Causes of Achilles \200\231 tendononpathy \200 \200 \200 \200 Spondylarthropathy. Acute or chronic trauma. Fluoroquinolone-induced. Associated conditions : \200 \200 \200 Injudicious use of glucocorticoid injection Plantar fasciitis (PF) Plantar fasciitis is an enthesopathy of the calcaneal tuberosity. Th ere are both mechanical and autoimmune in \202 ammatory aetiologies. Pure mechanically-ind uced PF is caused by over-use, repetitive strain, or microtrauma. PF is a common in lesion in spondylarthropathy conditions and chronic musculoskeletal sarcoidosis. \200 haemodialysis; hypercholesterolaemia (xanthomas); diabetes. There is pain and/or stiffness on the plantar heel surface occasionally extending along the proximal sole. Symptoms are often worse with the \201 rst few steps of the day. Ask abou t current or previous in \202 ammatory back pain (see p. 210), psoriasis, and pain at enth eses elsewhere. Tenderness is maximal over the medial calcaneal tubercle. A positive heel s queeze test can discriminate pain from os calcis stress fractures (os calcis squeezed betwe en the heels of your hands from both sides). Lateral os calcis radiograph and, if necessary , CT, can help rule out calcaneal stress fracture. Characteristic MR, 99mTc-MDP scintigraph y and US appearances have been described. In traumatically-induced lesions, 25% of injuries may be missed at the \201 rst presentat ion. The pathological changes described in the tendon may be broadly characterized as tendo nosis without in \202 ammation and in \202 ammation of the paratenon (surrounding tendon sheath). In cases of rupture, the site is usually in a relatively hypovascular region of th e tendon 2 \200\2236 cm proximally from the insertion. Rupture may also occur at the enthe- sis or at the muscle/tendon junction. The rupture is unusually painful in \202 uoroquino lone- induced tendonopathy. Otherwise, especially in chronically developing ruptures, the p ain is not severe or is totally absent. SpA-related lesions (enthesopathies) are characteri zed by tenderness over the posterior os calcis, irregularly de \201 ned erosions and/or de position of bone with de \201 ned excrescences in the healing stage. Examine with patient standing from behind and compare sides. Examine then with patient prone and feet over end o f couch. Pathology at muscle-tendon junction, Achilles tendon (cord) and insertion can be p alpated. Squeezing the calf plantar- \202 exes foot if tendon intact. US may predict the o utcome of achillodynia. Differentiation of full- and partial-thickness tears can be made wi th 92% accuracy using US and characteristic appearances at the enthesis has been described in SpA- related disease. MR imaging frequently shows intra-tendonous changes during \202 uoroquinolone treatment even in the absence of any clinical signs. 99mTc-MDP scintigraphy h ighlights enthesopathy at the site and other places in SpA. Management of PF Conservative management: rest, night splints, use of soft rubber heel pads , foot orthoses to support of the longitu- dinal arch, and physiotherapy may all have a rol e. \200 NSAIDs and local GC injection can be considered. Evidence for long-term ef \201 cacy of th e latter however is lacking. US-guided GC injection is no more effective than palpation-gui ded injection. Surgical release of the plantar fascia is rarely required. Healing problems of the overlying skin are relatively frequent. Endoscopic plantar fasciectomy is a recently - developed technique, which probably causes fewer com- plications compared with open surge ry. External beam radiotherapy can be helpful in recalcitrant cases. A number of alternativ e treatment modalities have been reported. The ef \201 cacy of lithotripsy, botulinum inje ction, autologous blood injection has not been proven in long- term robust studies compared with GC injection. Management of Achilles \200\231 tendonopathy Non-in \202 ammatory lesions Protection of th e foot and heel support is appropriate. Surgery is required in the case of complete rupture and provides good results but a rather high (15%) percentage of complications. Further reading Irving DB, Cook JL, Menz JB. Factors associated