Towards personalized treatment: predictors of short-term HAQ response in recent-onset active rheumatoid arthritis are different from predictors of rapid radiological progression.

OBJECTIVE: Personalized treatment depends on the treatment goals. Current prediction models to guide initial treatment choices focus on radiological damage progression. However, for some patients this outcome is less relevant, whereas short-term functional ability is relevant to all. Do these various treatment goals share the same predictors? METHODS: Data for 497 patients from the Dutch Behandel Strategieen (BeSt) study of treatment strategies for early rheumatoid arthritis (RA), randomized to initial monotherapy or combination therapy, were used. Predictors of short-term functional disability [Health Assessment Questionnaire (HAQ) score ≥ 1 after 3 months of treatment] were identified with logistic regression analyses. Predicted risks of a HAQ score ≥ 1 were determined for each treatment group and for each subpopulation. RESULTS: At baseline, 76% of patients had a HAQ score ≥ 1 (mean 1.7 ± 0.5). After 3 months of treatment this score was achieved by 40% (mean HAQ score 1.5 ± 0.5). Baseline HAQ score, pain, the Ritchie Articular Index (RAI), and treatment group were significant independent predictors for a HAQ score ≥ 1; the presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and baseline radiological damage were not. With cut-offs of 35% and 60%, the risk of a HAQ score ≥ 1 was high for 47% and low for 20% of the patients treated with initial monotherapy. Risks were markedly reduced in the combination therapy groups, also in unfavourable risk profiles. CONCLUSION: In recent-onset active RA, baseline HAQ score, pain, and initial treatment are predictors for a HAQ score ≥ 1 after 3 months. Known predictors of radiological damage were not predictive of short-term functional disability. The choice of the best initial treatment thus depends on the relevance of various outcome measures for an individual patient.

Swan neck deformities in rheumatoid arthritis: a qualitative study on the patients' perspectives on hand function problems and finger splints.

OBJECTIVE: To identify hand function problems and the reasons for choosing a specific finger splint in patients with rheumatoid arthritis (RA) and swan neck deformities. METHODS: A qualitative study was performed alongside a randomized, controlled cross-over trial comparing the effectiveness of two types of finger splints (the silver ring splint [SRS] and the prefabricated thermoplastic splint [PTS]) in 50 patients with RA and swan neck deformities. Questions on the patients' main hand function problem and reasons for choosing a specific splint type were performed at baseline and after using each splint. The qualitative analyses included the identification of meaning units and (sub)concepts related to hand function problems and splint preferences. RESULTS: RA patients with swan neck deformities experience problems with flexion initiation, painful proximal interphalangeal joint hyperextension, grip activities and comprehensive hand function activities. Reasons for preferring or not preferring a specific type of finger splint included: effect, ease of use, appearance, comfort and side effects. Apart from the splint slipping off and a negative attitude towards the appearance of the splint, which appeared to be more frequently mentioned in connection with the SRS, no clear pattern of positive or negative appreciation of either type of splint could be distinguished. CONCLUSION: RA patients with swan neck deformities experience a variety of problems, including impairments in functions and limitations in daily activities. With the prescription of finger splints, a substantial number of potentially positive and negative consequences of their use need to be taken into account.

Exploring the public health impact of an intensive exercise program for patients with rheumatoid arthritis: a dissemination and implementation study.

