Clinical Efficacy of Biosimilar Switch of Adalimumab for Management of Uveitis.

BACKGROUND: Adalimumab has demonstrated efficacy in non-infectious uveitis. With the introduction of biosimilar agents such as Amgevita, we aimed to quantify efficacy and tolerability compared to Humira in a multi-centre UK cohort. METHODS: Patients identified from tertiary uveitis clinics in 3 centres, after institution-mandated switching was implemented. RESULTS: Data collected for 102 patients, aged 2-75 years, with 185 active eyes. Following switch, rates of uveitis flare were not significantly different (13 events before, 21 after, p = .132). Rates of elevated intraocular pressure were decreased (32 before, 25 afterwards, p = .006) and dosing of oral and intra-ocular steroids was stable. Twenty-four patients (24%) requested to return to Humira, commonly due to pain from injection or technical difficulty with the device. CONCLUSION: Amgevita is safe and effective for inflammatory uveitis with non-inferiority to Humira. Significant numbers of patients requested to switch back due to side effects including injection site reactions.

Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain.

The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury.

Disruption of default mode network dynamics in acute and chronic pain states.

It has been proposed that pain competes with other attention-demanding stimuli for cognitive resources, and many chronic pain patients display significant attention and mental flexibility deficits. These alterations may result from disruptions in the functioning of the default mode network (DMN) which plays a critical role in attention, memory, prospection and self-processing, and recent investigations have found alterations in DMN function in multiple chronic pain conditions. Whilst it has been proposed that these DMN alterations are a characteristic of pain that is chronic in nature, we recently reported altered oscillatory activity in the DMN during an acute, 5  minute noxious stimulus in healthy control subjects. We therefore hypothesize that altered DMN activity patterns will not be restricted to those in chronic pain but instead will also occur in healthy individuals during tonic noxious stimuli. We used functional magnetic resonance imaging to measure resting state infra-slow oscillatory activity and functional connectivity in patients with chronic orofacial pain at rest and in healthy controls during a 20-minute tonic pain stimulus. We found decreases in oscillatory activity in key regions of the DMN in patients with chronic pain, as well as in healthy controls during tonic pain in addition to changes in functional connectivity between the posterior cingulate cortex and areas of the DMN in both groups. The results show that similar alterations in DMN function occur in healthy individuals during acute noxious stimuli as well as in individuals with chronic pain. These DMN changes may reflect the presence of pain per se and may underlie alterations in attentional processes that occur in the presence of pain.

The medial pterygoid muscle: a stabiliser of horizontal jaw movement.

There is limited information of the normal function of the human medial pterygoid muscle (MPt). The aims were to determine whether (i) the MPt is active throughout horizontal jaw movements with the teeth apart and (ii) whether single motor units (SMUs) are active during horizontal and opening-closing jaw movements. Intramuscular electrodes were placed in the right MPt of 18 participants who performed five teeth-apart tasks: (i) postural position, (ii) ipsilateral (i.e. right) jaw movement, (iii) contralateral movement, (iv) protrusive movement and (v) opening-closing movement. Movement tasks were guided by a target and were divided into BEFORE, OUT, HOLDING, RETURN and AFTER phases according to the movement trajectories recorded by a jaw tracking system. Increased EMG activity was consistently found in the OUT, HOLDING and RETURN phases of the contralateral and protrusive movement tasks. An increased RETURN phase activity in the ipsilateral task indicates an important role for the MPt in the contralateral force vector. Of the 14 SMUs active in the opening-closing task, 64% were also active in at least one horizontal task. There were tonically active SMUs at the postural jaw position in 44% of participants. These new data point to an important role for the MPt in the fine control of low forces as required for stabilisation of vertical mandibular position not only to maintain postural position, but also throughout horizontal jaw movements with the teeth apart. These findings provide baseline information for future investigations of the possible role of this muscle in oro-facial pain conditions.

Effect of experimental anterior temporalis muscle pain on jaw movements.

