Musculoskeletal System Clinical Examination PDF

Clinical examination of the musculoskeletal system General Assessment of Locomotor System (GALS) and Schöber's test Disorders of the musculoskeletal system affect all ages and ethnic groups. In the UK, about 25% of new consultations in general practice are for musculoskeletal symptoms. Musculoskelet...

Clinical examination of the musculoskeletal system General Assessment of Locomotor System (GALS) and Schöber's test Disorders of the musculoskeletal system affect all ages and ethnic groups. In the UK, about 25% of new consultations in general practice are for musculoskeletal symptoms. Musculoskeletal diseases may arise from processes affecting bones, joints, muscles, or connective tissues such as skin and tendon. The principal manifestations are pain and impairment of locomotor function. Diseases of the musculoskeletal system tend to be more common in women and most increase in frequency with increasing age. They are the most common cause of physical disability in older people and account for one-third of physical disability at all ages. Functional anatomy and physiology The musculoskeletal system is responsible for movement of the body, provides a structural framework to protect internal organs, and acts as a reservoir for storage of calcium and phosphate in the regulation of mineral homeostasis. The main components of the musculoskeletal system are depicted in Figure 24.1. Fig. 24.1 Structure of the major musculoskeletal tissues. Bone Bones fall into two main types, based on their embryonic development. Flat bones, such as the skull, develop by intramembranous ossification, in which embryonic fibroblasts differentiate directly into bone within condensations of mesenchymal tissue during early fetal life. Long bones, such as the femur and radius, develop by endochondral ossification from a cartilage template. During development, the cartilage is invaded by vascular tissue containing osteoprogenitor cells and is gradually replaced by bone from centres of ossification situated in the middle and at the ends of the bone. A thin remnant of cartilage called the growth plate or epiphysis remains at each end of long bones, and chondrocyte proliferation here is responsible for skeletal growth during childhood and adolescence. At the end of puberty, the increased levels of sex hormones halt cell division in the growth plate. The cartilage remnant then disappears as the epiphysis fuses and longitudinal bone growth ceases. Two types of bone tissue are present in the normal skeleton ( Fig. 24.1 ). Cortical bone is formed from Haversian systems, comprising concentric lamellae of bone tissue surrounding a central canal that contains blood vessels. Cortical bone is dense and forms a hard envelope around the long bones. Trabecular or cancellous bone fills the centre of the bone and consists of an interconnecting meshwork of trabeculae, separated by spaces filled with bone marrow. The most important cell types in bone are: Osteoclasts : multinucleated cells of haematopoietic origin, responsible for bone resorption. Osteoblasts : mononuclear cells of derived from marrow stromal cells responsible for bone formation. Osteocytes : cells that differentiate from osteoblasts that become embedded in bone matrix during bone formation. They are responsible for sensing and responding to mechanical stimuli and for coordinating osteoclast and osteoblast activity. Bone marrow stromal cells : cells that produce receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), which stimulate osteoclast formation, and other cytokines that support haematopoiesis ( p. 914 ). Bone lining cells : flattened cells lining the bone surface that differentiate from osteoblasts when bone formation is complete. Bone matrix and mineral The most abundant protein of bone is type I collagen, which is formed from two α1 peptide chains and one α2 chain wound together in a triple helix. Type I collagen is proteolytically processed inside the cell before being laid down in the extracellular space, releasing propeptide fragments that can be used as biochemical markers of bone formation. Subsequently, the collagen fibrils become ‘cross-linked’ to one another by pyridinium molecules, a process that enhances bone strength. When bone is broken down by osteoclasts, the cross-links are released into the circulation. These can be measured biochemically and are sometimes used clinically to assess levels of bone resorption. Bone is normally laid down in an orderly fashion, but when bone turnover is high, as in Paget's disease or severe hyperparathyroidism, it is laid down in a chaotic pattern, giving rise to ‘woven bone’ that is mechanically weak. Bone matrix also contains growth factors, other structural proteins and proteoglycans, thought to be involved in helping bone cells attach to bone matrix and in regulating bone cell activity. The other major component of bone is mineral, comprised of calcium and phosphate crystals deposited between the collagen fibrils in the form of hydroxyapatite [Ca 10 (PO 4 ) 6 (OH) 2 ]. Mineralisation is essential for bone's rigidity and strength but over-mineralisation causes the bone to become brittle. In clinical practice, increased mineralisation can occur in some types of osteogenesis imperfecta and in response to long-term bisphosphonate therapy. Bone remodelling Bone remodelling is required for renewal and repair of the skeleton throughout life. This is a cyclical process that has four phases; quiescence, resorption, reversal and formation, as illustrated in Figure 24.2. Remodelling starts with the attraction of osteoclast precursors in peripheral blood to the target site, probably by local release of chemotactic factors from areas of microdamage. The osteoclasts resorb bone and, after about 10 days,undergo programmed cell death (apoptosis), heralding the start of the reversal phase, when osteoblast precursors are recruited to the resorption site. The osteoblast precursors differentiate into mature osteoblasts and form new bone during the formation phase. Initially, the matrix is unmineralised (osteoid) but eventually becomes mineralised to form mature bone. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes, which play a key regulatory role in coordinating bone formation and resorption, whereas others differentiate into bone-lining cells. Fig. 24.2 The bone remodelling cycle. Bone is renewed and repaired by the process of bone remodelling. This begins by removal of old and damaged bone by osteoclasts during the phase of bone resorption. After about 10 days,the osteoclasts undergo programmed cell death (apoptosis) and during the reversal phase are replaced by osteoblasts, which begin to fill in the resorbed area with new bone matrix, heralding the start of bone formation. The bone matrix is initially uncalcified (osteoid) but then becomes mineralised to form mature bone. The cellular and molecular mediators of this bone remodelling are shown in more detail in Figure 24.3. Osteoclast precursors are derived from haematopoietic stem cells and differentiate into mature osteoclasts in response to M-CSF, produced by bone marrow stromal cells, and RANKL, produced by osteocytes, bone marrow stromal cells and osteoblasts. The RANKL binds to and activates a receptor called RANK (receptor activator of nuclear factor kappa B) on osteoclast precursors, promoting osteoclast differentiation and bone resorption. This effect is blocked by osteoprotegerin (OPG), which is a decoy receptor for RANKL that inhibits osteoclast formation. Once formed, mature osteoclasts attach to the bone surface by a tight sealing zone and secrete hydrochloric acid and proteolytic enzymes, including cathepsin K, into the space underneath, which is known as the Howship's lacuna. The acid dissolves the mineral and cathepsin K degrades collagen. Osteocytes also produce sclerostin (SOST), which is a potent inhibitor of bone formation. Under conditions of mechanical loading, sclerostin production by osteocytes is inhibited, allowing bone formation to proceed, stimulated by members of the Wnt family of signalling proteins. The Wnt molecules stimulate bone formation by activating members of the lipoprotein receptor-related protein (LRP) family, the most important of which are LRP4, LRP5 and LRP6. Sclerostin antagonises the effects of Wnt family members by blocking their interaction with LRP family members. Finally, osteocytes play a critical role in phosphate homeostasis by producing the hormone FGF23, which regulates renal tubular phosphate reabsorption. Key regulators of bone remodelling are summarised in Box 24.1. Fig. 24.3 Cellular and molecular regulators of bone remodelling Osteoclast precursors are derived from haematopoietic stem cells. They differentiate into mature osteoclasts in response to the receptor activator of nuclear factor kappa B ligand (RANKL), which is produced by osteocytes, bone marrow stromal cells, osteoblasts and activated T cells (not shown), and macrophage colony-stimulating factor (M-CSF), which is produced by bone marrow stromal cells. Osteoprotegerin (OPG) is also produced in the bone microenvironment, where it inhibits osteoclastic bone resorption by blocking the effect of RANKL. Osteoblasts, which are derived from bone marrow stromal cells, are responsible for bone formation. Osteoblast activity is stimulated by signalling molecules in the Wnt family but inhibited by sclerostin (SOST), which is produced by osteocytes. In addition to their role in regulating osteoclast and osteoblast activity, osteocytes have an endocrine function in regulating phosphate homeostasis by producing fibroblast growth factor 23 (FGF23), which acts on the kidney to promote phosphate excretion. 24.1 Key regulators of bone remodelling Mediator Source Effects Comment RANKL Osteocytes Stromal cells Osteoblasts Activated T cells Stimulates bone resorption Activates RANK Osteoprotegerin Stromal cells Lymphocytes Inhibits bone resorption Acts as decoy receptor for RANKL Wnt Stromal cells Stimulates bone formation Activates LRP receptors Sclerostin Osteocytes Inhibits bone formation Blocks effect of Wnt on LRP receptors Parathyroid hormone Parathyroid glands Increases bone resorption and formation Thyroid hormone Thyroid gland Increases bone resorption and formation Oestrogen Ovary Inhibits bone resorption Glucocorticoid Adrenal gland Exogenous Inhibits bone formation (LRP = lipoprotein receptor-related protein; RANKL = receptor activator of nuclear factor kappa B ligand) Mineralisation of bone is critically dependent on the enzyme alkaline phosphatase (ALP), which is produced by osteoblasts and degrades pyrophosphate, an inhibitor of mineralisation. Bone remodelling is predominantly regulated at a local level but can be influenced by circulating hormones or mechanical loading, which can up- regulate or down-regulate remodelling across the whole skeleton ( Box 24.1 ). Joints There are three main types of joint: fibrous, fibrocartilaginous and synovial ( Box 24.2 ). 