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Musculoskeletal System

Muscle Diseases by Dr Federico Roncaroli

Muscle diseases are a rapidly growing field, with over 300 diseases known. Classification is based on phenotype, genetics, metabolic/functional tests and pathology. Primary disease is where the muscle is the primary organ of the disease. This is genetically determined or non-genetically determined. Secondary disease is where the muscle is affected as part of a systemic disease. Examination of the patient may involve muscle biopsy, metabolic analysis, genetic analysis, blood tests, EMG, and MRI scans. The history should include a family history, age of onset, motor milestones (sitting, crawling, walking), presenting symptoms and severity, pain (intensity, at rest or exertional), cramps and medications (statins or steroids). The patient should be examined for distribution and severity of weakness, check their muscle bulk, laxity, contractures, stiffness, gait, reflexes, skin changes, etc. Common signs of muscle disease include atrophy of the quadriceps, scapular winging, ptosis, and Gower’s manoeuvre. The values of creatine phosphokinase (cytosolic enzyme, catalyses ADP to ATP) increasing are indicative of muscle damage. The patient may also lactate when mitochondrial myopathy is suspected. Inflammatory markers should also be looked for (ANCA, ANA) in inflammatory myopathies. An EMG is diagnostic in myasthenia, and is helpful to distinguish between neurogenic and myopathic. An MRI scan identifies selective muscle involvement. Congenital myopathies are typically non-progressive. Static weakness is present from birth or infancy. Most patients achieve the ability to walk independently. Typically the serum CK is normal or only mildly elevated, indicating a low degree of muscle damage. Congenital myopathies are characterised by generalised muscle thinning and muscle weakness. Severity depends on the degree of disruption of the excitation contraction coupling or the severity of dysfunction of sarcomeric proteins, not so much on the ‘class of disease’. At the mild end of the spectrum of congenital myopathies, you may see proximal muscle weakness, where the child has difficulty walking fast, running, getting up, etc. You may see axial weakness, and scoliosis is common, respiratory muscles are weak, and there is weakness common even in ambulant patients. Central core disease shows that different defects of the same gene give different phenotypes and pathologies. Nemaline myopathies are where different gene/protein defects give similar pathology but different clinical phenotypes. Muscle dystrophies can be congenital (birth or first 6 months of life) or childhood onset/adult onset, like Duchenne (only childhood) and Becker, or limb girdle muscular dystrophies. Muscular dystrophies often show progressive weakness. They have variable severity from congenital to adult onset depending on the subtype. The weakness is usually proximal, and rarely distal. Patients have respiratory muscle weakness, and limitation of joint movements often accompanies the weakness. Muscle atrophy is often with associated pseudohypertrophy in the same patient. Proteins involved include transarcolemma, enzymes, nuclear envelope, extracellular matrix, sarcomere, and others like cytoskeleton and ER proteins.

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Dystrophies show wide variation in fibre size, necrosis, fibrosis, fat, hypercontracted fibres, split and whorled fibres, internal nuclei, basophilic fibres. Duchenne muscular dystrophy occurs in 1 in every 3,500 male births, it is a genetic disorder. It is symptomatic between less than 1 to 5 years of age, and the child loses independent walking between 6 to 12 years of age. Death usually comes in mid teens to early twenties. 30% of patients have significant learning difficulties. There are currently trials testing gene transfer. Investigations for DMD include creatine phosphokinase, which between 50-100 is normal. Deletion in the gene is detectable in 70% of cases. A muscle biopsy will show histology dystrophic, and immunocytochemistry will show absent dystrophin. Motor difficulties include late walking, toe walking, inability to run or jump, falls, stairs and climbing hard, Gower’s manoeuvre, and progressive joint contractures like scoliosis and weakness of the respiratory muscles. Typical Becker’s dystrophy has a mean age of onset of symptoms at around 11 years old. The child experiences calf pains, and is slower than their peers. There is variable progression, and loss of walking ability is only seen in about 18% of patients (mean age around 37 years). Scoliosis is extremely uncommon. Dilated cardiomyopathy however is very common. Dystophies may occur late in life. For example, dysferlinopathy shows proximal involvement and very high CK. Onset is in the 2

nd or 3

rd decade of life, and it is slowly progressive. This is where there are missenses, deletions

and insertions on 55 exons on chromosome 2p13. Some mutations are associated with inflammation, mistaken as polymyositis. ATP/ADP is the immediate source of energy in muscle fibres. It is essential for oxidative phosphorylation, anaerobic glycolysis, creatine kinase reactions and adenylate kinase reactions. This can be the source of mitochondrial myopathies, glucose metabolism problems and lipid storage diseases. Mitochondrial myopathies are inherited from the mother. Onset can be at any age, with variable severity. It is a multisystemic disease, affecting the brain, muscle, heart and sensory system. It affects mitochondrial or nuclear DNA, and causes impairment of chain enzymes. Diagnosis is made by seeing high lactate, biopsy, test of respiratory chain enzymes, and DNA analysis. Mitochondrial myopathies typically involve multiple systems. Mitochondria Encephalopathy Lactate Acidosis Stroke has a variable age of onset, and patients experience seizure, dementia, myopathy, exercise intolerance, hearing loss, and short stature. Glycogenosis can be lysosomal or non-lysosomal. In lysosomal glycogenosis, acid maltase deficiency causes digestion of glycogen to glucose. Onset can be at any age, and causes exercise intolerance, cardiac involvement and rhabdomyolysis. McArdle’s disease is where glycogen phosphorylase removes glucose residues from α-(1,4)-linkages within glycogen molecules. The product of the reaction is glucose-1-phosphate. This causes exercise intolerance, and the age of onset is between 10 to 15 years. It is caused by mutations in the PYGM gene 11q13, and is autosomal recessive, and results in no protein expression or an unstable protein. Mainly there is impairment of aerobic glycogenolysis. Fatty acids are released from fat and used in muscle after long exercise when glycogen is exhausted to produce acetyl CoA to feed the Krebs cycle and produce ATP. Features of lipid metabolism disorders depend on the enzyme affected. Onset is at any age, and patients experience variable weakness, intolerance to exercise, cardiac involvement and rhabdomyolysis. Inflammatory myopathies have pathology caused by an inflammatory reaction against muscle fibres. They are common in adults, and are usually immune mediated with slow or acute onset. There is variable distribution of weakness, high CK and usually steroid responsive. Dermatomyositis is an example, and polymyositis is rare. There is overlap syndrome in the course of Lupus and Rheumatoid Arthritis. The presence of anti-synthetase antibodies is common, and there are also unusual forms like pipestem and COX-negative polymyositis.

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Dermatomyositis is seen in children and adults = acute onset, skin and muscle involvement, life threatening in children, high CK, steroid responsive, CD4/CD20 in perimysium (up-regulation of MHCI). Sporadic inclusion body myositis is the most common inflammatory myopathy after 50 years of age. There is asymmetrical, distal weakness. The patient has normal CK. The disease is progressive, and steroid unresponsive. Myopathies can be secondary to other conditions like infections, cancer (Paraneoplastic myopathies), endocrine related myopathies (thyroid diseases), toxic myopathies (drug induced), systemic diseases (sarcoidosis, diabetes), or excessive exercise or disuse. Ageing is by far the commonest “disease” of muscle. Sarcopenia is when there becomes more fat and less muscle.

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Regulation of Muscle Mass by Dr Paul Kemp

Ageing and muscle mass are intrinsically linked, as there is an increased risk of 1 year mortality at a BMI of less than 22 at age 65. In people over 50 the unintended loss of 10% of body mass in a year increases the likelihood of mortality by 60%. Cachexia or loss of muscle mass occurs in many chronic diseases including cancer, AIDS, heart disease, and chronic obstructive pulmonary disease (COPD). Muscle mass is an important regulator of survival/mortality in chronic illness and loss of muscle mass is more closely associated with death than many standard prognostic indicators. For example, COPD is a lung disease in which smoking results in damage to the lung tissue and restricts the amount that people can breathe. In this disease FEV1 (forced expiratory volume), as a % of the expected normal value, is a classic marker of disease progression and severity. However, this relationship affects only a few people and something else is important in determining survival in many others. One much better predictor of mortality is muscle mass, in this case measured by quadriceps strength. Not only are muscle mass and strength important predictors of how long we will live for the ability to use muscle (i.e. move) is also related to the quality of patient life measured using a questionnaire. So the amount and usability of our muscle is important. How does a cell become a muscle cell? To understand how muscle mass is regulated it is useful to understand where skeletal muscle cells come from and the basics about how their differentiation is controlled. If we look at adult skeletal muscle cells they are multinucleate fibres, but this is not the way they start out. If we look at the skeletal muscle in an embryo we can see that the nuclei are down the middle of the fibre but we still have one cell with lots of nuclei. But like all other cells skeletal muscle cells start life as individual cells with a single nucleus. There are two ways we could go from here to a multinucleated cell and they are:

To divide the nucleus multiple times without dividing the cell as happens in the formation of megakaryocytes (which produce platelets)

To fuse cells together. In fact, this is how the skeletal muscle syncitium (one cell with many nuclei) is formed.

So we start with several skeletal muscle myoblasts and under the appropriate conditions these will stop proliferating, start to express markers of the differentiated skeletal muscle phenotype and fuse together to form a myotube. This process is followed by the maturation of these myotubes into myofibres giving us our skeletal muscle. These steps in differentiation are principally controlled by a set of transcription factors, which are proteins of the basic-helix-loop-helix family. There are 4 of these transcription factors in total and the first discovered was the protein MyoD which was identified using a differential screen for genes that were up-regulated when a particular line of fibroblasts was treated with aza-cytidine (which causes de-methylation of DNA and allowed these cells to convert into other cell types particularly myocytes). Transfection of MyoD into a number of different cells converts them into myoblasts which can subsequently fuse into myotubes. Subsequent studies identified 3 similar proteins, Myf5, MRF-4 and myogenin, which have subsequently, using gene targeting, been shown to regulate specific parts of the differentiation of skeletal muscle cells. MyoD and Myf 5 play redundant roles in the differentiation of myoblasts into myocytes. These then require myogenin to increase and drive the formation of myotubes and finally MRF-4 is required for the maturation of these myotubes into myocytes. Once expression of these transcription factors is activated there is a positive feedback system which maintains and enhances their expression.

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Fusion to a myofibre is not the end of the story as there are different types of myofibre, some have fast contraction kinetics, contain few mitochondria so rely on anaerobic metabolism to provide energy, and are useful for fast responses and for strength. Others have slower contraction kinetics, contain more mitochondria and are useful for endurance activities. Different muscles have different functions and activities so express different amounts of each fibre type. The fraction of each fibre type we have is important in determining how good we are at particular activities. In a patient population the fraction of type I (slow fibres) is very important as it dictates how far they can move, and that is an important contributor to their quality of life. The relationship between activity and fibre type is not one way as the more someone moves in a day the more MHC1 they tend to express in their quadriceps. We can control muscle mass by regulating the amount of message made and the amount of protein made from each message. Transcription is controlled by differential activation of the promoter region of specific target genes using distinct transcription factors. Regulating the amount of message In determining how a cell becomes a skeletal muscle cell, the factors that control gene expression in skeletal muscle cells start with the myogenic basic helix loop helix proteins (MyoD, Myf5, MRF-4 and myogenin). The control of expression of a specific gene is likely to be a lot more complicated than that. There are a few more players that regulate skeletal muscle specific gene expression. Conceptually this approach can be used for any gene promoter as the questions are always:

a) where does the gene need to be expressed b) what level does it need to be expressed at under basal conditions c) in response to what stimulus does expression need to change

So for skeletal muscle we need to consider what factors should be built in to the system to allow expression of the gene in skeletal muscle cells, and what factors are likely to increase or reduce the expression of such a gene. The easiest place to start is to look at the control of one of the contractile proteins and consider when the gene needs to be expressed and what it needs to respond to. The first thing to consider is that we want the gene expressed in skeletal muscle cells once they have become skeletal muscle cells. The easiest way to do this is to use the same transcription factors that are involved in causing the cells to become skeletal muscle cells in the first place. The next thing to consider is that these proteins are contractile proteins and they need to be able to respond to changes in demand. These proteins make up a significant portion of the muscle cell and making them therefore consumes a significant portion of the cell's energy. We only want to have enough and not too much. The organism also needs to be able to grow and to respond to changes in demand so we need a system that will respond to that. So how do we achieve this control of protein amount? There are two things we could regulate, the first is the amount of protein, and the second is the amount of mRNA production at the level of transcription. To do that we increase or decrease the binding of proteins to the DNA predominantly in the promoter region of the gene we are interested in. To determine that the protein is expressed in the right tissue (skeletal muscle only) we can use tissue-specific transcription factors that bind to the promoter regions of the gene. In skeletal muscle the bHLH (basic-helix-loop-helix) transcription factors that we have already described bind to a recognition sequence in the appropriate promoter and here in the skeletal actin promoter we have the appropriate binding sites for the myoD class of factors. As we don’t want some of the proteins made when the cells are proliferating we can

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switch off gene expression by inhibiting these myogenic transcription factors with similar proteins like Id and twist. We also have binding sites for a range of different transcription factors that respond to environmental factors related to demand for the protein. So there are binding sites for serum response factor (SRF), nuclear factor of activated T cells (NF-AT) and myocyte enhancer factor 2 (MEF2). The amount and activity of these factors is important in determining which fibre type predominates. The mechanisms that control transcription factor activity can be quite complex but allow the cell to respond to different environmental ques. One example of the mechanism is as follows… Increasing contraction occurs alongside increased average Ca

2+ concentration in the cell as Ca

2+ is required for

contraction to occur. This increase in Ca2+

triggers an increase in the activity of two systems: the CaMKIV and calcineurin systems. Calcineurin targets the transcription factor NF-AT present in the cytoplasm and causes it to translocate into the nucleus, where it targets the transcription factor MEF-2. CaMKIV targets MEF-2. In both cases there is an increase in activity leading to an increase in the expression of the target gene in our case skeletal muscle α-actin. The regulation of MEF-2 is not direct; it involves a second protein and that is a histone deacetylase (HDAC4 and 5). These proteins inhibit the expression of genes when they are in the nucleus by increasing the positive charge on histone residues causing the DNA to become more compact and therefore less accessible. HDAC4 and 5 bind to MEF-2 when they are in the nucleus and inhibit the expression of genes to which MEF-2 is bound. Phosphorylation of these HDACs by CaMKIV causes them to exit the nucleus and bind to the 14-3-3 proteins in the cytoplasm. MEF-2 can then bind other factors that acetylate the histones and open up the chromatin and increase gene expression. Regulating the amount of protein There are two sides to regulating the amount of protein, the first is regulating the amount of protein synthesis and the second is regulating the amount of protein breakdown and it is the net turnover that is important. Once you are an adult these are in reasonable equilibrium so that we don’t keep growing and the amount of muscle we have stays relatively constant but this is a dynamic process so that if you increase the amount of exercise you do the amount of protein synthesis and degradation increases but synthesis increases more that degradation so that we make more muscle. In chronic disease the amount of breakdown decreases but so does the amount of synthesis and this occurs to a greater degree resulting in muscle loss. The regulation of protein levels involves both activity and hormonal control. For example growth hormone, testosterone and IGF-1 all act to promote muscle growth whereas glucocorticoids and myostatin inhibit muscle protein synthesis. Both of these proteins will also affect mRNA but their main effects are on protein synthesis and protein degradation. Regulation of protein synthesis Proteins are made by translating the mRNA code into a polypeptide chain one amino acid at a time. We can consider two phases of this process: one is the initiation phase where a ribosome binds to the 5’ end of an mRNA molecule and the second is the elongation phase where the ribosome moves along the mRNA adding more amino acids as it goes. We are most interested in the initiation phase because the rate of protein synthesis can be more effectively increased by increasing the rate of initiation than by increasing the rate of elongation. This does not mean that elongation isn’t also a target. IGF-1 is a small peptide hormone that is part of the insulin family. The predominant source of circulating IGF-1 is the liver where it is made in response to growth hormone. However, some tissues, including skeletal muscle can produce IGF-1 locally and in muscle changes in IGF-1 expression occur in response to stretch and load on the muscle. IGF-1 signals by binding to the IGF-1 receptor, a tyrosine kinase that exists in the membrane as a preformed homodimer. Binding of IGF-1 to this receptor causes a conformational change that activates the tyrosine kinase portion of the protein leading to phosphorylation of IRS-1. One of the immediate targets of IGF-1 signalling is PI3Kinase which in turn phosphorylates and activates protein kinase B (also known as Akt). Here we have the activation of a classic protein kinase cascade which allows for amplification of a signal as one kinase can phosphorylate more than one target at each step in the chain.

