Rheumatoid Arthritis Physiology

Introduction
Rheumatoid Arthritis (RA) is defined as a chronic, autoimmune condition that affects 400,000 people in the UK (Cooney et al. 2010). It is both bilateral and symmetrical in pattern and is typically presented in individuals between 30 to 50 years with females being more afflicted than men (Cooney et al. 2010).
Although, RA is of unknown aetiology, causes are said to be both genetic and environmental in nature (Abhishek et al.2010). More specifically, inflammation, inactivity and loss of mechanical stability around joints plays a role in causing pain, stiffness and swelling of multiple joints. Consequently, long-term effects of RA been associated with reduced muscle strength (Ekbolm et al. 1974) and aerobic capacity (Minor et al. 1988).

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Currently, there is no cure for RA and therefore, management emphasizes on decreasing symptoms and promoting quality of life through either Drug Modifying Anti-Rheumatic drugs (DMARD’s) or physiotherapy (Arthritis Research, UK). Indeed, DMARD’s are a first line treatment for RA; however, not everyone responds adequately to DMARD’s (Smolen and Keystone, 2012) and RA patients usually refrain from using this due to the potential occurrence of life-threatening side-effects (Kinder et al. 2005).
Today, physiotherapy for those with RA consist of many passive interventions such as patient education, delivery of heat or cold, massage and electro-magnetic energy (Wasserman,2011). However, despite earlier fear of aggravation of symptoms, increased disease activity and joint damage, there is now scientific evidence showing that exercise is safe and beneficial; making it an imperative part of rehabilitation (Stenstrom and Minor, 2003).
Specifically, the most valued by RA patients is Hydrotherapy treatment (Hall et al. 1996) due to its ability to alleviate symptoms suddenly through exercising in water. The use of water properties such as buoyancy and warm temperatures enables patient’s to move freely through decreased weight bearing on joints, increased range of motion and reduced pain (Campion, 1997). Although, Hydrotherapy is growing significantly in popularity, literature in regards to the effectiveness of Hydrotherapy for RA has not been evaluated adequately.
For example, Eversden et al. (2007) concluded that the Hydrotherapy group reported a greater perceived benefit in comparison to the land-based exercise group after six weeks.
Importantly, these authors conducted a fairly well-designed study in that they took some precautions to eliminate bias through true randomization and concealment processes. However, these findings were not reflected in the physical functional or pain scores. Alongside this, there was a greater number of participants in the Hydrotherapy group compared to the Land-based group leading to potential biases.
Secondly, Hall et al. (1996) found that all groups assessed (Hydrotherapy, Seated Immersion, Land Exercise and Progressive Relaxation) demonstrated joint tenderness and pain relief. However, Hydrotherapy presented the most improvements (26% mean decrease) after 4 weeks treatment.
This study demonstrates strengths over Eversden et al. (2007) in that they had assessed disease activity rather than just improvements in functionality. However, it was not clearly stated whether or not improvements in Hydrotherapy group were statistically significant and treatment dosage, if longer (>4 weeks) could have produced a greater therapeutic effect.
Thirdly, Bilberg and Mannerkorpi (2005) found significant improvements in muscle function and endurance of upper and lower extremities and grip force. However, this was not supported by an increase in aerobic capacity as indicated by their hypothesis and primary outcome measure (Cycle Ergometer Test; Astrand 2006). Unlike, Eversden et al. (2007) and Hall (1996) this study reported intensity of exercise (70% of HR) and addressed longer term effects (12 weeks). However, sample size was small (46 patients) and temperature of pool was not specified, making it difficult to generalise data.
Overall, there was inadequate reporting of depth, temperature of pool, type and intensity of exercises. Although, outcome measures differed between studies, they were appropriate for use (Al-Qubaiessy et al). Therefore, there is some evidence showing that Hydrotherapy plays a role in reducing pain (Hall et al. 1996). Finally, this highlights the importance of using standardised exercise procedures, longer term-interventions especially as RA is a chronic condition. This will help in making specific recommendations.
Therefore, in accordance to PICO, my research question is ‘The long term effects of using specific Hydrotherapy exercise protocols: Aqua-Aerobics Programme and The Bad-Ragaz Ring Methods for RA. A randomized Controlled Trial’.
Research Design
From a pragmatic viewpoint, a mixed methods approach will be best-suited for this study as pain is a multi-dimensional phenomenon.
However, a positivist would argue that this study should be carried out only objectively as this would allow generalizable conclusions to be drawn (Brooms and Willis, 2007). Alongside this, they would argue that researchers are detached from the investigation, thereby reducing bias (Bryman, 2004). Contrastingly, an interpretivist would support a qualitivate approach which would allow greater and richer insight into patient’s perceptions of pain (Bryman, 2001).
Therefore, yielding both qualitative and quantitative data will help increase findings and reliability of results (Bryman, 2004). For example, this study will be able to assess the subjective nature of pain whilst still observing the relation between pain and disease activity objectively. Thus, taking this stance, will allow to address the biopsychosocial approach rather just a biomedical model of care objectively (Engel, 1977).
Finally, an experimental, embedded design will be used in this study. Alternatively, an interpretivist would use a case-study that assesses an individual’s experiences; this will have high ecological validity but lacks the ability to produce generalizable conclusions.  By employing a multi-faceted approach, it will strengthen causal inferences by providing the opportunity to observe data convergence or divergence in hypothesis testing (Abowitz and Tool, 2010).
Research Method
In line with Rogers et al. (2003), the embedded experimental design utilised in this study will involve a two-phase sequential approach (Creswell et al. 2005). This will include qualitative analysis carried out before intervention to inform the development of the treatment and after to help explain treatment outcomes (Figure 1).