24.2 Types of joint Type Range of movement Examples Fibrous Minimal Skull sutures Fibrocartilaginous Limited Symphysis pubis Costochondral junctions Intervertebral discs Sacroiliac joints Synovial Large Most limb joints Temporomandibular Costovertebral Fibrous and fibrocartilaginous joints These comprise a simple bridge of fibrous or fibrocartilaginous tissue joining two bones together where there is little requirement for movement. The intervertebral disc is a special type of fibrocartilaginous joint in which an amorphous area, called the nucleus pulposus, lies in the centre of the fibrocartilaginous bridge. The nucleus has a high water content and acts as a cushion to improve the disc's shock-absorbing properties. Synovial joints These are complex structures containing several cell types. They are found where a wide range of movement is needed ( Fig. 24.4 ). Fig. 24.4 Structure of a synovial joint. Articular cartilage This avascular tissue covers the bone ends in synovial joints. Cartilage cells (chondrocytes) are responsible for synthesis and turnover of cartilage, which consists of a mesh of type II collagen fibrils that extend through a hydrated ‘gel’ of proteoglycan molecules. The most important proteoglycan is aggrecan, which consists of a core protein to which several glycosaminoglycan (GAG) side chains are attached ( Fig. 24.5 ). The GAGs are polysaccharides that consist of long chains of disaccharide repeats comprising one normal sugar and an amino sugar. The most abundant GAGs in aggrecan are chondroitin sulphate and keratan sulphate. Hyaluronan is another important GAG that binds to aggrecan molecules to form very large complexes with a total molecular weight of more than 100 million.Aggrecan has a strong negative charge and avidly binds water molecules to assume a shape that occupies the maximum possible volume available. The expansive force of the hydrated aggrecan, combined with the restrictive strength of the collagen mesh, gives articular cartilage excellent shock-absorbing properties. Fig. 24.5 Ultrastructure of articular cartilage. With ageing, the concentration of chondroitin sulphate decreases, whereas that of keratan sulphate increases, resulting in reduced water content and shock-absorbing properties. These changes differ from those found in osteoarthritis ( p. 1007 ), where there is abnormal chondrocyte division, loss of proteoglycan from matrix and an increase in water content. Cartilage matrix is constantly turning over and in health there is a perfect balance between synthesis and degradation. Degradation of cartilage matrix is carried out by aggrecanases and matrix metalloproteinases, responsible for the breakdown of proteins and proteoglycans, and by glycosidases, responsible for the breakdown of GAGs. Pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are released during inflammation, stimulate production of aggrecanase and metalloproteinases, causing cartilage degradation. Synovial fluid The surfaces of articular cartilage are separated by a space filled with synovial fluid (SF), a viscous liquid that lubricates the joint. It is an ultrafiltrate of plasma, into which synovial cells secrete hyaluronan and proteoglycans. Intra-articular discs Some joints contain fibrocartilaginous discs within the joint space that act as shock absorbers. The most clinically important are the menisci of the knee. These are avascular structures that remain viable because of diffusion of oxygen and nutrients from the SF. Synovial membrane, joint capsule and bursae The bones of synovial joints are connected by the joint capsule, a fibrous structure richly supplied with blood vessels, nerves and lymphatics that encases the joint. Ligaments are discrete, regional thickenings of the capsule that act to stabilise joints (see Fig. 24.4 ). The inner surface of the joint capsule is the synovial membrane, comprising an outer layer of blood vessels and loose connective tissue that is rich in type I collagen, and an inner layer 1–4 cells thick consisting of two main cell types. Type A synoviocytes are phagocytic cells derived from the monocyte/macrophage lineage and are responsible for removing particulate matter from the joint cavity; type B synoviocytes are fibroblast-like cells that secrete SF. Most inflammatory and degenerative joint diseases associate with thickening of the synovial membrane and infiltration by lymphocytes, polymorphs and macrophages. Bursae are hollow sacs lined with synovium and contain a small amount of SF. They help tendons and muscles move smoothly in relation to bones and other articular structures. Skeletal muscle Skeletal muscles are responsible for body movements and respiration. Muscle consists of bundles of cells (myocytes) embedded in fine connective tissue containing nerves and blood vessels. Myocytes are large, elongated, multinucleated cells formed by fusion of mononuclear precursors (myoblasts) in early embryonic life. The nuclei lie peripherally and the centre of the cell contains actin and myosin molecules, which interdigitate with one another to form the myofibrils that are responsible for muscle contraction. The molecular mechanisms of skeletal muscle contraction are the same as for cardiac muscle ( p. 446 ). Myocytes contain many mitochondria that provide the large amounts of adenosine triphosphate (ATP) necessary for muscle contraction and are rich in the protein myoglobin, which acts as a reservoir for oxygen during contraction. Individual myofibrils are organised into bundles (fasciculi) that are bound together by a thin layer of connective tissue (the perimysium). The surface of the muscle is surrounded by a thicker layer of connective tissue, the epimysium, which merges with the perimysium to form the muscle tendon. Tendons are tough, fibrous structures that attach muscles to a point of insertion on the bone surface called the enthesis. Investigation of musculoskeletal disease Clinical history and examination usually provide sufficient information for the diagnosis and management of many musculoskeletal diseases. Investigations are helpful in confirming the diagnosis, assessing disease activity and indicating prognosis. Joint aspiration Joint aspiration with examination of SF is pivotal in patients suspected of having septic arthritis, crystal arthritis or intra-articular bleeding. It should be carried out in all individuals with acute monoarthritis, and samples should be sent for microbiology and clinical chemistry. It is possible to obtain SF by aspiration from most peripheral joints and only a small amount is required for diagnostic purposes. Normal SF is present in small volume, is clear and either colourless or pale yellow, and has a high viscosity. It contains few cells. With joint inflammation, the volume increases, the cell count and the proportion of neutrophils rise (causing turbidity), and the viscosity reduces (due to enzymatic degradation of hyaluronan and aggrecan). Turbid fluid with a high neutrophil count occurs in sepsis, crystal arthritis and reactive arthritis. High concentrations of urate crystals or cholesterol can make SF appear white. Non-uniform blood-staining usually reflects needle trauma to the synovium. Uniform blood-staining is most commonly due to a bleeding diathesis, trauma or pigmented villonodular synovitis ( p. 1059 ) but can occur in severe inflammatory synovitis. A lipid layer floating above blood-stained fluid is diagnostic of intra-articular fracture and is caused by release of bone marrow fat into the joint. Crystals can be identified by compensated polarised light microscopy of fresh SF (to avoid crystal dissolution and post-aspiration crystallisation). Urate crystals are long and needle-shaped, and show a strong light intensity and negative birefringence ( Fig. 24.6A ). Calcium pyrophosphate crystals are smaller, rhomboid in shape and usually less numerous than urate crystals; they have weak intensity and positive birefringence ( Fig. 24.6B ). Fig. 24.6 Compensated polarised light microscopy of synovial fluids (× 400). A Monosodium urate crystals show bright negative birefringence under polarised light and needle-shaped morphology. B Calcium pyrophosphate crystals show weak positive birefringence under polarised light and are few in number. They are more difficult to detect than urate crystals. Imaging Plain X-rays X-rays show structural changes that are of value in the differential diagnosis and monitoring of many bone and joint diseases ( Box 24.3 ). 24.3 Radiographic abnormalities in selected rheumatic diseases Rheumatoid arthritis Periarticular osteoporosis Marginal joint erosions Joint subluxation Joint space narrowing Osteoporosis Osteopenia Vertebral fractures Non-vertebral fractures Cortical thinning Paget's disease Bone expansion Abnormal trabecular pattern Osteosclerosis and lysis Pseudofractures Psoriatic arthritis Sacroiliitis Syndesmophytes Bone sclerosis Proliferative enthesis erosions Enthesophytes Juxta-articular new bone Osteoarthritis Joint space narrowing Osteophytes Subchondral sclerosis Joint deformity Subchondral cysts They are of diagnostic value in osteoarthritis (OA), where they demonstrate joint space narrowing that tends to be focal rather than widespread, as in inflammatory arthritis. Other features of OA detected on X-rays include osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies within the synovium (see Fig. 24.21 , p. 1010 ). Erosions and sclerosis of the sacroiliac joints and syndesmophytes in the spine may be observed in patients with spondyloarthritis (SpA; see Fig. 24.40 , p. 1030 ). In peripheral joints, proliferative erosions, associated with new bone formation and periosteal reaction, occur in SpA. In tophaceous gout, well-defined punched-out erosions may occur (see Fig. 24.27 , p. 1015 ). Calcification of cartilage, tendons and soft tissues or muscle occurs mainly in chondrocalcinosis (see Fig. 24.28 , p. 1016 ), calcium-containing crystal diseases, tumoral calcinosis and autoimmune connective tissue diseases. X-rays are of limited value in the diagnosis of rheumatoid arthritis (RA) because features such as erosions, joint space narrowing and periarticular osteoporosis may be detectable only after several months or even years. The main indication for X-rays in RA is in the assessment of disease over time when structural damage to the joints is suspected. Bone scintigraphy Bone scintigraphy is useful in the diagnosis of metastatic bone disease and Paget's disease of bone. Abnormalities may also be observed in primary bone tumours, complex regional pain syndrome, osteoarthritis and inflammatory arthritis. It involves gamma-camera imaging following an intravenous injection of 99m Tc-labelled bisphosphonate. Early post-injection images reflect blood flow and can show increased perfusion of inflamed synovium, Pagetic bone or primary or secondary bone tumours. Delayed images taken a few hours later reflect bone remodelling as the 99m Tc-labelled bisphosphonate localises to sites of active bone turnover. Scintigraphy has a high sensitivity for detecting important bone and joint pathology that is not apparent on X-rays ( Box 24.4 ). Single photon emission computed tomography (SPECT) combines radionuclide imaging with computed tomography. It can provide accurate anatomical localisation of abnormal tracer uptake within the bone and is of particular value in the assessment of patients with chronic low back pain of unknown cause. 24.4 Conditions identified by 99m Tc-labelled bisphosphonate bone scintigraphy Skeletal metastases Paget's disease of bone Stress fractures and osteomalacia (e.g. Looser's zones) Complex regional pain syndrome ( p. 1055 ) Sclerosing bone disorders (e.g. hypertrophic pulmonary osteoarthropathy; p. 1057 ) Spondyloarthritides (abnormalities at sacroiliac joints and tendon/ligament insertions) Magnetic resonance imaging Magnetic resonance imaging (MRI) gives detailed information on anatomy, allowing three-dimensional visualisation of bone and soft tissues that cannot be adequately assessed by plain X-rays. The technique is valuable in the assessment and diagnosis of many musculoskeletal diseases ( Box 24.5 ). T1-weighted sequences are useful for defining anatomy, whereas T2-weighted sequences are useful for assessing tissue water content, which is often increased in synovitis and other inflammatory disorders ( Fig. 24.7 ). MRI sequences that suppress signal from fat, such as short TI inversion recovery (STIR), are helpful when evaluating inflammatory disease. Contrast agents, such as gadolinium, can be administered to increase sensitivity in detecting erosions and synovitis. 