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1.
Artigo em Inglês | MEDLINE | ID: mdl-38796685

RESUMO

BACKGROUND: In 2014 the incidence of anti-HMGCR myopathy in New Zealand was ∼1.7 case/million persons/year. OBJECTIVE: Re-estimate the population incidence and assess ethnic variation in those >40-year -olds. SETTING: An incidence cohort was defined by seropositivity for immunoprecipitating anti-HMGCR autoantibodies tested at a national reference laboratory between 1 October 2019-30 September 2021.Separately, ethnicity standardized incidence in > 40-year-olds discharged from New Zealand public hospitals for idiopathic and unspecified myopathy (ICD AM codes M60.8/60.9), was examined for concordance. RESULTS: The forty patients identified in the incidence cohort were all >40-years-old and all had a prior history of statin use. Annual incidence was 4 cases/million/year (95%CI 2.8-5.5). In those >40 years the incidence in Polynesians (Maori and Pacific peoples combined) was 25cases/million/year (95% CI 15.9 -40.1), in Asians 5.7cases/million/year (95% CI 0.7 -20.5) and in Europeans 7cases/million/year (95% CI 3.1 -8.4). The risk in statin users aged > 40 years was ∼1/9000 in Polynesians and ∼1/48000 in Europeans.Ethnic difference in incidence of idiopathic and unspecified myopathy (ICD AM codes M60.8/60.9) was also found in hospital discharges. CONCLUSION: In the past half decade the estimated incidence of anti-HMGCR myopathy in New Zealand has doubled. Polynesian peoples of New Zealand >40-years-old have an estimated 5-fold higher risk compared with European and Asian peoples. The estimated absolute risk in statin users >40-year-olds was 108 cases/million/year in Polynesians vs 21 cases/million/year in Europeans.

2.
Ther Drug Monit ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38648648

RESUMO

BACKGROUND: Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated. METHODS: Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA. RESULTS: Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA. CONCLUSIONS: Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.

3.
Clin Transl Immunology ; 13(2): e1493, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38410820

RESUMO

Objectives: Dominant-activating (DA) lesions in RAC2 have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in RAC2 p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum. Methods: Clinical and immunological information was collated for seven living individuals from the same kindred with RAC2 p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol-12-myristate-13-acetate (PMA) and N-formyl-MetLeuPhe (fMLP). Results: Patient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4+T and B-cell compartments. P1-3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls. Conclusion: RAC2 p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of RAC2 DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.

4.
J Rheumatol ; 51(3): 242-249, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38224989

RESUMO

OBJECTIVES: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations. METHODS: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses. RESULTS: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein (P < 0.001) and higher weight (P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations (r = -0.04, P < 0.01). CONCLUSION: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control.


Assuntos
Artrite Reumatoide , Interleucina-6 , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Adalimumab/uso terapêutico , Estudos Transversais , Artrite Reumatoide/tratamento farmacológico , Anticorpos , Citocinas
5.
Intern Med J ; 53(11): 2123-2127, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37997271

RESUMO

A review of laboratory results across New Zealand for therapeutic drug monitoring (TDM) of infliximab and adalimumab concentrations and antidrug antibodies (ADAs) over 4 years was completed. Of 6591 results, the median serum concentration for infliximab was 5.7 mg/L and for adalimumab was 5.5 mg/L. Subtherapeutic drug concentrations (<7 mg/L) were measured in 54% of samples. Drug concentrations <2 mg/L were measured in 23% of samples, with ADAs detected in 51% of these. The high number of samples with subtherapeutic drug concentrations and common ADA detection is consistent with failing therapy but could also suggest that standard dosing is frequently too low for patients. These results reinforce the value of antitumour necrosis factor drug TDM in making decisions to adjust dosing or switch agents in patients taking infliximab and adalimumab.


