentially determine the capacity of the pentraxin gene to be induced during acute inflammation. Nucleotide substitutions in coding regions have occurred at similar rates in the two pentraxin genes. Nonsynonymous substitution rates indicate that SAP and CRP are subject to similar, relatively low levels of constraint; at the amino acid sequence level the rate of evolution is approximately two replacements per site per 10(9) years. An estimate of the phylogenetic relationship among the pentraxin genes suggests that SAP and CRP arose as the result of a gene duplication event that occurred very early in mammalian evolution, but subsequent to the divergence of the reptilian ancestors of the mammalian and avian lineages. This raises doubts about the identity of proteins from fish, which have been previously characterized as CRP and SAP.
Background/Purpose: The efficacy and safety of tocilizumab (TCZ), an interleukin‐6 receptor inhibitor, were previously demonstrated at week 40 of CHERISH, a phase 3 trial in patients with polyarticular‐course juvenile idiopathic arthritis (pcJIA) (). Here we report the efficacy and safety of TCZ over 104 weeks of treatment in patients with pcJIA. Methods: Patients 2 to 17 years old with ≥6 months' active pcJIA who failed methotrexate received open‐label TCZ (weight ≥30 kg, 8 mg/kg [n = 119]; weight ≥30 kg, randomly assigned [1:1] to 8 [n = 34] or 10 [n = 35] mg/kg) every 4 weeks for 16 weeks. Patients with ≥JIA American College of Rheumatology (ACR) 30 response at week 16 entered a 24‐week, double‐blind withdrawal period and were randomly assigned (1:1) to placebo or continuation with TCZ. Patients with JIA ACR30 flare or who completed the withdrawal period entered an open‐label extension through week 104. Results: One hundred eighty‐eight patients entered the lead‐in period, 166 entered the withdrawal period, 160 entered the open‐label extension period, and 155 completed 104 weeks. In patients who received continuous TCZ throughout the study (n = 82), JIA ACR responses, improvement in JIA ACR core components, and proportions of patients with inactive disease or remission () were maintained through week 104. JADAS‐71 scores were maintained through week 104 (Figure); 73% of patients had JADAS‐71 <3.8 (minimal disease activity cutoff), 56% had JADAS‐71 <1 (inactive disease cutoff). The safety population comprised 188 patients with 307 patient‐years (PY). Rates/100 PY of adverse events (AEs) and serious AEs (SAEs) were 406.5 and 11.1, respectively; infections were the most common AE (151.4) and SAE (5.2). ALT and AST elevations ≥3× upper limit of normal occurred in 6.4% and 2.7% of patients, respectively. Grade 3 lowest neutrophil count and grade 2/3/4 thrombocytopenia occurred in 5.9% and 1.6% of patients, respectively. LDL cholesterol ≥110 mg/dL occurred in 16.2% of patients. Efficacy End Points and Percentage Change From Baseline in JIA ACR Componentsa (continuous TCZ, n = 82) Baseline Week 40 Change from baseline to week 40, % Week 104 Change from baseline to week 104, % JIA ACR70 responders, n (%)–65 (79.3)–71 (86.6)–JIA ACR90 responders, n (%)–65 (79.3)–71 (86.6)–Active joints (0–71)19.7 ± 14.04.7 ± 9.1−82.4 ± 24.93.3 ± 9.1−87.7 ± 27.1Joints with limitation of movement (0–67)16.5 ± 13.85.6 ± 10.1−73.5 ± 30.73.6 ± 7.3−81.3 ± 31.7Patient globalc (VAS 0–100 mm)45.5 ± 23.112.2 ± 19.0−62.5 ± 76.39.1 ± 18.4−75.4 ± 43.8Patient global (VAS 0–100 mm)45.5 ± 23.112.2 ± 19.0−62.5 ± 76.39.1 ± 18.4−75.4 ± 43.8Physician global (VAS 0–100 mm)57.8 ± 20.38.8 ± 10.9−85.3 ± 16.85.0 ± 10.5−89.7 ± 23.7CHAQ‐DI (0–3)1.2 ± 0.70.4 ± 0.5−66.0 ± 44.70.2 ± 0.4−76.7 ± 34.7ESR (mm/h)31.7 ± 22.95.4 ± 6.3−76.5 ± 22.05.1 ± 5.6−76.2 ± 27.3Inactive disease, n (%)–33 (40.2)–52 (63.4)–Remission, n (%)–5 (6.1)–31 (37.8)–Minimal disease activity (JADAS‐71 <3.8), n (%)0 (0)49 (59.8)–60 (73.2)–Inactive disease (JADAS‐71 <1), n (%)0 (0)24 (29.3)–4...
