Andrew P Cairns

Joseph G Mcveigh

Andrew P Cairns¹

J G Mcveigh²

A systematic review of the effects of dynamic exercise in rheumatoid arthritis

Keywords: Rheumatoid Arthritis, Exercise, Rehabilitation, Systematic Review

Exercise is commonly used in the management of patients with rheumatoid arthritis (RA), however there is little consensus in the literature to support its use. This systemic review aimed to determine the effects of dynamic exercise on patients with RA. A systematic search of Medline (1949-2007), Cinahl (1982-2007), Embase (1974-2007) and Cochrane library was performed for randomised controlled trials using the keywords "rheumatoid arthritis" and "exercise" or "training" or "sport". The methodological quality of studies was assessed using a ten point scale.

Eighteen papers relating to 12 different studies met inclusion criteria. The mean methodological quality score was 6.9/10. Studies using aerobic training, strength training and combinations of both were included. Patients with early, stable, and active RA were studied. A number of studies reported improvement in muscle strength, physical function and aerobic capacity with dynamic exercise. Some studies also reported improvements in disease activity measures, and small improvements in hip bone mineral density. One study reported significantly less progression of small joint radiographic damage of the feet in the dynamic exercise group. However, one study also reported worse large joint radiographic damage in patients using dynamic exercise who had pre-existing large joint damage, though this was a retrospective analysis. No studies reported worse outcomes for function, disease activity or aerobic capacity with dynamic exercise. Cardiovascular outcomes were not reported in any study, and no data were presented to assess the effect of exercise on patients with significant underlying cardiovascular disease. This systematic review suggests that the majority of patients with RA should be encouraged to undertake aerobic and / or strength training exercise. Exercise programmes should be carefully tailored to the individual, particularly for patients with underlying large joint damage or pre-existing cardiovascular disease.

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown aetiology that primarily involves joints. Patients with RA suffer increased morbidity and mortality from cardiovascular disease, largely due to accelerated atherosclerosis. [START_REF] Naz | Mortality in established rheumatoid arthritis[END_REF][START_REF] Szekanecz | Accelerated atherosclerosis in rheumatoid arthritis[END_REF] This is not all due to traditional cardiovascular risk factors. The vascular effects of chronic systemic inflammation are thought to play a significant role. [START_REF] Gerli | Precocious atherosclerosis in rheumatoid arthritis: role of traditional and disease-related cardiovascular risk factors[END_REF][START_REF] Snow | Rheumatoid arthritis and cardiovascular disease: the role of systemic and evolving strategies of prevention[END_REF] Traditionally patients with active RA were advised to rest from active exercise, particularly during exacerbations. [START_REF] Iversen | Rheumatologist-patient communication about exercise and physical therapy in the management of rheumatoid arthritis[END_REF] In the last two decades there has been increasing use of active exercise in patients with RA, with a number of studies looking at the effect of exercise on outcome measures as diverse as fitness, muscle strength, bone density, functional scores, disease activity and joint damage. [START_REF] Van Den Ende | Dynamic exercise therapy for rheumatoid arthritis[END_REF] However this remains a controversial area in rheumatology, with some clinicians discouraging active exercise for patients with RA, particularly during times of disease flare. While the benefits of exercise for healthy individuals in terms of cardiovascular health are clear, there has been little study of the cardiovascular benefits of exercise for patients with RA, who already have excess cardiovascular risk, and who have lower baseline levels of activity.

A Cochrane review of dynamic exercise therapy for treating RA concluded that dynamic exercise is effective at increasing aerobic capacity and muscle strength. [START_REF] Van Den Ende | Dynamic exercise therapy for rheumatoid arthritis[END_REF] No detrimental effects on disease activity and pain were observed at this time, however, the effects on functional ability and radiological progression were unclear, further there was no examination of the effect of exercise on cardiovascular outcomes. This Cochrane review [START_REF] Van Den Ende | Dynamic exercise therapy for rheumatoid arthritis[END_REF] published in 2000 included only six studies. In the years since this review was carried out there have been a number of studies looking at the effect of different types of exercise on a number of outcome measures in RA. The aim of this review therefore, was to determine the effectiveness of dynamic exercise in improving outcomes for patients with RA.

Methods

A systematic search of Medline (1949-2007) for randomised controlled trials using keywords "rheumatoid arthritis" and "exercise" or "training" or "sport" limited to human subjects and English language was performed in July 2007. Similar searches were also performed using the Cinahl (1982-2007), Embase (1974-2007) and Cochrane library. Abstracts were scanned and all potentially relevant papers requested for analysis. Existing reviews in the area were also scanned searching for additional references.

Inclusion criteria

All randomised controlled trials of adult patients with a confirmed diagnosis of RA, where the intervention included any form of dynamic physical exercise were examined. Primary outcome measures included radiographic damage, swollen and tender joint counts, laboratory measures of inflammation, bone density, functional scores, measures of fitness and muscle strength, and measures of cardiovascular outcomes. Studies presenting data from mixed groups of patients with different arthropathies were excluded. The analysis is qualitative rather than quantitative because of the wide variation in study subjects, interventions, and outcome measures used.

Methodological Quality

Each study was assessed for methodological quality using 10 criteria (see below and table 2). These criteria were modified from the Delphi list [START_REF] Verhagen | The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus[END_REF] , with reference to similar criteria published by Van den Ende et al. [START_REF] Van Den Ende | Dynamic exercise therapy for rheumatoid arthritis[END_REF] , Van Tulder et al. [START_REF] Van Tulder | Updated method guidelines for systematic reviews in the cochrane collaboration back review group[END_REF] , and the Pedro scale. [START_REF] Maher | Reliability of the PEDro scale for rating quality of randomized controlled trials[END_REF] The quality criteria relating to blinding of patient and blinding of care provider were not suitable for intervention involving dynamic physical exercise and were not included in this list. Each criterion was scored yes, no, or unclear with no weighting of results giving a maximum quality score of 10/10. For the purpose of this review drop out rates of 25% or less were deemed satisfactory. Studies fulfilling seven or more criteria are deemed high quality. Those with less than four out of 10 are deemed low quality.

Results

Selection of included trials

The search strategy yielded 62 potentially relevant papers, from which a total of 46 studies were identified. Of these 18 relevant papers that met inclusion criteria were included in this review. These papers relate to 12 separate studies. All trials were prospective randomised studies, though one paper reports a retrospective subgroup analysis. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF] Study characteristics and outcomes are directly compared in table 1.

Excluded papers

Excluded papers and reasons for exclusion are listed in table 3.

Intervention

Aerobic exercises:

The studies by Harckom et al. [START_REF] Harkcom | Therapeutic value of graded aerobic exercise training in rheumatoid arthritis[END_REF] and Melikoglu et al. [START_REF] Melikoglu | Association between dynamic exercise therapy and IGF-1 and IGFBP-3 concentrations in the patients with rheumatoid arthritis[END_REF] Exercises were performed on a bicycle ergometer 3 times a week for 12 weeks. Five bouts of exercise per session were performed, each separated by a one minute rest.

The protocols differed in the initial length of total exercise time, the rate of progression, and the final total duration of activity achieved. The control group continued with routine daily activities. Outcome measures were aerobic capacity (VO 2 max), grip strength, 50 foot walk time, muscle strength (knee flexors and extensors), functional status index, and joint counts (combined tender/swollen score). Melikoglu et al. [START_REF] Melikoglu | Association between dynamic exercise therapy and IGF-1 and IGFBP-3 concentrations in the patients with rheumatoid arthritis[END_REF] performed a prospective randomised study of short term (2 weeks) dynamic exercise therapy versus range of motion (ROM) controls in 40 female patients with non-active rheumatoid disease, functional class I or II, and on stable medication. The intervention was dynamic exercise on a treadmill to achieve 60% of age predicted maximum heart rate. Both groups exercised for five sessions per week, 20 minutes per session, for a total of 2 weeks. An additional healthy (non-RA) control group was also studied but is not included in this analysis. Primary outcome measures were levels of serum insulin-like growth factor (IGF-1), and serum insulin-like binding protein 3 (IGFBP-3). Pain VAS, HAQ, morning stiffness duration, RAI, ESR, and CRP were also recorded.

Strength training:

The studies by Hakkinen et al. [START_REF] Hakkinen | Dynamic strength training in patients with early rheumatoid arthritis increases muscle strength but not bone mineral density[END_REF][START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF][START_REF] Hakkinen | Effects of dynamic strength training on physical function, Valpar 9 work sample test, and working capacity in patients with recent-onset rheumatoid arthritis[END_REF][START_REF] Hakkinen | A home-based two-year strength training period in early rheumatoid arthritis led to good longterm compliance: a five-year followup[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF] and McMeekin et al. [START_REF] Mcmeekin | The effects of knee extensor and flexor muscle training on the timed-up-and-go test in individuals with rheumatoid arthritis[END_REF] [START_REF] Hakkinen | Dynamic strength training in patients with early rheumatoid arthritis increases muscle strength but not bone mineral density[END_REF][START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF][START_REF] Hakkinen | Effects of dynamic strength training on physical function, Valpar 9 work sample test, and working capacity in patients with recent-onset rheumatoid arthritis[END_REF][START_REF] Hakkinen | A home-based two-year strength training period in early rheumatoid arthritis led to good longterm compliance: a five-year followup[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF] None of the patients had commenced treatment with disease modifying drugs or corticosteroids at the beginning of the study. Mean duration of symptoms was 10.5 months at the start of the study. The exercise group performed home dynamic strength training twice weekly for 12 months with rubber bands and dumbbells for upper and lower extremities, abdominal and back muscles. The exercise group is also encouraged to engage in recreational physical activities such as walking, cycling, skiing and swimming two to three times a week. The control group performs range of motion and stretching exercises. Recreational activities are allowed except for strength training of any kind. Training diaries are kept by both groups.