Assuntos
Adalimumab , Infliximab , Humanos , Adalimumab/uso terapêutico , Monitoramento de Medicamentos/métodos , Infliximab/uso terapêutico , Nova Zelândia , Laboratórios
8.
BMC Health Serv Res ; 21(1): 521, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049540

RESUMO

BACKGROUND: Emergency department (ED) attendances are contributing to rising costs of the National Health Service (NHS) in England. Critically assessing the impact of new services to reduce emergency department use can be difficult as new services may create additional access points, unlocking latent demand. The study evaluated an Acute Visiting Scheme (AVS) in a primary care context. We asked if AVS reduces overall ED demand and whether or not it changed utilisation patterns for frequent attenders. METHOD: The study used a pre post single cohort design. The impact of AVS on all-cause ED attendances was hypothesised as a substitution effect, where AVS duty doctor visits would replace emergency department visits. Primary outcome was frequency of ED attendances. End points were reduction of frequency of service use and increase of intervals between attendances by frequent attenders. RESULTS: ED attendances for AVS users rose by 47.6%. If AVS use was included, there was a more than fourfold increase of total service utilisation, amounting to 438.3%. It shows that AVS unlocked significant latent demand. However, there was some reduction in the frequency of ED attendances for some patients and an increase in time intervals between ED attendances for others. CONCLUSION: The study demonstrates that careful analysis of patient utilisation can detect a differential impact of AVS on the use of ED. As the new service created additional access points for patients and hence introduces an element of choice, the new service is likely to unlock latent demand. This study illustrates that AVS may be most useful if targeted at specific patient groups who are most likely to benefit from the new service.


Assuntos
Serviço Hospitalar de Emergência , Medicina Estatal , Estudos de Coortes , Inglaterra/epidemiologia , Humanos
13.
J Immunol Methods ; 474: 112672, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31525368

RESUMO

Adalimumab is a TNF specific monoclonal widely used therapeutically. Monitoring adalimumab levels is important for guiding treatment strategies and is predominantly performed using an ELISA. The homogeneous mobility shift assay (HMSA) has many advantages over an ELISA for adalimumab monitoring but current HMSA methodologies do not discriminate between adalimumab and other TNF specific monoclonals such as infliximab. The development and validation of a competitive binding HMSA (cHMSA) specific for adalimumab is reported here. The cHMSA had a lower limit of quantitation of 1.25 µg/ml and the intra-assay and inter-assay coefficents of variation (CV) were <20%. No signal was detected in adalimumab naïve control serum including those containing rheumatoid factor or infliximab. The majority (14/20) of adalimumab patient samples containing anti-adalimumab antibodies gave a cHMSA signal >3 standard deviations lower than the controls. The performance of the cHMSA and an ELISA was compared using adalimumab patient samples (n = 82). There was a strong correlation between the assays (r = 0.91) and the intra-class correlation coefficient (0.88) was indicative of good-excellent inter-assay reliability. Bland-Altman plots showed little overall bias and comparison of the sub-groups defined using cut-points (1.25 or 7.3 µg/ml) gave percent agreement (>90%) and Cohens kappa (95% CI: 0.61-0.93) values indicative of substantial-almost perfect agreement. These results demonstrate that cHMSA provides an accurate and specific method for monitoring adalimumab levels and can additionally provide an initial screen for the presence of anti-adalimumab antibodies.


Assuntos
Adalimumab/sangue , Monitoramento de Medicamentos/métodos , Ensaio de Desvio de Mobilidade Eletroforética , Inibidores do Fator de Necrose Tumoral/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Limite de Detecção , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
14.
Intern Med J ; 49(4): 513-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30091273

RESUMO

BACKGROUND: Therapeutic drug monitoring of anti-tumour necrosis factor (TNF) drugs and anti-drug antibodies (ADA) is now recommended in the treatment of inflammatory bowel disease. However, assay types and drug concentration thresholds are still debated. AIM: To correlate inflammatory bowel disease activity in a New Zealand cohort with trough concentrations of infliximab and adalimumab, and ADA using locally developed competitive-binding enzyme-linked immunosorbent assays (ELISA) to establish threshold concentrations. METHODS: Patients with ulcerative colitis (UC) and Crohn disease (CD) from Christchurch and Dunedin on anti-TNF drugs >12 weeks were enrolled. Trough blood samples were assayed for drug and ADA concentrations. Other data included quality of life, blood count, C-reactive protein, albumin, renal function and disease activity indices. RESULTS: Of 103 patients, 53 were on infliximab (36 CD, 15 UC and 2 unclassified) and 50 adalimumab (48 CD and 2 UC). Median (range) infliximab and adalimumab concentrations were 10.5 (0-41) and 9.61 mg/L (0-30). CD remission, Crohn Disease Activity Index <150, correlated with infliximab and adalimumab concentration in CD (infliximab, P = 0.03; adalimumab, P = 0.04), with too few UC patients for analysis. Receiver operator curve analysis suggested a threshold value of 5.1 mg/L for distinguishing active disease from remission for infliximab and 7.3 mg/L for adalimumab in CD. Of 13 patients with infliximab <2 mg/L, 10 were ADA positive by homogeneous mobility shift assay (HMSA), including five with neutralising antibodies using ELISA. Of six with adalimumab <2 mg/L, three were ADA positive using HMSA, including one with neutralising antibodies. CONCLUSION: Using the New Zealand ELISA assay, threshold concentrations of 5 mg/L for infliximab and 7 mg/L for adalimumab are suggested to aid dosing decisions, consistent with results internationally. Both neutralising (ELISA) and non-neutralising ADA (HMSA) are associated with low drug concentrations.