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In skeletal muscle there are two Akt isoforms that we need to consider Akt1 and Akt2. These proteins appear to be coupled to different components because knockout of Akt1 in mice leads to growth retardation whereas knockout of Akt2 leads to type II diabetes. It appears in part from this, but also from direct assays of IGF-1 and insulin function, that Akt1 is a target of the IGF-1 receptor whereas Akt2 is a target of the insulin receptor. For the moment we will consider two targets of Akt that are involved in increasing protein synthesis as part of the hypertrophy signalling cascade. The first is glycogen synthase kinase (GSK3β) and the second is the mTOR complex (mammalian target of Rapamycin). So where in this system do mTOR and GSK3β function? GSK3β inhibits the activity of one of the initiation factors, eIF-2B, so inhibits protein synthesis by blocking the loading of Met-tRNA into the ribosome. Inactivation of GSK3β by Akt releases this block leading to increased RNA synthesis mTOR on the other hand phosphorylates S6 kinase leading to increased phosphorylation of the ribosomal protein s6. One further target of this system is the eIF4E binding protein, which sequesters eIF4E. Phosphorylation of eIF4E binding protein reduces its binding of eIF4E allowing eIF4E to participate in initiation of protein synthesis. Myostatin and the regulation of protein breakdown So that is a brief introduction to the control of muscle protein synthesis and hypertrophy. The flip side of this coin is muscle protein breakdown and atrophy. It must be remembered that although we think of this as a pathological process it is a normal and important system that has evolved to allow us to use the large amount of stored energy present in skeletal muscle protein during times of starvation. Myostatin was discovered by identifying the gene that was mutated in hypermuscular breeds of animals. These breeds include the Belgian blue cows and bully whippets. The animals don’t produce any of the protein myostatin an inhibitor of muscle growth. Not only is myostatin an inhibitor of muscle growth but it also affects fibre type and these animals have a lot of fast fibre but very little slow fibre. The cows are therefore not as good for meat production as the quality is not high (too tough) and the dogs may run fast but are susceptible to cramp. However in a normal person changes in myostatin do coincide with muscle wasting and a loss of strength where weak COPD patients have more myostatin than strong ones and the amount of myostatin they make is inversely correlated with the amount of activity they perform. One effect of increased myostatin is the increased expression of two proteins called MuRF1 and atrogin. Not only are these proteins increased by myostatin but they are also markedly up-regulated in a number of different atrophic conditions. MuRF1 and atrogin are both ubiquitin ligases and as such their job is to add ubiquitin moieties to proteins. Ubiquitin is a small protein that functions in the cell primarily as a label that indicates that a protein is to be degraded by the proteosomal system. So an increase in the expression of MuRF1 and atrogin suggests that we will see increased protein degradation. So how is the expression of these proteins is controlled apart from in response to myostatin? FOXO1 and FOXO3 are a pair of transcription factors that are important in the regulation of the expression of the genes for MuRF1 and atrogin. The transcription factors FOXO1 and FOXO3 and their activity are regulated by protein phosphorylation and nuclear localisation. The active form of each protein is not phosphorylated and is present in the nucleus, whereas the inactive form of each protein is phosphorylated and becomes localised to the cytoplasm. The regulation of the activity of FOXO transcription factors is therefore an important aspect of the regulation of atrophy. There are two important components. The first is Akt, which phosphorylates and inhibits FOXO, and the second is AMP kinase, which is involved in activating FOXO.

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AMP kinase is a protein that is central to the "energy sensing system". It is activated by AMP, a molecule that is present at a low concentration but is in equilibrium with ADP. This equilibrium allows the cell to measure its energy status in the following way. In a muscle contraction leads to the conversion of ATP into ADP; most (but not all) of the ADP is turned back into ATP by the creatine kinase reaction. The resulting small increase in ADP after a period of contractile activity is measurable by NMR spectroscopy of contracting muscle. Thus a sign of heavy ATP use is the increase in ADP, which results the conversion of 2 molecules of ADP into 1 ATP and 1 AMP. This does not have a big effect on ATP concentrations but increases the levels of AMP markedly as the amount of AMP in the cell is very low. You should remember that it is not the absolute concentration change that is important in triggering a response but the relative change so the percentage reduction in ATP is small but the percentage increase in AMP is very large. Hence when energy levels are low ADP increases and AMP increases by a much larger margin. This increase in AMP is then picked up by AMPK, which becomes activated. Activation of AMPK can be both allosteric and through post translational modification (phosphorylation). The stimulation of FOXO activity by AMPK may seem surprising as it is by phosphorylation and we have just said that phosphorylation of FOXOs leads to inhibition through nuclear exclusion. However AMPK phosphorylates a different part of the protein and this phosphorylation leads to activation of the transcription promoting activity of FOXO. AMPK has two other affects that are related to energy metabolism in muscle cells. Firstly it inhibits protein synthesis by inactivating the mTOR complex. Given the expense of making protein this is a sensible short term move and can be seen to be closely associated with protein breakdown. The second effect of AMPK activation is an increase in mitochondriogenesis. This has the effect of increasing the energy available from each glucose molecule, as the energy yield from each glucose is higher when it is fully oxidised by the Krebs cycle rather than by glycolysis. Mitochondriogenesis is obviously a much longer term effect and may be restricted to a subset of fibres. These pathways are interrelated. There are at least 2 nodal points mTOR and FOXO with activation of Akt increasing the activity of mTOR and protein synthesis and inhibiting the activity of FOXO. Conversely AMPK increases the activity of FOXO but suppresses the activity of mTOR. Myostatin is now a target for therapeutic intervention and there are a number of ways that people are trying to combat muscle wasting by inhibiting the ability of myostatin to bind to its receptor or the signalling of the receptor complex.

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Skeletal Muscle Contraction in vivo by Professor Nancy Curtin

A motor unit is one motor neuron and all the muscle fibres that it innervates (has synapses with, neuromuscular junctions). Cell bodies of motor neurons are found in the anterior horn of the spinal cord. Axons of motor neurons are found in the ventral roots. Branched terminals of motor axons are within muscle. The chain of command for voluntary skeletal muscle contraction is quite simple. Brain spinal cord peripheral nerve neuromuscular junction muscle fibre membrane transverse tubular system Ca

2+

release actin-myosin activation cross-bridge formation FORCE/POWER. Small distal muscles have fewer motor units and smaller motor units, like the intrinsic muscles of the hand. Large proximal muscles have more motor units and larger motor units, like brachioradialis, tibialis anterior, and gastrocnemius. But there are some exceptions, like the eye muscles and facial muscles are small muscles with many small motor units. Motor units are well arranged within muscles. Muscle fibres belong to one motor unit - they are localised, but not segregated from muscle fibres belonging to other motor units. Muscle Fibre Types There are three types of muscle fibre. Type I is slow and oxidative fibres. They have slow twitch speeds, slow maximum shortening speeds and are highly resistant to fatigue. These fibres usually have rich capillary supply and many mitochondria. Type IIA is fast, oxidative, glycolytic and fatigue resistant. They have fast twitch speeds and maximum shortening speeds, and have high resistance to fatigue. These fibres have rich capillary supply, many mitochondria and high glycogen. Type IIB is fast, glycolytic, and fatiguable. They have fast twitch speeds, fast maximum shortening speeds, but low resistance to fatigue. These fibres have poor capillary supply, few mitochondria and low glycogen. The duration of force in an isometric twitch is much longer lasting for type I fibres. The duration of force in an isometric twitch is about the same for type IIA and type IIB fibres. Maximum shortening speed is proportional to the maximum speed thick and thin filaments can slide over each other. This is set by the maximum rate of the myosin-actin crossbridge cycle. The myosin isoform is different in slow than fast muscle fibres, actin is the same. It is important for function because shortening speed giving maximum power is about a third of the maximum shortening speed. So fast fibres produce high power at higher shortening speed than slow fibres. Repeated isometric tetani in fatigue resistant fibres = capacity to sustain force. Slow fibres are very fatigue resistant. Type IIA fibres are fatigue resistant, so force stays reasonably high. Type IIB fibres are easily fatigued, so force declines rapidly. All of the muscle fibres in a motor unit are the same type. The CNS activates specific motor units with the contractile properties that match the task to be performed. Muscle Plasticity Strength training increases the force produced during voluntary contraction. Training is usually high force with few repetitions. Part, but not all, is due to muscle hypertrophy (increase in muscle fibre size). Hypertrophied muscle has the same number of fibres; just the diameter of each fibre has increased. Hypertrophied muscle fibres have more contractile filaments and therefore more crossbridges produce force. The number of fibres in a muscle appears to be genetically determined, and is not increased by strength training. “Skill” also contributes to strength. During strength training with equipment, you should observe increasing strength of e.g. knee extension and a decrease in the activity of an opposing muscle (e.g. quadriceps for knee extension and biceps femoris for knee flexion). The improvement in the strength of knee extension is partly due to increased strength of the knee extensor muscle, and partly due to a neural mechanism to learn to keep the opposing muscle relaxed.

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Endurance training increases duration of performance and improves fatigue resistance. In this type of training you should do many repetitions. Metabolic adaptations include increased capillary density and increased mitochondrial content and oxidative enzyme activity, but these adaptations decline quickly after stop training. Non-metabolic adaptations include the myosin isoform changing. Disuse of muscles leads to weakness and fatigue. Absence of load-bearing is the most potent cause, so bed rest is a good example. Anti-gravity muscles are the most affected (quadriceps, etc). This happens because of reduced recruitment of motor units = atrophy. Atrophied muscle has the same number of fibres as before; it’s just that the diameter of each fibre is decreased. This is reversible. The effects are the opposite of training effects. Injury is commonly caused by disease, external trauma, internal trauma, and eccentric exercise. Denervation and reinnervation results in clustering of fibres of the same type (rather than the mosaic pattern). Damage and repair of muscle fibres is the role of satellite cells. Ageing causes normal changes in function. There is a decline in muscle performance with age even in highly trained subjects. Much of this strength loss is due to a decrease in muscle mass, but motor neuron loss also contributes to functional changes during ageing.

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Metabolic Bone Disease by Dr Ann Sandison

The functions of bone are varied, for example mechanical (support and site for muscle attachment); protective (vital organs and bone marrow); and metabolic (reserve of calcium). The composition of bone is 65% inorganic, most of it being calcium hydroxyapatite (10Ca 6PO

4 OH2) acting as a storehouse for 99% of the

calcium in our body, as well as 85% of the phosphorus, and 65% of the sodium and magnesium. The other 35% of bone is composed of organic material, mainly bone cells and protein matrix. Bone has to be 50% mineralised to be seen on x-ray. Bones display articular surfaces at synovial joints. If small, these are called facet joints or fovea. Condyles are knuckle shaped and a trochlea is grooved like a pulley. Articular surfaces enable bone to act as a strut/lever. Articular cartilage provides a frictionless surface. Periosteum provides a protective covering to bone as well as providing pathways for blood vessels etc to enter the bone itself. The cortex of bone is thick and strong, and is the part of bone to which muscles attach. In the medulla is softer trabecular bone where most metabolism occurs. Cortical bones are usually long bones, comprising 80% of the skeleton. Cortical bone (shown on the right) is appendicular and 80-90% calcified, mainly with mechanical and protective functions. Cancellous bones include the vertebrae and the pelvis, comprising 20% of the skeleton. Cancellous bones are axial and are 15-25% calcified and mainly perform metabolic functions. They have a very large surface, and are more metabolically active than cortical bone. Types behave differently and exhibit different responses to metabolic changes and treatment. A bone biopsy is a diagnostic test. Indications for a biopsy include evaluating bone pain or tenderness, investigating an abnormality seen on an x-ray, bone tumour diagnosis (benign vs malignant), determining the cause of an unexplained infection, and evaluating therapy. Biopsies can be closed (Jamshidi needle core biopsy in the iliac crest) or open (for sclerotic or inaccessible lesions). Cartilage is a load bearing tissue composed predominantly of type 2 collagen and a variable amount of elastic fibres. Elastic cartilage is present in ears, nose, epiglottis and larynx. Hyaline cartilage is present on the ends of long bones and is very effective as a shock absorber and resists the large compressive forces generated by weight transmission. Bone Cells:

- Osteoblasts: build bone by laying down osteoid - Osteoclasts: multinucleate cells of macrophage family resorb or “chew” bone - Osteocytes: osteoblast like cells which sit in lacunae in bone

These cells form the Basic Multicellular Unit (BMU). RANK (Receptor Activator for Nuclear Factor kB) is expressed on the surface of osteoclast lineage cells. RANK Ligand is expressed on multipotential stem cells (MSCs) of osteoblast lineage and on T and B lymphocytes. When RANKL binds to RANK this causes the osteoclast precursor cell to differentiate and thus increase bone resorbtion. OPG (Osteoprotegerin) competes with RANK for RANKL, acting as an inhibitor of osteogenesis. OPG is also expressed by MSCs and osteoblast cells.

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Types of Bone: There are various classifications of bone. Classified anatomically, they can be flat, long or cuboid bones. Intramembranous ossification leads to flat bones, and endochondral ossification leads to the development of long bones. Trabecular bone is cancellous, and compact bone is cortical. Immature bone is referred to as woven bone, and mature bone is referred to as lamellar bone. Coritcal and cancellous bone are lamellar and this is particularly evident when viewed under polarized light. Collagen fibres are arranged in alternating orientations allowing for the highest density of collagen per unit of tissue. In woven bone the lamellae are absent. Collagen fibres are laid down in a disorganized fashion, such as states of high bone turnover (Paget’s disease of bone, certain stages of fluoride treatment, tumours). They are not so tightly packed, and are arranged in random bundles. Metabolic Bone Disease: Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals, etc). The overall effect is reduced bone mass (osteopaenia) often resulting in fractures with little or no trauma. There are three main categories of disease:

1. Related to endocrine abnormality (vitamin D; parathyroid hormone) 2. Non-endocrine (e.g. age related osteoporosis) 3. Disuse osteopaenia

The primary cause of osteoporosis is age and being post-menopausal. A secondary cause is drugs and systemic disease. Proper evaluation of osteoporosis or any metabolic bone disease requires quantitative analysis. Parameters measured are % bone tissue as opposed to marrow, and % bone actively laying down or resorbing bone compared with inactive surfaces. Osteomalacia is a condition of defective bone mineralization. This can be caused by deficiency of vitamin D, or deficiency of PO4. Vitamin D plays an integral role in calcium metabolism. Vitamin D deficiency from whatever cause results in increased parathyroid hormone (PTH) release and subsequent increased bone resorption. The most common cause of hypocalcaemia is vitamin D deficiency. Low blood calcium levels manifests itself as muscle twitching, spasms, tingling and numbness. A patient with osteomalacia is likely to suffer from bone pain and tenderness, fractures, proximal weakness and bone deformities. Seen in children as rickets, bowing of the leg bones is a common sign. An x-ray may show a fracture in Looser’s zone at the neck of the femur. Hyperparathyroidism is a condition that results in excess PTH. Signs include increased Ca

2+ and PO4 excretion in urine,

hypercalcaemia, hypophosphataemia, and also skeletal changes of osteitis fibrosa cystica. Four organs are directly or indirectly affected by PTH and between them control Ca

2+ metabolism. They are the

parathyroid glands, the bones, the kidneys and the proximal small intestine. Primary hyperparathyroidism can be caused by a parathyroid adenoma, or chief cell hyperplasia. Secondary hyperparathyroidism is often due to chronic renal deficiency, or vitamin D deficiency.

