Background: Fatigue is a prevalent burden in RA and a key management priority for patients, but current treatment is lacking because its mechanisms are unknown. Although pain has been identified as a possible cause of fatigue, the link between these symptoms is unclear. This project aimed to examine the prognosis of fatigue and determine the role of pain in symptom outcomes. Methods: Two disease registries were used to address these aims in early – the Norfolk Arthritis Register (NOAR) – and severe RA – the British Society for Rheumatology Biologics Register for RA (BSRBR-RA). In both registries, fatigue and pain were measured along with a variety of demographic, clinical and psychosocial data. The prevalence of high symptoms was determined in both cohorts and the prognosis of fatigue delineated in NOAR using group-based trajectory modelling (GBTM). Descriptive statistics and structural equation modelling (SEM) determined the magnitude and pathways of fatigue change following commencement of anti-TNF therapies in the BSRBR-RA. Results: High fatigue was reported by 56% of 413 eligible early-RA patients. Of those, 68% reported persistent high fatigue at year one, but GBTM showed the progression of fatigue to vary over 4 years. Key sex differences in trajectories were observed. Of 6835 eligible participants commencing anti-TNF therapies, 39% reported high fatigue at baseline, but 66% improved to a low fatigue status by six-months. SEM indicated that the effect of disease activity on changes in fatigue was indirect and that improvements were largely driven by pain. The particular importance of mental health and disability were also highlighted throughout analysis. Discussion/Conclusions: Fatigue is a common and often chronic burden in RA. The symptom is amenable to treatment by anti-TNF therapies, but improvements are not driven by reductions in disease activity. Instead pain is a mediator of improvement and likely a suitable treatment target, along with mental health and disability.

Experiments have been designed to investigate the physiological factors influencing the interrelationship between excitation and force generation that may counteractt he processesle ading to a decline in force (fatigue) during stimulatedi sometric contractions of the human adductor pollicis in vivo. Indices of isometric force, relaxation and contraction rates and evoked compound muscle action potentials (CMAP) were measured during defined patterns of stimulated activity (via the motor nerve). A computerized stimulator controller for precise generation of trains of electrical impulses was developed for this purpose. Forces generated at different frequencies were reproducible on separate occasions. Using an ascending frequency stimulation protocol (1-100Hz) the relationship between force decline and excitation (measured as the amplitude of the surface evoked CMAP) appeared to be dependent on stimulation frequency during ischaemic and nonoccluded activity. At high frequencies (50-100Hz), a `safety factor' was apparent, allowing preservation of force despite a marked fall in excitation, whereas at low frequencies (1-10Hz) force initially potentiated and then declined in excess of excitation. Maximum relaxation rate was reduced at all stimulation frequencies and was independent of stimulation frequency. Contractile activity performed was shown to be linearly related to maximum relaxation rate over a frequency range of 20-100Hz for up to 30max. seconds. Contractile activity performed was therefore used as a measure of the metabolic cost of a contraction. Force failure appeared to depend upon the numbers of stimuli delivered, independent of frequency, rather than on contractile activity performed, suggesting that electrophysiological factors are of importance in contributing to fatigue. Further studieso n CMAP characteristicsd emonstrateda broadeningo f the action potential, reflecting a slowing of conduction velocity, which is thought to lead to `runin' of action potentials, and hencet he reduction of CMAP amplitude associatedw ith the high-frequency `safety factor'. The broadening of the action potential recovered immediately during ischaemic conditions at 100Hz following 2400 stimuli but did not recover following prolonged activity at 20Hz until circulation was restored, whereas CMAP amplitude recovered immediately at both frequencies, suggesting that slowing of conduction velocity may be dependent on metabolic factors at low stimulation frequencies which in turn may depend on the contractile history of the muscle. Patients with myophosphorylase deficiency (and thus unable to utilize glycogen), were studied to investigate the importance of energy supply. A failure of ischaemic recovery of the CMAP amplitude and no broadening of the CMAP after stimulated activity at 20Hz was observed, suggesting a failure of excitation of individual muscle cells occurs resulting in force failure in these individuals. Reversing the pattern of stimulation resulted in an initial enhancement of low frequency (10Hz) force and a prolonged maintenance of this force throughout the period of contraction studied. This was independent of slowing of relaxation or excitation. The initial force enhancement may result from the increased slowing of relaxation, and in addition, a form of post-tetanic twitch potentiation operates to counteract the decline in force despite a loss in excitation. In conclusion, during stimulated contractile activity of the adductor pollicis, mechanisms act to maintain or increase force generated per action potential distal to the sarcolemmal membrane, at both high and low frequencies of stimulation, thereby counteracting mechanisms that lead to fatigue. It is postulated that the alterations in intramuscular processes may allow voluntary isometrically contracting muscle to optimize force production at the onset of a contraction where high motor unit discharge rates are initially developed, delaying or eliminating the influence of excitation failure which would lead to contractile failure once maximal force is achieved, and subsequently to optimize contractile activation in the light of possible excitation failure as motor unit discharge rates decline. These findings may have important functional implications and may form the basis of physiological strategies for optimizing force production in the development of stimulation regimes for `functional electrical stimulation' or to any area of skeletal muscle research in which fatigue resistance is of importance.