OBJECTIVE: To evaluate the implementation of an intensive group exercise program in patients with rheumatoid arthritis (RA). METHODS: In 4 regions in The Netherlands, the Rheumatoid Arthritis Patients In Training exercise program was implemented on a limited scale. Evaluation using the RE-AIM model included: Reach, the proportion of the target population participating; Efficacy, effects on muscle strength, aerobic capacity, functional ability, and psychological functioning; Adoption, program adoption by stakeholders; Implementation, intervention quality (quality audits); and Maintenance, stakeholders' willingness to continue the program in the future. RESULTS: Twenty-five physical therapists from 14 practices were trained to provide the program. In total, 150 RA patients were recruited (by estimation, 2% of the target population). Of the 81 patients who had finished the 12-month intervention and were available for followup directly after the intervention, 62 patients provided clinical data. Muscle strength improved significantly, whereas aerobic capacity, functional ability, psychological functioning, and disease activity did not change. All 9 informed local patient organizations facilitated patient recruitment, and 35 of 51 rheumatologists involved referred one or more patients. All 10 approached health insurance companies funded the program for 12 months. The quality audits showed sufficient quality in 9 of 12 practices. All of the providers of the program were willing to provide the program in the future, whereas future reimbursement by health insurance companies remained unclear. CONCLUSION: The implementation of an intensive exercise program for RA patients on a limited scale can be considered successful regarding its reach, adoption, and implementation. The limited effectiveness and the limited data regarding maintenance warrant additional research.

Motivation as a determinant of physical activity in patients with rheumatoid arthritis.

OBJECTIVE: A sufficient level of physical activity is important in reducing the impact of disease in rheumatoid arthritis (RA) patients. According to self-determination theory, the achievement and maintenance of physical activity is related to goal setting and ownership, which can be supported by health professionals. Our objective was to examine the association between physical activity and the extent to which RA patients 1) believe that physical activity is a goal set by themselves (autonomous regulation) or by others (coerced regulation) and 2) feel supported by rheumatologists (autonomy supportiveness). METHOD: A random selection of 643 RA patients from the outpatient clinics of 3 hospitals were sent a postal survey to assess current physical activity level (Short Questionnaire to Assess Health-Enhancing Physical Activity), regulation style (Treatment Self-Regulation Questionnaire), and the autonomy supportiveness of their rheumatologists (modified Health Care Climate Questionnaire). RESULTS: Of the 271 patients (42%) who returned the questionnaire, 178 (66%) were female, their mean +/- SD age was 62 +/- 14 years, and their mean +/- SD disease duration was 10 +/- 8 years. Younger age, female sex, higher education level, shorter disease duration, lower disease activity, and a more autonomous regulation were univariately associated with more physical activity. Hierarchical multiple regression analyses demonstrated that younger age and a more autonomous regulation were significantly associated with a higher physical activity level (P = 0.000 and 0.050, respectively). CONCLUSION: Regulation style was a significant determinant of physical activity in RA patients. This finding may contribute to further development of interventions to enhance physical activity in RA patients.

Effectiveness of two finger splints for swan neck deformity in patients with rheumatoid arthritis: a randomized, crossover trial.

OBJECTIVE: To compare the effectiveness and acceptability of silver ring splints (SRS) and commercial prefabricated thermoplastic splints (PTS) in treating swan neck deformities in patients with rheumatoid arthritis (RA). METHODS: Consecutive patients with RA and a mobile swan neck deformity were included in a randomized, crossover trial. In 2 different sequences, patients used both splints for 4 weeks, with a washout period of 2 weeks. Afterward, patients used the preferred splint for another 12 weeks. The primary outcome measure was dexterity measured with the Sequential Occupational Dexterity Assessment (SODA). Secondary outcome measures included other measures of hand function, satisfaction with the splints, and splint preference. RESULTS: Fifty patients were included, and 47 (94%) of those completed the study. Eighteen patients (36%) had 1 swan neck deformity, whereas the other patients had 2 or more. The improvement of the total SODA score with the SRS (11.2; 95% confidence interval [95% CI] 8.1, 14.3) and PTS (10.8; 95% CI 7.5, 14.1) was similar (difference -0.5; 95% CI -2.2, 1.2). In addition, there were no significant differences in change scores regarding the other clinical outcome measures, or satisfaction. Twenty-four patients preferred the SRS, 21 preferred the PTS, and 2 patients chose neither. A comparison in the 12-week followup period yielded similar clinical outcomes, with the exception of a significantly higher score in 3 items of satisfaction in the SRS group. CONCLUSION: For patients with RA and a mobile swan neck deformity, SRS and PTS are equally effective and acceptable.

Patient-reported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis.