- Stones (Ca2+

oxalate renal stones) - Bones (Osteitis fibrosa cystic, bone resorption) - Abdominal Groans (Acute pancreatitis) - Psychic Moans (Psychosis and depression)

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A hand x-ray often shows sub-periosteal bone erosions thought to be pathogonomic of hyperparathyroidism. Renal osteodystrophy comprises all the skeletal changes of chronic renal disease:

1. Increased bone resorption (osteitis fibrosa cystica) 2. Osteomalacia 3. Osteosclerosis 4. Growth retardation 5. Osteoporosis

The x-ray on the left shows features of osteitis fibrosa cystica affecting the tibia. In renal osteodystrophy there is PO4 retention, leading to hyperphosphataemia. There is also hypocalcaemia as a result of vitamin D deficiency, and secondary hyperparathyroidism can result, as well as metabolic acidosis and aluminium deposition.

Paget’s disease is a disorder of bone turnover. It is divided into three stages:

- Osteolyic - Osteolytic-osteosclerotic - Quiescent osteosclerotic

The onset of Paget’s disease is usually at around 40 years of age, and it affects approximately 3% of all Caucasians over 55 years of age. It is just as common in men as it is in women. It is a rare disease among Asian and African populations. In 15% of cases it is mono-ostotic, the remainder being polyostotic. The aetiology of Paget’s disease is relatively unknown. Familial cases show an autosomal pattern of inheritance with incomplete penetrance (mutation of the 5q35-qter-sequestosome 1 gene). Parvomyxovirus type particles have been seen on electron microscopy in Pagetic bone. The primary sites affected include the skull (65%) and vertebral column (76%), followed by pelvis, femur, tibia, sternum and humerus. The clinical symptoms of Paget’s disease include pain, microfractures, nerve compression (including spinal nerves and cord), skull changes may put medulla at risk, deafnes, haemodynamic changes, cardiac failure, hypercalcaemia and the development of sarcoma in the area of involvement in 1% of cases. Essential Bone Vocabulary: Cortical: dense outer bone Trabecullar: endosteal bone Lamellar: mature bone with type 1 collagen Haversian canal: blood vessels travel through periosteum Osteoblasts/Osteoclasts/Osteocytes Canaliculae: channels by which osteocytes communicate Howship’s lacunae: resorption pits on bone surfaces where osteoclasts are found

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Clinical and Biochemical Features of Metabolic Bone Disease by Dr Jeremy Cox

Metabolic bone disease is a group of diseases that cause a decrease in bone density and bone strength by increasing bone resorption and decreasing bone formation. The quantitative factors of bone strength include cortical thickness, mineral density and size. There can often be changes in bone mass and shape because of a person’s exercise habits. The qualitative factors of bone strength include architecture, bone turnover, mineralization, cortical porosity and trabecular connectivity. During growth bone strength is optimised, not by using a greater amount of bone, but by modifying strategically its deposition. The process here then is bone modelling, and the important point is that new bone can be added on the periosteal surface, with removal off the endosteal surface. This is different from remodelling where bone is reconstructed, and which mainly occurs on endosteal surfaces. In a study of peri-pubertal girls by Wang, it was found that the tibial cross-sectional shape became increasingly elliptical due to preferential periosteal apposition of bone anteriorly and posteriorly. Consequently, the bending strength of the tibia increased more in the anterioposterior (Imax) than mediolateral direction (Imin). The main metabolic bone diseases are:

- Primary hyperparathyroidism - Osteomalacia / Rickets - Osteoporosis - Paget’s Disease - Renal Osteodystrophy

People at risk of developing osteomalacia are those who are vitamin D deficient. 36% of the male and 47% of the female elderly community are dwelling adults between 71-76 years of age who have vitamin D deficiency. 80-100% of institutionalized older adults (mean age 85) also have vitamin D deficiency. Immigrant groups are also at risk, as seen by the statistic that 78% of Anglo-Asian rheumatology patients are deficient. 100% of US immigrants have “chronic musculoskeletal pain”. The Sick are at risk, with 57% of middle aged hospital in-patients who are vitamin D deficient (mean age 62). The Carers are also at risk, with 36% of the health workers in Boston aged 18-29 years being deficient. Bone is a metabolically active tissue, and exists as cortical bone or cancellous bone. Osteoblasts and osteoclasts are continually building and resorbing bone in a bone remodeling cycle. Bone has a structure designed to absorb energy. Cortical bone has a structure of individual osteons and a lamellar structure of alternating density. Irreversible plastic deformation can occur and this results in microfractures, which dissipate the excess energy, generally limited to the interstitial bone between osteons. If these accumulate bone strength will be compromised. Bone remodelling is the process by which these areas are repaired; each osteon essentially represents a previous remodelling event. Bone remodelling occurs in the basic multicellular unit, seen here. Activation occurs when a micro crack crosses canaliculi, so severing osteocyte processes causing osteocytic apoptosis. This is thought to act as a signal to the connected surface lining cells (which are osteoblast lineage), which along with the osteocytes release local factors that attract cells from blood and marrow into the remodelling compartment. For the resorption

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phase to start osteoclasts are generated locally and resorb matrix and the offending micro crack, then successive teams of osteoblasts deposit new lamellar bone. Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells. The average lifespan of a basic multicellular unit is about 6 to 9 months, growing at a speed of about 25μm per day. The lifespan of osteoclasts is about 2 weeks, and the lifespan of active osteoblasts is about 3 months. The interval between successive remodelling events at the same location is about 2 to 5 years. It is estimated that the rate of turnover of the entire skeleton is about 10% per year. Osteoclasts are involved in the resorption of bone, dentine and calcified cartilage. It models growing bone. In adults, remodelling maintains bone size, and provides calcium requirements by resorption. Osteoblasts synthesise and deposit matrix. They regulate hydroxyapatite deposition and secrete molecules to control osteoclast differentiation and apoptosis. They arise from pluripotential mesenchymal cells.

In 1997, a secreted form of the TNF receptor family was identified, which suppressed osteoclast formation in co-culture and caused osteopetrosis when over-expressed in mice. This was named OPG or osteoprotegerin and its ligand was identified, RANKL. RANK Ligand is the proposed osteoclast differentiating factor. It is a transmembrane protein that activates the RANK receptor, induced on pre-osteoclasts by the permissive action of M-CSF.

The osteoblast form is membrane-bound and therefore there must be cell-to-cell contact between the osteoblast and osteoclast progenitors. RANKL is both essential and sufficient for basal osteoclastogenesis and it acts as the signalling pathway for the previously identified osteoclastogenic factors . It acts at all levels of the pathway; proliferation/differentiation/fusion/activation, as well as being anti-apoptotic. Osteoblasts also produce OPG, a decoy receptor, which balances RANKL action at all these stages. Overall, it can be viewed that the RANK-L pathway serves to expand the pool of active osteoclasts, and that the balance between OPG and RANKL determines the end effect of multiple local and systemic converging factors. The essential nature of this system has been well demonstrated in the mouse knock-out models, which lead to a picture of osteopetrosis. X-rays of the hind-legs of the RANKL deficient mice show increased radiopacity of long bones, with a shortened, widened femur and club shaped metaphysis. Histology confirmed severe osteopetrosis, with accumulation of cartilage and bone in the marrow space of the diaphysis. Staining for TRAP, an osteoclast specific enzyme, showed them to totally lack osteoclasts, although osteoclast progenitors were present. RANK is expressed on other cells of haematopoietic lineage, it was of note that these mice lacked all peripheral lymph nodes, except Peyer’s patches, and had defects in T and B cell differentiation. Recently a human form of osteopetrosis due to RANKL inactivating mutations has been characterised, but most disorders affecting the system have been found to cause enhanced signalling. Familial expansile osteolysis, early onset Paget’s (in Japan) and expansile skeletal hyperphosphatasia all result from distinctive tandem duplications in the RANK gene, causing over-activation. They all share features of osteoclast overactivity with osteolytic and sclerotic areas causing bone deformity and cranial nerve impingement. A patient with early onset Paget’s disease shows facial deformity of the mandible and maxilla, as well as swelling of the proximal and distal interphalangeal joints. These are extremely uncommon in normal Paget’s. Common to these 3 RANK mutations are multiple areas of long bone involvement with typical Pagetic

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deformity which may be marked. Furthermore, early loosening of teeth and sensorineural hearing loss occur, although at varying ages. Bone structure and function may be assessed in different ways:

- Bone histology - Radiology - Bone mineral densitometry (e.g. osteoporosis) - Biochemical tests

Biochemical investigations include serum calcium (and corrected calcium), albumin, phosphate, parathyroid hormone and 25-hydroxyvitamin D. Investigations can also include urine NTX, calcium and phosphate. Calcium is the most abundant mineral in the body, as there is about 1kg of it. It is mainly stored in bone, but there are huge fluxes in and out of bone (it is not a metabolically inert tissue!). Thinking about calcium is easy - what’s coming in via the gut (1g per day recommended) and what’s going out via the kidneys. Bone flux is the body’s compensatory mechanism. What we measure in serum is the total free calcium (the active form). In blood, 50% of calcium is present as unbound ionised calcium (Ca

2+), 45% protein-bound to albumin and 5% left as

soluble salts, complexed with phosphorus and citrate. Only the free (unbound) Ca

2+ is bioactive. The total blood calcium ion

concentration is about 2.5mM. PTH has the predominant role in minute by minute regulation of plasma calcium levels.If plasma calcium drops, within seconds there is secretion of PTH from pre-formed stores. This acts on 2 systems:

1. Bone: acute release of available calcium; not in hydroxyapatite crystals. More chronically there is increased osteoclast activity to re-absorb bone.

2. Kidney: increased calcium re-absorption in the distal convoluted tubule; the only site where ca re-absorption is under active hormonal control. Stimulation of enzyme activity, so increasing activated vitamin D production, which leads to increased gut reabsorption of calcium; decreases enzyme activity and increases phosphorus excretion by inhibiting the NAP co-transporter in the proximal tubule.

PTH is an 84 amino acid peptide hormone, and N1-34 is the active PTH form we use to build bone. It is magnesium dependent, and low magnesium leads to low PTH and hypocalcaemia. This is useful to bear in mind, particularly with alcoholic patients. PTH has a short half life of about 8 minutes, which allows intraoperative sampling. The PTH receptor can also be activated by PTHrP, which is produced by some tumours, and so hypercalcaemia may be a first presenting feature for example in small cell carcinoma of the lung. The calcium sensing receptor links serum calcium to the PTH gland. A steep inverse sigmoidal function relates PTH levels and Cao

2+ in vivo. The minimum is important in diagnosis. Even at

high calcium levels there is base-line PTH secretion. The set point is the point of half the maximal suppression of PTH; it is the steep part of the slope. A small perturbation causes a large change in PTH. Primary hyperparathyroidism usually affects people in their 50s, with women being 3 times more affected than men. 2% of all post-menopausal women develop primary hyperparathyroidism. Common causes include parathyroid oedema (80%) and parathyroid hyperplasia (20%), and in less than 1% of cases parathyroid CA. There are familial syndromes like MEN1 and MEN2A, but these are rare.

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In primary hyperparathyroidism there is an increase in serum calcium, by absorption from the bones, gut and kidneys. There is an overall decrease in serum phosphate, as the increased absorption is overcome by marked renal excretion. There is an increase in urine calcium excretion, as increased renal resorption is overcome by the hugely increased filtered load. There is also an increase of markers of bone resorption, and thus secondarily formation. The key clinical features are mainly due to high calcium. Patients experience thirst, polyuria, tiredness, fatigue and muscle weakness. “Stones, bones, abdominal groans, and psychic moans” should be used to remember the features including renal colic, nephrocalcinosis, CRF, dyspepsia, pancreatitis, constipation, nausea, anorexia, depression, impaired concentration, drowsiness and coma. Patients may also suffer fractures secondary to bone resorption. Vitamin D Metabolism In the intestine, 1,25(OH)2 Vitamin D activates Ca and P absorption in the duodenum (TRPV6, Calbindin). In the bone, vitamin D synergises with PTH, acting on osteoblasts to increase formation of osteoclasts through RANKL. In the kidneys, vitamin D facilitates PTH action to increase Ca reabsorption in the distal tubule (TRPV5, Calbindin). Vitamin D has feedback on parathytoid glands directly to reduce PTH secretion. Metabolic Bone Diseases Osteomalacia is where inadequate vitamin D activity leads to defective mineralisation of the cartilaginous growth plate (before a low calcium). Symptoms include bone pain and tenderness (axial), muscle weakness (proximal), and lack of play. Signs include age dependent deformity, myopathy, hypotonia, short stature and tenderness on percussion. The causes of osteomalacia are vitamin D related, and this may be dietary. Otherwise there may be GI problems (e.g. small bowel malabsorption, pancreatic insufficiency, liver/biliary disturbance, or drugs like Phenytoin or Phenobarbitone increase P450 activity which inactivates vitamin D). Other problems may be renal (e.g. chronic renal failure), or in rare cases osteomalacia is hereditary (vitamin D dependent rickets type I and II). Biochemistry in osteomalacia:

- Serum calcium, phosphate and vitamin D are low, and alkaline phosphate is high and PTH is high. - Urine phosphate is high (glycosuria, aminoaciduria, high pH, proteinurea).

Osteomalacia also occurs with renal phosphate loss, when calcium and vitamin D levels are usually normal. Renal ‘isolated’ hypophosphataemia is related to X-linked hypophosphataemic Rickets, which has an incidence of 1 in 20,000, or may be oncogenic. Oncogenic osteomalacia presents with mesenchymal tumours. Menopausal bone changes increase the number of remodelling units and cause remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%) due to enhanced osteoclast survival and activity. The remodelling errors mean there are deeper and more resorption pits, which leads to trabecular perforation and cortical excess excavation. There is also decreased osteocyte sensing.