To test the hypotheses that experimental noxious stimulation of the anterior temporalis muscle results in significant decreases in jaw movement amplitude and velocity, and there are significant correlations between scores of mood or pain-related cognitions and amplitude and velocity. The jaw movements of 14 asymptomatic participants were recorded during standardised open/close jaw movements and free and standardised chewing tasks. Tonic infusion of hypertonic saline into the right anterior temporalis muscle maintained pain intensity between 40 and 60 mm on a 100-mm visual analogue scale. Tasks were performed in a single session in the following sequence: baseline condition, test 1 condition (during hypertonic or isotonic saline infusion), test 2 condition (during saline infusion) (10-min rest between conditions). Participants completed the Depression, Anxiety and Stress Scale (DASS-21) and the Pain Catastrophizing Scale (PCS). Amplitude and velocity of opening and closing were compared between conditions with a repeated-measures analysis of variance (anova), and Spearman's rank correlation coefficient explored correlations; statistical significance: P < 0·05. For any of the three tasks, there were no significant differences in kinematic variables between any condition and no significant correlations between DASS-21 or PCS scores and kinematic variables during hypertonic saline infusion. The absence of a significant reduction in velocity or amplitude of open/close or chewing jaw movements during experimental temporalis muscle pain is not consistent with the Pain Adaptation Model proposing decreases in kinematic measures in pain. The lack of significant correlations between psychological variables and measures of jaw movement may reflect the low scores reported by our study sample.

A retrospective epidemiological analysis of risk factors for a primary necropsy diagnosis of bovine respiratory disease.

Bovine respiratory disease (BRD) is a multifactorial disease and the primary cause of both bovine morbidity and mortality in Ireland. The risk factors associated with a primary necropsy diagnosis of BRD among cattle in the traditional (non-feedlot) husbandry systems prevalent in Ireland have not been investigated previously. The aim of this case-control study was to investigate those risk factors among cattle of all ages over an 8 year period. A total of 3,090 BRD cases and 5,236 controls were matched by submitting veterinary practitioner. Univariable and multivariable analyses were performed to examine the association of selected animallevel, herd-level and environmental risk factors with case or control status using a conditional logistical regression model. Male cattle aged more than 31 days were significantly more likely to record a primary necropsy diagnosis of BRD than female cattle. Older cattle of both sexes were at increased odds of a BRD necropsy diagnosis than younger calves with the exception of female cattle aged greater than 165 days. The risk of a primary necropsy diagnosis of BRD increased with increasing herd size and decreased with increasing time in days since the last animal movement into the submitting herd. There were significantly reduced odds of a primary necropsy diagnosis of BRD in the summer (June to August) when compared with the autumn (September to November). These findings identify significant risk factors for a necropsy diagnosis of BRD under non-feedlot-type husbandry conditions.

The effects of catastrophizing on central motor activity.

BACKGROUND: Pain catastrophizing significantly affects an individual's experience of pain. High pain catastrophizing is associated with increased fear avoidance behaviours, pain intensity and disability. The aim of this investigation was to determine the effect of pain catastrophizing on ongoing brain activity and movement-evoked brain activity during acute orofacial muscle pain. METHODS: Thirty-four healthy, pain-free subjects were recruited. In 17 subjects, the effect of catastrophizing on regional brain activity was determined. In 19 subjects, functional magnetic resonance imaging was used to determine the effects of pain catastrophizing on brain activation patterns during jaw movements in the presence of ongoing pain. RESULTS: We found that in the presence of pain, catastrophizing was significantly correlated with activity in multi-sensory integrative brain regions, including the dorsolateral and medial prefrontal cortices. Importantly, this relationship did not exist when subjects were not experiencing pain. In addition, during repetitive open-close jaw movements in the presence of pain, activity in the primary motor cortex, cerebellar cortex and the trigeminal motor nucleus was positively correlated with pain catastrophizing scores. In contrast, in the dorsolateral prefrontal cortex, as pain catastrophizing scores increased, the magnitude of signal intensity change during jaw movements decreased. Again, no such relationships occurred when the individual was not in pain. CONCLUSIONS: These data show that during pain, catastrophic thinking has a significant impact on activity in motor and sensory integrative regions. Reducing negative coping strategies may be an effective means in reducing fear avoidance behaviours and the intensity of ongoing pain.

Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain.

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections. These neural changes may be critical for the maintenance of pathological pain.

Jaw movements in patients with a history of pain: an exploratory study.