Hakkinen et al's first paper reports results after one year. [START_REF] Hakkinen | Dynamic strength training in patients with early rheumatoid arthritis increases muscle strength but not bone mineral density[END_REF] Outcome measures are strength, bone mineral density at hip and lumbar spine by Lunar DEXA, disease activity score (DAS28), pain VAS and functional capacity (HAQ). Hakkinen et al's second paper reports results after continuing the strength program for two years. [START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF] Outcome measures reported are strength, bone mineral density at hip and lumbar spine (Lunar DEXA); disease activity (DAS28), pain VAS, functional capacity (HAQ), and also the radiographic Larsen joint score of small joints. Hakkinen et al's third paper reports a separate outcome measure (physical function as assessed by the Valpar 9 work sample test) after two years in the same group. [START_REF] Hakkinen | Effects of dynamic strength training on physical function, Valpar 9 work sample test, and working capacity in patients with recent-onset rheumatoid arthritis[END_REF] Hakkinen et al's 2004 papers report five year follow up data following the initial two year exercise programme [START_REF] Hakkinen | A home-based two-year strength training period in early rheumatoid arthritis led to good longterm compliance: a five-year followup[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF] Both papers report muscle strength, radiological damage (Larsen small joint score of hands and feet), function (HAQ), and disease activity (DAS28).

Bone mineral density (by DEXA) is reported in the Annals of Rheumatic Disease paper only. [START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF] McMeekin et al. performed a prospective randomised six week study of knee extensor and flexor muscle training in 36 patients with RA (30 female), with a mean age 50.6 years. [START_REF] Mcmeekin | The effects of knee extensor and flexor muscle training on the timed-up-and-go test in individuals with rheumatoid arthritis[END_REF] The intervention was concentric quadriceps and hamstring training. Sessions were performed every three days for a total of six weeks, completing 14 sessions in total. Outcome measures were pain VAS, HAQ, timed up and go test (TUG), and peak torque of knee extensor and flexor muscle activity.

Aerobic / strength Combinations:

The following studies used exercise programmes with significant aerobic and strength training aspects: Bilberg et al. [START_REF] Bilberg | Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study[END_REF] , the RAPIT programme studies by de Jong et al. [START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF][START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] and Munneke et al. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF] , Komatireddy et al. [START_REF] Komatireddy | Efficacy of low load resistive muscle training in patients with rheumatoid arthritis functional class II and III[END_REF] , Lyngberg et al. [START_REF] Lyngberg | Elderly rheumatoid arthritis patients on steroid treatment tolerate physical training without an increase in disease activity[END_REF] , Van den Ende et al. [START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF][START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF] , and Westby et al. [START_REF] Westby | A randomized controlled trial to evaluate the effectiveness of an exercise program in women with rheumatoid arthritis taking low dose prednisone[END_REF] . Bilberg et al. studied 47 (42 women, 5 men) patients with RA aged 20-65 [START_REF] Bilberg | Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study[END_REF] . Disease duration was one to five years, and drug therapy was stable. The intervention was pool exercise twice weekly for 12 weeks. The control group continued normal activities. Outcomes were assessed at three months. Primary outcomes were aerobic capacity and physical SF-36. Secondary outcome measures were the chair test, shoulder endurance test, index of muscle function (IMF), and hand grip force.

de Jong et al published four papers from the multicentre RA patients in training (RAPIT) programme. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF][START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF][START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] This was a two year prospective study comparing an intensive exercise programme (RAPIT) with usual care physiotherapy (UC). Three hundred patients with RA (237 women) aged 20-70 were enrolled. All patients were on stable medication, functional class I-III and with no significant cardiopulmonary disease. The RAPIT programme consisted of supervised bi-weekly group exercise of 1.25 hrs per session. Each session had three parts: bicycle training (20 minutes), exercise circuit (20 minutes), sport or game (20 minutes). Primary outcome measures [START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF] were divided into measures of effectiveness: functional ability as assessed by the MACTAR and HAQ scores, and safety: Larsen large joints score of radiographic damage. Secondary outcome measures were physical capacity and emotional status (effectiveness) and disease activity score (DAS4) (safety). Outcomes were assessed after 24 months. The primary outcome measure reported in the paper published in Arthritis and Rheumatism [START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF] was bone mineral density at the hip and spine (by DEXA) at two years.

The primary outcome measure in the paper published in the Annals of Rheumatic Disease [START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] was radiological joint damage of the hands and feet. Munneke et al published a retrospective sub-group analysis of the RAPIT programme with the primary outcome measure the Larsen large joint radiographic score. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF] Komatireddy et al performed a prospective randomised 12 week study of circuit based training at home. [START_REF] Komatireddy | Efficacy of low load resistive muscle training in patients with rheumatoid arthritis functional class II and III[END_REF] The control group had no exercise intervention. Forty nine patients with RA (37 women) were studied. The mean age was 60.5, and patients were functional class II or III. 38 patients were receiving NSAIDs, 28 oral steroids, 48 DMARDs, and 17 combination DMARDs. Home circuit training using resistive exercises and 12-15 reps per set was performed. Efficacy of the exercise programme was assessed by evaluation of changes in muscle strength, cardiopulmonary function (VO 2 max, anaerobic threshold), functional ability (50 foot walk, sit-to-stand test, HAQ, arthritis impact measurement scales -AIMS), self-reported health status (pain and fatigue VAS and self-reported joint counts) and disease activity status (physician's global assessment and tender/swollen joint counts).

Lyngberg et al performed a prospective randomised study of progressive interval

training over three months in elderly patients with RA on oral steroids. [START_REF] Lyngberg | Elderly rheumatoid arthritis patients on steroid treatment tolerate physical training without an increase in disease activity[END_REF] Twenty four elderly patients who had been treated with low dose oral steroids for at least two years were studied. The mean age was 66. 5 HAQ, activity level (Caltrac accelerometer), and an aerobic fitness estimation (though this was by a self-completed questionnaire). This study had a relatively high drop out rate (21% exercise group, 38% control group). Compliance with the exercise programme was only 71% among the completers.

Methodological quality

Methodological quality of the included studies was independently evaluated by the two authors; disagreements were resolved by consensus, scores ranged between five and ten, with a mean score of 6.9. Half of the papers (9/18) had quality scores of seven or more and were deemed of high quality. According to inclusion criteria, only randomised studies were included in the review, although four papers did not describe clearly the method of randomisation in detail. Allocation concealment was either unclear or not done in eight of the papers. There were significant differences in the groups at baseline in six papers. All included papers specified inclusion criteria and described the intervention in sufficient detail. In one study [START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] assessments were carried out by an assessor not blinded to allocation groups. In five other papers blinding of outcome assessor was not clear. Co interventions were avoided or similar between groups in 10 papers. Co interventions were significantly different between groups in four papers, and this was unclear in another four papers. All papers presented point estimates and measures of variability for primary outcome measures. The drop out rate was described and acceptable in all but one paper. [START_REF] Westby | A randomized controlled trial to evaluate the effectiveness of an exercise program in women with rheumatoid arthritis taking low dose prednisone[END_REF] Only eight papers included an intention to treat analysis.

Effectiveness of interventions:

A summary of key outcome results is presented in table 1.

Aerobic exercises:

Harkcom et al. reported an increase in VO 2 max for the exercise groups compared with controls. [START_REF] Harkcom | Therapeutic value of graded aerobic exercise training in rheumatoid arthritis[END_REF] However this only reached statistical significance when the three exercise groups were combined together for analysis (p<0.01). Percentage increases in VO 2 max were 47.2%, 12.8%, and 32.9% respectively in the three exercise groups, compared with 0.5% in the control group. There was an improvement in the active joint count of 39.5% in the three combined active groups compared with 16.3% in the control group (p<0.01). No significant differences were seen in grip strength, muscle strength or functional status index. The small group sizes (4, 3, 4, and 6 respectively) make meaningful interpretation difficult.

Melikoglu et al. reported a significant increase in the mean serum IGF-1 level in the exercise group (+25.0%) compared with the control group (-16.8%, p<0.001). [START_REF] Melikoglu | Association between dynamic exercise therapy and IGF-1 and IGFBP-3 concentrations in the patients with rheumatoid arthritis[END_REF] This study also reported a significant improvement in the RAI in the exercise group (-27.2%) compared with controls (-9.3%, p<0.05), and in the pain VAS in the exercise group (-10.7%) compared with controls (+3.8%). No significant differences were seen in IGFBP-3 levels, morning stiffness, or inflammatory markers. Further study of the effect of exercise on key cytokines such as TNF alpha would be of interest.