24.5 Conditions detected by magnetic resonance imaging Osteonecrosis Intervertebral disc disease Nerve root entrapment Spinal cord compression Spinal stenosis Sepsis Complex regional pain syndrome Malignancy Fractures Meniscal disease Synovitis Sacroiliitis and enthesitides Inflammatory myositis Rotator cuff tears, bursitis and tenosynovitis Fig. 24.7 Magnetic resonance image showing joint synovitis. Coronal post-contrast T1-weighted image shows extensive enhancement consistent with synovitis (white areas, arrowed) in both wrists, at the second metacarpophalangeal joint and proximal interphalangeal joints of the right hand. Courtesy of Dr I. Beggs. Ultrasonography Ultrasonography is a useful investigation for confirmation of small joint synovitis and erosions, for anatomical location of periarticular lesions, for characterisation of tendon lesions and for guided injection of joints and bursae. Ultrasound is more sensitive than clinical examination for the detection of early synovitis and is used increasingly in the diagnosis and assessment of patients with suspected inflammatory arthritis. In addition to locating synovial thickening and effusions, ultrasound can detect increased blood flow within synovium using power Doppler imaging, an option that is available on most modern ultrasound machines ( Fig. 24.8 ). Fig. 24.8 Ultrasound image showing synovitis. Lateral image of a metacarpophalangeal joint in inflammatory arthritis. The periosteum (P) of the phalanx shows as a white line. The dark, hypo-echoic area indicates an effusion. The coloured areas demonstrated by power Doppler indicate increased vascularity. The inset shows a transverse image of the same joint. Courtesy of Dr N. McKay. Computed tomography Computed tomography (CT) is used selectively for assessing patients with bone and joint disease. CT may be used when skeletal configuration needs defining, when calcific lesions are being assessed (crowned dens syndrome, p. 1017 ), when MRI is contraindicated, or when articular regions are being evaluated in which an adjacent joint replacement creates signal artefacts on MRI, using specific metal artefact reduction algorithms. Dual X-ray absorptiometry Estimation of bone mineral density (BMD) has a key role in the diagnosis and management of osteoporosis and is best made using dual X-ray absorptiometry (DXA). Measurements at lumbar spine, hip and sometimes forearm are obtained. DXA works on the principle that calcium in bone attenuates passage of X-rays through the tissue in proportion to the amount of mineral present: the more bone mineral present, the higher the BMD value. Bone density measurements are often presented as T-scores, which measure of the number of standard deviations by which the patient's BMD value differs from that in a young healthy control ( Fig. 24.9 ). Osteoporosis is defined in postmenopausal women and men of more than 50 yearsold by a T-score of −2.5 or below (shaded red in the figure); osteopenia is diagnosed when the T-score lies between −1.0 and −2.5 (shaded pink). BMD values above −1.0 and below +2.5 are considered normal (yellow/green), whereas values above +2.5 indicate high bone mass, the most common cause being OA. The results need to be interpreted carefully and in reference to coexisting conditions, such as aortic calcification, vertebral fractures, degenerative disc disease and OA, all of which can artefactually raise BMD results. Radiographic correlation is then advisable. Fig. 24.9 Typical output from a dual X-ray absorptiometry (DXA) scan. A Image from hip DXA scan. B Bone mineral density (BMD) values plotted in g/cm 2 (left axis) and as the T-score values (right axis). The solid line represents the population average plotted against age, and the interrupted lines are ± 2 standard deviations. The BMD T-score result from the patient shown aged 70 years(arrow) is −3.0, indicating osteoporosis. Note that, while the patient's BMD is below average, it lies within the reference range for someone of that age, since BMD normally falls with age. Blood tests Haematology Abnormalities in the full blood count (FBC) often occur in inflammatory rheumatic diseases but changes are usually non-specific. Examples include neutrophilia in crystal arthritides and sepsis; neutropenia in lupus; and lymphopenia in autoimmune rheumatic and connective tissue diseases. Reduced levels of haemoglobin and raised platelets are a common and important finding in active inflammatory rheumatological disorders. Many synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) can cause marrow toxicity and require regular monitoring of the FBC. Additional tests that are useful in assessing rheumatic diseases include the direct antiglobulin test (which can indicate intravascular haemolysis in systemic lupus erythematosus (SLE); p. 948 ) and the dilute Russell viper venom test (a functional assay for a lupus anticoagulant; p. 978 ). Biochemistry Routine biochemistry is useful for assessing metabolic bone disease, muscle diseases and gout, and is essential in monitoring DMARDs and biologic drugs (renal and hepatic function). Several bone diseases, including Paget's disease, renal bone disease and osteomalacia, give a characteristic pattern that can be helpful diagnostically ( Box 24.6 ). Serum levels of uric acid are usually raised in gout but a normal level does not exclude it, especially during an acute attack, when urate levels temporarily fall. Equally, an elevated serum uric acid does not confirm the diagnosis, since most hyperuricaemic people never develop gout. Levels of C-reactive protein (CRP) are a useful marker of infection and inflammation, and are more specific than the erythrocyte sedimentation rate (ESR). An exception is in autoimmune connective tissue diseases, such as SLE and systemic sclerosis, where CRP may be normal but the ESR raised in active disease. Accordingly, an elevated CRP in a patient with lupus or systemic sclerosis suggests an intercurrent illness, such as sepsis, rather than active disease. More detail on the interpretation of CRP and ESR changes is given on page 72. Serum creatine phosphokinase levels are useful in the diagnosis of myopathy or myositis, but specificity and sensitivity are poor and raised levels may occur in some conditions ( Box 24.7 ). 24.6 Typical biochemical abnormalities in various skeletal diseases (in serum) Calcium Phosphate ALP PTH FGF23 25(OH)D Osteoporosis N N N ( after fracture) N or N N or Paget's disease N N N or N N or Renal osteodystrophy N or N or N or Vitamin D-deficient osteomalacia N or N or N or Hypophosphataemic rickets N N or N or Primary hyperparathyroidism / N or N or N or N or (ALP = alkaline phosphatase; FGF23 = fibroblast growth factor 23; PTH = parathyroid hormone) (N = normal; single arrow = increased or decreased; double arrow = greatly increased or decreased) 24.7 Causes of an elevated serum creatinine phosphokinase (CPK) Inflammatory myositis ± vasculitis Muscular dystrophy Motor neuron disease Alcohol, drugs (especially statins) Myocardial infarction * * The CK-MB cardiac-specific isoform is disproportionately elevated compared with total CPK. Trauma, strenuous exercise, prolonged immobilisation after a fall Hypothyroidism, metabolic myopathy Viral myositis Immunology Autoantibody tests are widely used in the diagnosis of rheumatic diseases. Whatever test is used, the results must be interpreted in light of the clinical picture and the different detection and assay systems used in different hospitals. Rheumatoid factor Rheumatoid factor (RF) is an antibody directed against the Fc fragment of human immunoglobulin. In routine clinical practice, immunoglobulin M (IgM) RF is usually measured, although different methodologies allow measurement of IgG and IgA RFs too. Positive RF occurs in a wide variety of diseases and some normal adults ( Box 24.8 ), particularly with increasing age. Although the specificity is poor, about 70% of patients with RA test positive. High RF titres are associated with more severe disease and extra-articular disease. 24.8 Conditions associated with a positive rheumatoid factor * * Normal healthy people can be positive for rheumatoid factor. Condition Approximate frequency (%) Rheumatoid arthritis with nodules and extra-articular manifestations 100 Rheumatoid arthritis (overall) 70 Sjögren's syndrome 90 Mixed essential cryoglobulinaemia 90 Primary biliary cholangitis 50 Infective endocarditis 40 Systemic lupus erythematosus 30 Tuberculosis 15 Age > 65 years20 Anti-citrullinated peptide antibodies Anti-citrullinated peptide antibodies (ACPAs) recognise peptides in which the amino acid arginine has been converted to citrulline by peptidylarginine deiminase, an enzyme abundant in inflamed synovium and in a variety of mucosal structures. ACPAs have similar sensitivity to RF for RA (70%) but much higher specificity (> 95%), and should be used in preference to RF in the diagnosis of RA. ACPAs are associated with more severe disease progression and can be detected in asymptomatic patients several years before the development of RA. Their pathological role is still debated but it is likely that they amplify the synovial response to an inflammatory stimulus. Antinuclear antibodies Antinuclear antibodies (ANAs) are directed against one or more components of the cell nucleus, including nucleic acids themselves and the proteins concerned with the processing of DNA or RNA. They occur in many inflammatory rheumatic diseases but are also found at low titre in normal individuals and in other diseases ( Box 24.9 ). ANAs are not associated with disease severity or activity. The most common indication for ANA testing is in patients suspected of having SLE or other autoimmune connective tissue diseases. ANA has high sensitivity for SLE (100%) but low specificity (10–40%). A negative ANA virtually excludes SLE but a positive result does not confirm it. 24.9 Conditions associated with a positive antinuclear antibody * * Low-titre positive antinuclear antibody can occur in people without autoimmune disease, without obvious clinical consequences, particularly in the elderly. Condition Approximate frequency (%) Systemic lupus erythematosus 100% Systemic sclerosis 60– 80% Sjögren's syndrome 40–70% Dermatomyositis or polymyositis 30–80% Mixed connective tissue disease 100% Autoimmune hepatitis 100% Rheumatoid arthritis 30–50% Autoimmune thyroid disease 30–50% Malignancy Varies widely Infectious diseases Varies widely Anti-DNA antibodies bind to double-stranded DNA (dsDNA) and are useful in SLE monitoring as very high titres are associated with more severe disease, including renal or central nervous system (CNS) involvement, and an increase in antibody titre may precede relapse. Anti-DNA antibodies are routinely tested by enzyme-linked immunosorbent assay (ELISA; see also p. 1036 ). Antibodies to extractable nuclear antigens (ENAs) act as markers for certain autoimmune connective tissue diseases and some complications of SLE but sensitivity and specificity are poor ( Box 24.10 ). For example, antibodies to Sm are found in a minority of patients with SLE but are associated with renal involvement. Antibodies to Ro occur in SLE and in Sjögren's syndrome (in association with anti-La antibodies), and are associated with a photosensitive rash and congenital heart block. Antibodies to ribonucleoprotein (RNP) occur in SLE and also in mixed connective tissue disease, where features of lupus, myositis and systemic sclerosis coexist. Anti-topoisomerase 1 (also termed Scl-70) antibodies occur in diffuse systemic sclerosis, whereas anti- centromere antibodies are more specific for limited systemic sclerosis. 