In osteoporosis, serum biochemistry should all be normal if primary. Check for vitamin D deficiency, check for secondary endocrine causes. Primary hyperparathyroidism will mean PTH is high, primary hyperthyroidism will

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mean free T3 is high and TSH is suppressed. Hypogonadism will mean testosterone is low. Exclude multiple myeloma and bear in mind the patient may have high urine calcium. Bone density is the single best predictor of fracture risk. The ‘gold standard’ for BMD is D.X.A. It has good precision, short scan times, and stable calibration in clinical use. Scan central sites include the spine and hip. DXA stands for Dual energy X-ray Absorptiometry. It measures transmission through the body of x-rays of two different photon energies. This enables densities of two different tissues to be inferred, i.e. bone mineral and soft tissue. Osteoporosis is defined by the World Health Organisation’s T-score. The T-score is your measured BMD minus the young adult mean BMD, divided by the young adult standard deviation. How many standard deviations are you off the average for a 25 year old? A score of -2.5 is indicative of osteoporosis. A score of -1 to -2.5 is indicative of osteopenia. A score of over -1 is normal. Vertebral measurements are used because this is a common place for fractures, with increasing incidence after age 60. It is a good measure of cancellous bone and it is a highly metabolically active bone, and so is quick in response to treatment. Hip measurements are taken because this is the second commonest place for fractures in patients over 70. The best predictor is the site itself. Certain situations interfere with interpretation, for example degenerative change, osteoarthritis, vertebral fractures, metal artefacts, osteomalacia, vascular calcification, scoliosis, and Paget’s disease. In most bone diseases the bone cycle is disrupted. Markers of bone formation and resorption give us insight into activity. Unlike BMD they are dynamic, and are divided into markers of formation and markers of resorption. Resorption markers are found as urine hydroxyapatite, urine collagen crosslinks, serum CTX and NTX, and tartate resistant acid phosphatase. Bone markers are used in the diagnosis of osteoporosis, prediction of fracture risk and monitoring of treatment. Bone marker levels are higher in osteoporotic patients. Bone marker levels are inversely proportional to BMD in osteoporotic patients. However, there is too much overlap with normals for this information to be clinically useful. Bone markers are also used in monitoring treatment. They can be used to monitor the response to treatment with anti-resorptive drugs. Bone resorption markers fall in 4 to 6 weeks, and bone formation markers fall in 2 to 3 months. Markers are not only used in osteoporosis, but also in Paget’s disease and primary hyperparathyroidism. Possible uses of markers of bone resorption include osteoporosis monitoring, primary hyperparathyroidism, hyperthyroidism, Paget’s disease, inflammatory arthritis, and osseous metastases. Osteoblast function and bone formation can be measured by serum alkaline phosphatase, both total and bone specific, as well as osteocalcin and the propeptides of type I collagen. Bone specific alkaline phosphatase is essential for mineralisation, as it regulates concentrations of phosphocompounds. BSAP is increased in Paget’s disease, osteomalacia, bone metastases, hyperparathyroidism, and hyperthyroidism. Hypercalcaemia of malignancy is common. The patient is usually unwell, and life-expectancy is a matter of months. The clinical signs are prominent, as the tumour is obvious, there is bone pain, fractures, and other systemic features. Chronic kidney disease mineral bone disorder is where there are skeletal remodelling disorders caused by CKD. These contribute directly to calcification, especially vascular. The disorders in mineral metabolism that accompany CKD are key factors in the excess mortality. CKD impairs skeletal anabolism, decreases osteoblast function and bone formation rates.

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Renal osteodystrophy can be seen as increasing serum phosphate, and a reduction in 1,25(OH)2D (calcitriol), so secondary hyperparathyroidism develops to compensate. However, this is unsuccessful and hypocalcaemia develops. Later on, parathyroids become autonomous, causing hypercalcaemia. Parathyroid bone disease shows increased bone turnover, acute anabolic reactions and chronic catabolic reactions. There ends up being more cortical bone than cancellous bone, and osteoblasts become dysfunctional, leading to more woven bone, fibrosis and increased osteoids. In osteomalacia, radiographically it is clear that the edges are less sharp. Pseudofractures can be seen as radiolucent lines and sclerosis.

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The Radiology of Metabolic Bone Disease by Dr Ranju Dhawan

Metabolic bone disease = systemic disorder of the skeleton resulting from a metabolic disturbance. The diseases include osteoporosis, osteomalacia and rickets, primary hyperparathyroidism, and secondary hyperparathyroidism / renal osteodystrophy. The radiographic signs are osteopenia and osteosclerosis. The tools used to see these include x-rays, CT scans, MRI scans, radionuclide bone scans and bone densitometry. X-rays show density. Densitometry and CT scans show density/attenuation. MRI scans show chemical/water content. Radionuclide bone scans show bone turnover, not density. Osteopenia = poverty of bone. It is a sign, not a disease, and is seen in both osteoporosis and osteomalacia. In osteoporosis there is decreased bone mass. In osteomalacia there is decreased bone mineralisation. In osteoporosis there is a decreased quantity of bone overall (bone mass), but the microstructure is normal. It is systematic bone loss. There is normal biochemistry, but fragility fractures, deformity and pain are common. In osteomalacia or rickets there is vitamin D deficiency, and so the biochemistry is changed. There is reduced vitamin D and reduced calcium, but PTH levels are increased. However, this still results in inadequate or delayed mineralisation. Radiology can show age and growth plate closures. In osteomalacia there is too little mineral, and so the osteopenic and soft bone bends and deforms. There is also too much osteoid, which presents as Looser’s zones. If calcium stays low, then secondary hyperparathyroidism may be superimposed. A pseudofracture or Looser’s zone is a narrow lucency, perpendicular to bone cortex. These are commonly seen in the pubic rami, proximal femur, scapula, and lower ribs. In osteomalacia, radiographic findings show “codfish vertebrae”, where there is biconcave loss of height, which is osteopenic.

Osteomalacia Osteoporosis

Less mineral Less bone

Osteopenia Osteopenia

Bend and bow before break Break

Codfish vertebrae - uniform spine deformity Anterior wedging

Rickets is osteomalacia of childhood. Osteomalacia shows changes in mature bone, but Rickets is before the growth plate closes. There are changes therefore related to growth plates that dominate, and changes of osteomalacia co-exist. In rickets, metaphysis shows the most rapid growth (this is the most obvious change). You can see indistinct frayed metaphyseal margins and a widened growth plate (no calcification). There may also be cupping or splaying metaphyses due to weight bearing. Bowing of weight bearing bones is also a distinct feature. There is also enlargement of the anterior ribs (rickety rosary) and osteopenia. Primary hyperparathyroidism is caused by a PTH adenoma. There is increased PTH and increased calcium and decreased phosphate. Secondary hyperparathyroidism (CRF / rickets / osteomalacia) shows increased PTH, decreased calcium and little or no phosphate. Tertiary hyperparathyroidism shows increased PTH, increased calcium and decreased phosphate, and this is autonomous. Primary hyperparathyroidism can be seen radiographically with bone resorption (hence the high calcium). Secondary hyperparathyroidism can be seen as renal osteodystrophy, resorption and increased density (anabolic and resorptive features of PTH). Bone resorption may be subperiosteal, subchondral (distal clavicle, pubis), intracortical (pepper-pot skull) or brown tumours (bigger, and more osteoclastic activity). Subperiosteal bone resorption is seen on the radial aspect of the middle and ring fingers.

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Bone loss may be slow (involutional osteoporosis, bone has time to remodel/bone loss occurs according to mechanical needs) or fast (hyperparathyroidism/disuse osteoporosis, bone loss is too rapid; loss does not cater to mechanical needs). Renal osteodystrophy (CRF) is seen with osteomalacia and osteoporosis, and this leads to secondary hyperparathyroidism. There are sub-periosteal erosions, brown tumours, sclerosis (axial skeleton/vertebral), and soft tissue calcification (arteries/cartilage). Bone is a dynamic system that is constantly turning over. Mediators of bone metabolism include calcium, phosphate, vitamin D, PTH and calcitonin. Other hormones include thyroxine, growth hormone, glucocorticoids, oestrogens, androgens and insulin. Other factors include vitamin C and other nutrients, cytokines, prostaglandins, and several growth factors.

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Bone Structure, Function and Healing by Professor Justin Cobb

Our development is programmed, and bones grow with nutrition and activity. Programmed cell death causes separation of bone into apophyses and epiphyses. Bone shapes and strength are dictated by activity and environment. The shapes of bones dictate gait and wear patterns, e.g. shoes. Bone shape determines function. The hip joint is a ball and socket joint, and the shape of the bones here maximise strength and mobility. The neck shaft is at an angle of inclination (130°), and the head and neck have an α angle (50°) relationship. The structure of bone reflects genes and development. In the animal world there are two sorts of hip: inline power coxa recta (alpha angle 90°) and maximum mobility coxa rotunda (alpha angle 30°). The coxa recta is seen in a kangaroo for their straight line action. The coxa rotunda is seen in beavers, for essential mobility. Another factor about bone structure is where soft tissues rub. The femoral head-neck junction is a fulcrum for iliopsoas, and other examples include the carpal tunnel and the rotator cuff. Different activity patterns will lead to different head/neck ratios, different muscle actions, different problems and therefore different treatments. The shape of adult bones dictates function in health, pattern of disease and treatment options. The shape and thickness of bone varies with age and sex. Bone Structure The skeleton weighs about 2kg, and there are 206 bones in a human. The bone has two major functions - support and stability, and a metabolic calcium band for calcium homeostasis. These functions determine its structural properties at the macroscopic, microscopic and ultra-structural levels. Bone is composed of mesenchymal cells, extracellular matrix, blood vessels, nerves, lymphatics, periosteum and marrow. There are two main forms of bone tissue. Lamellar/mature bone is cortical or cancellous. Cortical or compact bone is the bone in long bone diaphyses. Cancellous or trabecular bone is the bone found in the metaphyses of long bones and most short and flat bones. They consist of relatively thin shells of cortical bone with large volumes of cancellous bone. These differences make a difference to the healing of fractures and fixation of implants. Woven/immature bone is found in the embryonic skeleton and in the initial fracture repair tissue. There is a rapid rate of deposition and resorption, and an irregular woven pattern of collagen fibrils is seen. There is four times the number of cells per unit volume in woven bone. The periosteum consists of an outer fibrous layer, and an inner more cellular and vascular cambium layer. The thicker, cellular periosteum of infants and children has a very rich blood supply essential for growth. Osteoblasts line the surface of the bone. Cells close to the osteoblasts but away from the surface are called ‘preosteoblasts’. Osteoblasts take up an intense basophilic stain of alkaline phosphatase. It is seen that their nucleus is located away from the bone surface. Osteoblasts produce type I collagen, PTH and Vitamin D receptors, and also osteocalcin. Osteoclasts are resorptive cells that are large in size (100 microns). They lie in pits called Howship’s Lacunae, and may be inactive or active. They show brush borders. Matrix is organic or inorganic. Organic matrix forms 40%, and is comprised of collagen, proteoglycan, glycoproteins, growth factors, and cytokines. Inorganic matrix forms the mineral 60%, and is comprised of calcium hydroxyapatite (responsible for compressive strength, primary + secondary mineralisation), and osteocalcium phosphate (Bushite).

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A fracture forms in bone when the energy absorbed at an impact results in mechanical failure (tension/compression), loss of stability and collateral damage (blood vessels, nerves, possibly skin). Variables in healing depend on many factors, including injury type, patient (age, metabolism co-morbidities), tissues injured, and treatment modalities. Choice of management will depend on the skills available, equipment, environment, time pressures and budget. A plaster cast fixation needs skills. Traction is gentle and safe in a Balkan frame. External fixation is used for compound fractures. Internal fixation is used for closed injury. Local growth hormones are also quite useful in repair. Bone Morphogenic Protein is osteoinductive, and its target cell is undifferentiated perivascular mesenchymal cells. Transforming Growth Factor β induces mesenchymal cells to produce type II collagen and proteoglycans, which regulates cartilage and bone formation. ILGF and PDGF are also useful. Anabolic steroids have a positive effect due to enhanced callus formation. Corticosteroids have a negative effect due to decreased callus formation. Calcitonin has a positive effect. Thyroid hormones and PTH have positive effects due to bone remodelling. Growth hormone has a positive effect due to enhanced callus formation.

Type of Immobilisation Predominant Type of Healing

Cast (closed treatment) Periosteal bridging callus

Compression plate Primary cortical healing (remodelling)

Intramedullary nail Early = periosteal bridging callus, Later = medullary callus

External fixator Dependent on extent of rigidity. Less rigid = periosteal bridging callus, More rigid = primary cortical healing

Inadequate Hypertrophic non-union

Stiffness is the main function of bone. Osteocytes continually monitor this. Fracture (high strain environment) causes events leading back to restoration of a low strain environment.

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Articular Cartilage by Mr Vipin Asopa

Joint = the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support. Bone structure, the cartilage around the bone and soft tissues around the joint maintain the structure and function of the joint. Classified types of joint:

- Synovial joint (diarthroses): most joints, for example the knee and hip joints. - Fibrous (synarthroses): e.g. syndesmosis, sutures in the skull. - Cartilaginous (amphiartroses): e.g. in the spine, vertebrae are separated by discs made of type I and

type II collagen. Synovial joints are freely movable joints. The ends of the bones are covered with hyaline cartilage. A capsule encloses the joint, and the synovium secretes synovial fluid to lubricate the joint. Ligaments and muscles are important for stability of the joint. Articulating surfaces of adjacent bones are reciprocally shaped. Synovial joints are sub-classified into uniaxial (hinge and pivot joints), biaxial (condyloid and saddle joints), and triaxial (ball and socket joints and planar joints). In cartilaginous joints, the articular surfaces of the bones forming the joints are attached to each other by white fibro-cartilaginous discs and ligaments. These joints allow a limited degree of movement. Examples include between vertebrae, in the symphysis which binds the pubic bones together at the front of the pelvic girdle, and between the sacrum and the pelvis. Fibrous joints are held together by a thin layer of strong fibrous tissue. They do not allow any movement between bones. The main function of ligaments is in joint stability. The main functions of muscles include movement and stability. Articular cartilage lines synovial joints and provides a smooth gliding surface. It transfers weight and acts as a shock absorber. In the hip articular cartilage is found in the synovial ball and socket joint. In the spine the intervertebral discs are type I (Annulus fibrosis) and type II collagen, which are articular cartilage. Articular cartilage is composed of chrondrocytes, type II collagen and proteoglycans. In disease states, articular cartilage can play a very important role, for example in osteoarthritis. Under the microscope, normal cartilage has a smooth appearance with a Toluidine blue stain. In early osteoarthritis the colour is faded and the appearance begins to become flaky with a Toluidine blue stain. In late osteoarthritis, cartilage looks quite broken up with a Safranin O stain.