Strength training:

Hakkinen et al. reported significant improvements in knee extension, trunk flexion and grip strength at one and two years with persisting improvement in knee extension and trunk extension at five years in the exercise group. [START_REF] Hakkinen | Dynamic strength training in patients with early rheumatoid arthritis increases muscle strength but not bone mineral density[END_REF][START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF][START_REF] Hakkinen | Effects of dynamic strength training on physical function, Valpar 9 work sample test, and working capacity in patients with recent-onset rheumatoid arthritis[END_REF][START_REF] Hakkinen | A home-based two-year strength training period in early rheumatoid arthritis led to good longterm compliance: a five-year followup[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF] Significant differences between the exercise and control groups were seen for ESR (-59.6% versus -23.3%, p=0.015), HAQ (-65.3% versus -43.7%, p=0.01), and DAS28 (-48.9% versus -40.0%, p=0.019) at one year, in favour of the exercise group. At two years there was persistent significant difference in HAQ and pain VAS, in favour of the exercise group. At five years the DAS28 remained significantly better in the exercise group (-47.7% versus -38.8%, p=0.012), though HAQ and pain VAS were no longer different suggesting that exercise programmes need to be continued to maintain many of the beneficial effects There was a small but statistically significant difference in hip bone mineral density at one year in favour of the exercise group (+1.1% versus -2.85%, p=0.024). At five years the bone density was reasonably well maintained, but statistical significance was lost (+2.12% versus -0.45%, p>0.05). Spinal bone density did not show any significant difference at any stage. Bone density by DEXA is relatively insensitive to change, and further study of the effect of exercise on bone turnover markers and ultimately fracture rates would be of interest. There was no statistical difference in Valpar 9 scores at two years, or in Larsen scores at five years.

McMeekin et al. reported significant improvements in the timed up and go test (TUG)

(-11.1% versus -3.2%, p=0.005), pain VAS (-4.9% versus -44.2%, p=0.031), and HAQ (-30.0% versus +14.3%, p=0.036) all in favour of the strength training intervention. [START_REF] Mcmeekin | The effects of knee extensor and flexor muscle training on the timed-up-and-go test in individuals with rheumatoid arthritis[END_REF] She also reports significant improvements in knee flexor and extensor torque in the exercise group compared with the controls.

Aerobic / strength Combinations:

Bilberg et al. reported no significant differences in aerobic capacity or the physical component of the SF-36 with moderately intensive pool-based exercises. [START_REF] Bilberg | Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study[END_REF] The index of muscle function (IMF) however did show significant improvement in the exercise group compared with controls (-59.3% versus -4.3%, p=0.006), and the chair test was also significantly improved in the intervention group (+15% versus -4.3%, p=0.005).

There were also some significant differences in favour of the intervention for a number of muscle endurance outcomes, though the benefits were less marked than in some of the more intensive programmes in this review.

Outcomes from the RAPIT study are reported in four papers. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF][START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF][START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] The mean difference in change in function as measured by the MACTAR score was significantly different and in favour of the exercise group at 12, 18 and 24 months (RAPIT 6.8% improvement v usual care 1.3% improvement, p=0.017 at 24 months). There was no significant difference in function as measured by the HAQ score. The authors comment that the MACTAR score may be more relevant here because of its assessment of endurance and ability to perform repetitive complex tasks.

The RAPIT group had significantly more improvement in aerobic capacity (mean change +8.2W versus -6.7W, p<0.001) and muscle strength (mean change 26.1N versus 9.6N, p<0.001) at two years compared with the control group, in keeping with outcomes from other studies in this review. The mean difference in emotional status as measured by the HADS score was also significantly different and in favour of the RAPIT group at 12 and 24 months (-10% versus +0.9%, p=0.007 at 2 years).

Disease activity as measured by DAS4 (RAI and number of swollen joints) decreased in both groups throughout the study with no significant difference between the groups. There was no difference between the groups in terms of ESR or general health.

In the two years of the study the median radiographic damage of large joints did not increase in either group. However it was noted that the mean difference in change of the large joint Larsen score between the groups showed a non significant trend towards more damage in the RAPIT group. Patients with more baseline damage showed slightly more progression in damage, and this was more obvious in the RAPIT group. This trend was felt to be difficult to interpret by the authors and a retrospective subgroup analysis of the progression of large joint radiologic damage was undertaken. [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF] In this paper linear regression analysis was used to test which predefined variables at baseline (age, disease duration, disease activity, physical capacity, functional ability, joint damage) modified the effect of high intensity exercise on the progression of radiologic damage of large joints over 24 months.

Baseline radiographic joint damage was the only variable associated with the effect of the RAPIT programme on large joint damage progression. In patients with preexisting extensive damage of large joints (Larsen score >5, n=59) 85% of the RAPIT group had progression of damage compared with 48% of the usual care group (p<0.05). There was no significant difference in patients without pre-existing extensive large joint damage (Larsen score <5, n=218). In the subgroup with extensive baseline damage, a significantly higher percentage of shoulders and subtalar joints deteriorated in the RAPIT group compared with the usual care group when joints were analysed individually (no significant differences were noted for elbows, hips, knees or ankles). The authors propose that biomechanical instability may be particularly prevalent in these joints in RA, but these findings should be interpreted with caution, as this study was not powered to assess radiological damage.

In terms of bone loss there were only small changes in bone mineral density at the spine and hip over the two years in both groups. [START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF] There was a non-significant trend to less bone loss at the hip in the RAPIT group versus usual care (-1.1% versus -1.9%, p=0.06), and no difference between the groups for bone density in the spine (+0.9% versus +0.9%, p=0.697). However when analysed by mixed-effect ANOVA, the mean between-group difference in change of hip BMD over the 2 years was statistically significant (p=0.026) in favour of the RAPIT group. The change in hip bone mineral density was significantly and independently associated with changes in both muscle strength and aerobic fitness.

de Jong et al. reported the outcomes of small joint damage (Larsen score hands and feet) from the RAPIT study in 2004. [START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] The usual care group had slightly more baseline radiological damage than the RAPIT group. There was no significant difference in radiological progression of hands between the groups (12.2% versus13.0% increase -RAPIT versus usual care), however there was significantly less progression in feet in the RAPIT group (6.5%) compared with the usual care group (11.5%), p=0.047.

Multivariate subgroup analysis demonstrated that a higher rate of joint damage was independently predicted by higher baseline damage (unstandardised regression coefficient (standard error) 0.04 (0.02), p<0.005), more frequent use of glucocorticoids (0.17 (0.09), p<0.05), and a decrease in aerobic fitness (-0.01(0.02), p<0.05). Further long term study, powered to detect bony changes, using high resolution ultrasound or MRI scanning would be of interest.

Komaitreddy et al. reported the outcome of a 12 week study of resistive circuit

training exercises in patients with RA. [START_REF] Komatireddy | Efficacy of low load resistive muscle training in patients with rheumatoid arthritis functional class II and III[END_REF] Of note, in pre study screening the authors identified two cases of asymptomatic ischaemic heart disease, underlining the importance of coronary artery disease in this population. Significant improvements in the exercise group compared with the control group were reported for self-reported joint count (-13.9% versus +36.2%, p=0.02), sit to stand time (-23.4% versus -3.9%, p=0.02), night time pain (-20.6% versus +8.1%, p=0.05), and time to anaerobic threshold (-35.1% versus +10.1%, p=0.02). No significant between group differences were noted for morning stiffness, hours before fatigue, isokinetic strength, grip strength, self reported pain and fatigue, physicians joint count, 50 foot walk time, AIMS, HAQ, treadmill time, peak heart rate, time to anaerobic threshold, or V0 2 max.

Lyngberg et al. reports outcomes of progressive interval training over three months in

"elderly fragile patients" with RA on low dose oral steroids. [START_REF] Lyngberg | Elderly rheumatoid arthritis patients on steroid treatment tolerate physical training without an increase in disease activity[END_REF] There were no significant differences between groups for swollen/tender joints, ESR, morning stiffness, grip strength, 30m walk time or V0 2 max. There was a small statistical difference in favour of the exercise group for left ankle plantar flexion torque (-7.1% versus -53.6%, p=0.04) though the clinical significance of this is unclear. No significant differences for muscle torque of right ankle or either knee was noted, however, the study was limited by low numbers, short duration and relatively low intensity intervention. The study did note a doubling of the work capacity of the trained patients but this was not recorded for the control group.

In Van den Ende et al's first paper, the outcomes of four different exercise programmes (1.high intensity exercise, 2.low intensity exercise in a group, 3.low intensity individual exercise, and 4.home exercise) on 100 stable patients with RA from an outpatient population over 12 weeks are presented. [START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] The high intensity exercise group (group 1) had significantly more improvement in aerobic capacity (p<0.001), muscle strength (p=0.02), range of movement (EPM-ROM) (p<0.001) and the walk test (p<0.001) at 12 weeks than the other three exercise groups. The swollen joint count improved by 32.7% in group 1, when the swollen joint count either worsened or did not change in the other groups (p<0.001). It should be noted however that the baseline swollen joint count was higher in this group (5.2) than in the others (3.0, 4.4, and 3.6 respectively), with a wide standard deviation (3.2), so this finding should be interpreted with caution.

The exercise programmes lasted 12 weeks. The assessments were also completed after 24 weeks. All significant differences between groups were lost at 24 weeks with the exception of muscle strength (p<0.001), underlining the importance of continuing regular exercises. There were no significant between group differences at any time for HAQ, Dutch-AIMS, RAI, pain VAS, global disease activity VAS or ESR. Of note, the assessments in this study were performed by a single observer not blinded to treatment group.

