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BACKGROUND: Scleroderma renal crisis (SRC) is a rare but feared complication with high morbidity and mortality. Its aetiopathogenesis is unclear. AIM: To investigate epidemiological, serologic and clinical features of all patients with SRC listed on the population-based South Australian Scleroderma Register and to examine possible factors in aetiopathogenesis. METHOD: A case note review was performed on all SRC patients with relevant data extracted to determine incidence, clinical phenotype, presence of autoantibodies and survival. Possible precipitating and aetiopathogenic factors were also examined. Data from the South Australian Scleroderma Register and Australia Bureau of Statistics was sourced for comparative purposes. RESULTS: Over the 34-year period (1985-2018), 30 patients (21 females, 9 males) presented with SRC giving a South Australian mean annual incidence of 0.58/million/year (95% CI 0.39-0.89). Twenty-eight of these patients had diffuse cutaneous scleroderma and two with limited cutaneous scleroderma. The mean age at first symptom of scleroderma was 51.2 ± 15.9 (mean ± SD) years with SRC occurring 4.6 years later (median = 3.0 years, range 0.1-20 years). Possible precipitating factors for SRC included high dose steroids in five patients. Twelve patients were anti- RNA polymerase3 (RNAPol3) positive and two were anti-topoisomerase 1 (Topo1) positive. Renal outcome was poor with 13 patients requiring renal replacement therapy and two proceeding to renal transplantation. The mean age at death was 61.2 ± 11.6 years with SRC patient survival being significantly shorter than patients with diffuse scleroderma without renal involvement (P = 0.002). There was no significant difference in survival between the 1985-2002 and the 2003-2018 SRC cohorts (P = 0.2). Nailfold capillaroscopy performed in 10 patients revealed extensive microvascular damage with prominent capillary drop out. CONCLUSION: SRC is a rare occurrence with an incidence of 0.58/million/year in South Australia. This frequency has not changed over time. It continues to have a severe adverse outcome with frequent requirement for renal replacement therapy and poor survival. Nailfold capillaroscopy revealed evidence of extensive capillary damage. No improvement in survival was observed over the 34-year study period.
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Esclerodermia Difusa , Escleroderma Sistêmico , Adolescente , Adulto , Austrália/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Angioscopia Microscópica , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/terapia , Austrália do Sul/epidemiologia , Adulto JovemRESUMO
Aims: To determine real-life biologic/targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) retention rates in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), explore reasons for switching and to compare results to previously published data. Methods: Time-to-event analysis for mean treatment duration (estimated as the Restricted Mean Survival Time), b/tsDMARD failure, and b/tsDMARDs switching was performed for 230 patients (n = 147 RA, 46 PsA, 37 AS) who commenced their first b/tsDMARD between 2008 and 2018. Patients were managed in a dedicated "biologics" clinic in a tertiary hospital; the choice of b/tsDMARD was clinician driven based on medical factors and patient preferences. The effect of covariates on switching risk was analysed by a conditional risk-set Cox proportional-hazards model. Treatment retention data was compared to a historical analysis (2002-2008). Results: The proportions remaining on treatment (retention) were similar, throughout follow-up, for the first, second and third b/tsDMARDs across all patients (p = 0.46). When compared to RA patients, the risk of b/tsDMARD failure was halved in PsA patients [Hazard Ratio (HR) = 0.50], but no different in AS patients (HR = 1.0). The respective restricted mean (95%CI) treatment durations, estimated at 5 years of follow-up, were 3.1 (2.9, 3.4), 4.1 (3.7, 4.6), and 3.3 (2.8, 3.9) years, for RA, PsA, and AS, respectively. Age, gender, disease duration, smoking status and the use of concomitant csDMARDS were not associated with the risk of bDMARD failure. The most common reasons for switching in the first and subsequent years were secondary (n = 62) and primary (n = 35) failure. Comparison with historical data indicated no substantive differences in switching of the first biologic for RA and PsA. Conclusion: Similar retention rates of the second and third compared to the first b/tsDMARD in RA, PsA, and AS support a strategy of differential b/tsDMARDs use informed by patient presentation. Despite greater availability of b/tsDMARDs with differing mechanisms of action, retention rates of the first b/tsDMARD remain similar to previous years.