with chronic plantar heel p ain: a systematic review. J Sci Med Sport 2006; 9(1 \200\2232): 11 \200\22322. Paige NM, No uvong A. The top 10 things foot and ankle specialists wish every primary care physician kne w. Mayo Clin Proc 2006; 81: 818 \200\22322. Wearing SC, Smeathers JE, Urry SR, Henrig EM, Hills AP. The patho- mechanics of plantar fas ciits. Sports Med 2006; 36(7): 585 \200\223611. In \202 ammatory SpA-related lesions NSAIDs and orthotics for heel support. Physiotherapy in recovering cases to avoid shortening of posterior heel structures. Glucocorticoid inject ions over the enthesis can be considered in isolated enthesitis or where paratenon inflamma tion exists without intra-tendon substance changes (demonstrable on US). This page intentionally left blank CONDITIONS OF THE MID AND FOREFOOT 194 Conditions of the mid and forefoot Accessory navicular bone This is present in 4 \200\22321% of the population and can be a ca use of medial midfoot pain. An accessory navicular is a large triangle or heart-shaped ossi cle attached with a cartilaginous or \201 brocartilaginous synchondrosis to the navicular bone. It is thought to be a source of symptoms owing to a chronic stress reaction. \200 For differential diagnosis between Morton \200\231s neuroma and MTPJ arthritis, local anest hetics can be given either into the interspaces proximally to the metatarsal head or into t he corresponding MTPJ. This \200\230ex juventibus \200\231 effect may show what is the pro bable cause of pain. US or MR can also be used for differential diagnosis. Surgical excisio n of the neuroma may be undertaken in symptomatic cases. \200 The bone con \201 guration and its involvement in \200\230bony stress \200\231 can be dem onstrated on radiographs or CT and bone scintigraphy, respectively. An accessory navicular bone may also damage the posterior tibial tendon. The management consists of resting from s ports activities or surgical excision of the accessory bone. Stress fractures of the metatarsals These fractures are common in runners, ballet dancers a nd other sports where there is inadequate shoe support, but they are also found in the midd le-aged or the elderly doing sporting activities. Stress fracture also occurs in diabetic o steoarthropathy, and can indicate generalized or regional osteoporosis. Regional cortical-r ich bone osteoporosis is a feature of hyperparathyroidism. The Mueller \200\223Weiss syndrome Osteochondritis/necrosis of the navicular bone. This occ urs more frequently bilaterally in adult women. The management is conservative with rest an d orthotic foot support as necessary. A failure of conservative therapy can lead to permane nt degenerative midfoot arthritis. Radiologically occult fractures can be detected by MR imaging or bone scintigraphy if clini cal suspicion remains when radiographs are normal. With MR and/or bone scin- tigraphy even the pre-fracture state of stress injury can be diagnosed. Plantar plate disruption A common cause of metatarsalgia. It occurs frequently in women wea ring high-heeled shoes. The second MTPJ is most commonly affected. Diagnosis can be made by MR. Freiberg \200\231s infarction Probably an osteonecrosis of the second or third metatarsal h ead, causing secondary osteoarthritis of the adjacent MTPJ. High-heeled shoes, repetitive i njury or trauma may be causative factors. Intermetatarsal bursitis Overstrain of the MTPJ region often results in bursitis of the int ermetatarsal bursae or adventitial bursae beneath the metatarsal heads. Bursitis can also b e caused by repetitive trauma, infection, RA, SpA, or gout. Foreign body granulomas Granulomas due to thorns, glass, plastic, or wood particles are not rare on the plantar surface of the foot. The foreign bodies can be visualized by US or MR. MTPJ synovitis Pain and/or stiffness across the forefoot or on weight-bearing can denote sy novitis of MTPJs though the symptoms are not speci \201 c. \200 Plantar \201 bromatosis or \200\230Ledderhose \200\231 disease A benign, but locally oft en aggressive \200\230tumor \200\231 of the fascia, identical to Dupuytren \200\231s contr acture of the hand. \200 May be tender on