In Van den Ende et al's second paper the outcomes of a dynamic intensive exercise regimen on hospital inpatients with very active rheumatoid disease (baseline DAS 7.0) are presented. [START_REF] Van Den Ende | Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial[END_REF] Medical treatment was similar in both groups, and both groups had a gradual decline in disease activity throughout the 24 week study. No significant differences in disease activity were observed between the groups. At 24 weeks significantly more patients in the intensive group met modified ACR response criteria than in the conservative group (12 versus 3, p=0.04). Joint mobility, the 50 foot walk test and HAQ improved in both groups without significant differences between groups. Measures of muscle strength were significantly better in the intensive group than the conservative group at 24 weeks -(isokinetic extension +36.8% versus +0%, p<0.05; isometric extension +51.2% versus +4.2%, p<0.05). This study suggests that a short term programme of intensive exercises is well tolerated by inpatients with active disease, resulting in significant improvements in muscle strength without worsening of disease activity. However this study did not assess long term structural changes.

Westby et al. present results of a 12 month weight bearing aerobic exercise program

on disease activity, physical function and bone mineral density in women with RA taking low dose prednisolone. [START_REF] Westby | A randomized controlled trial to evaluate the effectiveness of an exercise program in women with rheumatoid arthritis taking low dose prednisone[END_REF] There were no significant differences in disease activity, physical function or bone density between the groups at the end of the study.

There was a significant improvement in fitness estimation (though this was by questionnaire) in the exercise group (+87.1% versus -12.1%, p=0.001).

Limitations

A number of the studies included in this review had relatively small numbers of patients. Power calculations to determine sample size are only presented for the RAPIT study group of papers, [START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF][START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] and for the two studies by Van den Ende et al. [START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF][START_REF] Van Den Ende | Effect of intensive exercise on patients with active rheumatoid arthritis: a randomised clinical trial[END_REF] increasing the risk of statistical type two error in the other studies. Many of the papers included in this review present a large number of outcome variables. In only a small number of papers is any statistical allowance made for this in the analysis [START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF][START_REF] Melikoglu | Association between dynamic exercise therapy and IGF-1 and IGFBP-3 concentrations in the patients with rheumatoid arthritis[END_REF][START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] increasing the risk of statistical type one error in the other studies.

The search strategy used in this review deliberately excluded studies that were not randomised controlled trials. Also some studies were excluded because patients with different arthropathies were analysed together. No quality assessment criteria specific to exercise intervention in RA have been validated though the quality assessment score used in this review is a modification of the Delphi list [START_REF] Verhagen | The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus[END_REF] , and similar to that used in the Cochrane review. [START_REF] Van Den Ende | Dynamic exercise therapy for rheumatoid arthritis[END_REF] It was not possible to perform a quantitative review of the outcomes of these studies because of the widely different patient characteristics, study design and outcome measures used in the different studies.

Summary

The aim of this review was to evaluate the effect of dynamic exercise on patients with RA. With the above caveats, improved outcomes with dynamic exercise in terms of muscle strength, physical function and aerobic capacity were reported in a number of studies. No studies reported worse outcomes for function, disease activity or aerobic capacity with dynamic exercise. Some studies also reported improvements in disease activity measures [START_REF] Hakkinen | Dynamic strength training in patients with early rheumatoid arthritis increases muscle strength but not bone mineral density[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF][START_REF] Harkcom | Therapeutic value of graded aerobic exercise training in rheumatoid arthritis[END_REF][START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] , and small improvements in hip bone mineral density. [START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF] One study reported significantly less progression of small joint radiographic damage of the feet in the dynamic exercise group. [START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] However, one study also reported worse large joint radiographic damage in patients using dynamic exercise who had pre-existing large joint damage [START_REF] Munneke | Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis[END_REF] , though this was a retrospective analysis. This is the only paper in this review to report a significantly worse outcome in any group performing dynamic exercise. This was seen only in shoulder and subtalar joints when joints were analysed individually. The reasons for this are not clear. This does deserve recognition, and the use of caution in recommending high impact exercise to some patients, particularly those with high levels of baseline joint damage. Further study to address this issue, using more sensitive imaging techniques are clearly required.

Perhaps the most surprising aspect of this review is that no studies addressed the effect of dynamic exercise on cardiovascular outcomes in terms of coronary artery disease or stroke, or major risk factors for these such as hypertension, dyslipidaemia, obesity or diabetes. Because excess cardiovascular mortality is the main cause of reduced life expectancy in RA, interventions to reduce cardiovascular disease or its risk factors are of vital importance. [START_REF] Naz | Mortality in established rheumatoid arthritis[END_REF][START_REF] Szekanecz | Accelerated atherosclerosis in rheumatoid arthritis[END_REF][START_REF] Gerli | Precocious atherosclerosis in rheumatoid arthritis: role of traditional and disease-related cardiovascular risk factors[END_REF] It should also be noted that all of these studies excluded patients with significant pre-existing cardiovascular or other serious disease.

Because these studies were of very different designs it is not possible to be definite about which forms of exercise should be encouraged. However when different intensities of exercise were compared [START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] , more benefits were seen with high intensity exercise compared with low intensity. Less intensive pool exercises did not result in any improvements in aerobic capacity. [START_REF] Bilberg | Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study[END_REF] Improvements in aerobic capacity were reported by a number of the aerobic and combined exercise programmes 12-14, 20, 25 , but not by the pure strength training programmes. [START_REF] Hakkinen | A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis[END_REF][START_REF] Hakkinen | Effects of dynamic strength training on physical function, Valpar 9 work sample test, and working capacity in patients with recent-onset rheumatoid arthritis[END_REF][START_REF] Hakkinen | A home-based two-year strength training period in early rheumatoid arthritis led to good longterm compliance: a five-year followup[END_REF][START_REF] Hakkinen | Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: a 5 year follow up[END_REF][START_REF] Van Den Ende | Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial[END_REF] Conversely the strength training programmes report significant increases in muscle strength but not in aerobic capacity.

It seems sensible therefore, to suggest combined training programmes to address both aerobic fitness as well as strength training. It may be prudent to avoid sports and games involving twisting and rapid joint loading or unloading activities as described in the RAPIT programme [START_REF] De Jong | Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial[END_REF][START_REF] De Jong | Slowing of bone loss in patients with rheumatoid arthritis by long-term high-intensity exercise: results of a randomized, controlled trial[END_REF][START_REF] De Jong | Long term high intensity exercise and damage of small joints in rheumatoid arthritis[END_REF] for patients with pre-existing large joint damage, pending further study. Exercise programmes should be individualised as much as possible taking into account individual patient and joint factors.

Linking powered by eXtyles [START_REF] Daltroy | Effectiveness of minimally supervised home aerobic training in patients with systemic rheumatic disease[END_REF] Pooled data of patients with RA and SLE Ekdahl et al. [START_REF] Ekdahl | Dynamic versus static training in patients with rheumatoid arthritis[END_REF] Baseline and final data not presented numerically Eversden et al. [START_REF] Eversden | A pragmatic randomised controlled trial of hydrotherapy and land exercises on overall well being and quality of life in rheumatoid arthritis[END_REF] Not dynamic exercise (hydrotherapy)

Hakkinen et al. [START_REF] Hakkinen | Effects of strength training on neuromuscular function and disease activity in patients with recent-onset inflammatory arthritis[END_REF] Mixed groups with RA and psoriatic arthritis Hakkinen et al. [START_REF] Hakkinen | Effects of concurrent strength and endurance training in women with early or longstanding rheumatoid arthritis: comparison with healthy subjects[END_REF] Healthy control group Hakkinen et al. [START_REF] Hakkinen | Effects of detraining subsequent to strength training on neuromuscular function in patients with inflammatory arthritis[END_REF] Mixed groups with RA and psoriatic arthritis Hall et al. [START_REF] Hall | A randomized and controlled trial of hydrotherapy in rheu matoid arthritis[END_REF] Not dynamic exercise (hydrotherapy)

Hansen et al. [START_REF] Hall | A randomized and controlled trial of hydrotherapy in rheu matoid arthritis[END_REF] Exercise programme not clearly described Lineker et al. [START_REF] Lineker | Improvements following short term home based physical therapy are maintained at one year in people with moderate to severe rheumatoid arthritis[END_REF] Details of intervention not given (follow up study of Bell et al. [START_REF] Bell | A randomized controlled trial to evaluate the efficacy of community based physical therapy in the treatment of people with rheumatoid arthritis[END_REF] )

Lyngberg et al. [START_REF] Lyngberg | The effect of physical training on patients with rheumatoid arthritis: changes in disease activity, muscle strength and aerobic capacity. A clinically controlled minimized cross-over study[END_REF] Numerical values, estimates of variability and p values not given for outcome measures Linking powered by eXtyles Marcora et al. [START_REF] Marcora | Can progressive resistance training reverse cachexia in patients with rheumatoid arthritis? Results of a pilot study[END_REF] Not randomised

Minor et al. [START_REF] Minor | Efficacy of physical conditioning exercise in patients with rheumatoid arthritis and osteoarthritis[END_REF] Mixed RA / osteoarthritis groups Minor, Hewett [START_REF] Minor | Physical fitness and work capacity in women with rheumatoid arthritis[END_REF] Not randomised Moffet et al. [START_REF] Moffet | Feasibility of an eight-week dance-based exercise program and its effects on locomotor ability of persons with functional class III rheumatoid arthritis[END_REF] Observational study (no control group)

Nordemar [START_REF] Nordemar | Physical training in rheumatoid arthritis: A controlled long-term study. II. Functional capacity and general attitudes[END_REF] Nordemar et al. [START_REF] Nordemar | Physical training in rheumatoid arthritis: a controlled long-term study. I[END_REF] Not randomised Noreau et al. [START_REF] Noreau | Effects of a modified dance-based exercise on cardiorespiratory fitness, psychological state and health status of persons with rheumatoid arthritis[END_REF] Not randomised

Neuberger et al. [START_REF] Neuberger | Effects of exercise on fatigue, aerobic fitness, and disease activity measures in persons with rheumatoid arthritis[END_REF] Observational study (no control group) Stenstrom et al. [START_REF] Stenstrom | Radiologically observed progression of joint destruction and its relationship with demographic factors, disease severity, and exercise frequency in patients with rheumatoid arthritis[END_REF] Not randomised Stenstrom et al. [START_REF] Stenstrom | Home exercise in rheumatoid arthritis functional class II: goal setting versus pain attention[END_REF] Intervention compared is cognitive therapy Stenstrom et al. [START_REF] Stenstrom | Home exercise and compliance in inflammatory rheumatic diseases--a prospective clinical trial[END_REF] Study group with mixed types of inflammatory arthritis van den Berg et al. [START_REF] Van Den Berg | Using internet technology to deliver a home-based physical activity intervention for patients with rheumatoid arthritis: A randomized controlled trial[END_REF] Internet study; primary outcome measure is physical activity

7 .