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The investigation of motor-unit fatigability in reduced-animal models has been dominated by a single fatigue test, one fatigue index, and an emphasis on changes in the magnitude of (usually peak) force. Although the standard fatigue test has been reported to elicit changes in the dynamic phases of an isometric tetanus, this has not been systematically studied in single motor units. Furthermore, changes in the profile of individual tetani during the fatigue test have led some investigators to suggest that other force parameters (i.e., integrated force) or fatigue indices may provide additional information about motor-unit performance during the test. The purposes of this project were to: (1) evaluate the time courses of a variety of force parameters characterizing both the magnitude of force and the dynamic aspects of force during a 4-min fatigue test of functionally isolated cat, tibialis posterior motor units; and (2) determine if motor units could be classified into the conventional motor-unit types based on these new parameters. There was considerable variability in the average time course of the magnitude of force during the fatigue test. The variability within the type FR and F(int) motor-unit groups resulted in several units whose characteristics bordered those which, by definition, separate unit types. The classification of these units depended on the force parameter and fatigue index used to quantify their fatigability. The time course of the magnitude of force also revealed differences in the behavior of potentiating and non-potentiating groups. There were many differences between motor-unit types in terms of dynamic-force parameters before, during and after the fatigue test. Comparison of initial and 2-min values revealed a preferential effect of stimulation on force development in type S and FR units (i.e., increased rate) and on force decay in type F(int) and FF units (i.e., prolonged duration and decreased rate). The time courses of these effects further revealed qualitative differences between different combinations of motor-unit types. Groups of units (or lack thereof) revealed by dynamic-force parameters were compared to conventional motor-unit types by discriminant analysis. The results were not always consistent with conventional types.

An equivalent constant amplitude fatigue loading (Miner's stress) is developed for stationary random amplitude loadings. The effects of rainflow cycle counting and fatigue crack closure are included. A method for determining the opening stress in a random loading is also proposed. This research takes a fatigue damage factor approach. The damage factor is defined as the ratio of the wide band rainflow fatigue damage to the equivalent narrow band fatigue damage. The mathematical form of the damage factor equations is derived from theoretical derivations using the analytically tractable local range cycle counting method. Simulations of stationary Gaussian random processes are used to empirically derive the values of certain parameters dependent on the spectral shape for the rainflow cycle counting equations. There are five tasks in this research. (1) A simulation program for generating a Gaussian process has been written and is used to generate random loading histories for this study. (2) A previously proposed rainflow damage factor has been verified and refined with these simulations, without considering crack closure. (3) Using a sinusoidal approximation, the joint probability density functions between peaks, valleys and rises counted by the local range method are derived. (4) The resulting joint probability distributions are used to determine the theoretical damage with crack closure; simulations are again used to calibrate the parameters for rainflow stress cycles. (5) A procedure for finding an equivalent constant fatigue crack opening stress for stationary random loadings is described. An example application of the procedures and equations is given.

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