Background:Infections are a major concern for patients affected by juvenile idiopathic arthritis (JIA) treated with immunosuppressive therapy. Evidence is inconsistent as to whether the start of synthetic or biological disease modifying anti-rheumatic drugs (DMARDs) is associated with an increased risk of serious and at least moderate infection.Objectives:To determine whether the addition of a TNF inhibitor (TNFi) to methotrexate (MTX) may increase the risk of serious and at least moderate infections in JIA patients included in the Pharmachild registry.(1)Methods:Serious and at least moderate infections were analysed in JIA patients, enrolled in the Pharmachild registry at September 30th, 2018, who started as first drug with MTX. We divided patients in 3 treatment groups: “MTX alone”, in which patients had received MTX as the only drug all over their history; “MTX Start”, in which patients had received MTX as first drug; “MTX+TNFi” for those patients who received a TNFi in addition to MTX after a period of “MTX Start”. All the 3 groups were pure, since they received only these drugs. We considered initial infections as related to the treatment if the infection occurred in the drug period or within 90 days after treatment stop.(2) For the group “MTX Start”, infection was related to treatment if occurring in the drug period stopped as soon as the second drug was introduced. For the group “MTX+TNFi”, we considered all the possible correlations between start and end dates of the two drugs, including the time lag of 90 days after any treatment stop. If the interval between two drugs was shorter than 90 days, treatment was considered continuous. Crude rates (number of infections divided by drug exposure, excluding off-drug periods) and true incidence rates (number of first infections divided by the time lag between first drug administration and the date of the infection if the patient experienced the infection, the last Pharmachild visit if the patient didn’t experience the event) were calculated.Results:We enrolled in Pharmachild a total of 8061 patients who experienced 1686 infections. We excluded 41 patients who had infections before any treatment start. Of the final number of 8020 patients, we considered: 1226 patients in the group “MTX alone”, 3128 in the group “MTX start” and 1026 in the group “MTX+TNFi”. 7.7% of the patients in the “MTX alone” group, 2.7% of the patients in the “MTX Start” group and 7.0% of the patients in the “MTX+TNFi” group experienced at least one infection. Crude rates of infections per 1000 person-years resulted: 48.0 for the group “MTX alone”, 22.0 for “MTX Start”, 74.0 for “MTX+TNFi”. Incidence rates per 1000 person-years were: 32.0 for the group “MTX alone”, 17.0 for “MTX Start”, 59.5 for “MTX+TNFi”. The percentage of drug exposure on the patient follow-up was variable among the 3 treatment groups (from 15.6% for the “MTX+TNFi” group to 51.5% for the “MTX alone” group).Conclusion:Pharmachild showed, through the analysis of pure treatment groups, that the addition of the anti-TNF biologic...