 7 Co interventions avoided or similar between groups 8. Presentation of point estimates and measures of variability for primary outcome measures 9. Drop out rate described and acceptable 10. Intention to treat analysis

A

  number of different exercise interventions were used in these studies, including aerobic fitness training, strength exercises, or combinations of both. With the exception of Bilberg et al.'s study 11 , which used moderately intense pool exercise, all exercises were performed on dry land.

  used largely aerobic interventions. Harckom et al. 20 studied 20 women with RA aged 27-68 years, of ARA functional class II for 12 weeks. Four intervention groups (3 exercise, 1 control) were used.

  used primarily strength training interventions. Hakkinen et al published five related papers on the effect of dynamic strength training on 70 patients (44 female) with early RA.

  years, and mean disease duration 12 years. Patients studied had "slight or moderate" disease activity. Patients with significant heart disease were excluded. The interventions were aerobic training on an ergometer, dynamic strength training exercises, and stretching exercises. Exercises were performed for 45 minutes, twice a week. Outcomes (swollen/tender joint counts, 30 metre walk time, grip strength, stair climbing, muscle strength, aerobic capacity, and ESR) were assessed after two weeks. In 1996 Van den Ende et al. reported a prospective randomised controlled study comparing four different exercise programmes in patients with stable RA , all lasting 12 weeks. 25 One hundred patients with RA (63 female), of mean age 52 yrs, and mean disease duration 10 years, were studied. Four intervention groups, each with 25 patients are described: high intensity exercise programme (HIE), low intensity group exercise (LIE-gr), low intensity individual exercise (LIE-ind), and a home exercise programme (HE) The following outcome measures were recorded at baseline, after the 12 week exercise programme and after another 12 weeks: aerobic capacity (VO 2 max), muscle strength, joint mobility (EPM-ROM score), functional ability (HAQ, Dutch-AIMS, timed 50 feet walk test, timed 10 flight up and down stair test), disease activity (0-20 swollen joint count, modified RAI 0-69, ESR, CRP), and patient VAS scores for pain, morning stiffness, and tiredness. In 2000 Van den Ende et al. reported a prospective randomised controlled study comparing intensive and conservative exercise programs in patients admitted to hospital because of active rheumatoid disease. 26 This is a very different patient group to most of the other studies where patients had relatively inactive disease. Sixty four patients, of mean age 60 years were studied. Mean disease duration was eight years. Active disease was defined by six or more swollen joints and at least two of: morning stiffness greater than 45 minutes, tender joint count greater than nine, ESR greater than 28. Patients were excluded if they had serious cardiorespiratory disease, knee arthroplasty, or were unable to walk 15 metres indoors. All patients had conservative range of motion exercises at low pace and isometric exercises of large joints without resistance, four times a week. In addition the intensive group also had isometric and isokinetic training of knee flexors and extensors. Intensive group patients also had isometric training of shoulder girdle muscles and performed cycling three times a week for 15 minutes to 60% of maximum heart rate. The mean admission length was 30 days. Patients were assessed at baseline, three, six, 12, and 24 weeks by an assessor blinded to study group. The primary outcome measure was the swollen joint count. Secondary outcome measures were tender joint count, ESR, DAS, patient pain VAS, knee extensor and flexor strength (isokinetic dynamometer), joint mobility (EPM-ROM scale), HAQ, timed 50 feet walk test, and grip strength (Martin vigorimeter). Westby et al. performed a prospective randomised 12 month study comparing weight bearing, aerobic exercise with usual care in women with RA on low dose oral steroids. 27 Thirty women with RA were studied, with a mean age of 56.2 years, functional class I or II, mean disease duration 156 months, and mean oral prednisolone dose of five mg/day. Patients were excluded if they had a known history of osteoporotic fractures, significant cardiovascular disease, planned or recent surgery, previous high dose steroid use, or methotrexate use. The intervention was an aerobic, weight bearing exercise programme three times a week lasting 45-60 minutes, for 12 months. The following outcome measures were assessed by a single rheumatologist, blinded to study group, at baseline and at 12 months: 70 joint swollen and tender joint count, ESR, bone density at lumbar spine and hip (Lunar DEXA) ,

Table 1 . Study Characteristics and Outcomes

 1

	Study	Participants	Intervention	Primary outcomes	Positive outcomes for	Quality
					exercise group	score / 10
	Bilberg et al. 11	47 stable RA	Moderately intense pool	VO 2 max, physical	Index of muscle function, chair	9
			exercises	SF-36	test, muscle endurance
			Duration: 12 weeks
	de Jong et al. 12	300 stable RA	RAPIT: cycling, circuits, game	MACTAR, HAQ,	MACTAR score, V02max,	9
			Duration: 2 years	Large joint Larsen	muscle strength, HADS score
	de Jong et al. 13	281 stable RA	RAPIT: cycling, circuits, game	Bone density	Hip bone density	9
			Duration: 2 years
	de Jong et al. 14	281 stable RA	RAPIT: cycling, circuits, game	Larsen score (hands &	Larsen score (feet)	9
			Duration: 2 years	feet)
	Hakkinen et al. 15	70 early RA	Home dynamic strength training	Muscle strength, bone	Muscle strength, ESR, HAQ,	6
			Duration: 12 months	density, DAS28, HAQ	DAS28,
	Hakkinen et al. 16	70 early RA	Home dynamic strength training	Muscle strength, bone	Hip bone density, HAQ, pain	6
			Duration: 2 years	density, DAS28, HAQ,	VAS
				Larsen (hands/feet)
	Hakkinen et al. 17	70 early RA	Home dynamic strength training	Valpar 9	None	6
			Duration: 2 years

Table 2 . Methodological Quality of Studies

 2

	Study	Adequate	Allocation	Groups	Eligibility	Description	Blinding of	Co-	Presentation of	Drop	ITT
		randomisation	concealment	similar at	criteria	of	outcome	intervention	point estimates	out rate	analysis
				baseline	specified	intervention	assessor	avoided	and measures
									of variability
	Bilberg et al. 11	Y	Y	Y	Y	Y	Y	Y	Y	Y	N
	de Jong et al. 12	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
	de Jong et al. 13	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
	de Jong et al. 14	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
	Hakkinen et al. 15	Y	U	Y	Y	Y	U	N	Y	Y	N
	Hakkinen et al. 16	Y	U	Y	Y	Y	U	N	Y	Y	N
	Hakkinen et al. 17	Y	U	Y	Y	Y	U	N	Y	Y	N
	Hakkinen et al. 18,19 Y	U	Y	Y	Y	U	N	Y	Y	N
	Harckom et al 20	Y	U	N	Y	Y	U	Y	Y	Y	U
	Komatireddy et al 21 U	U	Y	Y	Y	Y	U	Y	Y	N
	Lyngberg et al. 22	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
	McMeekin et al. 23	U	Y	Y	Y	Y	Y	Y	Y	Y	Y
	Melikoglu et al. 24	U	U	Y	Y	Y	Y	U	Y	Y	U
	Munneke et al. 10	Y	Y	N	Y	Y	Y	Y	Y	Y	Y
	Van den Ende et	U	U	Y	Y	Y	N	Y	Y	Y	Y

Table 3 . Excluded Studies Study Reason for exclusion

 3 Baslund et al.[START_REF] Baslund | Effect of 8 wk of bicycle training on the immune system of patients with rheumatoid arthritis[END_REF] Study group with mixed types of inflammatory arthritis Bearne et al.[START_REF] Bearne | Exercise can reverse quadriceps sensorimotor dysfunction that is associat ed with rheumatoid arthritis without exacerbating disease activity[END_REF] Control group of healthy subjects Bell et al.[START_REF] Bell | A randomized controlled trial to evaluate the efficacy of community based physical therapy in the treatment of people with rheumatoid arthritis[END_REF] Details of intervention not given Brighton et al.[START_REF] Brighton | The effect of a long-term exercise programme on the rheumatoid hand[END_REF] Non-dynamic hand exercises only Brus et al.[START_REF] Brus | Effects of patient education on compliance with basic treatment regimens and health in recent onset active rheumatoid arthritis[END_REF] Intervention is education; outcome is compliance with treatment Buljina et al.[START_REF] Buljina | Physical and exercise therapy for treatment of the rheumatoid hand[END_REF] Non-dynamic hand exercises only Daltroy et al.