OBJECTIVE: To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life. METHODS: A total of 508 patients with recent-onset RA were randomly assigned to 1) sequential monotherapy, 2) step-up combination therapy, both starting with methotrexate, 3) initial combination therapy, including a tapered high-dose prednisone, or 4) initial combination therapy with methotrexate and infliximab. Treatment was adjusted every 3 months if the Disease Activity Score (DAS) remained >2.4. The McMaster Toronto Arthritis Patient Preference Disability Questionnaire, the Short Form 36 (SF-36), and scores for pain, global health, and disease activity measured on a 100-mm visual analog scale (VAS) were compared between groups at baseline and every 3 months thereafter for 2 years. RESULTS: After 2 years, all patient-reported outcomes had improved significantly from baseline, irrespective of the treatment strategy. SF-36 subscale scores approached population norms for 3 physical components, and achieved population norms (P > 0.05) for bodily pain and 4 mental components. Improvement in functioning, VAS scores, and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies (all comparisons after 3 months: overall P < 0.001; P < 0.05 for groups 1 and 2 versus groups 3 and 4). CONCLUSION: All 4 DAS-driven treatment strategies resulted in substantial improvements in functional ability, quality of life, and self-assessed VAS scores after 2 years. Initial combination therapy led to significantly faster improvement in all patient-reported measures.

Assistive devices: usage in patients with rheumatoid arthritis.

We describe the usage of various assistive devices and identify factors associated with usage in patients with rheumatoid arthritis (RA). A cross-sectional, multicentre study was performed in three outpatient rheumatology clinics in the Netherlands. Two hundred forty patients with RA participated in the study. The main measures were questionnaires and a semi-structured interview regarding the possession and usage of 21 common assistive devices in the ISO9999 categories orthopaedic footwear, personal care, mobility, household and adaptations for housing. Potential factors associated with usage included sociodemographic variables, health status, quality of life, coping strategies, self-efficacy, outcome expectations and satisfaction. Out of 240 patients, 213 (89%) had one or more assistive devices in possession (median number of devices 3.0, interquartile range 3.0). The proportions of patients never using a device in possession varied between 8% for orthopaedic insoles and 23% for grab bars. The main factors related to usage varied among categories, but common determinants were a specific impairment or disability, satisfaction with the device or related services, self-efficacy and the number of devices in possession. In conclusion, in patients with RA, possession rates are high, with 23% or less of the devices in possession being abandoned. Overall, satisfaction rates were high. Factors associated with usage varied among categories and comprised, apart from the number of devices in possession and variables related to health status, also aspects of satisfaction with the device or related services or self-efficacy. The latter findings underline the need for a systematic evaluation of the outcomes of assistive devices by prescribing health professionals or suppliers in every individual case.

Probability of continued low disease activity in patients with recent onset rheumatoid arthritis treated according to the disease activity score.

OBJECTIVE: To assess the duration and the probability of maintaining low disease activity once a low disease activity score (DAS) is achieved in recent onset rheumatoid arthritis (RA) patients. METHODS: The BeSt study is a randomised trial comparing four different treatment strategies in patients with recent onset, active RA. Treatment adjustments were mandatory as long as the DAS was >2.4. If the DAS was

Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis.

OBJECTIVES: Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. METHODS: BMD of the total hip and the lumbar spine was measured using dual-energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score

Engagement and satisfaction with an Internet-based physical activity intervention in patients with rheumatoid arthritis.