24.10 Conditions associated with antibodies to extractable nuclear antigens Antibody (target/other name) Disease association Anti-centromere antibody Localised cutaneous systemic sclerosis (sensitivity 60%, specificity 98%) Anti-histone antibody Drug-induced lupus (80%) Anti-Jo-1 (anti-histidyl-tRNA synthetase) Polymyositis, dermatomyositis or polymyositis–systemic sclerosis overlap (20–30%) Particularly associated with interstitial lung disease Anti-La antibody (anti-SS-B) Sjögren's syndrome (60%) SLE (20–60%) Anti-ribonucleoprotein antibody (anti-RNP) Mixed connective tissue disease (100%) SLE (25–50%), usually in conjunction with anti-Sm antibodies Anti-Ro antibody (anti-SS-A) SLE (35–60%): associated with photosensitivity, thrombocytopenia and subacute cutaneous lupus Maternal anti-Ro antibodies associated with neonatal lupus and congenital heart block Sjögren's syndrome (40– 80%) Anti-RNA polymerase Diffuse systemic sclerosis (15%) Anti Sm (anti-Smith antibody) SLE (15–30%); associated with renal disease Anti- Scl-70 (anti-topoisomerase I antibody) Diffuse systemic sclerosis (15%); associated with more severe organ involvement, including pulmonary fibrosis (SLE = systemic lupus erythematosus) Antiphospholipid antibodies Antiphospholipid antibodies bind to a number of phospholipid binding proteins but the most clinically relevant are those that target beta 2 -glycoprotein 1 (β 2 GP1). They may be detected in SLE and other autoimmune connective tissue diseases and are key in diagnosing antiphospholipid antibody syndrome ( p. 977 ). Antineutrophil cytoplasmic antibodies Antineutrophil cytoplasmic antibodies (ANCAs) are IgG antibodies directed against the cytoplasmic constituents of granulocytes and are useful in the diagnosis and monitoring of systemic vasculitis. Two common patterns are described by immunofluorescence: cytoplasmic fluorescence (c-ANCA), which is caused by antibodies to proteinase-3 (PR3); and perinuclear fluorescence (p-ANCA), which is caused by antibodies to myeloperoxidase (MPO) and other proteins, such as lactoferrin and elastase. These antibodies are not specific for vasculitis and positive results may be found in autoimmune liver disease, malignancy, infection (bacterial and human immunodeficiency virus, HIV), inflammatory bowel disease, RA, SLE and pulmonary fibrosis. Complement Low complement C3 is an indicator of active SLE, owing to ‘consumption’ of complement by immune complexes (see Fig. 4.4 , p. 66 ). Low C4 is less specific for SLE activity. High C3 and functional measures of complement activation are non-specific features of inflammation. Tissue biopsy Tissue biopsy is useful in confirming the diagnosis in certain musculoskeletal diseases. Synovial biopsy can be useful in selected patients with chronic inflammatory monoarthritis or tenosynovitis to rule out chronic infectious causes, especially mycobacterial infections. Synovial biopsy can be obtained arthroscopically (by conventional means or by use of needle arthroscope) or by using ultrasound guidance under local anaesthetic. Temporal artery biopsy can be of value in patients suspected of having temporal arteritis, especially when the presentation is atypical, but a negative result does not exclude the diagnosis. Biopsies of affected tissues, such as skin, lung, nasopharynx, gut, kidney and muscle, should be sought by default in confirming a diagnosis of systemic vasculitis. Muscle biopsy plays an important role in the investigation of myopathy and inflammatory myositis. It is usually taken from the quadriceps or deltoid through a small skin incision under local anaesthetic. Since myositis can be patchy in nature, MRI is sometimes used to localise the best site for biopsy. Immunohistochemical staining, together with plain histology, gives information on primary and secondary muscle and neuromuscular disease. Repeat biopsies are sometimes used to monitor the response to treatment. Bone biopsy is occasionally required where non-invasive tests give inconclusive results, in the diagnosis of infiltrative disorders, in patients with renal bone disease, suspected chronic infection or malignancy, and rarely to confirm or exclude the presence of osteomalacia. Bone is taken from the iliac crest using a large-diameter (8 mm)trephine needle under local anaesthetic and processed without demineralisation. For focal lesions, the biopsy should be taken under X-ray guidance or at open surgery, from an affected site. Electromyography Electromyography ( p. 1076 ) is of value in the investigation of suspected myopathy and inflammatory myositis, when it shows the diagnostic triad of: spontaneous fibrillation short-duration action potentials in a polyphasic disorganised outline repetitive bouts of high-voltage oscillations on needle contact with diseased muscle. Presenting problems in musculoskeletal disease Acute monoarthritis The most important causes of acute arthritis in a single joint are crystal arthritis, sepsis, SpA and oligoarticular juvenile idiopathic arthritis (JIA; p. 1026 ). Other potential causes are shown in Box 24.11. 24.11 Causes of acute monoarthritis Common Gout Pseudogout Trauma Haemarthrosis Spondyloarthritis Psoriatic arthritis Reactive arthritis Enteropathic arthritis Less common Rheumatoid arthritis Juvenile idiopathic arthritis Pigmented villonodular synovitis Foreign body reaction Tuberculosis Leukaemia * Gonococcal infection Osteomyelitis * * In children, both leukaemia and osteomyelitis may present with monoarthritis. Clinical assessment The clinical history, pattern of joint involvement, speed of onset, and age and gender of the patient all give clues to the most likely diagnosis. Gout classically affects the first metatarsophalangeal (MTP) joint, whereas pseudogout, which can be a presenting feature of calcium pyrophosphate dihydrate (CPPD) disease, can affect the hand/wrist, ankle, knee or hip. A very rapid onset (6–12 hours)is suggestive of crystal arthritis; joint sepsis develops more slowly and continues to progress until treated. Haemarthrosis typically causes a large effusion, in the absence of periarticular swelling or skin change, in a patient who has suffered an injury. Pigmented villonodular synovitis ( p. 1059 ) also presents with synovial swelling and a large effusion, although the onset is gradual. A previous diarrhoeal illness or genital infection suggests reactive arthritis, whereas intercurrent illness, dehydration or surgery may act as a trigger for crystal-induced arthritis. Rheumatoid arthritis seldom presents with monoarthritis but psoriatic arthritis (PsA) can typically present this way. Osteoarthritis can present with pain and stiffness affecting a single joint, but the onset is gradual and there is usually no evidence of significant joint swelling unless it is complicated by crystal-induced inflammation. Investigations Aspiration of the affected joint is mandatory. If sepsis is suspected in a large joint, arthroscopic washout is advisable. The fluid should be sent for culture and Gram stain to seek the presence of organisms and should be checked by polarised light microscopy for crystals. Blood cultures should also be taken in patients suspected of having septic arthritis. CRP levels and ESR are raised in sepsis, crystal arthritis and reactive arthritis, and this can be useful in assessing the response to treatment. Serum uric acid measurements may be raised in gout but a normal level does not exclude the diagnosis. Ruling out primary hyperparathyroidism is essential if there is pseudogout. Management If there is any suspicion of sepsis, intravenous antibiotics (see Box 24.50 , p. 1020 ) should be given promptly, pending the results of cultures. Unless atypical infections/tuberculosis (requiring prolonged or special culture) are suspected, intra-articular glucocorticoid injection may be considered after 48 hoursof negative synovial fluid culture. Otherwise, management should be directed towards the underlying cause. Polyarthritis This term is used to describe pain and swelling affecting five or more joints or joint groups. The possible causes are listed in Box 24.12. 24.12 Common causes of polyarthritis Cause Characteristics Rheumatoid arthritis Symmetrical, small and large joints, upper and lower limbs Viral arthritis Symmetrical, small joints; may be associated with rash and prodromal illness; self-limiting Osteoarthritis Symmetrical, targets PIP, DIP and first CMC joints in hands, knees, hips, back and neck; associated with Heberden's and Bouchard's nodes Psoriatic arthritis Asymmetrical, targets all joints and entheses; associated with nail pitting/onycholysis, dactylitis Axial spondyloarthritis and enteropathic arthritis Tends to affect midsize and large joints and entheses, lower more than upper limbs; history of inflammatory back pain Systemic lupus erythematosus Symmetrical, typically affecting small joints; clinical evidence of synovitis unusual Juvenile idiopathic arthritis Various patterns ( p. 1026 ): polyarticular, oligoarticular and systemic but also enthesitis-predominant Chronic gout Affects distal more than proximal joints; history of acute attacks Chronic sarcoidosis ( p. 608 ) Varies: small and large joints, often involves ankles Calcium pyrophosphate arthritis Chronic polyarthritis with involvement of wrists, ankles, knees and oligoarticular small hand joints (CMC = carpometacarpal; DIP = distal interphalangeal; PIP = proximal interphalangeal) Clinical assessment The hallmarks of inflammatory arthritis are early-morning stiffness and worsening of symptoms with inactivity, along with synovial swelling and tenderness on examination. Clinical features in other systems can be helpful in determining the underlying cause ( Box 24.13 ). The most important diagnoses to consider are PsA, RA and inflammatory small joint OA. RA is characterised by symmetrical involvement of the small joints of the hands and feet, wrists, ankles and knees. PsA is strongly associated with enthesitis. Viral arthritis ( p. 1020 ), Poncet's disease (in regions where tuberculosis is highly prevalent; p. 588 ), polyarticular JIA (in children) and post-streptococcal arthritis should also be considered. 24.13 Extra-articular features of inflammatory arthritis Clinical feature Disease association Skin, nails and mucous membranes Psoriasis, nail pitting and dystrophy Psoriatic arthritis Raynaud's phenomenon Systemic sclerosis, antiphospholipid syndrome, SLE Photosensitivity SLE Livedo reticularis SLE, antiphospholipid syndrome Splinter haemorrhages, nail-fold infarcts, purpuric lesions Vasculitis Urticaria and erythemas SLE, adult-onset Still's disease, systemic JIA, rheumatic fever Oral ulcers SLE, reactive arthritis, Behçet's disease Nodules RA (mainly extensor surfaces), gout (tophi; eccentric, white deposits within), rheumatic fever Xerostomia, dry skin, various rashes Primary Sjögren's syndrome Eyes Uveitis SpA, sarcoid, JIA, Behçet's disease Conjunctivitis Reactive arthritis Episcleritis, scleritis RA, vasculitis Heart, lungs Pleuro-pericarditis SLE, RA, rheumatic fever Aortic valve/root disease HLA-B27-related SpA Interstitial lung disease RA, SLE, primary Sjögren's syndrome Abdominal organs Hepatosplenomegaly RA, SLE Haematuria, proteinuria SLE, vasculitis, systemic sclerosis Urethritis Reactive arthritis and SpA (sterile) Fever, lymphadenopathy Infection, systemic JIA, rheumatic fever (HLA = human leucocyte antigen; JIA = juvenile idiopathic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SpA = spondyloarthritis) The pattern of involvement can be helpful in reaching a diagnosis ( Fig. 24.10 ). Asymmetry, lower limb predominance, enthesitis and greater involvement of large joints are characteristic of the SpAs. In PsA there may be involvement of the proximal and distal interphalangeal (PIP and DIP) joints, as opposed to the metacarpophalangeal (MCP) and PIP joints in RA. Inflammatory OA can appear similar to small-joint PsA in the pattern of joint involvement. In PsA there may be nail pitting or early onycholysis. Psoriasis may not be present. SLE can be associated with polyarthritis but more usually causes polyarthralgia and tenosynovitis, mainly of distal limb joints/tendons ( p. 1035 ). Fig. 24.10 Patterns of joint involvement in different forms of polyarthritis. A Rheumatoid arthritis typically targets the metacarpophalangeal and proximal interphalangeal joints of the hands and metatarsophalangeal joints of the feet, as well as other joints, in a symmetrical pattern. B Psoriatic arthritis targets proximal and distal interphalangeal joints of the hands, entheses and larger joints in an asymmetrical pattern. Sacroiliitis (often asymmetrical) may occur. C Axial spondyloarthritis/ankylosing spondylitis targets the spine, sacroiliac joints, entheses and large peripheral joints in an asymmetrical pattern. D Osteoarthritis targets the proximal and distal interphalangeal joints of the hands, first carpometacarpal joint at the base of the thumb, knees, hips, lumbar and cervical spine. Investigations Blood samples should be taken for routine haematology, biochemistry, ESR, CRP, viral serology and an immunological screen, including ANA, RF and ACPA. Ultrasound examination or MRI may be required to confirm the presence of synovitis, if this is not obvious clinically. Management Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics will help. Systemic glucocorticoids can be considered if symptoms are very severe or having a great functional impact, but early immunotherapy (DMARDs) is required in RA and in some cases of PsA. An early accurate and specific diagnosis is very important. Fracture Fractures are a common presenting symptom of osteoporosis but they also occur in other bone diseases, in osteopenia and in some patients with normal bone. Clinical assessment The presentation is with localised bone pain, which is worsened by movement of the affected limb or region. There is usually a history of trauma but spontaneous fractures can occur in the absence of trauma in severe osteoporosis. Fractures can be divided into several subtypes, based on the precipitating event and presence or absence of an underlying disease ( Box 24.14 ). The main differential diagnosis is soft tissue injury but fracture should be suspected when there is marked pain and swelling, abnormal movement of the affected limb, crepitus or deformity. Femoral neck fractures typically produce a shortened, externally rotated leg that is painful to move. The pain from vertebral fracture is variable and a high index of suspicion is key to making the diagnosis by imaging, as discussed below. 