Susanna Esposito

Fabrizia Corona

Annacarla Defilippi

Antonella Petaccia

Giovanna Chidini

Laura Dell'era

Jelena Bojanin

Edoardo Calderini

Nicola Principi
email: nicola.principi@unimi.it

WEGENER'S GRANULOMATOSIS PRESENTING WITH LIFE-THREATENING LUNG HEMORRHAGE IN A 7-YEAR-OLD CHILD

Keywords: Wegener's granulomatosis, severe respiratory distress, lung hemorrhage, crescentic glomerulonephritis

come

INTRODUCTION

Wegener's granulomatosis (WG) is an idiopathic systemic disease that is characterised by necrotising vasculitis predominantly involving the small vessels, associated with granulomatous inflammation, pauci-immune necrotising crescentic glomerulonephritis and, in most patients, antineutrophil cytoplasmic antibodies (ANCA) [START_REF] Savage | Primary systemic vasculitis[END_REF][START_REF] Sacco | Rapidly progressing pulmonary nodules in a 14 yr old boy[END_REF][START_REF] Akikusa | Clinical features and outcome of pediatric Wegener's granulomatosis[END_REF][START_REF] Ozaki | ANCA-associated vasculitis: diagnostic and therapeutic strategy[END_REF]. It usually onsets in adolescence and is rare in young children [START_REF] Sacco | Rapidly progressing pulmonary nodules in a 14 yr old boy[END_REF][START_REF] Akikusa | Clinical features and outcome of pediatric Wegener's granulomatosis[END_REF]. Its diagnosis is usually based on the presence of fever with arthralgia and weight loss, associated with symptoms of upper and/or lower respiratory tract and renal involvement [START_REF] Savage | Primary systemic vasculitis[END_REF][START_REF] Sacco | Rapidly progressing pulmonary nodules in a 14 yr old boy[END_REF][START_REF] Akikusa | Clinical features and outcome of pediatric Wegener's granulomatosis[END_REF][START_REF] Ozaki | ANCA-associated vasculitis: diagnostic and therapeutic strategy[END_REF]. Massive hemoptysis has been described with the other signs and symptoms and, when particularly acute, can be associated with a very poor prognosis [START_REF] Leavitt | The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis[END_REF][START_REF] Avital | Pulmonary haemorrhagic syndromes in children[END_REF][START_REF] Chan | Massive hemoptysis in an 11-year-old girl with isolated pulmonary arteritis[END_REF].

We describe the appearance of a life-threatening lung hemorrhage in the absence of hemoptysis in a 7-year-old girl with a completely negative previous clinical history, who was subsequently diagnosed as having WG.

CASE REPORT

This 7-year-old Caucasian girl with a completely negative previous clinical history was admitted to hospital after experiencing fever (maximum axillary temperature: 38.5°C) and a dry cough for two days. In the previous month, she had received a 10-day course of antibiotic treatment with oral amoxicillin-clavulanate 80 mg/kg/day (as amoxicillin) for acute otitis media. The admission physical examination showed she had a deep pallor, severe respiratory distress with shortness of breath (respiratory rate, 46 breaths per min; peripheral oxygen saturation -SpO 2 -87% in room air; arterial oxygen pressure -PaO 2 -73 mmHg in room air, chest pain and cough with the emission of apparently blood-free sputum, and a chest examination revealed coarse crackles in the lower part of the left and the middle part of the right lung. Laboratory tests indicated a hemoglobin concentration of 8.3 g/dL and C-reactive protein (CRP) levels of 12.8 mg/dL. Her cardiac function, and the size of her liver, spleen and lymph nodes were normal. A chest roentgenogram revealed bilateral patchy alveolar infiltrates (Fig. 1) and suggested a diagnosis of severe community-acquired pneumonia, for which combined antimicrobial therapy with intravenous cefotaxime 100 mg/kg/day and oral clarithromycin 15 mg/kg/day was started together with oxygen supplementation.

During the following hours, she showed increasing respiratory failure (56 breaths/min, SpO 2 81% and PaO 2 66 mmHg) despite oxygen administration, and auscultation of both lungs demonstrated a significant breath reduction. After 12 hour since hospitalization, hemoglobin concentration was 5.6 g/dL and CRP was 19.1 mg/dL. Moreover, laboratory data regarding renal function showed a slight decrease decrease in creatinine clearance (76 mL/min), and urinalysis was positive for proteinuria (1.56 g/24 hrs) and microhematuria.

Taking in account the concomitant loss of more than 2.5 g/dL of hemoglobin in 12 hours and progressive respiratory failure as well as renal involvement, the suspicion of diffuse alveolar hemorrhage occurring as a result of the inflammation of capillaries was raised. The child was immediately transferred to our pediatric intensive care unit where she was intubated and mechanical ventilation was started. A further chest roentgenogram revealed the progressive involvement of both lungs and, in addition to confirming these findings, a high-resolution chest CT scan showed widespread interstitial involvement (Fig. 2). Bronchoscopy was immediately performed and examination of the bronchoalveolar lavage fluid confirmed the presence of a diffuse alveolar hemorrhage syndrome with a characteristic increasingly bloody return in the sequential aliquots and a red blood cell count of 236,000 cells/µL. Subsequenly available laboratory tests showed After the transfusion of several units of packed red blood cells, she was administered steroid therapy with prednisone (1 mg/kg/day) and intravenous-pulse cyclophosphamide (20 mg/kg/month). Mechanical ventilation was required for two days and after only four days of treatment, radiographic checks of her lungs showed a progressive reduction in pulmonary infiltrates.

A further reduction was found one month later and no pulmonary abnormality was observed at the chest CT scan after 3 months.

After six months of therapy, the girl is in good clinical condition with normal lung function and a significant reduction in renal involvement.

DISCUSSION

This report is justified by the peculiar clinical presentation of WG. WG is a severe disease that is very rare in children aged less than eight years, and it usually has a relatively progressive course, with recurrent episodes that increasingly involve the upper and/or lower respiratory tract and the kidney, accompanied by fever, arthralgia and weight loss [START_REF] Savage | Primary systemic vasculitis[END_REF][START_REF] Sacco | Rapidly progressing pulmonary nodules in a 14 yr old boy[END_REF][START_REF] Akikusa | Clinical features and outcome of pediatric Wegener's granulomatosis[END_REF][START_REF] Ozaki | ANCA-associated vasculitis: diagnostic and therapeutic strategy[END_REF]. Hemorrhagic pulmonary involvement at presentation is not uncommon but usually it is accompanied by hemoptysis and by signs and symptoms of systemic involvement lasting for several weeks. In our case, on the contrary, the previous clinical history was completely silent, the period of incubation very short and the sudden diffuse alveolar hemorrhage syndrome leading to severe respiratory distress and profound anemia occurred in absence of hemoptysis. To the best of our knowledge, the most recent literature mentions only one case of WG presenting with life-threatening pulmonary hemorrhage in a 14year-old boy with type 1 diabetes [START_REF] Lorini | Wegener's granulomatosis presenting with life-threatening pulmonary hemorrhage in a boy with type 1 diabetes[END_REF]. This can explain why the initial diagnosis was only that of severe community acquired pneumonia and why the suspicion of diffuse alveolar hemorrhage due to capillaritis was made only some hours later when the drop in hemoglobin level occurred and the kidney involvement was demonstrated. Only the detection of c-ANCA in the serum and the result of renal biopsy finally permitted to define that the child was suffering from WG.

An acute diffuse alveolar hemorrhage can be a symptom of various syndromes, with or without histological evidence of pulmonary capillaritis (PC). PC can be an idiopathic or part of a more complex syndrome, such as microscopic polyangiitis, Churg-Strauss syndrome, systemic lupus erythematosus, Goodpasture's syndrome, polyarteritis nodosa, retinoic acid use and, finally, WG [START_REF] Susarla | Diffuse alveolar hemorrhage syndromes in children[END_REF]. Among acute diffuse alveolar hemorrhage syndromes without capillaritis both cardiovascular and non cardiovascular diseases are included. The most common are idiopathic pulmonary emosiderosis, cow's milk hypersensitivity and acute idiopathic pulmonary hemorrhage of infancy.

Differential diagnosis among all these illnesses is not easy, although in all the cases without PC renal manifestations are absent and systemic signs and symptoms are mild or present only when cardiovascular disorders are the cause of the alveolar hemorrhage. The rarity of these conditions in children often makes diagnosis and treatment difficult, and the prognosis is uncertain; however, they can have different prognoses and may need different therapeutic approaches [START_REF] Fullmer | Pulmonary capillaritis in children: a review of eight cases with comparison to other alveolar hemorrhage syndromes[END_REF]. This means that every alveolar hemorrhage syndrome needs a specific diagnostic approach to allow the best final prognosis. This is particularly important when WG is the cause of PC because early death is considerably more common in patients who initially present with alveolar hemorrhage, both due to the seriousness of the condition and to secondary infections cause by the immunosuppressive treatment used. However, renal involvement even if previously unknown and demonstrated only by a slight decrease in creatinine clearance as well as by mild proteinuria and hematuria at the urinalysis, can be very useful to direct the physician to the correct diagnosis. The presence of c-ANCA permits to solve the problem, although unfortunately not all the cases of WG are positive for ANCA and in these cases only the combination of clinical signs and symptoms together with bioptic findings permit the diagnosis. On the other hand, WG classification requires the presence of three out of six criteria [START_REF] Leavitt | The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis[END_REF][START_REF] Ozen | EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides[END_REF] and our patient showed the presence of four of these features (abnormal urinanalysis, granulomatous inflammation on biopsy, abnormal chest radiograph and CT, PR3 and c-ANCA staining). Considering that the required criteria were positive, no further biopsy has been performed.