BackgroundThe efficacy of SC abatacept (ABA) in patients (pts) with polyarticular-course juvenile idiopathic arthritis (pJIA) was shown in a 2-year (yr), Phase III, open-label international study (NCT01844518).1 However, it is unknown whether each individual pt within a treatment group consistently achieves the same efficacy endpoint at all time points.ObjectivesTo investigate whether ABA efficacy is maintained by individual pts with pJIA over time.MethodsIn this subgroup analysis, pts in two age cohorts (2–5 yrs and 6–17 yrs) who achieved clinical response to weekly SC ABA (10 to <25 kg [50 mg], 25 to <50 kg [87.5 mg], ≥50 kg [125 mg]) at Day 113 (time point of primary pharmacokinetics endpoint1) were followed for 2 yrs. Stringent efficacy outcomes selected for analysis included JIA-ACR70, JIA-ACR100, Juvenile Arthritis Disease Activity Score 71 (JADAS71) minimal disease activity (MDA; ≤3.8) and JADAS71 inactive disease (ID; ≤1) rates. Prognostic factors for sustained response were investigated using logistic regression.ResultsA total of 219 pts entered the study (46 [21.0%] 2–5 yrs; 173 [79.0%] 6–17 yrs) and a subgroup of these pts achieved a clinical response at Day 113 (Table). Most pts who achieved JIA-ACR70, JIA-ACR100, JADAS71 MDA and JADAS71 ID at Day 113 sustained their response at Day 393 and at Days 393 and 645 in the 2–5-yr and 6–17-yr cohorts (Figure). Across cohorts, more than 75% and 60% of pts maintained a JIA-ACR 70 and JADAS71 MDA response through Day 645, respectively. Prior biologic (b)DMARD use was an important prognostic factor. In pts aged 6–17 yrs, sustained JIA-ACR70 response rate at Days 393 and 645 was 81% (57/70) in pts who did not have prior bDMARDs vs 57% (12/21) in pts who had prior bDMARDs (p=0.0715); sustained JADAS71 MDA response rate was 71% (37/52) vs 37% (7/19; p=0.0320). Prognostic factors for JIA-ACR100 response and JADAS71 ID in pts aged 6–17 yrs and for all outcomes in pts aged 2–5 yrs could not be determined due to low pt numbers.ConclusionThe majority of individuals with pJIA who achieved stringent efficacy endpoints with weekly SC abatacept by Day 113 sustained that clinical endpoint over time. Prior bDMARD use may be a prognostic factor for sustained response over 2 yrs.Reference[1] Brunner HI, et al. Arthritis Rheumatol2018;70:1144–54.AcknowledgementProfessional medical writing: Stacey Reeber, PhD, Caudex; funding: Bristol-Myers SquibbDisclosure of InterestsNicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus (< 10.000 USD each) from the following pharmaceutical companies in the past 3 years: Ablynx, AbbVie, ...
BackgroundJIA comprises an heterogeneous group of diseases characterized by chronic arthritis, of unknown etiology, and onset age before 16. (1)Juvenile Idiopathic Arthritis(1) is the most common chronic rheumatic disease in children, being an important cause of disability, affecting quality of life (2).There are several subtypes of the disease, despite oligoarticular course has been described as the most frequently seen, up to 50% of JIA cases presented a polyarticular disease (4 3).Data suggest that patients who receive early therapeutic intervention are more likely to reach clinical remission. In a systematic review, Wallace’s criteria were used to determine drug remission and inactive disease. They reported 7% and 47% of patients reached remission at 1.5 and 10 years, respectively. Oligoarticular patients had a shorter time to remission, while polyarticular positive rheumatoid factor were the least likely to achieve it (5).Mexico belongs to a group of developing countries where there is limited information about incidence, prevalence, clinical features, age and time to diagnosis, treatment, and remission of JIA patients.ObjectivesThe aim of the study is to describe demographics, clinical data and long-term follow-up of a cohort of juvenile idiopathic arthritis patients in a Mexican center.MethodsThe study design was observational with no intervention, ambispective, among patients with JIA, according to ILAR criteria of pediatric rheumatology clinic from University Hospital “Dr. José Eleuterio González” over a 2-year period (2016-2018). Medical records of patients were retrospectively reviewed and collected information as demographics, age at diagnosis, disease activity, joints involved, treatment, adverse events, clinical inactivity and remission.Figure 1Statistical analysis was descriptive with measure of central tendency. For continuous variables, mean, median, interquartile range and standard deviation were used to present data.ResultsWe enrolled 70 patients with JIA, 52 (74%) female, with a median age at diagnosis of 11.7 years. The most frequent subtype was polyarticular positive rheumatoid factor (25, 36%). Eighty adverse events were reported; 45 of special interest.The median time to remission observed was 61 months (95% CI 43.3-78.6); 33 (47%) patients reached inactive disease (Figure 1).ConclusionThe rates of adverse events was low, demonstrating a good safety profile of the treatment, however time to remission is greater than reported in literature.References[1] Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767–78.[2] Ruperto N, Ravelli A, Levinson JE, Shear ES, Murray K, Link Tague B, et al. Long-term health outcomes and quality of life in American and Italian inception cohorts of patients with juvenile rheumatoid arthritis. II. Early predictors of outcome. J Rheumatol [Internet]. 1997;24(5):952–8. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9150088[3] Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalen...
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