The aims were to determine whether individuals with a past history of pain exhibit (i) altered jaw movement (e.g. reduced amplitude, increased jaw movement variability) in comparison with matched asymptomatic controls, and (ii) correlations between psychological measures (e.g. catastrophising) and altered jaw movement variables. Sixteen participants with a history of trigeminal neuropathic pain (TNP) and 15 age- and gender-matched healthy controls had jaw movements recorded during open/close, free gum chewing and chewing at standardised rates. All completed the Pain Catastrophising Scale (PCS), the Pain Self-Efficacy Questionnaire (PSEQ), and the Depression, Anxiety and Stress Scales (DASS). Velocity and amplitude for open/close and chewing, as well as variability, bias and mean square error for open/close jaw movements were compared between groups. Spearman's rank correlation coefficient was used to relate kinematic variables with psychological variables. Statistical significance: P < 0·05. There were no significant differences in mean jaw velocity and amplitude between the TNP and control groups during the open/close jaw movements or free or standardised chewing. In comparison with control, the TNP participants exhibited significantly greater variability, bias and/or mean square error during slow and/or fast opening, and significantly greater variance in velocity and/or amplitude during free and standardised chewing. There were significant negative correlations between PCS scores and velocity and/or amplitude of free and/or standardised chewing. This exploratory study suggests that individuals with a history of pain have altered patterns of jaw movements in comparison with asymptomatic control participants and that catastrophising may play a role in the manifestation of these altered jaw movements.

Isotonic resistance jaw exercise alters jaw muscle coordination during jaw movements.

The aim was to investigate the effects of isotonic resistance exercise on the electro-myographic (EMG) activity of the jaw muscles during standardised jaw movements. In 12 asymptomatic adults surface EMG activity was recorded from the anterior temporalis and masseter muscles bilaterally and the right anterior digastric muscle during right lateral jaw movements that tracked a target. Participants were randomly assigned to a Control group or an Exercise group. Jaw movement and EMG activity were collected (i) at baseline, before the exercise task (pre-exercise); (ii) immediately after the exercise task (isotonic resistance at 60% MVC against right lateral jaw movements); (iii) after 4 weeks of a home-based exercise programme; and, (iv) at 8-weeks follow-up. There were no significant within-subject or between-group differences in the velocity and amplitude of the right lateral jaw movements either within or between data collection sessions (P > 0.05). However, over the 8 weeks of the study, three of the tested EMG variables (EMG Duration, Time to Peak EMG from EMG Onset, and Time to Peak EMG activity relative to Movement Onset) showed significant (P < 0.05) differences in the five tested muscles. Many of the significant changes occurred in the Control group, while the Exercise group tended to maintain the majority of the tested variables at pre-exercise baseline values. The data suggest a level of variability between recording sessions in the recruitment patterns of some of the muscles of mastication for the production of the same right lateral jaw movement and that isotonic resistance exercise may reduce this variability.

The reproducibility of temporomandibular joint vibrations over time in the human.

The aim of the study was to assess the reproducibility of vibrations recorded from the temporomandibular joint (TMJ) in a group of healthy subjects. The vibrations from TMJ were recorded bilaterally from 34 healthy subjects by electrovibratography in three sessions at intervals of 3 min and again after 1 week. The total integral of the vibration energy, the ratio of the integral between frequencies above 300 Hz and below 300 Hz (ratio of >300 Hz/<300 Hz), peak frequency, median frequency, peak amplitude and distance to centric occlusion position were calculated. Data were analysed with intraclass correlation coefficients (ICC) and two-way anova for repeated measures. All variables showed good to excellent reliability across different sessions (ICCday1 : 0·935-0·987; ICCday2 : 0·910-0·992) and across different days (ICC: 0·738-0·907). According to anova for repeated measures, all variables showed good reproducibility (P > 0·05) between sessions at the same day. There was no significant difference between the 2 days for the frequency-related variables including peak frequency (P = 0·083), median frequency (P = 0·188) and ratio of >300 Hz/<300 Hz (P = 0·26). There was a statistical difference between the 2 days for the intensity-related vibration variables including total integral (P = 0·045) and peak amplitude (P = 0·026). The wave patterns of the power-frequency spectra were qualitatively similar over both the sessions and days. Joint vibration analysis could provide a fast, non-invasive, and repeatable method to record the status of TMJ. Further studies are needed to identify the characteristic waveforms for different subgroups of temporomandibular disorders and to evaluate the possibility of diagnostic value.

Masseter motor unit recruitment is altered in experimental jaw muscle pain.

Some management strategies for chronic orofacial pain are influenced by models (e.g., Vicious Cycle Theory, Pain Adaptation Model) proposing either excitation or inhibition within a painful muscle. The aim of this study was to determine if experimental painful stimulation of the masseter muscle resulted in only increases or only decreases in masseter activity. Recordings of single-motor-unit (SMU, basic functional unit of muscle) activity were made from the right masseters of 10 asymptomatic participants during biting trials at the same force level and direction under infusion into the masseter of isotonic saline (no-pain condition), and in another block of biting trials on the same day, with 5% hypertonic saline (pain condition). Of the 36 SMUs studied, 2 SMUs exhibited a significant (p < 0.05) increase, 5 a significant decrease, and 14 no significant change in firing rate during pain. Five units were present only during the no-pain block and 10 units during the pain block only. The findings suggest that, rather than only excitation or only inhibition within a painful muscle, a re-organization of activity occurs, with increases and decreases occurring within the painful muscle. This suggests the need to re-assess management strategies based on models that propose uniform effects of pain on motor activity.