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AIM: Discrepancies exist between international treatment guidelines and current Australian Pharmaceutical Benefits Scheme (PBS) criteria for funding biologic disease-modifying antirheumatic drug (bDMARD) prescribing in psoriatic arthritis (PsA). We aimed to determine the prevalence of minimal disease activity (MDA) achievement and differences in inflammatory marker levels between PsA patients who have and have not met the Australian PBS criteria for bDMARDs. METHOD: Consecutive participants diagnosed with PsA were assessed for MDA components and serum inflammatory markers. For those on bDMARDs, joint counts and inflammatory markers at the time of bDMARD qualification were compared with matched rheumatoid arthritis (RA) controls. RESULTS: Minimal disease activity was achieved by 56/105 participants overall. There were no differences in inflammatory marker levels or involved joint count patterns between the PsA and RA groups at the time of bDMARD qualification. Seventy-three percent of the 53 PsA patients on bDMARD achieved MDA, vs 33% in the non-bDMARD group (P < 0.001). More bDMARD than non-bDMARD patients achieved four out of seven MDA components. Of those with any enthesitis, its prevalence was higher in the non-bDMARD group (22 vs 10, P = 0.009). Regardless of treatment, there was no difference in inflammatory marker levels between those who did and did not achieve MDA. CONCLUSION: The Australian PBS criteria, funding bDMARD prescribing for PsA, select well for MDA achievers. A high prevalence of MDA non-achievement remains in patients ineligible for bDMARD funding, and enthesitis in this population is more common. Inflammatory markers were not discriminators between treatment or MDA achievement groups.
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Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/epidemiologia , Produtos Biológicos/uso terapêutico , Tomada de Decisão Clínica , Articulações/efeitos dos fármacos , Avaliação de Processos e Resultados em Cuidados de Saúde , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico por imagem , Biomarcadores/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Articulações/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prevalência , Indução de Remissão , Índice de Gravidade de Doença , Austrália do Sul/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: Psoriatic arthritis (PsA) can be treated using biologic therapies targeting biomolecules such as tumor necrosis factor alpha, interleukins (IL)-17 and IL-23. Although 70% PsA patients respond well to therapy, 30% patients show no or limited clinical improvement. Biomarkers that predict response to therapy would help to avoid unnecessary use of expensive biologics in nonresponding patients and enable alternative treatments to be explored. EXPERIMENTAL DESIGN: Patient synovial tissue samples from two clinical studies were analysed using difference in-gel electrophoresis-based proteomics to identify protein expression differences in response to anti-TNF-α treatment. Subsequent multiplexed MRM measurements were used to verify potential biomarkers. RESULTS: A total of 119 proteins were differentially expressed (p<0.05) in response to anti-TNF-α treatment and 25 proteins were differentially expressed (p<0.05) between "good responders" and "poor responders". From these differentially expressed proteins, MRM assays were developed for four proteins to explore their potential as treatment predictive biomarkers. CONCLUSION AND CLINICAL RELEVANCE: Gel-based proteomics strategy has demonstrated differential protein expression in synovial tissue of PsA patients, in response to anti-TNF-α treatment. Development of multiplex MRM assays to these differentially expressed proteins has the potential to predict response to therapy and allow alternative, more effective treatments to be explored sooner.
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Adalimumab/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Etanercepte/uso terapêutico , Proteoma/imunologia , Adulto , Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Biomarcadores Farmacológicos/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Proteoma/genética , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
INTRODUCTION: With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (ΔDAS28) or magnetic resonance imaging synovitis scores (ΔMRI) in patients with PsA treated with a biologic agent. METHODS: Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The ΔDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between ΔDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated. RESULTS: Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (ΔCD3) and CD68 expression in the synovial sublining layer (ΔCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). ΔCD3, but not ΔCD68 or ΔFVIII, correlated with both ΔDAS28 (r = 0.49, P = 0.025) and ΔMRI (r = 0.58, P = 0.009). CONCLUSIONS: The correlation of ΔCD3 with ΔDAS28 and ΔMRI following biologic treatment in this cohort contributes to the validation of ΔCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of ΔCD3 for predictive properties of future clinical outcomes.
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Antirreumáticos/uso terapêutico , Artrite Psoriásica/imunologia , Biomarcadores/análise , Complexo CD3/análise , Sinovite/tratamento farmacológico , Subpopulações de Linfócitos T/imunologia , Adulto , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/patologia , Artroscopia , Complexo CD3/imunologia , Etanercepte , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imunoglobulina G/uso terapêutico , Imuno-Histoquímica , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Articulação do Joelho/imunologia , Articulação do Joelho/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/uso terapêutico , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/imunologia , Sinovite/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFalpha) therapy and to examine possible predictors of response. METHODS: Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected. RESULTS: A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P<0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P<0.001). CONCLUSIONS: DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.