Figure 1: Experimental Embedded Design. (Creswell 2005).
Alongside this, an RCT will be used. In accordance to the hierarchy of evidence an RCT is suggested to be one of the most powerful in research (Akobeng, 2005) due to its ability to reduce risk of bias and systematic error (Bryman, 2004; Suresh, 2011). Contrastingly, a cross-over design would be difficult due potential carry-over effects even with a washout period (Saks and Allsop, 2013).
Intervention Details
The CONSORT statement will be used in order to enhance completeness and transparency of the study (Schulz et al. 2010). For example, attrition bias will be reduced through reporting drop-outs and reasons for this will also be included (Schulz et al. 2010).
Reporting of eligibility criteria is essential to determine whether results can be applied to others in the same condition (Bluml et al. 2011).  In this instance, patients (men and women) aged 18+ (in line with the American College of Rheumatology) with chronic RA who meet Steinbrocker Functional Class I, II, or III (Steinbrocker, 1949) will be recruited from NHS outpatient settings in the West Midlands.
Those who sustain a steady drug intake for 30 days in relation to Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) & 3 months and DMARD’s will be included in the trial. Although injections and corticoid injections in the 4 weeks leading up to the study will not be permitted, drug changes and injections will be during; this reflects the pragmatic nature of this study. Consequently, recruiting in this manner will increase ecological validity as it represents a real-world situation (Broom and Willis, 2007).
Those, which have received physiotherapy treatment within 30 days of assessment will be excluded in order to avoid any carry over effects. Also, patients who have had joint-replacement surgery within the last 6 months will be excluded. Likewise, contraindications of exercise and immersion in water needs to be taken into account (e.g. patients with uncontrolled epilepsy or fear of water) will also be excluded.
It is true that greater exclusion criteria can reduce generalisability of results. However, such steps have to be taken in order to eliminate occurrence of confounding data which could potentially have a negative impact on the results of the clinical trial (Broom and Willis, 2007)
Group Details
Patients will be randomized using sealed opaque envelopes with treatment allocation. Random sequence of numbers will be established through flipping a virtual coin (Eversden et al. 1996) to either:

Hydrotherapy 1 (Aqua Aerobics Group) (Eccentric, Concentric Exercises).
Hydrotherapy 2 (The Bad Ragaz-Ring Group).
Home-Exercise group that continue with daily activities.

Unlike previous research (e.g. Hall 1996; Eversden et al. 1996), this study will consider intensity at moderate level (70%) as it has been shown to demonstrate physiological improvements (Astrand, 1986); assessed via a heart rate monitor throughout sessions. Additionally, depth of pool will be just under chest height whereby 50%+ of bodyweight is offloaded through buoyancy and hydrostatic pressure has been suggested to reduce swelling at this level (Becker, 2009). Importantly, temperature will range from 33.5-35.5 degrees which is safe and sufficient enough to produce therapeutic benefits (Becker, 2009). Finally, treatment dosage will be twice a week consisting of 30 minute sessions for a 20 week period. This will address longer-term effects.
Outcome Measures
A research assistant blinded to the treatment allocations will evaluate the outcomes measures in order to reduce detection bias. Bilberg and Mannerkorpi (2005) used a C Reactive Protein (CRP) (i.e. higher levels demonstrates active inflammation) in order to test assess disease activity. However, it is said that more than 40% of RA patients have normal CRP levels (Sokka and Pincus, 2009), thus decreasing validity and clinical applicability. Therefore, this study will use Magnetic Resonance Imaging (MRI) as the primary objective measure due its ability to present visual aspects of inflammation within the synovial membrane; shown to be a superior method and very relevant for RA (e.g. Østergaard, 2009) (Figure 1). This will be taken, baseline and post treatment for all groups.
Secondary outcome measures will include Visual Analogue Scale (VAS) (Figure 1) assessed on a 10cm scale, whereby 0cm indicates no pain. This is widely used to assess rheumatic diseases and a number of studies have established data showing that VAS results are very reproducible (e.g. Dixon and Bird, 1981).  Other physical measures will include the Ritchie Articular Index in order to assess joint tenderness; intra-reliability of this test has been shown to be acceptable (Levy and Dick, 1975) and is easy to perform. Finally, aerobic capacity will be analyzed through a submaximal test in accordance to Astrand’s Principle (Astrand and Rodahl, 1986); shown to have satisfactory reliability in RA populations (e.g. Mannerkorpi and Ekdahl, 1997). Both of which taken pre-post.
Statistical Considerations and Analysis
Analysis will be completed via the Fisher’s exact test and continuous variables by Wilcoxon signed rank tests for within group comparisons. Importantly, data analyses will be completed according to the intention to treat principles.
Ethical Considerations
In line with Beauchamp and Childress (2001) it will be essential to have respect for autonomy. Respecting this value, means to protect participants through data protection/confidentiality and ensuring they are adequately informed about what is proposed. In order to keep data anonymised personal details of quantitative data sets will be replaced with numbers. Most importantly, informed consent will be obtained before commencing the study to ensure participants are not subject to an intervention they do not want. To further fulfil these requirements, an information sheet for participants will be written which will also state risks as well as what data will be used for.
Conclusion
The main advantage of this study is that is assesses disease activity on a physiological level objectively and also observes the impacts subjectively via VAS scale; an unpopular approach in the Hydrotherapy literature (E.g. Hall, 1996, Bilberg et al. Eversden et al, 2007). Findings from this study, will hopefully assist in creating structured and standardised exercise programmes that could be used throughout healthcare systems. Finally, limitations of this study include the high costs that are associated with MRI scans and Hydrotherapy facilities. Nevertheless, this will address the longer term effects of Hydrotherapy for RA.
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