Our case shows that, in the presence of severe respiratory distress and bilateral lung as well as renal involvement, even if without hemoptysis, immediate bronchoscopy with bronchoalveolar lavage is advisable and, if a diffuse alveolar hemorrhage syndrome is demonstrated, WG should be considered among the main causes even if the patient is a relatively young child with an unsuggestive clinical history. Obviously, before beginning immunosuppressive treatment, the clinical suspicion needs to be confirmed by specific laboratory findings, such as the presence of c-ANCA and PR3 ANCA as well as a positive lung or renal biopsy. Awareness of the possible association of acute alveolar hemorrhage with WG can lead to early intervention and a better final prognosis.

  cytoplasmic ANCA and anti-proteinase 3 ANCA positivity (c-ANCA, titre 1:320; PR3 ANCA, titre 19.1 ELISA units), without perinuclear ANCA (p-ANCA), anti-nuclear, anti-DNA, antiphospholipid or anti-glomerular basement membrane antibodies, or rheumatoid factor. A renal biopsy revealed crescentic glomerulonephritis, vasculitis and granulomatous inflammation. All the tests for viral (cytomegalovirus, Epstein-Barr virus, herpes viruses, influenza viruses, parainfluenza viruses, metapneumovirus, Adenovirus, respiratory syncytial virus, human immunodeficiency virus), bacterial (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes, Mycoplasma pneumoniae, Chlamydophila pneumoniae), and fungal (Candida spp., Aspergillus spp.) pathogens performed in blood and respiratory secretions resulted negative. Both polymerase chain reaction and serum antibody determination were negative for infectious etiology. All these findings drove us the diagnosis of WG and no further biopsy has been performed.

Figure 1 .

 1 Figure 1. Chest roentgenogram upon admission showing bilateral patchy alveolar infiltrates.

Figure 2 .

 2 Figure 2. High-resolution chest CT scan showing the presence of confluent exudates with air

Figure 1 Figure 2

 12 Figure 1

ACKNOWLEDGMENTS

We would like to thank the parents of the child for their conset to the publication of this report.

DISCLOSURES

No author has any commercial or other association that might pose a conflict of interest.


J Teichmann
email: j.teichmann@st.josefskrankenhaus.de

M J Voglau

U Lange

Dr.med Joachim Pd

Teichmann

metabolism in ankylosing spondylitis and psoriatic arthritis

Keywords: anti-human-t issue-Transglutaminase IgA, vitamin D metabolites, Ankylosing Spondylitis, Psoriatric A rthritis

Objectives: Both in Ankylosing Spondylitis (ASP) and Psoriatic Arthritis (Ps A), osteopenia is present in onethird of women and men, whereas osteoporosis mainly affects men, even in their 30s. Subclin ical gut inflammat ion has been described in patients with AS or PsA. Joint involvement also occurs with other gastrointestinal diseases such as celiac disease. We tested the hypothesis, whether elevated serum levels of human anti-tissue-Transglutaminase-IgA (htTG) are associated with changes in disease activity, vitamin D metabolism and bone mineral density (BMD) in patients with ASP and PsA..

Methods:

In a cross-sectional study, we evaluated both biochemical markers of bone turnover, BMD and htTG in 76 patients with ASP and 120 patients with PsA..

Results:

A reduction of BMD in lu mbar spine was determined both in ASP (42.7%) and in PsA (57.3%).

Furthermore, a significantly higher prevalence of htTG was detected only in ASP (14/76). ASP-patients with negative htTG status have significant higher 25-vitamin D3 levels. ASP-patients with positive htTG status are younger.

Conclusion:

A positive htTG status entails the risk of a bad vitamin D supply, which should be considered in young patients since this constellation favours a reduction in bone density. The coincidence of ASP along with detection of htTG and clin ically asympto matic celiac disease as an accessory source of inflammation with a negative influence on the bone metabolism is also conceivable. Clinicians need to be aware of patients younger than 45 years with ASP, wh ich have important imp licat ions for the correct treatment and vitamin D supplementation.

INTRODUCTION

Patients with both Ankylosing Spondylitis (ASP) and Psoriatric Arthritis (PsA) have local and systemic bone loss, and may be at an increased risk of suffering fro m bone fractures [1 -4]. Various factors such as treatment, hormone disorders, and decreased mobility or physical activ ity may contribute to development of osteopenia (osteoporosis in ASP and PSA [START_REF] Zonneveld | Methotrexate osteopathy in long-term, low-dose methotrexate treat ment fo r psoriasis and rheumatoid arthritis[END_REF][START_REF] Walsh | Bone loss in inflammatory arthrit is: mechanis ms and treatment strategies[END_REF]. A prospective study demonstrated a significant loss of bone mass in early ASP with strong association with inflammation activity [START_REF] Hahn | Modulation of monocyte activation in patients with rheu matoid arthrit is by leukapheresis therapy[END_REF]. Celiac disease is a gluten sensitive enteropathy charactericed by a wide spectrum of clin ical man ifestations, such as diarrhoea, weight loss, anaemia and herpetiform dermatit is. Most of these are related to malabsorption which may be limited to one or a few nutrients up to a complete malabsorptive syndrome. Ho wever, joint involvement e.g. in sacroiliac jo ints has also been reported related to celiac disease [START_REF] Lubrano | The arthritis of coeliac disease: prevalence and pattern in 200 adult patients[END_REF].

In this cross sectional study we tested the hypothesis, weather positive htTG status is associated with alterations of vitamin D metabolis m, osteoporosis/osteopenia, marker of inflammat ion, age of patients and HLA B 27 marker in a large and well-characterized cohort of patients with ASP or PsA.

PATIENTS AND METHODS

Seventy six patients with ASP as defined by the New York clin ical criteria [START_REF] Moll | New York clin ical criteria for ankylosing spondylitis (1973) A statistical evaluation[END_REF] (age range 19 -58 years, mean 49.5 years, duration of disease 1 -34 years, mean 19.3 years) and 116 patients with PsA as defined by the Classification of Psoriatic Arthritis -CASPA R [START_REF] Taylor | CASPAR study group. Classification criteria for psoriatic arthritis: develop ment of new criteria fro m a large international study[END_REF] (age range 22 -61 years, mean 50.7 years, duration of disease 1 -24 years, mean 17.1 years) were studied from March to November 2005. All the wo men were premenopausal with a physiologic sexual hormone status. A selective IgA-deficiency was excluded. Seru m creatinine levels were normal in the entire study population. Criteria for exclusion were the presence of inte stinal disease (terminal ileit is, ulcerative colit is), malnutrition, maras mus and drug intake known to affect bone metabolism and the endocrine system. All study persons had been physically active twice a week during the preceding 12 month.

A medical history was obtained, 61 of 76 ASP patients and 107 of 116 PsA patients received intermittent nonsteroidal antirheumatic (NSAID) therapy in the previous 12 months. No patient was receiving glucocorticoid med ication at the time of the study, only 7 patients had received such medication for a short time in the past (10 mg /day for 2 -3 months during the disease duration) 32 PsA patients got a disease modify ing medicat ion at the time of the study (methotrexate 15 mg weekly in 24 cases and sulfasalazine in 8 cases ).

Disease status in terms of d isease activity, disease progression and prognosis, is difficult to define in ASP and PsA. We used C-react ive protein, and the Westergren erythrocyte sedimentation rate (ESR).

BIOCHEMICAL MEASUREMENTS

Blood examp les were taken fro m all participants every morning at the same fixed t ime. The collected serum samples were immed iately stored in aliquots at -20°C in our serum bank before testing. Informed consent was obtained before blood sampling. The specific serum parameters of this study were calcitriol ("1,25 (OH)2 Vitamin D"-kit fro m Biermann Bad Nauheim, Germany); and calcefediol ("25 (OH) Vitamin D"-kit fro m Biermann Bad Nauheim, Germany)mun Diagnostik, Bensheim, Germany; co mpetitive protein -b inding-assay).

The Microtiter ELISA was intended for the determination of human anti-t issue-Transglutaminase-IgA (htTG) antibodies in serum (Euroimmun Medizinische Labordiagnostik A G, Lübeck, Germany ). (Expected value: htTG IgA Seru m cut off > 22 A U/ ml positive. htTG IgA .Seru m cut off < 16 A U/ ml negative. Results between 16 -22 AU/ml are in the grey range). C reactive protein (CRP; normal range: < 5 ng/l, immunonephelometry using Behring Nephelo meter Systems, N Latex CRP mono, Behring Diagnostics, Marburg, Germany).

ASSESSMENT OF BONE MINERAL DENSITY

BMD was measured at the lumbar spine and the left femoral neck by dual-energy X-ray absorptiometry (DEXA) using Prodigny Lunar (Milwaukee, WI). The coefficient of variation of repeated measurements was 0.9% for the lu mbar spine and 1.6% for the femoral neck. Osteopenia (T-score between -1.0 and -2.5) and osteoporosis (Tscore below -2.5) were defined according to the criteria of the World Health Organizat ion.