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In the upper limb, the sternoclavicular joint is fibrous with an interosseous disc. The acromioclavicular joint is fibrous with a synovium. The shoulder joint is a ball and socket joint, and is a good example of a synovial joint (the Glenohumeral joint). The elbow joint between the humerus and the ulna is a hinge joint, which is a synovial joint. The superior radioulnar joint is synovial (pivot joint), and distally is fibrous with a triangular fibrocartilage. There is also a fibrous joint along the length due to an interosseous membrane and syndesmosis. The wrist joint is a synovial joint, and the interphalangeal joints are hinge/saddle/condyloid synovial joints. Between the radius and ulna there are three joints. The inferior radio-ulna joint is fibrous (has interosseous cartiliage). The superior radio-ulna joint is a pivot joint (annular ligament). Between the radius and ulna is an interosseous membrane = syndesmosis for support in pronation and supination. In the lower limb, the sacroiliac joint (which is the largest joint in the body) is a stable synovial joint. The hip joint is a ball and socket joint, and so it is a synovial joint. The knee joint is a synovial joint. There are six movements possible at the knee joint that make it vulnerable to injuries. There are two flat surfaces and a curved surface. Soft tissues maintain stability at the knee joint, for example the popliteus and condensation of the capsule. The joint between the tibia and fibula is much like the radio-ulnar joint, it is a fibrous joint (syndesmosis). The ankle joint is a true hinge joint allowing flexion and extension. It is therefore a synovial joint, but also has a fibrous component (syndesmosis). The sacroiliac joint is the largest fibrous joint in the body (synovial articulation), formed between the sacrum and the pelvis. In the standing position it transfers body weight onto the lower limbs. It can be affected by inflammatory conditions and autoimmune diseases such as Ankylosing Spondylitis. The hip joint is a ball and socket joint. If the ball and socket is shallow, there is developmental dysplasia and the person is prone to dislocation. If you compare the hip joint to the shoulder joint, the shoulder is less stable and more likely to dislocate. The hip joint has a bony configuration, which provides extra stability. The knee joint has six degrees of movement - flexion, extension, valgus, varus, internal rotation, and external rotation. Its stability is maintained by strong ligaments, but the joint remains very vulnerable to injury. It is a very complex structure with bone, muscle, cartilage, menisci, and ligaments. The ankle joint is a hinge joint. Its bony configuration maintains stability, but ligaments are also very important in stabilising the joint. Injuries and Joint Failure Joints are generally damaged due to trauma or degenerative diseases. Inflammatory conditions are seen to by Rheumatologists. Damage can also be infective, or neoplastic (synovium, bone, cartilage). There can also be neuromuscular injuries (Charcot joints). The result is that bone collapses and the joint is destroyed, leading to deformity, instability and destruction. Trauma can be simple or high energy, and damage can be to different structures - bone, soft tissues (inside and outside), and cartilage. Shoulder dislocations are common in sport when stability is compromised for movement (lateral rotation and excessive extension), and also knee injuries are common, as there can be multiple soft tissue injuries e.g. to the anterior cruciate ligament, tibial collateral ligament, and the medial meniscus if the foot is fixed and there is a twisting motion. This is known as the “unhappy triad” of knee injuries. Inside the knee joint there can be injury to the meniscus, ACL/PCL, and the cartilage. Outside the knee joint there can be damage to muscle, tendon or ligaments. A torn medial co-lateral ligament results in valgus deformity, where the lower leg is abducted. Anterior cruciate ligament tear increases gliding movement and the knee gives way, which can result in the rupture of the quads tendon. Synovial fluid stops blood clotting and the tendon healing. Meniscal damage leads to locking and instability - 20% of patients who have had a meniscectomy show degenerative changes within 2 years. Direct cartilage injury is also a common form of soft tissue injury at the knee joint. Damage to a joint means it is altered, and is subject to abnormal stresses, blood and inflammation. This results in degenerative joint diseases such as osteoarthritis.

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Examination and Investigation The set procedure for examining a joint injury is as follows: look, feel and then move (actively or passively). It is important to always compare both sides when examining, i.e. look at both left and right knees. Examination of radiographs is essential as is arranging further investigations. Looking involves noticing deformities, swellings, scars and any neurological symptoms. There are then different types of movement. Objective movement can be abduction, adduction and rotation etc. Subjective or functional movement can involve asking the patient to reach for their hair, middle of their back or buttocks, throwing a cricket ball. There are special tests in the knee. For example, an anterior draw is the test for an ACL rupture, and a posterior draw is the test for a PCL rupture. Valgus and varus strains can also be done. Thomas’ test is common for the hip joint. There are various investigations that can be done. An x-ray is usually the choice initial method for showing bones. CT scans are good for 3D imaging, and a reconstructive CT can give further information. MRI scans are good for soft tissues, including inflammatory responses. Other scans and tests include radioisotope tests that can demonstrate abnormalities like infection and malignancy, DEXA, and there is also arthroscopy which is an invasive procedure that is both investigative and therapeutic. An x-ray will easily show the features of osteoarthritis, such as subchondral sclerosis, cysts, loss of joint space and osteophytes. They also show fractures and dislocations, as well as joint destruction caused by infection. Principles of Treatment Conservative treatments include analgesia, glucosamine, physiotherapy and steroid injection. This sort of treatment will most commonly be carried out by rheumatologists and physiotherapists. Steroids and local anaesthetics will only provide temporary relief. Arthroscopy is both diagnostic and therapeutic in that it a procedure used in the debridement of cartilage (cleaning and removing torn cartilage) and in joint reconstruction. In anterior cruciate ligament injury (intra-articular), synovial fluid prevents healing. Repair will not occur when the ends are put together due to a lack of fibrinogen induced by synovial fluid. Therefore, cruciate ligament reconstruction is the main treatment. Reconstruction is common treatment following trauma, for example in a fracture involving a joint surface (if loss of congruity, fracture is reduced and fixed with plates and screws), or in medial and lateral co-lateral ligament injuries (heal with rest followed by physiotherapy). Osteotomy is another form of surgical treatment used to treat bone deformity. This treatment is common in Hallux Valgus, which is corrected by re-aligning the knee joint. Arthrodesis is where bones are fused so there can be no further movement or pain, e.g. sub-talar or spinal.

Excision of the joint is sometimes seen in the carpal metacarpal joint in the hand to make a false joint (e.g. excision of the trapezium in the hand, which may weaken the hand but will relieve pain).

Hip joint replacement can involve re-surfacing, or the procedure can be a total hip replacement. Arthroplasty / joint replacement can be uni-compartmental (e.g. on one side of the knee joint), or the procedure may be a total knee replacement.

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Ligaments, Tendons and Muscle by Mr Chinmay Gupté

Skeletal soft tissue injuries are very common, especially in many sports. Damage can occur to the ligaments, tendons and muscles of the body. In order to recognise and treat these conditions we need an understanding of structure, function and repairing properties to come to an effective diagnosis and plan of treatment. Skeletal Muscle Muscles are effectors which enable movement to be carried out. They are also involved in the maintenance of posture. Skeletal muscles cause the skeleton to move at joints. They are attached to skeleton by tendons. Tendons transmit muscle force to the bone. Tendons are made of collagen fibres and are very strong and stiff. Muscles are either contracted or relaxed. When contracted, the muscle exerts a pulling force, causing it to shorten. Since muscles can only pull (not push), they work in pairs called antagonistic muscles. The muscle that bends the joint is called a flexor muscle. The muscle that straightens the joint is called the extensor muscle. The best known example of antagonistic muscles is the bicep and triceps muscles. Muscle macrostructure varies. For example, muscle in the biceps is described as parallel; muscle in pectoralis major is described as convergent; rectus/deltoid muscle is described as pennate. The muscle of orbicularis oris is described as circular. A single muscle e.g. biceps contains approximately 1000 muscle fibres. These fibres run the whole length of the muscle. Muscle fibres are joined together at the tendons. Each muscle fibre is actually a single muscle cell. This cell is approximately 100μm in diameter and a few cm long. These giant cells have many nuclei, and their cytoplasm is packed full of myofibrils. These are bundles of protein filaments that cause contraction. The sarcoplasm (muscle cytoplasm) also contains mitochondria to provide energy for contraction. A sarcomere is a basic contractile unit of muscle tissue. There are many sarcomeres in a myofibril (actin or myosin), and there are many myofibrils in a bundle of muscle fibres, and there are many muscle fibres in skeletal muscle. Endomysium surrounds each cell (each muscle fibre), perimysium surrounds each bundle of fibres (fascicle), and epimysium becomes the muscle sheath which fuses with the tendon. A tendon is either at an origin or an insertion. An origin is the fixed attachment of the muscle, and an insertion is the moveable attachment of the muscle. An electron micrograph shows that each myofibril is made up of repeating dark and light bands. In the middle of the dark band is the M-line. In the middle of the light band is the Z line. The repeating unit from one Z line to the next is called the sarcomere. A very high resolution electron micrograph reveals that each myofibril is made up of parallel filaments. There are two kinds of filament called thick and thin filaments. These two filaments are linked at intervals called cross-bridges, which actually stick out from the thick filaments. The thick filament consists of the protein called myosin. A myosin molecule is shaped a bit like a golf club, but with two heads. The heads stick out to form the cross bridge. Many myosin molecules stick together to form a thick filament. The thin filament consists of a protein called actin. The thin filament also contains tropomyosin. This protein is involved in the control of muscle contraction. The thick filaments produce the dark A band, and the thin filaments extend in each direction from the Z line. Where they do not overlap the thick filaments, they create the light I band. The H zone is that portion of the A

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band where the thick and thin filaments do not overlap. The entire array of thick and thin filaments between the Z lines is called a sarcomere. The sarcomeres shorten when muscle contracts. Shortening of the sarcomeres in a myofibril produces the shortening of the myofibril and of the muscle fibre of which it is a part. When the muscle contracts, the sarcomeres become shorter but the filaments do not change in length. Instead they slide past each other (overlap). So actin filaments slide between myosin filaments and the zone of overlap is larger. This is sliding filament theory. One ATP molecule is split by each cross-bridge in each cycle. This takes only a few milliseconds. During a contraction 1000’s of cross-bridges in each sarcomere go through this cycle. However, the cross-bridges are all out of sync, so there are always many cross-bridge attached at any one time to maintain force. Tendon Skeletal muscles are attached to skeleton by tendons, which transmit muscle force to the bone. They are made of collagen fibres and are very strong and stiff. Not only do they transmit muscle forces, they are also important in elastic energy storage/recoil. Collagen resists tensile stresses, and proteoglycan resists compressive stresses. Tendon microstructure consists of various components. There are parallel arrays of collagen fibres closely packed together. The dry mass is 30% of the total mass in water. All in all 86% is collagen (type 1), 2% is elastin, 1 to 5% is proteoglycans, and 0.2% is inorganic components such as copper, manganese and calcium. The collagen in tendons are held together with proteoglycan components, including decorin and, in compressed regions of tendon, aggrecan, which are capable of binding to the collagen fibrils at specific locations. The proteoglycans are interwoven with the collagen fibrils and that their GAG side chains have multiple interactions with the surface of the fibrils. The major GAG components of the tendon are dermatan sulphate and chondroitin sulphate, which associate with collagen and are involved in the fibril assembly process during tendon development. Dermatan sulphate is thought to be responsible for forming associations between fibrils, while chondroitin sulfate is thought to be more involved with occupying volume between the fibrils to keep them separated and help withstand deformation. The dermatan sulphate side chains of decorin aggregate in solution, and this behaviour can assist with the assembly of the collagen fibrils. Collagen fibres are crimped, so they extend with load. Tendons are living tissue and respond to mechanical forces by changing the metabolism as well as their structural and mechanical properties. For example, tendons exhibit increase cross sectional area and tensile strength, with increased tendon fibroblast production of collagen type I in response to appropriate physical training. However, inappropriate physical training leads to tendon overuse injuries or tendinopathy and excessive repetitive stretching of tendon fibroblast increases the production of inflammatory mediators. The Golgi tendon organ is a proprioceptive sensory receptor organ that is found at musculotendinous junctions. It provides the sensory component of the tendon reflex. Tendinopathy can be of several forms. For example: tendinosis, tendinitis, or rupture. Tendon rupture is treated with casting or surgery (usually both). Surgery is best when a tear is complete, as it results in maximal restoration of both optimal length and tensile strength. After surgery, the foot is immobilised in a plantar flexed position. At 4 weeks, the foot is brought to a neutral position and re-casted. At 6 weeks the cast is removed and gentle weight bearing and ROM exercise begins. Bounding type exercises begin no earlier than 12 weeks. Casting alone is best in partial tears and in older non-competitive athletes. On the right is surgical repair of the Achilles tendon using Bunnell cross-stitch sutures to approximate the fibres.

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Ligaments These connect bone to bone to stabilise a joint. They are also involved in proprioception. Ligaments can be intra-articular (for example the anterior cruciate ligament), or extra-articular (for example the medial collateral ligament). An example of an intracapsular ligament is the glenohumeral ligaments. Ligaments have functional subunits that tighten or loosen depending on joint position. Ligaments are not densely innervated or densely vascularised. They do contain some blood vessels and nerves in their outer covering (epiligament), and do contain proprioceptors and transmit pain signals via type C fibres. A normal ligament consists of 90% type 1 collagen (strong) and 9% type 3 collagen (immature; greater proportion in healing tissue). The remaining 1% is fibroblast cells, which produce collagen. Ligament injury classifications:

- Grade I: slight incomplete tear, no notable joint instability - Grade II: moderate/severe incomplete tear, some joint instability, maybe 1 ligament complete tear - Grade III: complete tearing of 1 or more ligaments, obvious instability, surgery usually required

Anterior cruciate ligament injuries occur when bones of the leg twist in opposite directions under full body weight. ACL injuries can be debilitating knee injuries, most often seen in athletes. The pivot-shift test, anterior drawer test and the Lachman test are used during the clinical examination of suspected ACL injury. The ACL can also be visualized using an MRI scan. If the tear is severe, surgery may be necessary because the ACL can not heal independently because there is a lack of blood supply going to this ligament. Medial collateral ligament rupture is another common injury, and total knee dislocation occurs due to rupture of the anterior cruciate ligament, posterior cruciate ligament and medial collateral ligament. The structural properties of ligaments/tendons/muscle depend on shape and area. In terms of the material, Young’s modulus is intrinsic to the tissue itself. In terms of viscoelastic properties, there is load and time dependent behaviour of tissues. Creep (load elongation) means there is increased length with constant load. Stress relaxation is another viscoelastic property. There is always a set mechanism of repair: inflammation repair remodelling. Stage Pathology - Healing Treatment Implications Inflammatory Intra-articular injury RICE (Protect & Immobilize <48 hrs) (days 0 - 4) u intra-articular pressure & hemarthrosis Immobilize (r d osteoarthritis)

Extra-articular injury NSAID drugs subcutaneous hematoma light passive ROM exercise (>48 hrs)

Fibrin clot is formed in ligament tears in minutes exercises that “cross” the joint (straight leg raises for ACL injury) Fibroblastic fibroblasts & angiogenic cells r scar matrix progress to full active ROM exercise Proliferation macrophages remove damaged ligament debris resistance & weight bearing exercise (day 4 - weeks) “decent” tensile strength within 3 weeks u intensity of all types of exercises biomechanical evals began at 3 wks Remodeling u density of scar matrix progression of activity Maturation replacement of initial or inferior collagen tissues (u intensity & duration) (weeks to years) u strength of molecular bonds of scar matrix near maximum strength reach within 1 year ** but not back to 100% of original

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Factors affecting tissue healing include the mechanical environment (movement and forces) as well as the biological environment (blood supply, immune function, infection and nutrition). During healing there is a fine line between the pros and cons of immobilisation and mobilisation. Immobilisation is good because it means there is less ligament laxity (lengthening), but the down side is there is less overall strength of the ligament repair scar, and protein degradation exceeds protein synthesis in collagen quantity. There is also the production of inferior tissue by blast cells, and resorption of bone at the site of ligament insertion. Mobilisation is good for injured ligamentous tissue because the ligament scars are wider, stronger and are more elastic. There is also better alignment and quality of collagen. ACL ligament repair surgery has several stages. Firstly a suture anchor is placed in the condyle of the femur in and through the site of normal ACL origin. Then the ends of ACL are approximated using the sutures from the anchor. A clot of the patients own blood is then formed and attached to the suture site.