OBJECTIVE: To assess the engagement in and satisfaction with an Internet-mediated physical activity intervention with individual supervision in patients with rheumatoid arthritis (RA). METHODS: The intervention studied was one of the two strategies aimed at enhancing physical activity in RA patients that were being compared in a randomized controlled trial. A total of 82 patients, all experienced in using Internet and e-mail and registered at three different rheumatology out-patient clinics, were randomly allocated to the Internet-mediated individualized intervention (52 weeks). They had access to personal physical activity schedules and received individual supervision by a physical therapist by means of weekly e-mail feedback. In addition, telephone contacts, an online discussion forum, six face-to-face group meetings and electronic newsletters were offered. Besides registration of returned physical activity schedules, engagement and satisfaction were measured through questionnaires. RESULTS: The median physical activity schedule return rate of the 82 participants was 55%. The mean number of patients logging into the website at least once a week was 53 (70%) over 12 months. Of all patients, 69 returned the questionnaires (response 84%). Telephone contacts were used by 38/67 patients (57%), the mean (SD) number of attended group meetings was 3.1 (1.5) and the discussion forum comprised 15 posted messages. Overall, the proportions of patients being (very) satisfied with the amount of e-mail contacts, telephone contacts, usefulness of website information, physical activity schedules, group meetings and website layout were >/=85%. A smaller proportion of patients were satisfied with the links to other websites (68%), the newsletters (55%) and the online discussion forum (32%). CONCLUSION: Physical activity schedules with weekly feedback by e-mail, telephone contacts and a limited number of group meetings were frequently used website tools and modes of communication of an Internet-based physical activity intervention, with high-satisfaction rates from RA patients. Discussion forum and newsletters were less used and appreciated. Caution should be taken when extrapolating the results found to groups of patients who are not experienced Internet and e-mail users or patients with more severe physical disabilities.

Using internet technology to deliver a home-based physical activity intervention for patients with rheumatoid arthritis: A randomized controlled trial.

OBJECTIVE: To compare the effectiveness of 2 Internet-based physical activity interventions for patients with rheumatoid arthritis (RA). METHODS: A total of 160 physically inactive patients with RA who had a computer with Internet access were randomly assigned to an Internet-based physical activity program with individual guidance, a bicycle ergometer, and group contacts (individualized training [IT] group; n = 82) or to an Internet-based program providing only general information on exercises and physical activity (general training [GT] group; n = 78). Outcome measures included quantity of physical activity (questionnaire and activity monitor), functional ability, quality of life, and disease activity (baseline, 3, 6, 9, and 12 months). RESULTS: The proportion of physically active patients was significantly greater in the IT than in the GT group at 6 (38% versus 22%) and 9 months (35% versus 11%; both P < 0.05) regarding a moderate intensity level for 30 minutes in succession on at least 5 days a week, and at 6 (35% versus 13%), 9 (40% versus 14%), and 12 months (34% versus 10%; all P < 0.005) regarding a vigorous intensity level for 20 minutes in succession on at least 3 days a week. In general, there were no statistically significant differences regarding changes in physical activity as measured with an activity monitor, functional ability, quality of life, or disease activity. CONCLUSION: An Internet-based physical activity intervention with individually tailored supervision, exercise equipment, and group contacts is more effective with respect to the proportion of patients who report meeting physical activity recommendations than an Internet-based program without these additional elements in patients with RA. No differences were found regarding the total amount of physical activity measured with an activity monitor.

How plants cope with complete submergence.

Flooding is a widespread phenomenon that drastically reduces the growth and survival of terrestrial plants. The dramatic decrease of gas diffusion in water compared with in air is a major problem for terrestrial plants and limits the entry of CO(2) for photosynthesis and of O(2) for respiration. Responses to avoid the adverse effects of submergence are the central theme in this review. These include underwater photosynthesis, aerenchyma formation and enhanced shoot elongation. Aerenchyma facilitates gas diffusion inside plants so that shoot-derived O(2) can diffuse to O(2)-deprived plant parts, such as the roots. The underwater gas-exchange capacity of leaves can be greatly enhanced by a thinner cuticle, reorientation of the chloroplasts towards the epidermis and increased specific leaf area (i.e. thinner leaves). At the same time, plants can outgrow the water through increased shoot elongation, which in some species is preceded by an adjustment of leaf angle to a more vertical position. The molecular regulatory networks involved in these responses, including the putative signals to sense submergence, are discussed and suggestions made on how to unravel the mechanistic basis of the induced expression of various adaptations that alleviate O(2) shortage underwater.

Expression of alpha-expansin genes during root acclimations to O2 deficiency in Rumex palustris.