palpation. Also there may be a small tender mass palpabale. Fibrous tissue can be palpated at the medial and proximal aspect of the plantar fascia. It can be visuali zed by both US and MR; however, physical examination is often suf \201 cient for a reliabl e diagnosis. The treatment is subtotal fasciectomy, but recurrences are not rare. External beam radiotherapy may arrest progression and prevent the need for surgery. Bilateral forefoot stiffness can occur in RA and psoriatic arthritis notably. There may be visible forefoot spreading (look for sepa- ration of toes). Toe bases are tender. Squeezing across MTPJs can elicit pain, although this is not a speci \201 c test. With advanced pol yarticular MTPJ synovitis there may be metatarsal head subluxation. Abnormal callus distrib ution may be evident on the sole of the foot. Poly ( \202 exor) tenosynovitis can co-exist with, or mimic, MTPJ synovitis. The usual diagnosis is RA. Prior to erosive changes in MTP Js, or joint space loss \200\223 both evident in advanced disease on radiographs, US and M R may highlight in \202 ammatory lesion site and distribution. Sesamoiditis A painful in \202 ammatory condition caused by repetitive injury to the plant ar aspect of the forefoot. Reactive soft- tissue in \202 ammation, such as tendonitis, syn ovitis, or bursitis often accompanies the condition. Morton \200\231s neuroma Morton \200\231s neuroma is located most often between the 3rd and 4th metatarsal heads. The neuroma is not a true neoplasm, but is caused by peripheral \201 brosis of the com- pressed inter-digital nerve. Histology of the neuroma is undistingu ishable from normal intermetatarsophalangeal nerves. \200 Hallux rigidus This usually results from OA or PsA changes at the \201 rst MTPJ. Loss of motion is due to new growth of bone around dorsal articular surface of \201 rst metatarsa l head. Epidemiology \200 \200 \200 Most common osteoarthritic joint in the foot. Second commonest great toe condition to hallu x valgus 1 in 40 individuals over 50 years develop hallux rigidus. Females > males (2:1). P soriatic dactylitis/periostitis is also a cause. The nerve compression can be caused by the metatarsal heads, inter-metatarsal ligaments and bursae. The pain presents on the opposing sides of the two toes, accompanied by hypoparaes thesia. CHAPTER 5 Regional musculoskeletal anatomy and conditions 195 Dactylitis and psoriatic onycho pachydermo periostitis (POPP) Dactylitis is a common \201 nding in two of the SpA conditions notably \200\223 PsA, ReA. Dactylitis is also a featur e of AS, USpA, and chronic sarcoidosis. Acute gout involving the whole toe can also cause a dactylitis \200\223 although classically the swelling may be more eccentrically-orientate d. Clinical features \200 There is pain or paraesthesia aggravated by standing, walking, and wearing shoes with heels . Dactylitis and nail disease may suggest PsA. Skin irritation due to pressure from footwea r over dorsal exostoses. Limitation of motion, especially dorsiflexion though often normal or adequate plantar- \202 exion. Affected feet are often long, narrow and pronated with un stable arches. Feet are frequently hyper-mobile or have an elevated (and long) \201 rst m etatarsal. \200 In the SpAs dactylitis may be acute, involve one or a number of toes, and is often asymmetr ical. More indolent forms of dactylitis can be easily overlooked. In psoriatic onycho pachydermo periostitis there may be swelling, pain, and stiffness of th e toe extremities associ- ated with nail changes. A range of features probably exist. The c ondition can occur in children. \200 Differential diagnosis There is a need to rule out \200\230pseudo-hallux rigidus \200\231: Nodular swelling of the proximal \202 exor hallucis longus (FHL) also limits hallux dors i \202 exion. However, in this condition hallux motion is restored when the ankle is plant ar \202 exed. Periosteal changes in the great toe in PsA are common and exist 20 \200\22350% of patients with PsA. Indolent dactylitis of the great toe in PsA associated with periosteal apposition and juxta-articular new bone formation is probably an under-recognized cause of hallux lim