24.14 Characteristics of different fracture types Fracture type Precipitation factor Disease Fragility fracture Fall from standing height or less Osteoporosis Osteopenia Vertebral fracture Bending, lifting, falling Osteoporosis Stress fracture Running, excessive training Normal High-energy fracture Major trauma Normal Pathological fracture Spontaneous, minimal trauma Malignancy Paget's disease Osteomalacia Investigations X-rays of the affected site should be taken in at least two planes and examined for discontinuity of the cortical outline ( Box 24.15 ). In addition to demonstrating the fracture, X-rays may also show evidence of an underlying disorder, such as osteoporosis, Paget's disease or osteomalacia. If the X-ray fails to show evidence of a fracture but clinical suspicion remains high, MRI should be obtained. Patients who are over the age of 50 and present with fragility fractures should be screened for osteoporosis by DXA. 24.15 How to investigate a suspected fracture Order X-rays in two projections at right angles to one another Include the whole bone and the joints at either end (this may reveal an additional unsuspected fracture) Check for evidence of displacement Check for a break in the cortex In suspected vertebral fracture, check for depression of the end plate If clinical suspicion is high but no fracture is seen, request magnetic resonance imaging Management Management of fracture in the acute stage requires adequate pain relief, with opiates if necessary, reduction of the fracture to restore normal anatomy, and immobilisation of the affected limb to promote healing. This can be achieved either by the use of an external cast or splint, or by internal fixation. Femoral neck fractures present a special management problem since non-union and avascular necrosis are common. This is especially true with intracapsular hip fractures, which should be treated by joint replacement surgery. Following the fracture, rehabilitation is required with physiotherapy and a supervised exercise programme. If the DXA scan shows evidence of osteoporosis or other metabolic bone disease, this should be treated appropriately ( p. 1046 ). Options for management of painful vertebral fracture are discussed on page 1002. Generalised musculoskeletal pain Clinical assessment Clinical history and examination need to be wide-ranging ( Box 24.16 ). Relentlessly progressive pain occurring in association with weight loss suggests malignant disease with bone metastases. Generalised bone pain may also arise in severe osteomalacia, primary hyperparathyroidism and polyostotic Paget's disease. Widespread pain can occur in PsA if there is enthesial as well as, or instead of, joint involvement; fatigue is also often present. Polyarticular RA or OA pains tend to be localised to sites of involvement, such as the lumbar spine, hips, knees and hands. Fibromyalgia (FM) syndrome ( p. 1018 ) presents with generalised pain that particularly affects the trunk, back and neck. Accompanying features include fatigue, poor concentration and focal areas of hyperalgesia. Widespread pain may also occur in association with hypermobility, most notably Ehlers–Danlos syndrome hypermobility subtype (hEDS; p. 1059 ). 24.16 Some common causes of generalised pain Myopathies Psoriatic arthritis (enthesopathic) Fibromyalgia Parvovirus arthromyalgia Rheumatic fever/post-streptococcal infection Metastatic cancer Severe osteomalacia Investigations Bone scintigraphy is of value in patients suspected of having osteomalacia, bone metastases or Paget's disease, and in characterising lesions at joints and/or entheses in SpAs, including PsA. Myeloma ( p. 966 ) should be screened for with an FBC, measurement of CRP, and plasma and urinary protein electrophoresis. If these results are positive, a radiological skeletal survey should be obtained. Routine biochemistry, vitamin D and parathyroid hormone (PTH) should be measured if osteomalacia is suspected. In Paget's disease, ALP may be elevated but can be normal in localised disease. Any persistently elevated ESR, CRP, angiotensin-converting enzyme (ACE), immunoglobulins, C3/C4 or platelets invariably indicates inflammatory disease. Laboratory investigations are normal in patients with FM alone and in hEDS. Management Management should be directed towards the underlying cause. Chronic pain of unknown cause and that associated with FM respond poorly to analgesics and NSAIDs, but may respond partially to antineuropathic agents, such as amitriptyline, duloxetine, gabapentin and pregabalin. Back pain Back pain is a common symptom that affects 60–80% of people at some time in their lives. Although the prevalence has not increased, reported disability from back pain has risen significantly in the last 30 years.In Western countries, back pain is the most common cause of sickness-related work absence. In the UK, 7% of adults consult their GP each year with back pain. Globally, low back pain is thought to affect about 9% of the population. The most important causes are summarised in Box 24.17. 24.17 Causes of low back pain Mechanical (soft-tissue lesion) back pain Intervertebral disc lesions (e.g. prolapse, disc degeneration) Facet joint disease (osteoarthritis, psoriatic arthritis) Vertebral fracture ( p. 994 ) Paget's disease Axial spondyloarthritis Spondylodiscitis Bone metastases Spondylolisthesis ( p. 1059 ) Scheuermann's disease ( p. 1055 ) Clinical assessment The main purpose of clinical assessment is to differentiate the self-limiting disorder of acute mechanical back pain from serious spinal pathology, as summarised in Figure 24.11. Mechanical back pain is the most common cause of acute back pain in people aged 20–55. This accounts for more than 90% of episodes, and is usually acute and associated with lifting or bending. It is exacerbated by activity and is generally relieved by rest ( Box 24.18 ). It is usually confined to the lumbar–sacral region, buttock or thigh, is asymmetrical and does not radiate beyond the knee (which would imply nerve root irritation). On examination, there may be asymmetric local paraspinal muscle spasm and tenderness, and painful restriction of some, but not all, movements. Low back pain is more common in manual workers, particularly those in occupations that involve heavy lifting and twisting. The prognosis is generally good. After 2 days,30% are better and 90% have recovered by 6 weeks.Recurrences of pain may occur and about 10– 15% of patients go on to develop chronic back pain that may be difficult to treat. Psychological elements, such as job dissatisfaction, depression and anxiety, are important risk factors for the transition to chronic pain and disability. Fig. 24.11 Initial triage assessment of back pain. 24.18 Features of mechanical low back pain Pain varies with physical activity (improved with rest) Onset often sudden and precipitated by lifting or bending Recurrent episodes Pain limited to back or upper leg No clear-cut nerve root distribution No systemic features Prognosis good (90% recovery at 6 weeks)Back pain secondary to serious spinal pathology has different characteristics ( Box 24.19 ). If there is clinical evidence of spinal cord or nerve root compression, sepsis including tuberculosis, or a cauda equina lesion ( Box 24.20 ), urgent investigation is needed. Spinal stenosis presents insidiously with leg discomfort on walking that is relieved by rest, bending forwards or walking uphill. Patients may adopt a characteristic simian posture, with a forward stoop and slight flexion at hips and knees. The most common cause is the gradual development of coexisting contributing lesions such as facet joint arthritis, ligament flavum thickening or degenerative spondylolisthesis. 24.19 Red flags for possible spinal pathology History Age: presentation < 20 yearsor > 55 years Character: constant, progressive pain unrelieved by rest Location: thoracic pain Past medical history: carcinoma, tuberculosis, HIV, systemic glucocorticoid use, osteoporosis Constitutional: systemic upset, sweats, weight loss Major trauma Examination Painful spinal deformity Severe/symmetrical spinal deformity Saddle anaesthesia Progressive neurological signs/muscle-wasting Multiple levels of root signs 24.20 Clinical features of radicular pain Nerve root pain Unilateral leg pain worse than low back pain Pain radiates beyond knee Paraesthesia in same distribution Nerve irritation signs (reduced straight leg raising that reproduces leg pain) Motor, sensory or reflex signs (limited to one or adjacent nerve roots) Prognosis reasonable (50% recovery at 6 weeks)Cauda equina syndrome Difficulty with micturition Loss of anal sphincter tone or faecal incontinence Saddle anaesthesia Gait disturbance Pain, numbness or weakness affecting one or both legs Degenerative disc disease is a common cause of chronic low back pain in middle-aged adults. Prolapse of an intervertebral disc presents when discs are still well hydrated (in young and early middle age) with nerve root pain, which can be accompanied by a sensory deficit, motor weakness and asymmetrical reflexes. Examination may reveal a positive sciatic or femoral stretch test. About 70% of patients improve by 4 weeks. Inflammatory back pain (IBP) due to axial spondyloarthritis (axSpA) or PsA has a gradual onset and almost always occurs before the age of 40. It is associated with morning stiffness and improves with movement. Spondylolisthesis ( p. 1059 ) may cause back pain that is typically aggravated by standing and walking. Occasionally, diffuse idiopathic skeletal hyperostosis (DISH; p. 1058 ) can cause back pain but it is usually asymptomatic. Arachnoiditis is a rare cause of chronic severe low back pain. It is caused by chronic inflammation of the nerve root sheaths in the spinal canal and can complicate meningitis, spinal surgery or myelography with oil-based contrast agents. Investigations Investigations are not required in patients with acute mechanical back pain. Those with persistent pain (> 6 weeks)or red flags (see Box 24.19 ) should undergo further investigation. MRI is the investigation of choice because it can demonstrate spinal stenosis, cord compression or nerve root compression, as well as inflammatory changes in axSpA, malignancy and sepsis. Plain X-rays can be of value in patients suspected of having vertebral compression fractures, OA and degenerative disc disease. If metastatic disease is suspected, bone scintigraphy should be considered. Additional investigations that may be required include routine biochemistry and haematology, ESR and CRP (to screen for sepsis and inflammatory disease), protein and urinary electrophoresis (for myeloma), human leucocyte antigen (HLA)-B27 status in IBP and prostate- specific antigen (for prostate carcinoma). Management Education is important in patients with mechanical back pain. It should emphasise the self-limiting nature of the condition and the fact that exercise is helpful rather than damaging. Regular analgesia and/or NSAIDs may be required to improve mobility and facilitate exercise. Return to work and normal activity should take place as soon as possible. Bed rest is not helpful and may increase the risk of chronic disability. Referral for physical therapy should be considered if a return to normal activities has not been achieved by 6 weeks.Low-dose tricyclic antidepressant drugs may help pain, sleep and mood. Other treatment modalities that are occasionally used include epidural and facet joint injection, traction and lumbar supports, though there is limited randomised controlled trial evidence to support their use. Malignant disease, osteoporosis, Paget's disease and SpAs require specific treatment of the underlying condition. Surgery is required in less than 1% of patients with low back pain but may be needed in progressive spinal stenosis, in spinal cord compression and in some patients with nerve root compression. Regional musculoskeletal pain Regional musculoskeletal pain is a common presenting complaint, usually occurring as the result of age-related degenerative disease of tendons and ligaments, OA and trauma. Neck pain Neck pain is a common symptom that can occur following an injury or falling asleep in an awkward position, as a result of stress or in association with OA of the spine. The causes are shown in Box 24.21. Most cases resolve spontaneously or with a short course of NSAIDs or analgesics and some exercise therapy. Patients with persistent pain that follows a nerve root distribution and those with upper or lower limb neurological signs should be investigated by MRI and, if necessary, referred for a neurosurgical opinion. 