Thirteen alpha-expansin genes were isolated from Rumex palustris , adding to the six already documented for this species. Five alpha-expansin genes were selected for expression studies in various organs/tissues of R. palustris , with a focus on roots exposed to aerated or O2)-deficient conditions, using real-time RT-PCR. Several cases of differential expression of alpha-expansin genes in the various root types of R. palustris were documented, and the identity of the dominant transcript differed between root types (i.e., tap root vs. lateral roots vs. adventitious roots). Several genes were expressed differentially in response to low O2. In situ hybridizations showed expansin mRNA expression in the oldest region of the tap root was localized to cells near the vascular cambium; this being the first report of expansin expression associated with secondary growth in roots. In situ hybridization also showed abundant expression of expansin mRNA in the most apical 1 mm of adventitious roots. Such early expression of expansin mRNA in cells soon after being produced by the root apex presumably enables cell wall loosening in the elongation zone of roots. In addition, expression of some expansin mRNAs increased in 'mature zones' of roots; these expansins might be involved in root hair formation or in formation of lateral root primordia. The present findings support the notion that large gene families of alpha-expansins enable flexibility in expression for various organs and tissues as a normal part of plant development, as well as in response to abiotic stress.

[CO2-laser decortication: an efficient alternative to radiotherapy in the treatment of T1a carcinomas of the glottis]. / Decorticatie met CO2-laser; een doelmatig alternatief voor radiotherapie in de behandeling van T1a-carcinomen van de glottis.

OBJECTIVE: Given that CO2-laser decortication and radiotherapy are equally effective in the treatment of T1a glottic carcinomas, to determine which of the two is most efficient with respect to treatment costs. DESIGN: Retrospective analysis. METHOD: The costs of both treatment modalities from the first visit to the Free University Medical Centre, Amsterdam, the Netherlands, until two years after the start of the treatment were calculated, based on the medical consumption of 89 patients who were treated with curative intent for a T1a glottic carcinoma in the years 1995-1999. RESULTS: The total costs from diagnosis until two years after the start of treatment were [symbol: see text] 7,253,- for radiotherapy and [symbol: see text] 3,864,- for CO2-laser decortication. These amounts included the costs of diagnosis and treatment of any recurrence or benign laryngeal disorders occurring within the two-year interval. The difference was statistically significant. CONCLUSION: Radiotherapy was significantly more expensive than CO2-laser decortication. Therefore CO2-laser decortication is an efficient alternative to radiotherapy in the treatment of eligible patients with T1a glottic carcinoma.

Interactions between plant hormones regulate submergence-induced shoot elongation in the flooding-tolerant dicot Rumex palustris.

Rumex palustris has the capacity to respond to complete submergence with hyponastic (upward) growth and stimulated elongation of petioles. These adaptive responses allow survival of this plant in habitats with sustained high water levels by re-establishing contact with the aerial environment. Accumulated ethylene in submerged petioles interacts with ethylene receptor proteins and operates as a reliable sensor for the under-water environment. Further downstream in the transduction pathway, a fast and substantial decrease of the endogenous abscisic acid concentration and a certain threshold level of endogenous auxin and gibberellin are required for hyponastic growth and petiole elongation. Interactions of these plant hormones results in a significant increase of the in vitro cell wall extensibility in submerged petioles. Furthermore, the pattern of transcript accumulation of a R. palustris alpha-expansin gene correlated with the pattern of petiole elongation upon submergence.

A QTL for flowering time in Arabidopsis reveals a novel allele of CRY2.

Variation of flowering time is found in the natural populations of many plant species. The underlying genetic variation, mostly of a quantitative nature, is presumed to reflect adaptations to different environments contributing to reproductive success. Analysis of natural variation for flowering time in Arabidopsis thaliana has identified several quantitative trait loci (QTL), which have yet to be characterized at the molecular level. A major environmental factor that determines flowering time is photoperiod or day length, the length of the light period, which changes across the year differently with geographical latitude. We identified the EDI locus as a QTL partly accounting for the difference in flowering response to the photoperiod between two Arabidopsis accessions: the laboratory strain Landsberg erecta (Ler), originating in Northern Europe, and Cvi, collected in the tropical Cape Verde Islands. Positional cloning of the EDI QTL showed it to be a novel allele of CRY2, encoding the blue-light photoreceptor cryptochrome-2 that has previously been shown to promote flowering in long-day (LD) photoperiods. We show that the unique EDI flowering phenotype results from a single amino-acid substitution that reduces the light-induced downregulation of CRY2 in plants grown under short photoperiods, leading to early flowering.