itus/rigidus. Investigations Radiological features include non-uniform joint space narrowing, widening of the \201 rst metatarsal head and base of proximal phalanx, subchondral sclerosis and cys ts, horseshoe-shaped osteophytes, more osteophyte formation on lateral compared with medial side, sesamoid changes. Further reading Gehrmann RM, Renard RL. Current concepts review: stress frac- tures of the foot. Foot Ankle Int 2006; 27(9): 750 \200\2237. Treatment \200 Healy PJ, Groves C, Chandrmohan M, Helliwell PS. MRI changes in psoriatic dactylitis \200 \223 extent of pathology, relationship to tender- ness and correlation with clinical indice s. Rheumatology (Ox) 2008; 47: 92 \200\2235. Conservative therapy includes molded stiff orthoses, with rigid bar or rocker bottom shoe. Surgical treatment includes cheilectomy for mild to moderate deformity. Arthrodesis is the treatment of choice following failed cheilectomy or where advanced degenerative changes are present. Implant arthroplasty provides good results. The use of mosaicplasty has been rece ntly reported. Keiserman LS, Sammarco VJ, Sammarco GJ. Surgical treatment of the hallux rigidus. Foot Ankle Clin 2005; 10: 75 \200\22396. Ugolini PA, Raikin SM. The accessory navicular. Foot Ankle Clin 2004; 9: 165 \200\22380. This page intentionally left blank 197 Chapter 6 Rheumatoid arthritis Guidelines for the management of rheumatoid arthritis 208 RHEUMATOID ARTHRITIS 198 De \201 nition Rheumatoid arthritis (RA) or, more correctly, rheumatoid disease, is a hete rogeneous, multisystem autoin \202 ammatory disorder of unknown etiology manifest chie \202 y as synovitis, however, extra-articular involvement is common. The disease is associa ted with signi \201 cant disability and prema- ture mortality. As no diagnostic test exist s for RA its identi \201 cation relies on the clinical picture supplemented by laboratory and radiological investigations. Peak age of onset occurs between 30 and 50 years in females. Incidence increases with age i n males First-degree relatives have a 2 \200\2233-fold increased incidence. Monozygotic twi ns share 30 \200\22350% concordance, 4-fold greater than dizygotic twins. Uncontrolled seve re disease leads to increased mortality, but the expression of RA is heterogeneous, and the re- fore prognostication, is difficult. Life expectancy is reduced by 3 years in women and 7 years in men. Premature mortality is chie \202 y due to an increase in cardiovascular di sease, infections, and respiratory complications. Spontaneous remission may occur especiall y early disease; however, this is less likely once joint damage has developed. The direct a nd indirect costs (including loss of produc- tivity and reduced quality of life) associated with RA are enormous, with indirect costs accounting for up to 2/3 of the total. \200 Diagnostic criteria Due to the heterogeneity of RA and the variable expres- sion of disease , precise categorization of the condition is problematic. \200 This complexity is compounded when dealing with early RA or early undifferentiated in \202 ammatory arthritis. This has a profound effect on management as the current paradigm is to capture RA as early as possible in the \200\230window of opportunity \200\231 to switch o ff the in \202 ammatory process. The diagnosis therefore rests upon a constellation of sig ns and symptoms supported by serological investiga- tion and appropriate imaging. Exclusion of other in \202 ammatory arthritides is paramount. Classification is based on the Americ an College of Rheumatology 1987 criteria. These criteria were originally devised to classif y established disease and therefore do not apply for early arthritis. New diagnostic and cl assi \201 cation criteria are therefore required. Etiology/pathogenesis The etiology of RA is unknown, but is likely to be multi- factorial. Disease is possibly precipitated by an environ- mental trigger/s or potentially stochastic event occurring in a genetically predisposed individual. No conclusive evidence exists impl icating an infective cause such as bacteria or mycoplasma. The potential role of parvovirus B19 is controversial. Cigarette smoking is a risk and