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Anticorpos Monoclonais/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/metabolismo , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Coortes , Progressão da Doença , Etanercepte , Feminino , Inquéritos Epidemiológicos , Humanos , Infliximab , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Estudos Prospectivos , Indução de Remissão , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To determine whether the correlation between the mean change in disease activity and the mean change in synovial sublining (sl) CD68 expression could be demonstrated across different academic centers. METHODS: Synovial biopsies obtained at arthroscopy from patients with rheumatoid arthritis before and 160 days after rituximab therapy were selected and coded. Paired sections were processed independently at Amsterdam Medical Center (AMC) and at St. Vincent's University Hospital (SVUH), Dublin. Digital image analysis (DIA) was employed at both centers to quantify sublining CD68 expression. RESULTS: After analysis of CD68sl expression at centers in 2 different countries, high levels of intracenter and intercenter agreement were observed. For the pooled sections stained at AMC, the correlation between 2 investigators was R = 0.942, p = 0.000, and for sections stained at SVUH, R = 0.899, p = 0.001. Similarly, the intracenter correlations for DeltaCD68sl expression after treatment were R = 0.998, p = 0.000, for sections stained at AMC and R = 0.880, p = 0.000, for sections stained at SVUH. The intercenter correlation for the pooled scores of sections stained at AMC was R = 0.85, p = 0.000, and for the sections stained at SVUH, R = 0.62, p = 0.001. The consistent correlation between DeltaDAS (Disease Activity Score) and DeltaCD68sl expression across different studies (Pearson correlation = 0.895, p < 0.001) was confirmed. The standardized response mean values for DeltaCD68sl, calculated from analyses at both AMC and SVUH, were consistently 0.5 or greater, indicating a moderate to high potential to detect change. CONCLUSION: The correlation between mean DeltaDAS and mean DeltaCD68sl expression was confirmed across 2 centers. Examination of serial biopsy samples can be used reliably to screen for interesting biological effects at the site of inflammation at an early stage of drug development.
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Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biópsia , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Humanos , Macrófagos/patologia , Reprodutibilidade dos Testes , Rituximab , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
Previous studies have demonstrated an increased risk of breast cancer among patients with systemic sclerosis (scleroderma). To describe the clinical characteristics of 21 patients with both systemic sclerosis and breast cancer, and compare their risk factors to female scleroderma patients without breast cancer, in a population-based cohort study of South Australia. Subjects with scleroderma and breast cancer were identified from the South Australian Scleroderma Register with cross-linking to the South Australian Cancer Registry, last updated to the end of December 2005. Clinical information was obtained from standardised self-administered questionnaires and case note reviews. Odds ratios for the risk factors for breast cancer in scleroderma were determined, and clinical variables were analysed using chi square, Fisher's exact, Mann-Whitney and t tests. At the end of December 2005 there were a total of 389 female patients with scleroderma. Of these, 21 (5.4%) had been diagnosed with breast cancer. The mean age of onset of scleroderma was 43.5 years, and the mean age of breast cancer was 60.5 years in those with scleroderma and breast cancer. The majority (71.4%) had limited scleroderma, with anti-centromere antibody being the most prevalent serological abnormality. In 16 (76%) patients the diagnosis of breast cancer occurred on an average of 22.3 years after the onset of their first scleroderma symptom. When compared to 48 controls, scleroderma patients with breast cancer were found to have a higher incidence of a positive family history of breast cancer (Fisher's exact test, p = 0.04) and a lower incidence of hormone-replacement therapy use (Fisher's exact test, p = 0.0026). This population-based cohort study provides evidence that the majority of patients with scleroderma and breast cancer have limited scleroderma and anti-centromere antibody. Given the increased incidence of solid tumours in systemic sclerosis, we suggest regular screening of female patients for breast cancer, especially in those with a family history.
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Neoplasias da Mama/complicações , Sistema de Registros , Escleroderma Sistêmico/complicações , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Austrália do SulRESUMO
OBJECTIVES: To study potential risk factors for the development of lung cancer in patients with scleroderma and explore the chronological relationship between onset of scleroderma symptoms and subtypes of lung cancer. METHOD: Linkage of two population-based registers to identify lung cancer cases and gender-matched controls with scleroderma, followed by retrospective case note review for clinical details. RESULTS: Patients with scleroderma who smoke are seven times more likely to develop lung cancer than non-smokers (p=0.008). Smokers with scleroderma and cancer smoke more than smokers with scleroderma without cancer (p=0.019). Pulmonary fibrosis and anti-topoisomerase antibody do not increase the risk of lung cancer. Peripheral lung tumours occur earlier after the onset of scleroderma symptoms than bronchogenic tumours (p=0.05). CONCLUSIONS: Smokers with scleroderma should be monitored for the presence of lung cancer and counselled to quit smoking. The earlier development of peripheral lung tumours is not consistent, with pulmonary fibrosis being an aetiological factor.