24.21 Typical causes of neck pain Mechanical Postural Whiplash injury Facet joint Cervical spondylosis Inflammatory Infections Axial spondyloarthritis Psoriatic arthritis Rheumatoid arthritis Polymyalgia rheumatica Discitis Metabolic Axial calcium pyrophosphate dihydrate disease Fibrous dysplasia Paget's disease Neoplastic Metastases Myeloma Lymphoma Intrathecal tumours Other Fibromyalgia Torticollis Referred Pharynx Cervical lymph nodes Teeth Angina pectoris Aortic aneurysm Pancoast tumour Diaphragm Shoulder pain Shoulder pain is a common complaint over the age of 40 ( Box 24.22 ). Varying pain patterns associated with common lesions are shown in Figure 24.12. For most shoulder lesions, general management is with analgesics, NSAIDs, local glucocorticoid injections and physiotherapy aimed at restoring normal movement and function. Surgery may be required in patients who have debilitating or persistent symptoms in association with rotator cuff lesions or severe acromioclavicular joint arthritis. If there is subacromial impingement, without evidence of a rotator cuff tear on MRI, subacromial glucocorticoid injection and physiotherapy constitute a reasonable first step. Calcific supraspinatus tendonitis unresponsive to glucocorticoid injection can be treated with barbotage (needle disruption of deposit under ultrasound guidance). Complete rotator cuff tears in people under 40 yearsof age may respond well to full surgical repair but results are less good in older people. Adhesive capsulitis (frozen shoulder) presents with pain associated with marked restriction of elevation and external rotation. Adhesive capsulitis is commonly associated with diabetes mellitus and neck/radicular lesions. Treatment in the early stage is with analgesia, intra- and extracapsular glucocorticoid injection, and regular ‘pendulum’ exercises of the arm to mobilise. Complete recovery sometimes takes up to 2 years.For severe or persistent symptoms, joint distension and manipulation under anaesthesia are surgical options. 24.22 Clinical findings in shoulder pain Rotator cuff and subacromial lesions Pain reproduced by resisted active movement: Abduction: supraspinatus External rotation: infraspinatus, teres minor Internal rotation: subscapularis Acromioclavicular joint Pain on full abduction and adduction (at 90° of forward elevation) Bicipital (long head) tendinitis Tenderness over bicipital groove Pain reproduced by resisted active wrist supination or elbow flexion Fig. 24.12 Pain patterns around the shoulder. The dark shading indicates sites of maximum pain. Elbow pain The most common causes are repetitive trauma causing lateral epicondylitis (tennis elbow) and medial epicondylitis (golfer's elbow) ( Box 24.23 ). SpAs, including psoriatic disease, can present with the same symptoms (tendon insertion enthesitis). Management is by rest, analgesics and topical or systemic NSAIDs. Local glucocorticoid injections may be required in resistant cases. Olecranon bursitis can also follow local repetitive trauma but other causes include infections and gout. 24.23 Typical local causes of elbow pain Lesion Pain Examination findings Lateral humeral epicondylitis (e.g. traumatic ‘tennis elbow’ or SpA-related enthesitis) Lateral epicondyle Tenderness over epicondyle Radiation to extensor forearm Pain reproduced by resisted active wrist extension Medial humeral epicondylitis (e.g. traumatic ‘golfer's elbow’ or SpA-related enthesitis) Medial epicondyle Tenderness over epicondyle Radiation to flexor forearm Pain reproduced by resisted active wrist flexion Olecranon bursitis (e.g. gout, rheumatoid arthritis or infective, as in tuberculosis) Olecranon Tender swelling (SpA = spondyloarthritis) Hand and wrist pain Pain from hand or wrist joints is well localised to the affected joint, except for pain from the first carpometacarpal (CMC) joint, commonly targeted by OA or PsA; although maximal at the thumb base, the pain often radiates down the thumb and to the radial aspect of the wrist. Non-articular causes of hand pain include: Tenosynovitis : affects flexor or extensor digital tendons. Pain and tenderness are well localised to the tendon lesions. There is often early-morning ‘claw-like’ digit stiffness. De Quervain's tenosynovitis involves the tendon sheaths of abductor pollicis longus and extensor pollicis brevis. It produces pain maximal over the radial aspect of the distal forearm and wrist and marked pain on forced ulnar deviation of the wrist with the thumb held across the patient's palm (Finkelstein's sign). This test is not specific for this lesion alone. Raynaud's phenomenon : digital vasospasm triggered mostly by cold ( p. 1035 ). C6, C7 or C8 radiculopath y. Carpal tunnel syndrome : hand position-dependent and/or nocturnal pain, numbness and paraesthesia of thumb and second to fourth digits. Hip pain Pain from the hip joint is usually felt deep in the groin, with variable radiation to the buttock, anterolateral thigh or knee ( Fig. 24.13 ). Patients who report ‘hip pain’ sometimes point to greater trochanter or buttock areas. Greater trochanter pain syndrome is usually due to either gluteus medius insertional tendonitis/enthesitis, trochanteric bursitis or referred pain ( Box 24.24 ). Pain at this site may also be referred from the lumbosacral spine. A differential diagnosis of hip joint conditions (groin pain) is symphysitis (SpAs, including psoriasis disease, need ruling out). Other less common causes of pain in the hip/groin area include inguinal hernia, adductor tendonitis and enthesitis of anterior superior/inferior iliac spines. Fig. 24.13 Pain patterns of hip disease and trochanteric pain syndrome. The dark shading indicates sites of maximum pain. 24.24 Local causes of hip pain Lesion Pain Examination findings Gluteus medius enthesitis Upper lateral thigh, worse on lying on that side at night Tenderness over greater trochanter Trochanteric bursitis As above As above Adductor tendinitis (usually an SpA-enthesitis or sports-related trauma lesion) Upper inner thigh Tenderness over adductor origin/tendon/muscle Pain reproduced by resisted active hip adduction Ischiogluteal enthesitis/bursitis Buttock, worse on sitting Tenderness over ischial prominence Pubic symphysitis (can mimic intra-articular hip lesions) Medial groin pain, can radiate to inner or even outer upper thighs Tenderness over symphysis joint If pain is worse on trunk curl/rectus activation under symphysis-resting hand, it may be insertional rectus enthesitis (SpAs) (SpA = spondyloarthritis) Knee pain In middle and older age, the most common cause of knee pain is OA, the features of which are described on page 1008. Pain that is associated with locking of the knee (sudden painful inability to extend fully) is usually due to a meniscal tear or osteochondritis dissecans. Referred pain from the hip may present at the knee and is reproduced by hip, not knee, movement. Pain from periarticular lesions is well localised to the involved structure ( Box 24.25 ). Anterior knee pain may be due to patellar ligament or retinacular lesions (enthesitis, tendonitis, fat-pad syndrome) occurring typically from overuse and/or an SpA condition. Anterior knee pain is relatively common in adolescents and may be the result of patellar articular cartilage or ligament insertion osteochondritis. 24.25 Local causes of knee pain Lesion Pain Examination findings Pre-patellar bursitis Over patella Tender fluctuant swelling in front of patella Superficial and deep infrapatellar bursitis and fat-pad syndrome Anterior knee, inferior to patella Tenderness in front of (superficial) or behind (deep) patellar tendon Pain on full flexion Anserine bursitis/enthesitis Upper medial tibia Tenderness (± swelling) over upper medial tibia Medial collateral ligament lesions (e.g. enthesitis) Upper medial tibia Localised tenderness of upper medial tibia Pain reproduced by valgus stress on partly flexed knee Popliteal cyst (Baker's cyst) Popliteal fossa Tender swelling of popliteal fossa Patellar ligament enthesopathy Anterior upper tibia Tenderness over tibial tubercle Osteochondritis of patellar ligament (Osgood–Schlatter disease) Anterior upper tibia Adolescents are affected Pain on resisted active knee extension Ankle and foot pain Pain from the ankle (tibiotalar) joint due to OA or osteochondral defect is felt between the malleoli and is worse on weight-bearing. Pain from the subtalar joint (from the same lesions) is also worse on weight-bearing. Inflammatory arthritis of either of these joints (RA, PsA, CPPD arthritis or gout) often worsens and swells with rest. These diagnoses can be associated with hindfoot tenosynovitis (peroneal or posterior tibial). Pain under the heel is typically due to plantar fasciitis. This can occur as the result of overuse, which case it may respond to rest, padded footwear and local glucocorticoid injections, but can also arise in SpA as a manifestation of enthesitis. Pain affecting the back of the heel may be due to Achilles tendinitis or enthesitis. The MTP joints of the feet are commonly involved symmetrically in RA. The presentation is with pain on walking felt below the metatarsal heads, often described as ‘walking on marbles’. Patients with active inflammation of the MTP joints have pain when the forefoot is squeezed ( p. 982 ). Involvement of the first MTP joint is common in OA or PsA and is associated, respectively, with hallux valgus and dactylitis. The hallux also a classical target in acute gout. Morton's neuroma is a neuropathy of an interdigital nerve and is usually located between the third and fourth metatarsal heads. Women are most commonly affected (tight shoes can be to blame). Local sensory loss and a palpable tender swelling between the metatarsal heads may be detected. Footwear adjustment, with or without a local glucocorticoid injection, often helps but surgical decompression may be required if symptoms persist. Muscle pain and weakness Muscle pain and weakness can arise from a variety of causes. It is important to distinguish between a subjective feeling of generalised weakness occurring with fatigue, and an objective weakness with loss of muscle power and function. The former is a non-specific manifestation of many systemic conditions. Clinical assessment Proximal muscle weakness suggests the presence of a myopathy or myositis, which typically causes difficulty with standing from a seated position, walking up steps, squatting and lifting overhead. The causes are shown in Box 24.26. Worsening of symptoms on exercise and post-exertional cramps suggest a metabolic myopathy, such as glycogen storage disease ( p. 370 ). A strong family history and onset in childhood or early adulthood suggest muscular dystrophy ( p. 1143 ). Alcohol excess can cause an inflammatory myositis and atrophy of type 2 muscle fibres. Proximal myopathy may be a complication of glucocorticoid therapy, prolonged/severe hypercalcaemia and osteomalacia. Myopathy and myositis can also occur in association with many drugs (see ‘ Further information ’, p. 1060 ) and viral infections, including HIV; in the latter case, it may be due to HIV itself or to treatment with zidovudine. Polymyositis and dermatomyositis ( p. 1039 ) are associated with coexisting/co-presenting malignancy, especially gonadal tumours. Clinical examination should document the presence, pattern and severity of muscle weakness ( p. 1081 ), assessed using the Medical Research Council (MRC) scale (no power (0) to full power (5)). 