Assuntos
Adalimumab/sangue , Monitoramento de Medicamentos/métodos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adolescente , Adulto , Idoso , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos Neutralizantes/sangue , Ligação Competitiva , Ensaio de Imunoadsorção Enzimática , Feminino , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Curva ROC , Adulto Jovem
15.
Ther Drug Monit ; 40(6): 705-715, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30439789

RESUMO

BACKGROUND: The measurement of anti-drug antibody (ADA) levels in adalimumab (ADAL)-treated and infliximab (IFX)-treated patients is critical for guiding therapeutic strategies. The homogeneous mobility shift assay (HMSA) and affinity capture elution (ACE) assay provide effective, drug-tolerant formats for measuring total ADA levels. However, their ability to discriminate between ADA from samples with or without neutralizing capacity is unclear and therefore was analyzed in this study. METHODS: Sera from ADAL and IFX patients with low drug levels (<1 mcg/mL) were analyzed by ACE, HMSA, and bridging assay. Neutralizing capacity was determined by competitive ligand-binding assay. RESULTS: HMSA and ACE detected high ADA levels in all ADAL (19/42) and IFX (27/64) samples with neutralizing capacity. ADA was also detected in most of the samples without neutralizing capacity, but levels were significantly lower (P < 0.0001). Receiver operator characteristic curve analysis demonstrated that for both assays, ADA levels were a strong discriminatory marker of neutralizing ADA (area under the curve > 0.9, P < 0.0001). Using a signal >8× background as a cut-point, neutralizing ADA could be identified with high specificity (HMSA > 95%, ACE > 85%) and sensitivity (HMSA > 70%, ACE > 80%). The detection of multimeric drug-ADA complexes after HMSA was also a highly specific marker (specificity > 95%) of neutralizing ADA in both ADAL and IFX patients. Results using ACE and HMSA were highly correlated. CONCLUSIONS: Results obtained after HMSA and ACE analysis are strongly correlated, and in both assays, high ADA levels are a specific marker of neutralizing capacity. The detection of multimeric complexes by HMSA also selectively identifies sera with neutralizing capacity. These data support the use of these assays as quantitative rather than simple qualitative measures of ADA.


Assuntos
Adalimumab/imunologia , Anticorpos Neutralizantes/sangue , Ensaio de Desvio de Mobilidade Eletroforética/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Infliximab/imunologia , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Criança , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
17.
Compr Child Adolesc Nurs ; 41(4): 276-292, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28915072

RESUMO

Caring for a child with complex health care needs places additional stress and time demands on parents. Parents often turn to their peers to share their experiences, gain support, and lobby for change; increasingly this is done through social media. The WellChild #notanurse_but is a parent-driven campaign that states its aim is to "shine a light" on the care parents, who are not nurses, have to undertake for their child with complex health care needs and to raise decision-makers' awareness of the gaps in service provision and support. This article reports on a study that analyzed the #notanurse_but parent-driven campaign videos. The purpose of the study was to consider the videos in terms of the range, content, context, perspectivity (motivation), and affect (sense of being there) in order to inform the future direction of the campaign. Analysis involved repeated viewing of a subset of 30 purposively selected videos and documenting our analysis on a specifically designed data extraction sheet. Each video was analyzed by a minimum of 2 researchers. All but 2 of the 30 videos were filmed inside the home. A variety of filming techniques were used. Mothers were the main narrators in all but 1 set of videos. The sense of perspectivity was clearly linked to the campaign with the narration pressing home the reality, complexity, and need for vigilance in caring for a child with complex health care needs. Different clinical tasks and routines undertaken as part of the child's care were depicted. Videos also reported on a sense of feeling different than "normal families"; the affect varied among the researchers, ranging from strong to weaker emotional responses.