STATISTICAL ANALYSIS

Results are presented by mean values and standard deviation. The following methods were applied for statistical analysis: a single factor variance analysis, the exact Fisher's -Test and the Mann-Whitney-U-Test. The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) fo r Windows [START_REF] Bühl | SPSS für Windows Version 6[END_REF].

RESULTS

In comparison with the PsA group (n = 4), ASP patients (n = 14) showed significantly higher prevalence of htTG antibodies in serum. In 18 of 196 (9.81) patients we found positive htTG antibodies in serum (Table 1). However, we found no statistically significant association of positive htTG antibodies with the biochemical markers of inflammat ion: CRP and ESR (Table 2). Measurement of BM D of ASP and PsA patients revealed osteoporose in 35/76 patients (42.7% ) and 47/120 (57.3%). No associations were found between ASP or PsA and osteoporose (p value of exact Fisher's Test p= 0. 374) or positive htTG antibodies in ASP or PsA and osteoporose (p value of exact Fisher's Test p= 0.130). Finally, in ASP patients HLA B 27 marker is not associated with positive htTG antibodies.

Seru m levels of both 25 (OH) D3 and 1,25 (OH)2 D3 in the combined cohort of female and male patients with PsA were higher compared with the ASP group. (Table3). The 25 (OH) D3 levels in PsA were significant highered compared to those of ASP (p < 0.0005). Pooled cohort of patients both with ASP and PsA showed a statistically significant negative correlat ion between CRP and 25(OH) D3 levels (p < 0.0005); (Tab le 4).

In patients with positive htTG antibodies the mean of 25 (OH) D3 levels was 17.4 ng/ml whereas patients with negative htTG antibodies presented 41.5 ng/ml. (Table 5). This difference was statistically significant (p < 0.005). There was a similar trend in 1,25 (OH)2 Vitamin D3 but without any statistical significance (p = 0.274).

Patients with positive htTG antibodies were younger than those of a negative antibody titre. More than 61 % of the ASP and PsA patients with positive htTG antibodies were younger than 45 years (Table 6).

DISCUSSION

The aim of our study was to find unidentified or neglected cases of positive htTG antibodies by using serological screening in a large and well-characterized cohort of patients with ASP or PsA. In 14 / 76 ASP patients, positive htTG antibodies in serum were detected. In the consecutive endoscopy none of these patients presents the typical villous atrophy with crypt hyperplasia in small bowel biopsy specimen, which confirmed the diagnosis of celiac disease according to Marsh criteria [START_REF] Marsh | Studies of intestinal ly mphoid tissue. XIV--HLA status, mucosal morphology, permeability and epithelial ly mphocyte populations in first degree relatives of patients with coeliac disease[END_REF]. Therefore we had to discuss possibly the elevated prevalence of positive htTG antibodies in ASP and PsA patients as a part of an autoimmune overlap syndrome.

There are conflicting data about autoimmune d isorders and both htTG antibodies and celiac d isease. Kallikorm et al. found an association of seronegative spondylarthropathy with celiac d isease in one patient out of 74 [START_REF] Kallikorm | Coeliac disease in spondyloarthropathy: usefulness of serological screening[END_REF] Altogether, 74 patients (28 females and 46 males, fro m15 to 72 years of age, mean age 40.4 + 1.6 years) with seronegative spondylarthropathy were examined. Of these, 23 patients had reactive arthritis, 12 Reiter's syndrome, 11 PsA, 18 ASP and 10 undifferentiated spondylarthropathy . From this reason our results may differ, too. The study of Riente et al. failed to show an increased prevalence of autoantibodies associated with celiac disease in patients with ASP or PsA [START_REF] Riente | Antibodies to tissue transglutaminase and Saccharomyces cerevisiae in anky losing spondylitis and psoriatic arthritis[END_REF]. The prevalence of previously undiagnosed celiac disease, tested serologically with endomysial antibody, in rheumatoid arthrit is is 0 in 160 patients [START_REF] Francis | The prevalence of coeliac d isease in rheumatoid arthritis[END_REF].

Given the conflict ing results of our study and Riente's and Kallikorm's group, the estimat ion of htTG antibodies in serum of patients with seronegative spondylarthropathy including ASP or PsA differed possibly by the used ELISA or other laboratory methods. In Kallikorm's study IgA-type endomysium-antibodies were measured by an immun fixation method, using cryostat sections from hu man umb ilical cord as the antigen substrate [START_REF] Kallikorm | Coeliac disease in spondyloarthropathy: usefulness of serological screening[END_REF]. The available ELISA based on the commercial guinea pig tTG antigen may possibly detect antibodies that are non specific for celiac d isease, and hence a test based on pure human tTG may yield increased specificity.

What were the clinical consequences of positive htTG antibodies in patients with ASP or PsA? We were able to present both a serological observation and a functional link between positive htTG antibodies and alterations of the vitamin D metabolis m. Our ASP patients have been shown expressed both a higher prevalence of positive htTG antibodies and lowered levels of 25 (OH) D3. Co mpared to recent studies, the prevalence of osteopenia and osteoporosis was highest in newly diagnosed celiac patients and in patients with disease not in remission. A low 25 (OH)D3 vitamin concentration was a typical biochemical abnormality in celiac patients (64% of men and 71% of wo men) [START_REF] Challa | Osteoporosis in adult patients with celiac d isease[END_REF].

Vitamin D metabolites have important functions in regulating inflammatory processes and act on both types of bone cells: osteoblasts and osteoclasts. Furthermore, decreased levels of 1,25 (OH)2 Vitamin D3 in ASP patients may induce a reduction in intestinal calcium absorption and periods of disease activity may contribute to a further acceleration of a pre-existing negative calciu m balance. Lo wered levels of 1,25 (OH)2 Vitamin D3 as an endogeneous immune modulator suppressing activated T cells and the proliferation of cells may accelera te the inflammatory process. [START_REF] Lange | Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spond ylitis[END_REF]. However, 25 (OH) D3 have been shown to be within normal range in ASP patients in the Lange study [START_REF] Lange | Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormone in ankylosing spond ylitis[END_REF]. The addit ional positive htTG antibodies in ASP patients of our study were directly related to lowered 25 (OH) D3. The cohort of PsA patients with a small nu mber of positive htTG antibodies presented marked ly elevated levels of 25 (OH) D3. The immune response is more severe expressed in younger ASP patients with additional positive htTG antibodies . However, the younger patients with ASP were well characterized with higher physical activity and longer sun light exposure. Therefore, these patients were able to compensate for lower 25 (OH) D3 and presented 1,25 (OH)2 Vitamin D3 within the normal range.

The major aim of this study was to define whether serum measurement of htTG antibodies, which can easily be performed in daily clinical pract ice, had a diagnostic or predictive value regarding vitamin D metabolism in patients suffering fro m ASP or PsA. Based on our results, we conclude that the assessment of htTG in ASP may be of interest fro m a pathophysiological point of view; however its role in clinical routine as a biochemical marker remains questionable [START_REF] Armagan | Serological screening for celiac disease in premenopausal women with idiopathic osteoporosis[END_REF].

Acknowledgements: Special thanks to Jörg Reitze (M ORE-Data, 35390 Giessen, Germany) for assistance with the statistical analysis. D3 in the combined cohort of female and male patients with PsA and ASP.

Disclosures

Table 5 :

 5 Association of positive htTG antibodies with 25 (OH) D3 and 1,25 (OH)2 D3 in the combined cohort of female and male patients with PsA and ASP. (The number of estimated Vitamine D metabolites differed from total number of patients because of haemolytic probes).

Table 1 :

 1 : htTG status in 196 patients with ASP or PsA

	Potential (financialI conflicts of interests:	PD Dr.med. Joachim Teich mann: none
		Dr.med. Markus Voglau:	none
		Prof. Dr.med. Uwe Lange:	none

Table 2 :

 2 Association of positive htTG antibodies with the biochemical markers of inflammation: CRP

	and ESR
	CRP	Mean Value Std. Dev.	N Min Max	MV ranks
	htTG neg.	3.81	8.20	178 0 76,3	96.29
	htTG pos.	6.36	9.58	18	0 38,0	120.36
	ESR	Mean Value Std. Dev.	N Min Max MV ranks
	htTG neg.	16.66	13.51	178 1	100	98.44
	htTG pos.	17.50	14.16	18	2	47	99.08
	p-value of Mann-Whitney-U-Tests concerning differences in means of ranks:
	CRP: p=0,085; ESR: p=0,963.

Table 3 :

 3 Serum levels of both 25 (OH) D3 and 1,25 (OH)2 D3 in the combined cohort of female and male patients with PsA and ASP. (The numbers of estimated Vitamine D differ from total number of patients because of haemolytic probes).

	1,25 (OH)2 D3 [pg/ml]	Means	Std. Dev.	N	Min Max	MV ranks
	PsA	41.523	38.099	115	1	350	66.73
	ASP	42.520	53.7	15	2	220	56.10
	25 (OH) D3 [ng/ml]	Means	Std. Dev.	N	Min Max	MV ranks
	PsA	48.403	46.359	119	0	219	114.10
	ASP	24.935	32.114	76	1	250	72.80

Table 4 :

 4 Inverse correlation (Spearman's Rankcorrelation Test) between ESR/CRP and 25 (OH)