24.26 Causes of proximal muscle pain or weakness Inflammatory Polymyositis Dermatomyositis Other autoimmune connective tissue disease Inclusion body myositis Sarcoid Myasthenia gravis Endocrine ( Ch. 18 ) Hypothyroidism Hyperthyroidism Cushing's syndrome Addison's disease Metabolic ( Ch. 14 ) Myophosphorylase deficiency Phosphofructokinase deficiency Hypokalaemia Carnitine deficiency Osteomalacia ( p. 1049 ) Hypercalcaemia Genetic Muscular dystrophy (various; p. 1143 ) Drugs/toxins Alcohol Cocaine Glucocorticoids Statins and fibrates Tumour necrosis factor inhibitors Zidovudine Infections ( Ch. 11 ) Viral (HIV, cytomegalovirus, rubella, Epstein–Barr, echo) Parasitic (schistosomiasis, cysticercosis, toxoplasmosis) Bacterial ( Clostridium perfringens , staphylococci, tuberculosis, Mycoplasma ) Investigations Investigations should include routine biochemistry and haematology, ESR, CRP, creatine kinase, serum 25(OH)-vitamin D, PTH, parvovirus, hepatitis B/C, HIV and streptococcus serology, serum and urine protein electrophoresis, serum ACE, ANAs/ENAs, RF, complement and myositis-specific autoantibodies such as Jo-1. Open muscle biopsy (site guided by MRI detection of abnormal muscle) and electromyography (EMG) are usually required to make the diagnosis. The initial imaging screening for malignancy is usually a CT scan of the chest, abdomen and pelvis; upper gastrointestinal endoscopy and colonoscopy may also be considered. Management Management is determined by the cause but all patients with muscle disease should benefit from physiotherapy and graded exercises to maximise muscle function after the initial inflammation is controlled. Principles of management The management of rheumatological disorders should be tailored to the underlying diagnosis. Certain aspects are common to many disorders, however, and the general principles are discussed here. The therapeutic aims are: to educate patients about their disease to control pain, if it is present to optimise function to modify the disease process where this is possible to identify and treat comorbidity. These aims are interrelated and success in one area often benefits others. Successful management requires careful assessment of the person as a whole. The management plan should be individualised and patient- centred, should involve relevant members of the multidisciplinary team, and should be agreed and understood by both the patient and all the practitioners that are involved. It must also take into account: the patient's activity requirements and occupational and recreational aspirations risk factors that may influence the disease the patient's perceptions and knowledge of the condition medications and coping strategies that have already been tried comorbid disease and its therapy the availability, costs and logistics of appropriate evidence-based interventions. The simplest and safest interventions should be tried first. Symptoms and signs may change with time, so the management plan for most patients will require regular review and re-adjustment. Core interventions that should be considered for everyone with a painful musculoskeletal condition are listed in Box 24.27. There are also other non-pharmacological and drug options, the choice of which depends on the nature and severity of the diagnosis. 24.27 Interventions for patients with rheumatic diseases Core interventions Education Aerobic conditioning Muscle strengthening Simple analgesics Disease-modifying therapy Reduction of adverse mechanical factors Pacing of activities Appropriate footwear Weight reduction if obese Other options Other analgesic drugs: Oral non-steroidal anti-inflammatory drugs Topical agents Opioid analgesics Amitriptyline Gabapentin/pregabalin Local glucocorticoid injections Physical treatments: Heat, cold, aids, appliances Surgery Coping strategies (see Box 24.28 ) Education and lifestyle interventions Education Patients must always be informed about the nature of their condition and its investigation, treatment and prognosis, since education can improve outcome. Information and therapist contact can reduce pain and disability, improve self-efficacy and reduce the health-care costs of many musculoskeletal conditions, including OA and RA. The mechanisms are unclear but in part may result from improved adherence. Benefits are modest but potentially long- lasting, safe and cost-effective. Education can be provided through one-to-one discussion, written literature, patient-led group education classes and interactive computer programs. Inclusion of the patient's partner or carer is often appropriate; this is essential for childhood conditions but also helps in many chronic adult conditions, such as RA and FM. For children and adolescents with chronic diseases such as JIA, education and support of the whole family, schooling and psychological support is essential and best delivered through a multidisciplinary team. Exercise Several types of exercise can be prescribed: Aerobic fitness training can produce long-term reduction in pain and disability. It improves well- being, encourages restorative sleep and benefits common comorbidity, such as obesity, diabetes, chronic heart failure and hypertension. Local strengthening exercise for muscles that act over compromised joints also reduces pain and disability, with improvements in the reduced muscle strength, proprioception, coordination and balance that associate with chronic arthritis. ‘Small amounts often’ of strengthening exercise are better than protracted sessions performed infrequently. Weight-bearing exercise is of value in osteoporosis, where it can result in modest increases in bone density and slow bone loss. Joint protection Excessive impact-loading and adverse repetitive use of a compromised joint or periarticular tissue can worsen symptoms in patients with arthritis. This can be mitigated by cessation of contact sports and by pacing of activities by dividing physical tasks into shorter segments with brief breaks in between. Other strategies include adaptations to machinery or tools at the workplace; the use of shock-absorbing footwear with thick soft soles, which can reduce impact-loading through feet, knees, hips and back; and the use of a walking stick on the contralateral side to a painful hip, knee or foot. Non-pharmacological interventions Physical and occupational therapy Local heat, ice packs, wax baths and other local external applications can induce muscle relaxation and provide temporary relief of symptoms in a range of rheumatic diseases. Hydrotherapy induces muscle relaxation and facilitates enhanced movement in a warm, pain-relieving environment without the restraints of gravity and normal load-bearing. Various manipulative techniques may also help improve restricted movement. The combination of these with education and therapist contact enhances their benefits. Splints can give temporary rest and support for painful joints and periarticular tissues, and can prevent harmful involuntary postures during sleep. Prolonged rest must be avoided, however. Orthoses are more permanent appliances used to reduce instability and excessive abnormal movement. They include working wrist splints, knee orthoses, and iron and T-straps to control ankle instability. Orthoses are particularly suited to severely disabled patients in whom a surgical option is inappropriate and often need to be custom-made for the individual. Aids and appliances can provide dignity and independence for patients with respect to activities of daily living. Common examples are a raised toilet seat, raised chair height, extended handles on taps, a shower instead of a bath, thick-handled cutlery, and extended ‘hands’ to pull on tights and socks. Full assessment and advice from an occupational therapist maximise the benefits of these ( Box 24.27 ). Self-help and coping strategies These help patients to cope better with, and adjust to, chronic pain and disability. They may be useful at any stage but are particularly so for patients with incurable problems, who have tried all available treatment options. The aim is to increase self-management through self-assessment and problem-solving, so that patients can recognise negative but potentially remediable aspects of their mood (stress, frustration, anger or low self- esteem) and their situation (physical, social, financial). These may then be addressed by changes in attitude and behaviour, as shown in Box 24.28. 24.28 Self-help and coping strategies Yoga and relaxation techniques to reduce stress Avoidance of negative situations or activities that produce stress and increase in pleasant activities that give satisfaction Information and discussion to alter beliefs about and perspectives on disease Reduction or avoidance of catastrophising and maladaptive pain behaviour Imagery and distraction techniques for pain Expansion of social contact and better use of social services Involvement of the spouse or partner in mutual goal-setting can improve partnership adjustment. Such approaches are often an element of group education classes and pain clinics but may require more formal clinical psychological input. Tailored multidisciplinary approaches are required for patients with JIA and other chronic childhood diseases, dependent on age and maturity. Adolescents and young adults have specific demands, different to those of young children and adults, which are influenced by many issues in their lives impinging on the disease process, its impact and their ability to cope with it. Weight control Obesity aggravates pain at most sites through increased mechanical strain and is a risk factor for progression of joint damage in patients with OA and other types of arthritis. This should be explained to obese patients and strategies offered on how to lose and maintain an appropriate weight ( p. 700 ). Excessive weight loss can be counterproductive and adults with a BMI of < 20 kg/m 2 are at increased risk of fractures. Patients should therefore be advised to maintain BMI within the 20–25 g/m 2 range. Surgery A variety of surgical interventions can relieve pain and conserve or restore function in patients with bone, joint and periarticular disease ( Box 24.29 ). Soft tissue release and tenosynovectomy can reduce inflammatory symptoms, improve function and prevent or retard tendon damage for variable periods, sometimes indefinitely. Synovectomy does not prevent disease progression but may be indicated for pain relief when drugs, physical therapy and intra-articular injections have provided insufficient relief. The main approaches for damaged joints are osteotomy (cutting bone to alter joint mechanics and load transmission), excision arthroplasty (removing part or all of the joint), joint replacement (insertion of prosthesis in place of the excised joint) and arthrodesis (joint fusion). Surgical fixation of fractures is frequently required in patients with osteoporosis and other bone diseases. 