The effect of food bolus location on jaw movement smoothness and masticatory efficiency.

Masticatory efficiency in individuals with extensive tooth loss has been widely discussed. However, little is known about jaw movement smoothness during chewing and the effect of differences in food bolus location on movement smoothness and masticatory efficiency. The aim of this study was to determine whether experimental differences in food bolus location (anterior versus posterior) had an effect on masticatory efficiency and jaw movement smoothness. Jaw movement smoothness was evaluated by measuring jerk-cost (calculated from acceleration) with an accelerometer that was attached to the skin of the mentum of 10 asymptomatic subjects, and acceleration was recorded during chewing on two-colour chewing gum, which was used to assessed masticatory efficiency. Chewing was performed under two conditions: posterior chewing (chewing on molars and premolars only) and anterior chewing (chewing on canine and first premolar teeth only). Jerk-cost and masticatory efficiency (calculated as the ratio of unmixed azure colour to the total area of gum, the unmixed fraction) were compared between anterior and posterior chewing with the Wilcoxon signed rank test (two-tailed). Subjects chewed significantly less efficiently during anterior chewing than during posterior chewing (P = 0·0051). There was no significant difference in jerk-cost between anterior and posterior conditions in the opening phase (P = 0·25), or closing phase (P = 0·42). This is the first characterisation of the effect of food bolus location on jaw movement smoothness at the same time as recording masticatory efficiency. The data suggest that anterior chewing decreases masticatory efficiency, but does not influence jerk-cost.

Occlusion on implants - is there a problem?

Oral rehabilitation restores form and function and impacts on general health. Teeth provide a discriminating sense of touch and directional specificity for occlusal perception, management of food with mastication and swallowing, and awareness of its texture and hardness. Peripheral feedback for control of jaw muscles includes the enamel-dentine-pulp complex and mechanoreceptors in the periodontal tissues. The implications of feedback from periodontal and other intra-oral mechanoreceptors as well as changes in central representation are significant for function and adaptation to oral rehabilitation. With implants, in the absence of the periodontium and periodontal mechanoreceptor feedback, fine motor control of mastication is reduced, but patients are still able to function adequately. Further, there is no significant difference in function with full-arch fixed prostheses on teeth in comparison with implants. Predictable implant outcomes depend on bone support. Optimum restoration design appears to be significant for bone remodelling and bone strains around implants with occlusal loading. Finite element analysis data confirmed load concentrations at the coronal bone around the upper section of the implant where bone loss is commonly observed clinically. Load concentration increased with steeper cusp inclination and broader occlusal table and decreased with central fossa loading and narrower occlusal table size. It is recommended that occlusal design should follow a narrow occlusal table, with central fossa loading in intercuspal contact and low cusp inclination to minimise lateral loading in function and parafunction. Acknowledging these features should address potential problems associated with the occlusion in implant therapy.

A comparison between jerk-cost derived from a jaw-tracking system with that from an accelerometer.

Jerk-cost is an inverse measure of movement smoothness and can be calculated from the first-time derivative of acceleration obtained from a tri-axial piezoelectric accelerometer (TPA), or from the third-time derivative of position obtained from a jaw-tracking device. The aims of this study were to determine, in 10 asymptomatic subjects who are chewing gum, (i) jerk-cost measures derived from displacement/time data obtained from the JAWS3D jaw-tracking device and from acceleration data obtained from a TPA used in the same jaw movement recordings, (ii) whether there was a significant relationship between jerk-cost measures derived from both devices and (iii) the degree of agreement between the two measures. Jerk-cost data were calculated in the opening phase, the closing phase, and over the full chewing cycle as the first-time derivative from acceleration obtained from the TPA, and the third-time derivative from JAWS3D for each of the X-, Y- and Z-direction series. There was a significant correlation between both measures of jerk-cost over the full chewing cycle and during jaw-opening (r = 0·65, 0·75, respectively; P < 0·001). There was no significant correlation in the closing phase (r = -0·02, P = 0·99). The Bland-Altman test showed that jerk-cost derived from the JAWS3D can differ by up to 78% below and 21% above that derived from the TPA. These results suggest that jerk-cost measures derived from a jaw-tracking system cannot substitute for jerk-cost measures derived from an accelerometer.

