Rheumatologic conditions featuring systemic inflammation are characterised by
profound loss of physical function, which is in part caused by skeletal muscle wasting.
This thesis aims to add to the current knowledge on disability in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) by determining the physiological properties of the tendon-muscle complex in these conditions, and by investigating causes of muscle loss in RA at the cellular level.
The results section is divided into five main research chapters (chapters 3 to 7).
Chapter 3 reports that physiological properties of muscle that determine specific force are preserved in a community-based population with stable RA compared to a healthy age- and sex-matched control group. Despite having deficits in physical function, no differences in vastus lateralis (VL) specific force, contractile properties, voluntary activation capacity and contraction velocity were observed in the RA patients. Body composition using DXA shows a trend towards lower appendicular lean mass and increased total body fat in patients relative to controls, and consistent with this, VL physiological cross-sectional area (PCSA) is reduced with RA (results published in Medicine and Science in Sports and Exercise 2010;42:2149-55).
A considerable proportion of patients with RA are cachectic which indicates that
processes have taken place which alter their muscle. Therefore, in Chapter 4 a group of cachectic RA patients was chosen to assess whether parameters of muscle quality are changed in these patients. However, the results show that even in cachectic RA patients, muscle specific force and activation are not compromised compared with healthy age and sex-matched controls and thus are unlikely to contribute to the observed reduced function. As expected, VL PCSA and force were reduced (albeit non-significantly), and pennation angle also tended to be lower in RA. No differences were observed for
muscle fibre fascicle length (results published in The Journal of Rheumatology
2010;37(2):282-84).
Chapter 5. To investigate intracellular processes in the muscle of RA patients, biopsies were taken from the VL of patients with stable RA, healthy controls, and patients with active RA before and 3 months after achieving disease control. No differences were found in the distribution of myosin heavy chains (MHC) and in caspase-3, a marker of muscle apoptosis and atrophy, between stable RA patients and healthy controls. Thus, in concurrence with chapter 3 and 4, intracellular muscle quality was preserved in stable RA.
In patients with active RA before and after disease control with the first-line disease modifying antirheumatic drug methotrexate or with anti-TNF agents ( etanercept or adalimumab), there was also no significant difference in caspase-3. However, pAkt, a key factor promoting muscle hypertrophy, was suppressed in patients with active RA compared to controlled disease in the same patients 3 months later, and could therefore be one of the principal reasons for muscle loss during the active phase of RA. In contrast to this, atrogin-1, a marker of muscle atrophy, was low in active disease as well, and IKBa, a downstream transcription factor of TNF-a, did not change in patients with active disease before and after disease control. Thus, the complex mechanism leading to muscle atrophy in RA warrants further investigation.
Chapter 6 presents the case of a localised knee effusion in the context of active, newly diagnosed RA. It shows that an inflammatory knee effusion markedly impairs physical function, leads to quadriceps wasting and adversely affects patellar tendon (PT) stiffness and Young's modulus (YM, a measure of tendon stiffness normalised for tendon size) locally. In addition to loss of muscle quantity, and in contrast to the observations in stable RA in chapter 3 and 4, this case study indicates impaired muscle quality in newly
diagnosed active RA. At reassessment of these parameters one year later, resolution of disease activity and continued physical activity resulted in partial recovery of muscle quality and physical function, but did not resolve the tendon abnormalities. Furthermore, the development of reduced PT stiffness in the contralateral leg at 1 year suggests a systemic effect of the inflammatory process on tendons in RA (results published in Arthritis Care and Research, 10 May 2011, epub ahead of print).
Chapter 7 investigates this systemic effect by assessing the properties of the PT
alongside muscle characteristics and physical function in a group of stable RA patients and in a group of patients with stable ankylosing spondylitis (AS). Adverse changes in PT properties are demonstrated in both RA and AS compared to age- and sex-matched healthy controls. PT stiffness and physical function are significantly lower in RA and AS patients, whilst there is no significant difference in force production between patients and controls. In AS, but not RA, PT cross-sectional area is significantly larger leading to reduction in YM. AS, but not RA, therefore leads to PT thickening without increasing PT stiffness, suggesting that PT thickening in AS is a disorganised repair process (results submitted for publication).
This research is the first to measure qualitative characteristics of muscle and tendon in inflammatory arthropathies. The key findings of this thesis are:
• Muscle properties are preserved in stable RA, even in muscle-wasted patients.
• MHC distribution and the apoptosis marker caspase-3 are similar in patients
with stable RA and healthy controls. Markers of muscle hypertrophy, but also of
muscle atrophy, are upregulated in active RA, with no significant change in
caspase-3 and IKBa between active and controlled disease.
• In active RA with an acute knee joint effusion, local VL muscle properties are
adversely affected, but improve with control of the disease activity; in the acute
phase, reductions in PT stiffness only occur locally on the leg affected by the
joint effusion, but in time these effects spread systematically i.e. to the
contralateral PT.
• PT stiffness is reduced in both RA and AS patients with stable disease.
However, PT size is only increased in AS, highlighting the different pathologies
of the two conditions.