Assuntos
Doença Crônica/psicologia , Motivação , Pais/psicologia , Instituições de Caridade/organização & administração , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Crianças com Deficiência/psicologia , Feminino , Humanos , Masculino , Pesquisa Qualitativa , Mídias Sociais , Inquéritos e Questionários , Reino Unido , Gravação em Vídeo/métodos
19.
Ther Drug Monit ; 38(1): 32-41, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26222874

RESUMO

BACKGROUND: There is increasing interest in measuring both drug and antidrug antibody (ADA) levels in patients receiving anti-tumor necrosis factor treatment as part of algorithms for guiding therapeutic strategies. Many of the current assays for ADA detection have limitations with respect to specificity, sensitivity, and/or laboratory requirements. Specific identification of ADA based on their inhibitory activity in a simple competitive binding assay remains problematic. The development of an enzyme-linked immunosorbent assay (ELISA)-based method for detection of both drug and ADA in patients receiving either adalimumab or infliximab would widen availability of monitoring for these patients. METHODS: An ELISA for the specific detection of adalimumab and infliximab using widely available reagents was developed. A simple modification for the detection of ADA capable of competitively inhibiting the in vitro binding of drug to solid phase tumor necrosis factor was also developed. Drug and ADA levels were analyzed in patients with rheumatoid arthritis and inflammatory bowel disease. RESULTS: The ELISA specifically detected drug concentrations in patient sera with no evidence of positive or negative interference by rheumatoid factor positive control sera. A subset of those patients with low drug concentrations had detectable levels of ADA with inhibitory activity in a competitive binding assay. Spiking with both drugs confirmed the specificity of the ADA detected. CONCLUSIONS: A modified ELISA protocol can be used to for the detection of both drug concentrations and ADA in patients receiving either adalimumab or infliximab. The ELISA incorporates those features identified in the literature as important for the accurate analysis of these antibodies and uses laboratory facilities and reagents that are widely available. It therefore provides a relatively simple and low cost assay for therapeutic drug monitoring of inpatients receiving adalimumab or infliximab.


Assuntos
Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Ensaio de Imunoadsorção Enzimática/métodos , Infliximab/administração & dosagem , Adalimumab/imunologia , Adalimumab/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Anticorpos/sangue , Antirreumáticos/imunologia , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Ligação Competitiva , Monitoramento de Medicamentos/métodos , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/imunologia , Infliximab/farmacocinética , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
20.
Autoimmunity ; 48(4): 208-21, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25427822

RESUMO

The regulation of cytokine expression by immune deviation from a pro-inflammatory to anti-inflammatory or "regulatory" milieu is crucial to the prevention of permanent central nervous system (CNS) damage in neuroinflammation. Earlier studies in the murine experimental autoimmune encephalomyelitis (EAE) model pointed to an anti-inflammatory role for the Th2 cytokine, IL-4, which was not confirmed in IL-4Rα-deficient mice (IL-4Rα(-/-)). To examine the pathological consequences of loss of responsiveness to Th2 cytokines, we compared lesion evolution in IL-4Rα(-/-) and wild type (WT) BALB/c mice immunized with PLP180-199 and investigated how altering the magnitude of the antigen-specific autoimmune response in this model affected the pathology. We found that while changing the magnitude of the peripheral antigen-specific response differentially affected the incidence of clinical disease in WT BALB/c relative to IL-4Rα(-/-) mice, the differences in incidence did not correlate to differences in pro-inflammatory cytokine production. Additionally, although only approximately 75% of WT mice developed clinical disease, lesions were observed in 100% of the mice, principally in the cerebellum, mid-brain and cerebral hemispheres, and lesion load increased with increasing pro-inflammatory cytokine production. Despite being resistant to disease induction with increasing pro-inflammatory cytokine production, lesion incidence in IL-4Rα-deficient animals was equal to their WT counterparts. However, lesion severity in IL-4Rα-deficient animals was preferentially reduced in the mid-brain and cerebral hemispheres. From these studies, we conclude that signaling through IL-4Rα has little effect on regulating the peripheral pro-inflammatory cytokine profile in this EAE variant but has distinct effects on the determination of lesion topography.


Assuntos
Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Deleção de Genes , Predisposição Genética para Doença , Receptores de Superfície Celular/genética , Animais , Antígenos/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/biossíntese , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Proteína Proteolipídica de Mielina/efeitos adversos , Nervo Óptico/imunologia , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia
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