24.29 Surgical procedures in rheumatology and bone disease Procedure Indication Soft tissue release Carpal tunnel Median nerve compression Tarsal tunnel Posterior tibial nerve entrapment Flexor tenosynovectomy Relief of ‘trigger’ fingers Ulnar nerve transposition Ulnar nerve entrapment at elbow Fasciotomy Severe Dupuytren's contracture Tendon repairs and transfers Hand extensor tendons Extensor tendon rupture Thumb and finger flexor tendons Flexor tendon rupture Synovectomy Wrist and extensor tendon sheath (+ excision of radial head) Pain relief and prevention of extensor tendon rupture in RA, resistant inflammatory synovitis Knee synovectomy Resistant inflammatory synovitis Osteotomy Femoral osteotomy Early OA of hip Tibial osteotomy Unicompartmental knee OA Deformed tibia in OA or Paget's disease Excision arthroplasty First metatarsophalangeal joint (Keller's procedure) Painful hallux valgus Radial head Painful distal radio-ulnar joint Lateral end of clavicle Painful acromioclavicular joint Metatarsal head Painful subluxed metatarsophalangeal joints Joint replacement arthroplasty Knee, hip, shoulder, elbow Painful damaged joints in OA and RA Arthrodesis Wrist Damaged joint: pain relief, improvement of grip Ankle/subtalar joints Damaged joint: pain relief, stabilisation of hindfoot Fracture repair Hip arthroplasty Fractured neck of femur External fixation Multiple fractures, open fractures Intramedullary nailing Tibial and femur fractures Screw, plating and wiring Wrist and other fractures Other procedures Nerve root decompression Spinal stenosis, nerve entrapment Kyphoplasty Painful vertebral fracture (evidence base poor) Vertebroplasty Painful vertebral fracture (evidence base poor) The main aims of surgery are to provide pain relief and improve function and quality of life. If surgery is to be successful, the aims and consequences of each operation should be considered as part of an integrated programme of management and rehabilitation by multidisciplinary teams of surgeons, allied health professionals and physicians, and carefully explained to the patient. Assessment of motivation, social support and environment is no less important than careful consideration of patients' general health, their risks for major surgery, the extent of disease in other joints, and their ability to mobilise following surgery. For some severely compromised people, pain relief and functional independence are better served by provision of a suitable wheelchair, home adjustments and social services than by surgery that is technically successful but following which the patient cannot mobilise. Pharmacological treatment Analgesics Paracetamol (1 g up to 4 times daily) is the oral analgesic of first choice for mild to moderate pain. It is thought to work by inhibiting prostaglandin synthesis in the brain while having little effect on peripheral prostaglandin production. It is well tolerated and has few adverse effects and drug interactions. An increased risk of gastrointestinal events and cardiovascular disease has been reported with chronic usage in observational studies, but this may be due to channelling of patients at higher risk of these events for treatment with paracetamol rather than NSAID. Paracetamol can be combined with codeine (co-codamol) or dihydrocodeine (co-dydramol). These compound analgesics are more effective than paracetamol but have more side-effects, including constipation, headache and delirium, especially in the elderly. The centrally acting opioid analgesics tramadol and meptazinol may be useful for temporary control of severe pain unresponsive to other measures but can cause nausea, bowel upset, dizziness and somnolence, and withdrawal symptoms after chronic use. The non-opioid analgesic nefopam (30– 90 mg3 times daily) can help moderate pain, though side-effects (nausea, anxiety, dry mouth) often limit its use. Patients with severe or intractable pain may require strong opioid analgesics, such as oxycodone and morphine. Non-steroidal anti-inflammatory drugs NSAIDs are among the most widely prescribed drugs but their use has declined over recent years because long-term prescription is associated with an increased risk of cardiovascular disease. Oral NSAIDs are useful in the treatment of a range of rheumatic diseases with an inflammatory component. There is variability in response and patients who do not gain benefit from one NSAID may well do so with another. They inhibit the cyclo-oxygenase (COX) and prostaglandin H synthase enzymes, which convert arachidonic acid, derived from membrane phospholipids, to prostaglandins and leukotrienes by the COX and 5-lipoxygenase pathways, respectively ( Fig. 24.14 ). There are two COX isoforms, encoded by different genes. The COX-1 enzyme is constitutively expressed in gastric mucosa, platelets and kidneys, and production of prostaglandins at these sites protects against mucosal damage and regulates platelet aggregation and renal blood flow. The COX-2 enzyme is induced at sites of inflammation, producing prostaglandins that cause local pain and swelling. Inflammation also up-regulates COX-2 in the spinal cord, where it modulates pain perception. Ibuprofen, diclofenac and naproxen are non-selective drugs that inhibit both COX enzymes, whereas celecoxib and etoricoxib are selective inhibitors of COX-2. While NSAIDs have anti-inflammatory activity, they are not thought to have a disease-modifying effect in either OA or inflammatory rheumatic diseases. Fig. 24.14 Mechanism of action of non-steroidal anti-inflammatory drugs. Non-selective NSAIDs can damage the gastric and duodenal mucosal barrier and are associated with an increased risk of upper gastrointestinal ulceration, bleeding and perforation. The adjusted increased risk (odds ratio) of bleeding or perforation from non-selective NSAIDs is 4–5, though differences exist between NSAIDs ( Box 24.30 ). Dyspepsia is a poor guide to the presence of NSAID-associated ulceration and bleeding, and the principal risk factors are shown in Box 24.31. Co-prescription of a proton pump inhibitor (PPI) or misoprostol (200 µgtwice or 3 times daily) reduces the risk of NSAID-induced ulceration and bleeding but H 2 -antagonists in standard doses are ineffective. The COX-2 selective NSAIDs are much less likely to cause gastrointestinal toxicity but benefit is attenuated in patients on low-dose aspirin. The National Institute for Health and Care Excellence (NICE) guidelines advise that a PPI should be co-prescribed with all NSAIDs, including COX-2-selective NSAIDs, even though the risk of gastrointestinal events with these is low. Since chronic PPI therapy is associated with an increased risk of hip fracture, the merits of giving PPI therapy with a COX-2-selective drug need to be weighed up carefully. 24.30 Commonly used NSAIDs and their risk of gastrointestinal bleeding and perforation (CNS = central nervous system; COX = cyclo-oxygenase; PPI = proton pump inhibitor) 24.31 Risk factors for NSAID-induced ulcers Age > 60 years* * The most important risk factors. Past history of peptic ulcer * Past history of adverse event with NSAID Concomitant glucocorticoid use High-dose or multiple NSAIDs High-risk NSAID (see Box 24.30 ) Other side-effects of NSAIDs include fluid retention and renal impairment due to inhibition of renal prostaglandin production, non-ulcer-associated dyspepsia, abdominal pain and altered bowel habit, and rashes. Interstitial nephritis, asthma and anaphylaxis can also occur but are rare. Recommendations for NSAID prescribing are summarised in Box 24.32. Because of the risk of adverse effects, NSAIDs should be used with great care in the elderly ( Box 24.33 ). 24.32 Recommendations for the use of NSAIDs Use the lowest dose for the shortest time possible to control symptoms Avoid NSAIDs in patients on warfarin Allow 2–3 weeksto assess efficacy. If response is inadequate, consider a trial of another NSAID Never prescribe more than one NSAID at a time Co-prescribe a proton pump inhibitor for patients with risk factors for gastrointestinal adverse effects (see Box 24.31 ) Avoid in patients with vascular disease 24.33 Use of oral NSAIDs in old age Gastrointestinal complications : age is a strong risk factor for bleeding and perforation, and for peptic ulceration. Elderly patients are more likely to die if they suffer NSAID-associated bleeding or perforation. Cardiovascular disease : use NSAIDs with caution in patients with cardiovascular disease. Therapy with NSAIDs may exacerbate hypertension and heart failure. Renal disease : use of NSAIDs may cause renal impairment. Topical agents Topical NSAID creams and gels and capsaicin cream (chilli extract; 0.025%) can help in the treatment of OA and superficial periarticular lesions affecting hands, elbows and knees. They may be used as monotherapy or as an adjunct to oral analgesics. Topical NSAIDs can penetrate superficial tissues and even reach the joint capsule, though intrasynovial levels mainly reflect blood-borne drug delivery. Capsaicin selectively binds to the protein transient receptor potential vanilloid type 1 (TRPV1), which is a heat-activated calcium channel on the surface of peripheral type C nociceptor fibres. Initial application causes a burning sensation but continued use depletes presynaptic substance P, with subsequent pain reduction that is optimal after a period of 1–2 weeks.Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) are a group of small-molecule inhibitors of the immune response. They are employed in a range of inflammatory rheumatic diseases, as well as in other chronic inflammatory conditions. The most common indications are summarised in Box 24.34. Most of these drugs have the potential to cause bone marrow suppression or liver dysfunction and they require regular blood monitoring. Monitoring requirements for commonly used DMARDs are also summarised in Box 24.34. If toxicity occurs, treatment may need to be stopped temporarily and resumed at a lower dose. If toxicity is severe, therapy may have to be withdrawn completely and another drug substituted. 24.34 Disease-modifying antirheumatic drugs Drug Maintenance dose Monitoring * Indications FBC LFTs Other Methotrexate 10– 25 mgweekly orally RA, PsA, AxSpA, JIA Sulfasalazine 2–4 gdaily orally RA, PsA, AxSpA, JIA Hydroxychloroquine 200–400 mgdaily orally – – Visual function RA, SLE Leflunomide 10–20 mgdaily orally BP RA, JIA, PsA Azathioprine 1–2.5 mg/kg daily orally SLE, SV Apremilast 30 mgtwice daily orally – – – PsA Tofacitinib 5 mgtwice daily orally Infection RA Baricitinib 2–4 mgdaily orally Infection RA Cyclophosphamide 2 mg/kg daily orally 15 mg/kg IV eGFR SLE, SV Mycophenolate mofetil (MMF) 2–4 gdaily orally – SLE, SV Gold (myocrisin) 50 mg4-weekly IM – Urinalysis RA Penicillamine 500–1500 mgdaily orally Urinalysis RA Ciclosporin A 3–5 mg/kg daily orally – – BP, eGFR RA, PsA * Monitoring tests are usually done every 2 weekson initiation of treatment for 6 weeks,then monthly for 3 months,then 3-monthly. (AxSpA = axial spondyloarthritis; BP = blood pressure; eGFR = estimated glomerular filtration rate; FBC = full blood count; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; LFTs = liver function tests; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SV = systemic vasculitis) Methotrexate Methotrexate (MTX) is the core DMARD in RA, JIA and PsA. It inhibits folic acid reductase, preventing formation of tetrahydrofolate, which is necessary for DNA synthesis in leucocytes and other cells. It is given orally in a starting dose of 10–15 mgweekly and escalated in 2.5 mgincrements every 2–4 weeksto a maximum of 25 mgweekly until benefit or toxicity occurs. Folic acid (5 mg/week) should be co-prescribed to be taken the day after MTX since it reduces adverse effects without impairing efficacy. Benefit is usually observed after 4–8 weeksbut treatment should continue for 3 months before the conclusion is reached that MTX has been ineffective. The most common adverse effects are nausea, vomiting and malaise, which usually occur one 1– 2 daysafter the weekly dose. Individuals who experience these effects can sometimes be successfully treated with subcutaneous MTX. Patients should be warned of drug interaction with sulphonamides and the importance of avoiding excess alcohol, which enhances MTX hepatotoxicity. Acute pulmonary toxicity (pneumonitis) is rare but can occur at any time during treatment, and patients should be warned to stop therapy and seek advice if they develop any new respiratory symptoms. If pneumonitis occurs, treatment should be withdrawn and high- dose glucocorticoids given. MTX must be co-prescribed with robust contraception in women of child-bearing potential and treatment must be stopped for 3 monthsin advance of planning a pregnancy. Sulfasalazine Sulfasalazine (SSZ) can be used alone and or combination with MTX and another DMARD. Its mechanism of action is incompletely understood. Nausea and gastrointestinal intolerance are the main adverse effects but leucopenia, abnormal LFTs and rashes may also occur. The usual starting dose is 500 mgdaily, escalating in 500 mgincrements every 2 weeksto a maintenance dose of 2–4 gdaily until benefit or toxicity occurs. Benefit may be observed after 4–8 weeksbut treatment should be continued for 3 monthsbefore the conclusion is reached that it has been ineffective. Orange staining of urine and contact lenses may occur. Hydroxychloroquine Hydroxychloroquine (HCQ) is used in the treatment of RA and SLE in a dose of 200–400 mgdaily. Its mechanism of action is incompletely understood. A wide range of side-effects can potentially occur but HCQ is usually well tolerated in practice. With long-term use, there is a risk of ocular toxicity due to accumulation in the retina, although this is uncommon. It is usual to check visual function before starting treatment and to repeat this periodically while treatment is continued. HCQ is generally considered to be safe during pregnancy Leflunomide Leflunomide can