The replacement ligament is harvested from a donor site (e.g. patellar tendon, plantaris tendon, gracillis tendon). The replacement is then grafted into holes drilled into the femur and tibia. Summary: Muscle is a tissue that facilitates locomotion and maintenance of posture by contraction, and also plays a role in proprioception. On a macro-scale, muscle structure varies. For example, muscle is described as “parallel” in biceps, “convergent” in pectoralis major, “pennate” in the deltoids, or “circular” in orbicularis oris. The microstructure of muscle consists of epimysium, perimysium, and endomysium. The structure comprises thick filaments of myosin and thin filaments of actin/tropomyosin forming myofibrils with sarcomeres. Injury to muscle can be direct (cut contusion) or indirect (strain/tear/myositis). Tendon is a tissue that connects muscle to bone and transmits muscle forces. It improves muscle’s mechanical advantage, and also plays a role in proprioception. Its macrostructure consists of paratendon, epitendon and endotendon. In terms of microstructure, it is formed of type 1 collagen (98%) and elastin and cells. There is also a component of proteoglycans with GAG chains and chondroitin. There are also Golgi tendon organs at the muscle-tendon junction. Injury can be a direct injury, a rupture or tendinitis. Ligament is a tissue that connects bone to bone (except for meniscofemoral ligaments) and plays an important role in joint stability and also proprioception. Its macrostructure is discrete. Ligaments can be intracapsular (e.g. the ACL), or extracapsular (e.g. LCL of the knee), or capsular (e.g. the GHL). Ligament is actually two thirds water, and one third solid. 75% of this solid is collagen, of which 85% is type 1, forming bundles. Injury can be direct, for example to the medial collateral ligament, or indirect through stretch. Repair has a set pathway in most cases. Firstly there is inflammation, involving platelets, neutrophils, monocytes and macrophages. Next there is repair, involving fibroblasts and collagen and prostaglandins. Finally there is remodelling, where the result is actually less cells but more collagen. GAG later has increased strength.

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Introduction to Orthopaedic Biomechanics by Professor Andrew Amis

Static equilibrium is an analysis based on Newton’s laws. The first is that every action has an equal and opposite reaction. The second is that an object will persist in its state of motion or rest unless acted upon by a resultant force. The third is that when a force acts on an object it will cause it to accelerate in proportion to the size of the force and inversely to its mass. There are several areas of mechanical analysis:

- Statics: in which we analyse the state of equilibrium without reference to motion. - Kinematics: in which we analyse the motion without reference to the forces acting. - Dynamics: in which we analyse both the motion and the forces affecting the motion.

For static equilibrium, we must analyse both linear and rotational effects together. Forces cause linear translations, and moments cause rotations. Both are vectorial variables, as they must be defined by how large they are and also by their direction. Scalar variables, such as mass, do not have any inherent directionality. Force is measured in Newtons, a single unit of which is defined as the amount of force which when acting on a body with a mass of 1kg will cause it to accelerate at a rate of 1ms

-1. Weight is a force, not a mass, due to the action of

gravitational acceleration on the mass, so a mass of 1kg has a weight of 9.81N. Combining forces by adding force vectors gives a “resultant” force. For equilibrium, the addition of all the force vectors has zero resultant force, and the arrows lead back to the origin. For example, three force vectors may lead to a Force Vector Triangle if they are in equilibrium. Moments, or torques, cause a turning effect about an axis (e.g. a joint axis). The units of a moment are Nm, thus for a given force (N), its moment (Nm) increases as its distance (m) from the axis increases. It is vectorial - clockwise vs anticlockwise. A moment is the magnitude of the force times the perpendicular distance from the line of action of the force to the axis. For rotational equilibrium, all the moments acting about an axis must sum to zero. to ensure equilibrium, we most often examine the equilibrium of forces and also of moments acting on a body. To simplify matters, we usually examine the force components acting in orthogonal directions, e.g. horizontal and vertical, after resolving the forces into these components. There are some special cases in equilibrium, such as a One Force Problem, Two Force Problem, and Three Force Problem. In a Three Force Problem, there is a force that points at an axis so it has no moment about that axis, so three forces must intersect at a point. These concepts can be applied to, for example, the knee joint, or the ankle joint (the tibio-talar joint). The magnitude and direction of the tibio-talar joint force can be calculated. We start by drawing the foot in isolation (this is called a Free-body diagram). It doesn’t matter what forces are inside the free-body, all we need to do is to analyse all the forces and moments acting on it. Start with a known force, think what it does to the foot, and think how to attain rotational equilibrium. In vivo, there is greater complexity. Due to the 3D reality, it is important to simultaneously ensure equilibrium about the x, y, and z axes. There are many co-operating muscles, so how do you assign tensions to each of them? Motion entails forces resulting from acceleration of masses such as limb segments, these are inertial effects. These concepts of biomechanics are useful when developing treatments such as total hip replacement. Usually a metal implant is inserted into the femur, with a shape similar to that of the head of the femur to that it can insert into the hip. If the forces acting at this joint are not understood, complications can arise. For

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example, if there is a reduced head-stem offset, the abductor muscle forces and bending moment acting on the stem of the implant will be reduced. But it the moment arms of the muscles controlling internal/external rotation will also be reduced. So the forces acting in the AP direction will increase, and the reduced offset stem will fracture in AP bending. In the elbow flexion analysis on the right, this situation is ‘indeterminate’. We must find a way to assign each muscle force, such as EMG or PCSAs. Complexity increases with hand grasping, wrist stability, triceps antagonism for elbow stability and forearm rotation equilibrium. Gait Analysis: Main tools of a gait lab

• Movement analysis: measures kinematic information (kinematics) with multiple cameras, so you can see 3D joint positions at any point in time.

• Force Plate: measures kinetic information -> Ground Reaction Force -> loading of the foot on the ground.

• Combination of both: calculation of joint moments and joint powers. • Electromyography (EMG): information on which muscles are active at which time during the gait

cycle. Example with Cerebral Palsy: Foot “hangs down“(plantar flexion) during the swing phase this disconnect parts of the calf muscle in and connected to the front of the leg, so there is a problem with the muscle that lifts the foot during swing. The surgery to treat this is irreversible, so very careful gait analysis is performed prior to this. Other tools and gadgets are:

• Breath gas analysis (for energy consumption studies) • Goniometers (angle measurement device, which can for example be attached to the body for simple

movement analysis) • Pressure distribution measurement (in-shoe, flexible mat, platform type) • Bicycle and isokinetic ergometers • Material testing machines (for material biomechanists)

An example on the right is a knee joint flexion graph, and the subject is also filmed with the targets on their limbs. Another example is the use of Force Plates to assess the forces in gait. There are a few main stages: heel strike, weight acceptance, mid stance phase and the push off. The forces at each of these stages in the vertical, forwards/backwards and sidewards directions can be measured and plotted on a graph.

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Pathogenesis of Autoimmune Rheumatic Disease by Professor Patrick Venables

The human leukocyte antigen (HLA) system is subdivided into Class I (A, B, C) and Class II (DR). Class I is involved with the presentation of intracellular antigens to CD8 (cytotoxic) T cells. Class II is involved in the presentation of extracellular antigens to CD4 (helper) T cells. They are encoded by the major histocompatability complex (MHC) on chromosome 6. Each HLA molecule locus is highly polymorphic between individuals. HLA is analogous to a passport or an identity card in the body. In a healthy cell, the HLA class I antigen will signal to cytotoxic T cells that it is normal. In an infected cell (viral or bacterial), the HLA class I antigen is altered with a bacterial peptide, so the cytotoxic T cells recognise this and they destroy the infected cell. The T cells communicate this to each other via IL-2. Class II antigens will present with a bacterial peptide to CD4 helper T cells, which release IL-2 and IL-6 to recruit more CD4 cells, CD8 cells and B cells. The major histocompatability complex is important because if, for example, there is a foreign cell trapped in a different body, there will be an HLA mismatch with the T cell receptor and the cytotoxic T cell will kill the transplanted cell. Historically, there is great clinical significance of the HLA system in organ transplants. At least 2 out of 4 (A, B, C, DR) must be matched for a successful transplant, so live sibling donors are most likely to be successful. Recently, there is clinical significance of the HLA system in disease susceptibility. HLA B27 is was first described in 1966 and is associated with Seronegative arthritis; HLA DR4 was first described in the 1980s and is associated with Rheumatoid arthritis; and HLA DR3 was also first described in the 1980s and is associated with SLE and organ specific autoimmune disease. Gamma interferon was the first described cytokine. It interferes with viral infections because it up-regulates antigen presenting cells and it also interferes with intracellular processing of the viral transcript. The clinical relevance of cytokines is that they are targeted by monoclonal antibodies in treatments. IL-2 antibodies are useful in organ transplants, IL-6 antibodies are used in the treatment of rheumatoid arthritis, as are antibodies of TNF-α. Autoimmune disease can be organ specific, or non-organ specific. Examples of organ specific autoimmune diseases include diabetes, Hashimoto’s thyroiditis, Graves’ disease, pernicious anaemia, multiple sclerosis, inflammatory bowel disease, and myasthenia gravis. These are really horrible illnesses. Diabetes, for example, affects 2% of the population. It shortens life by 10 years, leads to horrific vascular disease, can cause impotence by the age of 40 and sentences the patient to a lifetime of insulin. 30% of women over the age of 65 have Hashimoto’s thyroiditis. In the 20

th Century putting iodine in the water has lead to antibodies that

cause the autoimmune condition in so many elderly women today. Examples of non-organ specific autoimmune disease include inflammatory rheumatic diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Other non-organ specific examples include Sjorgren’s syndrome, polymyositis, scleroderma, and vasculitis. In organ specific autoimmune disease, cellular autoantigens can be cellular enzymes, hormones or receptors specific to the organ. In non-organ specific disease the antigens are not specific to a particular cell type, but may in fact be nuclear antigens (DNA, nRNPs), or the immune system can also target cytoplasmic components (cRNPs, enzymes) or membrane components (phospholipids). Clinical observation of SLE will show the classic rash. The photosensitive component is to ultraviolet light, which is a risk factor. The rash spares protected areas like the nasolabial folds. The antigens are mainly components within the nucleus, such as DNA, histones, ribonucleoproteins and negatively charged phospholipids.

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Ribonucleoproteins like nRNP and Sm are involves in splicing. Ro and La are involved in RNA polymerase transcription. Genetics tell us that complement deficiencies (rare) strongly predispose an individual to SLE, which is linked to DR3. CRP knockouts are associated with lupus in mice, although this cannot be done in humans as they would probably die instantly. Complement and CRP are the “hoovers” of the body. Lupus is mediated by apoptosis. It all starts with a healthy cell with a positively charged membrane etc. A cellular insult like exposure to UV light or a virus causes the cell to undergo apoptosis. The nucleus becomes very small, and nuclear antigens such as DNA, histones and nRNPs are presented on the cell surface. The charge on the cell surface changes from positive to negative. Apoptosis happens all the time in the body, so there is a very efficient system for cleaning it up, which is a primary role of complement and CRP. They clear up the mess before it causes an immune response. A defect in this system or a complement deficiency causes a high frequency of lupus. Failure of clearance of apoptotic material causes anti-nuclear antibodies. They form immune complexes containing antigen, antibody and complement. These complexes circulate, and deposit in the kidney (causing glomerulonephritis), in the skin (causing rashes), and in blood vessels (causing vasculitis). So to summarise, a cellular insult causes apoptosis. The antigens and negative phospholipids produced are expressed as blebs on the cell surface, and failure to clear these causes an immune response - antibodies to the nuclear antigens and phospholipids. These immune complexes then circulate and cause tissue damage. This is the Garbage Disposal Hypothesis. Clinical observation in rheumatoid arthritis tells us that there is prominent destruction and inflammation of joints. There is improvement if treated with TNF and IL-1 inhibitors. There are autoantibodies to citrullinated proteins. Citrulline is a post-translational modification of Arginine. You also get rheumatoid factors. A rheumatoid factor is an IgM auto-antibody against the Fc portion of IgG. Immune complexes containing rheumatoid factors form at the joints. Synovial macrophages are then activated, and they eat up the immune complexes, and produces various cytokines, a key one being TNF-α, but also γ-IFN, IL-1, IL-2 and IL-6. There are then high levels of TNF in the joint. TNF induces metalloproteinase secretion, which is a protease (collagenase) and requires metal ions as co-factors. These enzymes eat away at collagen, and the other proinflammatory cytokines cause inflammation. These are the two features of rheumatoid arthritis - inflammation and joint destruction. Rheumatoid arthritis improves with TNF inhibitors.

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Rheumatology by Dr Matthew Pickering

Rheumatoid arthritis is the commonest joint condition you are likely to come across in medical practice. There are various classifications of rheumatic disease. The ones we to be interested in for the ICSM MBBS Year 2 course are Type I (systemic connective tissue disease), Type IV (arthritis associated with an infectious agent), and Type VI (bone and cartilage disorders). A rheumatologist is a medically qualified physician with experience in the management of rheumatic and musculoskeletal disease. Qualifications needed include a medical degree, MRCP, possibly an MSc or PhD, and specialist registration with the GMC after completion of supervised training. Rheumatology is a very multi-disciplinary field, as patient care can require physiotherapists, orthopaedic surgeons, occupational therapists, podiatrists, specialist nurses, social workers and psychologists. Rheumatoid arthritis is a chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis (inflammation of the synovial membrane) of diarthrodial joints. The clinical features of rheumatoid arthritis may include early morning stiffness, symmetrical polyarthritis, joint damage and destruction, extra-articular disease (e.g. vasculitis), rheumatoid nodules and rheumatoid factor in the serum. 1% of the population is affected by rheumatoid arthritis. The male to female ratio is 1 to 3, with no racial predilection. It is a relatively common cause of significant disability in young adults. It has an important genetic component, with the familial concordance rate for siblings and dizygotic twins at 2 to 3%. Genetically, HLA-DR4 is an important susceptibility factor, and other genes have recently been identified in genome-wide studies. Key features of rheumatoid arthritis are morning stiffness in and around joints, symmetrical arthritis, polyarthritis, swelling of the small joints of the hand & wrists, subcutaneous nodules, rheumatoid factor in the serum and joint erosions visible on radiographs. The commonest affected joints are the metacarpo-phalangeal joints, the proximal interphalangeal joints, wrists, knees, ankles and metatarso-phalangeal joints. Classically the distal interphalangeal joints are spared. The picture on the right shows swelling of the metacarpo-phalangeal joints, the wrist looks swollen, and there is abnormal alignment due to partial destruction. This can occur in the feet too. Erosive joint destruction causes structures to become unstable, and any abnormal forces can cause deformities such as “swan-neck” and “Boutonnière” deformities. The primary site of pathology is in the synovium of joints, bursae and tendon sheaths. Patients present with proximal interphalangeal joint synovitis, and it is a good idea to look out for nicotine staining on their finger tips, as smoking worsens the condition. Another presentation is olecranon bursitis, as an example of pathology in a bursa. Tendon sheaths can also be affected, and if the tendon is inflamed, there is a higher risk of infiltration and ruptured tendons, e.g. as seen in extensor tenosynovitis. An additional key feature is subcutaneous nodules. These consist of a central area of fibrinoid necrosis surrounded by histocytes and a peripheral layer of connective tissue. They occur in around 30% of patients, and are associated with severe disease, extra-articular manifestations and rheumatoid factor. A patient with nodules is more likely to get joint damage, and this is often important in a drug risk-benefit analysis. Rheumatoid nodules are classically found along the ulnar border under the skin. You can also get them on joints e.g. in the hand, and oddly they can occur internally as well when strongly associated with smoking (these nodules will show up on a chest x-ray). Another additional key feature is rheumatoid factor. This is seen in a blood test. Rheumatoid factor is an antibody that recognises the Fc portion of IgG as its target antigen. They are typically IgM antibodies.