Bilateral activation of the trigeminothalamic tract by acute orofacial cutaneous and muscle pain in humans.

The conscious perception of somatosensory stimuli is thought to be located in the contralateral cerebral cortex. However, recent human brain imaging investigations in the spinal system report bilateral primary somatosensory cortex (SI) activations during unilateral noxious stimuli and that this ipsilateral spinal representation may be independent of transcallosal connections. In the trigeminal system, there is primate evidence for an ipsilateral somatosensory pathway through the thalamus to the face SI. However, the organization of the trigeminal nociceptive pathway in the human is not clear. The aim of this study was to determine whether noxious stimuli applied to the face are transmitted to the cerebral cortex by bilateral pathways. We used functional magnetic resonance imaging (fMRI) to compare ipsilateral and contralateral activation of the thalamus, SI and secondary somatosensory cortex (SII) during muscle and cutaneous orofacial pain and innocuous facial stimulation in healthy human subjects. We found that both muscle and cutaneous noxious stimuli, from injections of hypertonic saline into the right masseter or overlying skin, evoked bilateral increases in signal intensity in the region encompassing the ventral posterior thalamus as well as the face region of SI and SII. In contrast, innocuous unilateral brushing of the lower lip evoked a strict contralateral ventroposterior thalamic activation, but bilateral activation of SI and SII. These data indicate that, in contrast to innocuous inputs from the face, noxious information ascends bilaterally to the face SI through the ventroposterior thalamus in humans.

How does pain affect jaw muscle activity? The Integrated Pain Adaptation Model.

Pain and limitation of movement are two cardinal symptoms of temporomandibular disorders but it is unclear how one influences the other. The relationship between pain and movement is clinically significant but controversial with two major theories having been proposed: the Vicious Cycle Theory and the Pain Adaptation Model. The Vicious Cycle Theory proposes a vicious cycle between pain and muscle activity. This theory has little scientific basis but underpins many management strategies. The Pain Adaptation Model is more evidence-based and proposes that pain causes changes in muscle activity to limit movement and protect the sensory-motor system from further injury. The Pain Adaptation Model has many positive features but does not appear to explain the relation between pain and muscle activity in all situations. We propose that the relationship is influenced by the functional complexity of the sensory-motor system and the multidimensional nature of pain. This new Integrated Pain Adaptation Model states that pain results in a new recruitment strategy of motor units that is influenced by the multidimensional (i.e., biological and psychosocial) components of the pain experience. This new recruitment strategy aims to minimize pain and maintain homeostasis. This model emphasizes the individual reaction to pain and suggests a tailored approach towards management.

Noxious lingual stimulation influences the excitability of the face primary motor cerebral cortex (face MI) in the rat.

The mechanisms whereby orofacial pain affects motor function are poorly understood. The aims were to determine whether 1) lingual algesic chemical stimulation affected face primary motor cerebral cortex (face MI) excitability defined by intracortical microstimulation (ICMS); and 2) any such effects were limited to the motor efferent MI zones driving muscles in the vicinity of the noxious stimulus. Ketamine-anesthetized Sprague-Dawley male rats were implanted with electromyographic (EMG) electrodes into anterior digastric, masseter, and genioglossus muscles. In 38 rats, three microelectrodes were located in left face MI at ICMS-defined sites for evoking digastric and/or genioglossus responses. ICMS thresholds for evoking EMG activity from each site were determined every 15 min for 1 h, then the right anterior tongue was infused (20 microl, 120 microl/h) with glutamate (1.0 M, n = 18) or isotonic saline (n = 7). Subsequently, ICMS thresholds were determined every 15 min for 4 h. In intact control rats (n = 13), ICMS thresholds were recorded over 5 h. Only left and right genioglossus ICMS thresholds were significantly increased (< or =350%) in the glutamate infusion group compared with intact and isotonic saline groups (P < 0.05). These dramatic effects of glutamate on ICMS-evoked genioglossus activity contrast with its weak effects only on right genioglossus activity evoked from the internal capsule or hypoglossal nucleus. This is the first documentation that intraoral noxious stimulation results in prolonged neuroplastic changes manifested as a decrease in face MI excitability. These changes appear to occur predominantly in those parts of face MI that provide motor output to the orofacial region receiving the noxious stimulation.