Abstract
Objectives
A considerable proportion of patients with rheumatoid arthritis (RA) also suffer from hand osteoarthritis (OA). We here assess the association between conventional synthetic (cs) ...and biological (b) disease-modifying antirheumatic drugs (DMARDs) and radiographic distal interphalangeal-(DIP) OA in patients with RA.
Methods
Adult RA patients from a longitudinal Swiss registry of rheumatic diseases who had ≥ 2 hand radiographs were included at the first radiograph and followed until the outcome or the last radiograph. Patients were grouped into two cohorts based on whether DIP OA was present or absent at cohort entry (cohorts 1 and 2, respectively). Modified Kellgren-Lawrence scores (KLS) were obtained by evaluating DIP joints for the severity of osteophytes, joint space narrowing, subchondral sclerosis, and erosions. KLS ≥ 2 in ≥ 1 DIP joint indicated incident or existing OA, and increase of ≥ 1 in KLS in ≥ 1 DIP joint indicated progression in existing DIP OA. Time-varying Cox regression and generalized estimating equation (GEE) analyses were performed. We estimated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) of DIP OA incidence (cohort 2), or progression (cohort 1), in bDMARD monotherapy, bDMARD/csDMARD combination therapy, and past or never DMARD use, when compared to csDMARD use. In post hoc analyses, we descriptively and analytically assessed the individual KLS features in cohort 1.
Results
Among 2234 RA patients with 5928 radiographs, 1340 patients had DIP OA at baseline (cohort 1). Radiographic progression of DIP OA was characterized by new or progressive osteophyte formation (666, 52.4%), joint space narrowing (379, 27.5%), subchondral sclerosis (238, 17.8%), or erosions (62, 4.3%). bDMARD monotherapy had an increased risk of radiographic DIP OA progression compared to csDMARD monotherapy (adjusted HR 1.34 95% CI 1.07–1.69). The risk was not significant in csDMARD/bDMARD combination users (HR 1.12 95% CI 0.96–1.31), absent in past DMARD users (HR 0.96 95% CI 0.66–1.41), and significantly lower among never DMARD users (HR 0.54 95% CI 0.33–0.90). Osteophyte progression (HR 1.74 95% CI 1.11–2.74) was the most significantly increased OA feature with bDMARD use compared to csDMARD use. In 894 patients without initial DIP OA (cohort 2), the risk of incident OA did not differ between the treatment groups. The results from GEE analyses corroborated all findings.
Conclusions
These real-world RA cohort data indicate that monotherapy with bDMARDs is associated with increased radiographic progression of existing DIP OA, but not with incident DIP OA.
Background and purpose:
Doxorubicin causes a chronic cardiomyopathy in which reactive oxygen species (ROS) accumulate over time and are associated with genetic and functional lesions of mitochondria. ...Dexrazoxane is a cardioprotective iron chelator that interferes with ROS production. We aim to analyze the effects of dexrazoxane on mitochondria in the prevention of doxorubicin‐induced chronic myocardial lesions.
Experimental approach:
Wistar rats (11 weeks of age) were injected with intravenous doxorubicin (0.8 mg kg‐1 weekly for 7 weeks) with or without simultaneous dexrazoxane (8 mg kg‐1). Animals were killed at 48 weeks. Cardiomyopathy was scored clinically and histologically and cardiac mitochondria were analyzed.
Key results:
Compared to control rats receiving saline, rats treated with doxorubicin alone developed a clinical, macroscopic, histological and ultrastructural cardiomyopathy with low cytochrome c‐oxidase (COX) activity (26% of controls). The expression of the mtDNA‐encoded COX II subunit was reduced (64% of controls). Myocardia exhibited a high production of ROS (malondialdehyde 338% and superoxide 787% of controls). Mitochondria were depleted of mitochondrial DNA (mtDNA copy number 46% of controls) and contained elevated levels of mtDNA deletions. Dexrazoxane co‐administration prevented all these effects of doxorubicin on mitochondria, except that hearts co‐exposed to doxorubicin and dexrazoxane had a slightly lower mtDNA content (81% of controls) and mtDNA deletions at low frequency.
Conclusions and Implications:
Dexrazoxane prevented doxorubicin induced late‐onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage.
British Journal of Pharmacology (2007) 151, 771–778; doi:10.1038/sj.bjp.0707294
A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, ...classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc).
DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked.
A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU.
For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted.
Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).
Systemic sclerosis (SSc) is characterised by a progressive microangiopathy that contributes significantly to the morbidity of patients with SSc. Besides insufficient angiogenesis, defective ...vasculogenesis with altered numbers of endothelial precursor cells (EPCs) might also contribute to the vascular pathogenesis of SSc. However, different protocols for isolation, enrichment, culture and quantification of EPCs are currently used, which complicate comparison and interpretation of the results from different studies. The aim of the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group expert panel was to provide recommendations for standardisation of future research on EPCs. Consensus statements and recommendations were developed in a face to face meeting by an expert panel of the basic science working group of EUSTAR. The findings were: cardiovascular risk factors and medications such as statins should be described in detail. A detailed description of methods considering isolation, culture, enrichment and detection of EPCs should be given. For in vitro culture of EPCs, no protocol has been shown to be superior to another, but coating with laminin and type IV collagen would resemble most closely the situation in vivo. The endothelial phenotype should be confirmed in all in vitro cultures at the end of the culture period. We recommend using CD133, vascular endothelial growth factor type 2 receptor (VEGFR2) and CD34 in combination with a viability marker for quantification of EPCs in the blood. Finally, exact standard operating procedures for fluorescence-activated cell sorting (FACS) analysis are given that should be strictly followed. In summary, the EUSTAR recommendations will help to unify EPC research and allow better comparison between the results of different studies.
Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab ...(RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit.
To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients.
A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders.
Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI -1.54 to -1.15) vs -0.93 (95% CI -1.28 to -0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug.
This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.
To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc).
A list of items provided by European League Against Rheumatism (EULAR) ...Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores.
Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting.
The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.
Many rheumatic diseases have been observed in HIV-infected persons. We, therefore, conducted a comprehensive literature search in order to review the prevalence, presentation and pathogenesis of ...rheumatic manifestations in HIV-infected subjects. Articular conditions (arthralgia, arthritis and SpAs) are either caused by the HIV infection itself, triggered by adaptive changes in the immune system, or secondary to microbial infections. Muscular symptoms may result from rhabdomyolysis, myositis or from side-effects of highly active anti-retroviral therapy (HAART). Osseous complications include osteonecrosis, osteoporosis and osteomyelitis. Some conditions such as the diffuse infiltrative lymphocytosis syndrome and sarcoidosis affect multiple organ systems. SLE may be observed but may be difficult to differentiate from HIV infection. Some anti-retroviral agents can precipitate hyperuricaemia and are associated with arthralgia. When indicated, immunosuppressants and even anti-TNF-α agents can be used in the carefully monitored HIV patient. Thus, rheumatic diseases and asymptomatic immune phenomena remain prevalent in HIV-infected persons even after the widespread implementation of highly active anti-retroviral therapy.
BackgroundLong-term use of both zidovudine (AZT) and stavudine (d4T) is associated with lipoatrophy, but it occurs possibly through different mechanisms MethodsSurgical biopsy specimens of ...subcutaneous adipose tissue were obtained from 18 human immunodeficiency virus type 1 (HIV-1)–infected lipoatrophic patients (the LA+ group) who were treated with either zidovudine (the AZT+LA+ group; n=10) or stavudine (the d4T+LA+ group; n=8) and from 10 nonlipoatrophic HIV-1–infected patients (the LA− group) who received antiretroviral therapy. Mitochondrial DNA (mtDNA) copy numbers, gene expression, and immunohistochemistry data were analyzed ResultsmtDNA copy numbers were significantly reduced in the LA+ group, compared with the LA− group, and in the d4T+LA+ group, compared with the AZT+LA+ group. The ratio of mtDNA-encoded cytochrome COX3 to nuclear DNA–encoded COX4 expression was significantly lower in the LA+ group than in the LA− group. Compared with the LA− group, the LA+ group had significantly lower expression of genes involved in adipogenesis (SREBP1cand CEBPB) lipid (fatty acid synthase), and glucose (GLUT4) metabolism. Expression of genes involved in mitochondrial biogenesis (PGC1B) apoptosis (FAS) inflammation (IL1B) oxidative stress (PCNA and SOD1) and lamin B was significantly higher in the LA+ group than in the LA− group. The d4T+LA+ group had significantly lower expression of genes involved in mitochondrial biogenesis (POLG1) energy metabolism (the COX3/COX4 ratio), adipogenesis (SREBP1c and CEBPA) perilipin, and hexokinase than did the AZT+LA+ group. There were 7-fold more macrophages in adipose tissue specimens obtained from patients in the LA+ group, compared with the LA− group ConclusionsLipoatrophy is characterized by mtDNA depletion, inflammation, and signs of apoptosis. Changes were more profound in the d4T+LA+ group than in the AZT+LA+ group
Background: Retroperitoneal fibrosis (RPF) and inflammatory aneurysm of the abdominal aorta (IAAA) are regarded as two manifestations of the same disease, termed “chronic periaortitis”. Objective: To ...determine the optimal therapeutic and diagnostic approaches to IAAA. Methods: The outcome of medical immunosuppressive and surgical treatment of 20 patients was examined. Measurements of the C reactive protein (CRP) were compared with contrast enhanced imaging studies in the follow up of the patients. Results: The diameter of the periaortic mantle and its contrast enhancement improved in 13/15 (87%) patients given immunosuppressive treatment for a period of more than 6 months. Strong contrast enhancement was associated with a substantial rise in CRP, but no correlation between the CRP value and thickness of the fibrotic mass was found, even at intraindividual follow up. Conclusions: Immunosuppressive treatment should be included in the first line treatment of patients with RPF and should be maintained long term. Imaging studies are better than CRP measurements in the evaluation of response to treatment.
Systemic sclerosis (SSc) is a vasculopathy with increased tissue deposition of collagen. The aetiology is unknown. Genetic and environmental susceptibility factors have been implicated. It is unknown ...whether disease presentation varies within Europe.
The baseline data of all SSc patients entered in the EULAR Scleroderma Trials and Research (EUSTAR) database up to April 2007 were analysed for geographical differences with regard to organ involvement, and geographical clusters with regard to clinical subsets (diffuse vs limited SSc) and autoantibodies (anticentromere vs anti-Scl70).
3661 patients from 79 centres in 62 cities and 23 countries were analysed. There was no clear trend between geographical coordinates and SSc subsets, although there appeared to be an increased prevalence of Scl70 in the more eastern centres. There was no association between geographical longitude or latitude and the age at the onset of Raynaud's phenomenon or the onset of non-Raynaud's symptoms. There was also a trend for the more eastern centres to care for patients with a higher prevalence of more severe organ manifestations (pulmonary arterial hypertension, cardiac involvement). Between different centres within one city there was a large variability in the frequency of organ complications.
This analysis suggests that eastern centres care for more severe SSc manifestations in Europe. Large differences in patient referral account for a large local variability of SSc presentations and preclude the identification of genetic or environmental factors.
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