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70% of patients are positive for rheumatoid factor at disease onset, and the other 30% who are not will probably become so over time. Anti-cyclic citrullinated peptide antibodies (CCP) are highly specific for rheumatoid arthritis. A combination of rheumatoid factor and anti-CCP positivity is extremely suggestive of a diagnosis of rheumatoid arthritis. Rheumatoid factor positivity is associated with more severe disease, and extra-articular manifestations including rheumatoid nodules. The most common extra-articular features of rheumatoid arthritis are fever and weight loss. Patients present with joint pain, but what distinguishes rheumatoid patients is that they also feel generally ill. Other extra-articular features are quite uncommon, for example subcutaneous nodules, palmar erythema, vasculitis, ocular inflammation (e.g. episcleritis), neuropathies, amyloidosis, lung disease (nodules, fibrosis, pleuritis), and Felty’s syndrome (splenomegaly, leukopenia and rheumatoid arthritis). Early treatment means these complications such as episcleritis and vasculitis are very uncommon. Another additional key feature is joint erosion on radiographs. Radiographic abnormalities are seen at different stages as the disease progresses. Early on, you may see juxta-articlar osteopenia. Later you may see joint erosions at margins of the joint. Later still there will be joint deformity and destruction. Osteopenia is where bone resorption occurs and so bones look lighter around the joints. Erosions occur as time goes on. Pathogenesis To understand the pathogenesis of rheumatoid arthritis, it is important to understand the structure of a joint, so revise this first. “Synovium” means “egg-like”. Synovium is a lining that is three cells deep. There are cells such as Type A Synoviocytes, which are macrophage like and are phagocytic. Type B Synoviocytes are fibroblast like and produce hyaluronate. Type I collagen is also found here. Synovial fluid is a hyaluronate-rich viscous fluid. In rheumatoid arthritis, the synovium starts to proliferate, and forms pannus tissue. This is almost like a locally invasive tumour, which starts to erode the joint. The cartilage narrows, and so does the joint space. The proliferated mass of tissue (pannus) causes neovascularisation and lymphangiogenesis. It contains inflammatory cells like activated B and T cells, plasma cells, mast cells and activated macrophages. Recruitment, activation and effector functions of these cells are controlled by a cytokine network.

There is significant cytokine imbalance in rheumatoid arthritis.

The cytokine TNF- is the dominant pro-inflammatory cytokine in the rheumatoid joint. In rheumatoid

arthritis, TNF- is mainly produced by activated macrophages in synovium. TNF has multiple actions. It is responsible for cachexia, anorexia, and bone damage.

Physiological actions of TNF-α include chemokine release, proinflammatory cytokine release, Hepcidin induction, PGE2 production, osteoclast activation, chondrocytes activation, angiogenesis, leukocyte accumulation, and endothelial cell activation. Treatment involves biological therapy, by the production of a monoclonal antibody that targets TNF-α. It can be given intravenously or subcutaneously to treat patients with rheumatoid arthritis. It stops joint inflammation, stops joint damage and returns the patient to good quality of life.

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Many other cytokines are under investigation as possible therapeutic targets in rheumatoid arthritis. Monoclonal antibodies can inhibit a whole host of targets, and TNF-α was the start of a new generation of treatment against proinflammatory targets that will soon replace using steroids to switch off inflammation. The treatment goal is to prevent joint damage. Drugs that control the disease process are termed ‘disease-modifying anti-rheumatic drugs (DMARDs). These agents are started early in the disease, as joint destruction depends on inflammation and time. New biological therapies offer potent and targeted treatment strategies, e.g. anti-TNF treatment. The treatment of rheumatoid arthritis requires a multi-disciplinary approach. Non-steroidal anti-inflammatory drugs (NSAIDs) can be used in the treatment of pain and inflammation. The beneficial effects include analgesia, antipyretic action, anti-inflammatory action, and anti-platelet action. The major mechanism of action is inhibiting cyclo-oxygenase (COX), an enzyme involved in prostaglandin synthesis. NSAIDs are very commonly prescribed. There are some unwanted effects, including gastritis and peptic ulcer formation with complications such as perforation and bleeding. In fact, NSAID stomach injury causes 16,500 deaths annually in the USA. Unwanted effects can also include liver toxicity, renal toxicity, and hypersensitivity reactions. Glucocorticoids (corticosteroids) suppress inflammation and modify the immune response. They are extremely useful drugs and in many circumstances are life-saving. They have quite a complex mechanism of action, and can be given orally, intramuscularly, intravenously, or can actually be injected into tendon sheaths, soft tissue or joints. Glucocorticoids may also have many adverse effects, including diabetes, osteoporosis, suppression of growth in children, obesity, infection, skin changes, hirsutism, and peptic ulcer disease. Cushing’s like symptoms may form. DMARDs are drugs that may induce remission (not cure) of rheumatoid arthritis. This is achieved by reducing the amount of inflammation in the synovium, and by slowing or preventing structural joint damage (e.g. bone erosions). These drugs are introduced in early disease, and they have a complex mechanism of action. They all have a relatively slow onset of action, i.e. weeks. Examples of DMARDs include Methotrexate, Sulphasalazine and Hydroxychloroquine. There is also Leflunomide, and rarely used are Gold and Penicillamine. They all have significant adverse effects and thus require regular blood test monitoring during therapy. Biological therapies are new agents that include antibodies or fusion proteins, which target specific inflammatory proteins involved in the pathogenesis of rheumatoid arthritis. For example, the inhibition of TNF, a molecule that causes inflammation in rheumatoid joints (Infliximab, Etanercept, Adulimumab). Another example is the inhibition of IL-6. These therapies can also target antigens on specific cells, for example B-cell depletion therapy with antibody against CD20, a surface antigen on B cells (Rituximab).

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Reactive Arthritis by Dr Matthew Pickering

Direct infection of the joints leads to septic arthritis. Septic arthritis is most commonly bacterial. Inflammatory arthritis following infection causes reactive arthritis, which is defined as sterile inflammatory synovitis following an infection. This is particularly seen following urogenital and gastrointestinal infections. This has important extra-articular manifestations, including enthesopathy, skin inflammation, and eye inflammation, all of which are important diagnostic clues. ‘Sterile’ means there is no need for antibiotics, as it is just an inappropriate immune response. Technically, any infection can give you reactive arthritis. The classic ones, however, are urogenital infections such as Chlamydia trachomatis, and enterogenic infections such as Salmonella, Shigella, and Campylobacter infections. Reactive arthritis may be the first manifestation of HIV or hepatitis C infection. Reactive arthritis is most commonly seen in young adults aged between 20 and 40 years. There is always a genetic predisposition and an environmental trigger. For example, this can be HLA-B27 and an environmental hit of Salmonella infection. After the initial infection, the symptoms of reactive arthritis follow one to four weeks afterwards. The initial reaction may be mild or inapparent in 10% of cases. The symptoms can be broadly split into those of arthritis, enthesitis and spondylitis. With arthritis, the patient will experience symptoms of inflammation and morning joint stiffness. The patterns of joints involved are asymmetrical, and it will usually be oligoarthritis (less than 5 joints affected). The lower limbs are typically affected. With enthesitis, the patient will have inflammation where a ligament, tendon, fascia or capsule inserts into the bone. Examples are heel pain (Achilles tendon, plantar fascia), swollen fingers (dactylitis), and painful feet (metatarsalgia due to plantar fasciitis). With spondylitis, there is inflammation of the spine. Sacroiliitis is inflammation of the sacro-iliac joint. This can exclude rheumatoid arthritis in a diagnosis without the need for any investigations. The ocular extra-articular features of reactive arthritis include sterile conjunctivitis. The genito-urinary features include sterile urethritis. The mucocutaneous features include circinate balanitis (inflammation of the glans of the penis), and also psoriasis-like rashes on the hands and feet (Keratoderma blennorrhagica). Reiter’s syndrome is the clinical triad of arthritis, conjunctivitis and urethritis following infectious dysentery.

Rheumatoid Arthritis Reactive Arthritis

Sex Ratio Female > Male Male > Female

Age All ages 20 - 40 years

Arthritis

Polyarticular Symmetrical MCP, PIP, wrists, MTPs

Oligoarticular Asymmetrical Large joints

Enthesitis no yes

Spondylitis no (cervical spine only) yes

Urethritis no yes

Skin Subcutaneous nodules Skin vasculitis

Keratoderma blennorrhagica Balanitis

Rheumatoid Factor yes no

HLA association HLA-DR4 HLA-B27

Diagnosis of reactive arthritis is established by clinical diagnosis and investigations to exclude other causes of arthritis, e.g. septic arthritis. Examples of important investigations are in microbiology and immunology. In microbiology there are microbial cultures (blood, throat, urine, stool, urethral, cervical, etc) and also serology (for HIV and hepatitis C). In immunology there are tests for rheumatoid factor and HLA-B27. Synovial fluid examination may also be carried out. In an acute swollen knee, pus is aspirated from the joint. Gram staining and culturing will define the causative organism and its antibiotic sensitivities.

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In septic arthritis the synovial fluid cultures will be positive for microbes and antibiotics and joint lavage are advised. In reactive arthritis the synovial fluid will be sterile, and there is no need for antibiotics. There are some predisposing factors for septic arthritis. For example impaired host defence, if the patient is elderly or young, if they have chronic illnesses such as diabetes or liver disease, and also if they are on immunosuppressive medication e.g. corticosteroids. Another predisposing factor is direct penetration of joints by invasive procedures (e.g. arthroscopy), IVDA, or puncture wounds. People are also predisposed to septic arthritis if they have joint damage, if they have prosthetic joints or a chronic arthritis like rheumatoid arthritis. Septic arthritis is usually associated with impaired host immunity or direct injury to the joint. This needs rapid diagnosis to prevent joint destruction. Treatment is with antibiotic therapy and drainage of the joint. If you know what is causing the septic arthritis, then you give the appropriate antibiotic. If you don’t know, then just give the most likely one to work (e.g. the most like cause is Staphylococcus, so give a broad spectrum antibiotic). In the majority of patients there is complete resolution within two to six months. The articular manifestations of reactive arthritis are treated with NSAIDs and intra-articular corticosteroid therapy. The extra-articular manifestations are typically self-limiting, and hence symptomatic therapy is used (e.g. topical steroids and keratolytic agents). There is no role for antibiotics.

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Osteoarthritis by Dr Matthew Pickering

Osteoarthritis is a slowly progressive disorder that typically affects the joints of the hand, the spine, and the weight-bearing joints of the lower limbs. Joints such as the distal and proximal interphalangeal joints and the first carpo-metacarpal joints are affected in the hand. Joints like the knees and hips are affected in the lower limbs, as well as the first metatarso-phalangeal joints. Osteoarthritis is ‘wear and tear’ arthritis. The patient typically experiences joint pain, which is worse with activity and better with rest, and also joint crepitus (creaking, cracking, grinding sounds on moving the affected joint). There is joint instability, and also joint enlargement (e.g. Heberden’s nodes). Joint stiffness after immobility is known as ‘gelling’, and there is significant limitation of motion. Osteoarthritis develops due to defective articular cartilage and damage to the underlying bone. This is caused by excessive loading on joints, and abnormal joint components. The pathological changes in osteoarthritis are focal areas of damage to articular cartilage. There is new bone formation at the joint margins (osteophytosis) and changes in the subchondral bone (sclerosis). Unfortunately there is irreversible loss of articular cartilage. The normal weight-bearing properties of articular cartilage depend on an intact collagen scaffold and a high aggrecan content. Collagen and aggrecan turnover is slow, with the half life of collagen being decades and the half life of aggrecan being around 3 to 4 years. Normal articular cartilage is an avascular and aneural structure. 90% of the collagen is type I, there are many chondrocytes and also proteoglycan monomers (aggrecan). The monomers are arranged into supramolecular aggregates consisting of central hyaluronic acid filament and non-covalently linked aggrecan. Negatively charged chemical groups of GAGs attract water into cartilage - 80% of the wet weight is water. In osteoarthritis, there is reduced proteoglycans and increased cartilage hydration (these two together are called chondromalacia), and an overall reduced collagen. Chondromalacia is the softening of cartilage because of increased water to proteoglycan ratio in the cartilage matrix. Cleavage of aggrecan in osteoarthritis is mediated by ADAMTS aggrecanases. Aggrecan fragments are present in anosteoarthritis joint. Small molecule inhibitors of ADAMTS-4 and ADAMTS-5 could be future therapies for osteoarthritis. There is also increased chondrocytes proliferation in osteoarthritis. This is an intrinsic repair mechanism for matrix synthesis. Abnormal stress leads to chondrocytes producing inflammatory mediators in osteoarthritic tissue, e.g. growth factors and cytokines which may have important roles in the disease. There are also focal areas of chondrocytes apoptosis. Examples of cytokines promoting cartilage matrix and degradation include IL-1 and TNF-α. Cytokines that promote synthesis are TGF-β, IGF-1 and bFGF. There are changes in denuded sub-articular bone. There is proliferation of superficial osteoblasts, which results in production of sclerotic bone. Focal stress on sclerotic bone can result in focal superficial necrosis in underlying bone and bone marrow. In other words, the exposed bone tries to thicken up, you get sclerosis, abnormal forces cause fractures, and this causes necrosis. Osteoarthritis is mainly seen in the elderly population, as its onset is insidious over many years. Patients present with mechanical pain that worsens with activity. There are bony enlargements, but no true swelling, warmth or erythema. It leads to a progressive loss of the joint’s range of motion, and patients experience short-term stiffness (less than 30 minutes) in the morning and after rest.

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Osteophytes at the distal interphalangeal joints are termed Heberden’s nodes. Osteophytes at the proximal interphalangeal joints are termed Bouchard’s nodes. Radiographic changes in osteoarthritis can be easily seen. There is joint space narrowing, subchondral bony sclerosis, osteophytes and subchondral cysts.

Rheumatoid Arthritis Osteoarthritis

Joint space narrowing Yes Yes

Sclerosis uncommon Yes

Osteophytes uncommon Yes

Osteopenia Yes No

Erosions Yes, initially at the margins of the joint No, rarely central erosions can occur

It is important to be able to differentiate between rheumatoid arthritis and osteoarthritis. The bony changes are predominantly something you’d see in osteoarthritis, and erosions are uncommon in osteoarthritis. Early radiographic signs of osteoarthritis will show a lack of joint space, representing worn cartilage and bone-on-bone contact. Advanced signs will show bone spurs. Osteoarthritis classically occurs in the medial compartment of the knee joint, and joint replacement is the best option for treatment. Non-pharmacological treatment involves education, physical therapy (physiotherapy and hydrotherapy), occupational therapy, weight loss where appropriate and exercise. Treatment of pain is with analgesia, NSAID therapy, and intra-articular corticosteroids (e.g. injection of corticosteroids into osteoarthritic knee joint). Therapeutic approached that are not approved in the UK include glucosamine and chondroitin sulphate. These are dietary supplements, and are controversial as they are not approved by NICE. Intra-articular injections of hyaluronic acid are also not approved in the UK. Hyaluronic acid is to increase lubrication (viscosupplementation). It is only used in the knee joint and is still experimental. Unlike rheumatoid arthritis, there are no disease modifying osteoarthritis drugs. Future therapies could stop matrix breakdown, for example aggrecanases inhibitors, cytokine inhibitors, or factors that stimulate the repair of matrix.