The TRANSPARENT TESTA12 gene of Arabidopsis encodes a multidrug secondary transporter-like protein required for flavonoid sequestration in vacuoles of the seed coat endothelium.

Phenolic compounds that are present in the testa interfere with the physiology of seed dormancy and germination. We isolated a recessive Arabidopsis mutant with pale brown seeds, transparent testa12 (tt12), from a reduced seed dormancy screen. Microscopic analysis of tt12 developing and mature testas revealed a strong reduction of proanthocyanidin deposition in vacuoles of endothelial cells. Double mutants with tt12 and other testa pigmentation mutants were constructed, and their phenotypes confirmed that tt12 was affected at the level of the flavonoid biosynthetic pathway. The TT12 gene was cloned and found to encode a protein with similarity to prokaryotic and eukaryotic secondary transporters with 12 transmembrane segments, belonging to the MATE (multidrug and toxic compound extrusion) family. TT12 is expressed specifically in ovules and developing seeds. In situ hybridization localized its transcript in the endothelium layer, as expected from the effect of the tt12 mutation on testa flavonoid pigmentation. The phenotype of the mutant and the nature of the gene suggest that TT12 may control the vacuolar sequestration of flavonoids in the seed coat endothelium.

The late flowering phenotype of fwa mutants is caused by gain-of-function epigenetic alleles of a homeodomain gene.

The transition to flowering in Arabidopsis thaliana is delayed in fwa mutant plants. FWA was identified by loss-of-function mutations in normally flowering revertants of the fwa mutant, and it encodes a homeodomain-containing transcription factor. The DNA sequence of wild-type and fwa mutant alleles was identical in the genomic region of FWA. Furthermore, the FWA gene is ectopically expressed in fwa mutants and silenced in mature wild-type plants. This silencing is associated with extensive methylation of two direct repeats in the 5' region of the gene. The late flowering phenotype, ectopic FWA expression, and hypomethylation of the repeats were also induced in the ddm1 hypomethylated background. Mechanisms for establishment and maintenance of the epigenetic mark on FWA are discussed.

The Arabidopsis aldehyde oxidase 3 (AAO3) gene product catalyzes the final step in abscisic acid biosynthesis in leaves.

Abscisic acid (ABA) is a plant hormone involved in seed development and germination and in responses to various environmental stresses. The last step of ABA biosynthesis involves oxidation of abscisic aldehyde, and aldehyde oxidase (EC ) is thought to catalyze this reaction. An aldehyde oxidase isoform, AOdelta, encoded by AAO3, one of four Arabidopsis aldehyde oxidase genes (AAO1, AAO2, AAO3, and AAO4), is the most likely candidate for the enzyme, because it can efficiently catalyze the oxidation of abscisic aldehyde to ABA. Here, we report the isolation and characterization of an ABA-deficient Arabidopsis mutant that maps at the AAO3 locus. The mutant exhibits a wilty phenotype in rosette leaves, but seed dormancy is not affected. ABA levels were significantly reduced in the mutant leaves, explaining the wilty phenotype in rosettes, whereas the level in the mutant seeds was less reduced. No AOdelta activity could be detected in the rosette leaves of the mutant. Sequence data showed that the mutant contains a G to A substitution in the AAO3 gene. The mutation causes incorrect splicing of the ninth intron of AAO3 mRNA. We thus conclude that the ABA-deficient mutant is impaired in the AAO3 gene and that the gene product, AOdelta, is an aldehyde oxidase that catalyzes the last step of ABA biosynthesis in Arabidopsis, specifically in rosette leaves. Other aldehyde oxidases may be involved in ABA biosynthesis in other organs.