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Systemic Lupus Erythematosus by Professor Justin Mason

SLE is a relatively rare disease - a GP with 10,000 patients will see about 3 cases of it. It is a difficult diagnosis to make, so you must always think about SLE. It is one of a family of chronic overlapping allergic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis and Sjögren’s syndrome. Diagnoses may fit within this spectrum, so you need to consider overlap of any of these diseases. SLE is considerably more common in women (1:9 ratio). This chronic autoimmune disease presents between 15 to 40 years of age, and is increased in Afro-Caribbean, Asian and Chinese people. The prevalence varies from 4 to 280 out of 100,000. It principally affects the joints and skin, but can also have effects on the lungs, kidneys and in haematology. There are also genetic associations, with multiple genes implicated, and this is an area of research currently. In patients who have complement deficiency (e.g. C1q and C3) there is a hugely increased risk (albeit rare) of developing SLE. There are also influences of Fc receptors, IRF5, CTLA4, and MHC class II HLA genes. Clinical features: The early features are very non-specific, such as malaise, fatigue, fever, and weight loss, and also perhaps lymphadenopathy. Specific features include butterfly rash, alopecia, arthralgia, and Raynaud’s phenomenon. Other features include inflammation of the kidneys, CNS, heart or lungs. There may also be accelerated atherosclerosis and digital vasculitis. Achieving four or more of these criteria may be indicative of SLE:

Malar rash

Discoid rash

Photosensitivity

Oral ulcers

Arthritis

Serositis: (a) pleuritis or (b) pericarditis

Renal disorder e.g. proteinuria > 0.5g/24h

Neurological disorder e.g. seizures/ pyschosis

Haematological disorder

Immunologic disorder e.g anti-dsDNA Abs

Antinuclear antibody in raised titre The rash can be fairly subtle, on the cheeks, bridge of the nose and forehead. Subtle rashes could easily be missed. The patients will generally look miserable, because they do feel pretty unwell. The rash may be more severe, with dermal infiltration. This can cause de-pigmentation, and there may also be scarring alopecia. Pathogenesis This is fairly complex. The primary central factor revolves around the B lymphocyte. Normal functions of B cells include activating antigen presenting function, regulating T cell activation, cytokine production, antigen presentation, and antibody production. This is a tightly controlled system, but in a patient with SLE the regulation is lost. EBV is one factor that can contribute to this. Hyperactivated B cells and failure to clear apoptotic cells allows the production of autoantibodies. Autoantibody formation = abnormal clearance of apoptotic cell material, dendritic cell uptake of autoantigens and activation of B cells, B cell Ig class switching and affinity mutation, IgG autoantibodies, immune complexes, complement activation and cytokine generation etc. This is a type 3 hypersensitivity reaction.

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Diagnosis These are mainly laboratory tests. The first thing to do is an antinuclear antibody test (ANA), which is relatively non-specific, but the pattern is important. This is a serum test used to detect fluorescent antibodies, and you look at the pattern. A strong homogenous ANA pattern will suggest SLE. A speckled pattern may be more SLE overlap syndromes. Antinuclear antibodies:

ANA relatively non-specific, pattern important

Homogenous - Abs to DNA

Speckled - Abs to Ro, La, Sm, RNP

Nucleolar - topoisomerase - scleroderma

Centromere - limited cutaneous scleroderma Anti-dsDNA and Sm

More specific but less sensitive Anti-Ro and/or La

Common in subacute cutaneous LE

Neonatal lupus syndrome & Sjögren’s Other tests look for increased complement consumption, anti-cardiolipin antibodies, lupus anticoagulant, and β1 glycoprotein. Haematological tests look for lymphopaenia, normocytic anaemia, leukopaenia, AIHA and thrombocytopenia, which may be life threatening due to cerebral haemorrhage. Renal tests look for proteinurea, haematuria, and active urinary sediment. Assessing disease severity involves identifying the pattern of organ involvement and monitoring the function of the affected organs. Renal = BP, U&E, urine sediment and the prot:crea ratio. Lungs/CVS = lung function, ECG. Skin, haematology and eyes should also be assessed. It is also important to identify the pattern of autoantibodies expressed in the specific patient. Anti-dsDNA, anti-Sm may indicate renal disease, and there may also be anti-cardiolipin antibodies for example. As a clinician, you must try to pre-empt severe attacks. Look for the clinical features (weight loss, fatigue, malaise, hair loss, alopecia, rash), and laboratory markers like ESR (very useful test, rising ESR but no rise in CRP is indicative, unlike rheumatoid arthritis), increased complement consumption, and increased anti-dsDNA. Other antibody tests like ANA and CRP are poor indicators. Treatment Disease is divided into three groups: mild, moderate and severe. Mild disease may involve the joints and skin. Moderate disease is inflammation of other organs, pleuritis, pericarditis, and mild nephritis. Severe disease involves severe inflammation in vital organs (severe nephritis, CNS disease, pulmonary disease, cardiac involvement, AIHA, thrombocytopenia, and TTP). Treatment of mild disease is using drugs such as paracetamol with or without an NSAID. Another drug that is used is hydroxychloroquine (arthropathy, cutaneous manifestations, mild disease activity), as well as topical corticosteroids. Treatment of moderate disease will be indicated by the failure of hydroxychloroquine/NSAIDs, and the patient will be presenting with organ or life threatening disease. In this case high initial doses of corticosteroids are used to suppress the disease activity. IV methylprednisolone is given every 24 hours, with an initial oral dose for 4 weeks. This is reduced slowly over two or three months to 10mg daily, and then reduced slowly at 1mg per month. Azathioprine is a very useful drug for treating moderate to severe disease (2.5mg/kg/day), and is an effective steroid sparing agent. It treats 20% neutropenia (3/1000 severe BM suppression). Regular FBC and biochemistry monitoring is needed. Cyclophosphamide is used in severe organ involvement, IV pulsed or orally. It is used for example in nephritis, with six 1 monthly IV pulses. It can, however, cause BM suppression, infertility and cystitis (acrolein).

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Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase, which is the rate limiting enzyme in de novo purine synthesis. Lymphocytes are also dependent upon de novo purine synthesis. Rituximab is used in anti-CD20 mAb therapy, and it leads to the depletion of B cells. It is effective in lupus nephritis. Prognosis is usually a 15 year survival. With no nephritis, this is 85%, and with nephritis this is 60%. Prognosis is also worse if black, male, or of low socio-economic status. The bimodal mortality pattern of SLE is that in early disease of active lupus there is renal failure and CNS disease, as well as infection. In later disease these patients are at risk of myocardial infarction. Case Report Miss PM, a 48 year old lady with an 8 year history of SLE. HPC = 2 months malaise, rash, arthralgia, alopecia, SOBOE. PMH = autoimmune hypothyroidism. DH = moderate dose prednisolone (12.5mg OD), azathioprine (100mg OD), nifedipine, ranitidine, thyroxine. On examination she had pyrexia (38°C), butterfly rash, oral ulceration, BP 190/110, displaced apex beat, signs of consolidation R lung base, peripheral oedema. On further investigation, a chest X-ray confirmed she has right lower zone consolidation (pneumonia) and cardiomegaly. The blood film showed abnormal cells, with clear evidence of thrombocytopenia. There were also schistocytes, spherocytes, anisocytes, poikilocytosis, and fibrin strands. A renal biopsy showed a glomerulus packed full of cells, swollen and with lost shape. This was a rapidly proliferative crescentic glomerulonephritis. The working diagnosis for this was SLE, complicated by nephritis and nephrotic syndrome, microangiopathic haemolytic anaemia, and right lower lobe pneumonia. Treatment included prednisolone (60mg daily), cyclophosphamide (750mg iv pulse), intravenous antibiotics, blood/plasma/platelet transfusions, and quadruple anti-hypertensive therapy. Summary SLE = autoimmune multisystem disease. It is a rare disease, with female preponderance. Severity ranges from mild joint pain to fulminant and life threatening, and the clinical features depend on the organ affected. Treatment is symptomatic, immune-modulating and immunosuppressive.

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The GALS examination by Dr Matthew Pickering

The aim of the locomotor examination is to see if any of the joints are abnormal. What is the nature of the joint abnormality? What is the extent (distribution) of the joint involvement? Are any other features of diagnostic importance present? Look at the video on the intranet, which demonstrates the GALS examination. There are key screening questions to detect rheumatological disease - pain or stiffness in muscles, joints or back, can you dress yourself completely, can you walk up and down stairs, etc. These are tests of joint mobility and muscle weakness. Patients with proximal myopathy find it difficult to brush hair and rise from a squat. There is initial rapid joint screening, and then there is detailed examination of abnormal joints. Abnormal Joints The rapid joint screening examination is the GALS test = Gait, Arms, Legs, and Spine. First, observe the patient walking, turning and walking back, look for smoothness and symmetry of legs, pelvis and arm movements, normal stride length, and the ability to turn quickly. For spine examination, look for if the paraspinal and shoulder girdle muscle bulk is symmetrical. Is the spine straight? Are the iliac crests level? Is the gluteal muscle bulk normal? Are there popliteal swellings? Are the Achilles tendons normal? Press over the mid-point of each supraspinatus and squeeze the skinfold over the trapezius - tenderness suggests fibromyalgia. This is associated with hypersensitivity to pain, depression, and IBD. From the side note the normal spinal curvatures. Ask the patient to bend forward and touch their toes, with knees straight, to assess lumbar spine and hip flexion. Ask the patient to try to place ear on the shoulder each side - this tests lateral cervical flexion. For arms, check normal girdle muscle bulk and symmetry. Ask the patient to put elbows straight and in full extension. Patients with rheumatoid arthritis may not be able to do this. Ask the patient to attempt to place both hands behind the head, and then push elbows back. Examine the hands palms down, with fingers straight. Observe normal supination and pronation. Observe normal grip. Place the tip of each finger onto the tip of the thumb to assess normal dexterity and precision grip. Squeeze across 2

nd to 5

th metacarpal

(metacarpal squeeze test) - discomfort suggests synovitis. In healthy individuals, all these commands are quite simple. For legs, observe any knee or foot deformities. Assess flexion of the hip and knee, whilst supporting the knee. Passively internally rotate each hip, in flexion. Examine each knee for presence of fluid using “bulge” sign and “patella tap” sign. Squeeze across the metatarsals to detect any synovitis. Inspect the soles of the feet for rashes and or callosities. Nature of Joint Abnormality Look for active inflammation, irreversible joint damage, and mechanical defects. Detailed examination of abnormal joints involves inspection (swelling, redness, deformity), palpation (warmth, crepitus, tenderness), movement (active, passive, against resistance), function (loss of function). Arthritis refers to definite inflammation of a joint, i.e. swelling, tenderness and warmth of affected joints. Arthralgia refers to pain within a joint without demonstrable inflammation by physical examination. The most important signs of active inflammation are swelling and tenderness, and may also include warmth, erythema and loss of function. Acute joint inflammation includes acute gout - ‘podagra’. This is a very painful condition. Gout is a disease in which tissue deposition of monosodium urate (MSU) crystals occurs as a result of hyperuricaemia and leads to one or more of the following: gouty arthritis, or Tophi (aggregated deposits of MSU in tissue). Gouty arthritis commonly affects the metatarsal-phalangeal joint of the big toe (first MTP joint). There is abrupt onset, it is extremely painful, the joint will be red, warm, swollen and tender. This resolves spontaneously over 3-10 days.

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The site of swelling will tell you the type of tissue involved, and what disease this is indicative of. In articular soft tissue the tissue involved is the joint synovium or effusion, and this is indicative of inflammatory joint disease. In periarticular soft tissue the tissue involved is subcutaneous tissue, and this is also indicative of inflammatory joint disease. In non-articular synovial areas, the tissue involved is bursa/tendon sheath, and this is indicative of inflammation of the structure itself. Swelling in bony areas means the tissue involved is the articular ends of bone, and this is indicative of osteoarthritis. Enthesopathy is a non-articular soft tissue swelling. The pathology is at the enthesis (i.e. the site where ligament or tendon inserts into bone). Examples include plantar fasciitis and Achilles tendinitis. Irreversible joint damage refers to things like joint deformity (malalignment of two articulating bones), crepitus (audible and palpable sensation resulting from movement of one roughened surface on another, classic feature of osteoarthritis e.g. patellofemoral crepitus on flexing the knee), and loss of joint range or abnormal movement. Terms commonly used to describe peripheral joint abnormalities include ‘dislocation’ (articulating surfaces are displaced and no longer in contact), ‘sublaxation’ (partial dislocation), ‘valgus’ (lower limb deformity whereby distal part is directed away from the midline e.g. hallux valgus), and ‘varus’ (lower limb deformity whereby distal part is directed towards the midline e.g. varus knee with medal compartment OA). Joint damage and destruction may present with Swan-neck and Boutonnière deformities, and in an x-ray you can see erosive arthritis and deformity of the hands for example. In spondyloarthropathies, rheumatoid factor is negative. Ankylosing spondylitis is where you get fusing of the vertebrae. Other spondyloarthropathies include Reiter’s syndrome and reactive arthritis, arthritis associated with psoriasis (psoriatic arthritis) and arthritis associated with gastrointestinal inflammation (enterohepatic synovitis). Ankylosing spondylitis is a chronic inflammatory disease affecting the sacroiliac joints and spine, which leads to spinal fusion (ankylosis) and deformity. It is an enthesopathy and non-axial joints such as the hips and shoulders can also be affected. There is a strong associated of the disease with HLA-B27, and rheumatoid factor is negative. Mechanical defects may be a consequence of inflammation, degenerative arthritis or trauma. They can be identified by painful restriction of motion in absence of features of inflammation e.g. knee ‘locking’ due to meniscal tear or bone fragment. Instability is another thing e.g. side-to-side movement of tibia on femur due to ruptured collateral knee ligaments. The Extent (Distribution) of Joint Involvement The number of joints involved should be determined. Polyarthritis is where over 4 joints are affected. Oligoarthritis is where 2 to 4 joints are affected. Monoarthritis is where one joint is affected. Note if the involvement is symmetrical, note the size of the involved joints and if there is axial involvement. Bilateral and symmetrical involvement of large and small joints is typical of rheumatoid arthritis. Lower limb asymmetrical oligoarthritis and axial involvement are typical of reactive arthritis. Exclusive inflammation of the first metatarso-phalangeal joints is highly suggestive of gout. In rheumatoid arthritis, the commonly involved joints include the PIPs, MCPs, wrist, elbow, shoulder, cervical spine, hip, knee, ankle, tarsal and MTPs. The joints commonly spared include the DIPs, thoracic spine and lumbar spine. In osteoarthritis, the joints commonly involved include the 1

st CMC, DIP, PIP, cervical spine, thoracolumbar

spine, hip, knee, 1st

MTP and toe IP. The joints commonly spared include the MCP, wrist, elbow, shoulder, ankle, and tarsal joints. In polyarticular gout, the joints commonly involved are the 1

st MTP, ankle, and knee. The joints commonly

spared include are axial joints.

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Other Features of Diagnostic Importance Rheumatoid nodules are a giveaway in rheumatoid arthritis. These can be along the ulnar line, in PIPs and show up on a chest x-ray. Tophi are small bumps that are characteristic in gout. These show up on the sides of the ears and in the PIPs. The malar rash is characteristic of systemic lupus erythematosus.