severity factor. No other single ext ernal environmental factor shows a clear or consistent association with RA. \200 Table 6.1 American College of Rheumatology classi \201 cation criteria for rheumatoid arth ritis (1987). Four of the seven criteria must be met. Criteria 1 \200\2234 must have been p resent for at least 6 weeks. Genetic The shared epitope of the HLA-DRB1*04 cluster, present in over 80% of RA patients, shares a highly homologous amino acid sequence at the third hypervariable region of the HLA -DR chain. It is associated with the development of disease and is a severity factor. This sequence is common to most RA patients although disease develops only in a small portion of those with the epitope. Thus, RA is most likely a polygenic disease. 1 Morning stiffness in and around joints, lasting at least 1 h before maximal improvement 2 Arthritis in three of more joint areas. Soft tissue swelling or \202 uid (not bony overgr owth) observed by a physician. Possible areas include right or left PIP, MCP, wrist, elbow, knee, ankle and MTP joints Immunopathology RA is characterized by destruction of articular cartilage and subchondral b one by invading synovial hyperplasia (pannus). In chronic RA, in \202 ammatory cells accum ulate and lymphocytes may organize into discrete aggregates. A diffuse mononuclear cell in \201 ltration or relatively acellular \201 brous tissue may also be present. \200 3 Swelling (arthritis) of the PIP, MCP, or wrist joints 4 Symmetrical arthritis. Simultanous involvement of the same joint areas (de \201 ned in 2) on both sides of the body. Absolute symmetry not necessary 5 Subcutaneous nodules 6 Positive test for rheumatoid factor Immune dysfunction is central to the pathogenesis with upregulation of pro-in \202 ammator y cells and cytokines (i.e. T cells, B cells, macrophages, dendritic cells, TNFA, IL-1, IL- 6, and INFG) and autoantibody production [rheuma- toid factors (RF), anti-citrullinated pep tide (CCP) anti- bodies]. TNFA and IL-6 appear to be pivotal cytokines in the in \202 amma tory cascade and have pleiotropic effects. 7 Radiographic erosions and/or peri-articular osteopaenia in hand and/or wrist joints PIP: proximal interphalangeal; MCP: metacarpophalangeal; MTP: metatarsophalangeal. Epidemiology RA is the most frequent chronic in \202 ammatory disease of joints and is fou nd ubiquitously. \200 Autoantibodies Serum-detected RFs are immunoglobulins (usually IgM) with antibody speci \201 city for the Fc region of IgG. \200 Prevalence approaches 1% in the industrialized world and varies with ethnicity. Low \201 gures in certain developing countries may be confounded by age distribution Incidence estim ated to be 3.4/10 000 in women and 1.4/10 000 in men highlighting the female preponderance (3:1). The gender difference equilibrates in older age groups. Hormonal and reproductive fa ctors contribute to the female excess. The distribution and extent of RFs in tissue is less clear. IgA and IgG dimer RFs clearly e xist, however. Anti-citrullinated antibodies are directed against pep- tides such as viment in, \201 brinogen and cyclic citrullinated peptide (their speci \201 city determined by their ability to bind citrulline, a modi \201 ed arginine residue). CHAPTER 6 Rheumatoid arthritis 199 Some patients show evidence of autoimmunity prior to clinical disease with autoantibodies d etectable in blood years prior to the onset of clinical disease. of various mediators does not necessarily result in down- regulation of in \202 ammation. The window of opportunity for immunotherapy In relation to the pathogenesis, a discrete per iod in early disease (within 3 months of symptom onset), during the acute in \202 ammatory response, may produce a \200\230window of opportunity \200\231 where a disproportionate b enefit for intervention exists. Once the chronic phase of disease is established prolonged therapy is most likely required. Innate immunity Initiation of the in \202 ammation may not, however, be autoan- tibody med iated and may occur via the innate immune system in the synovium. \200 This process involves Toll-like receptors (primitive pattern recognition molecules) express ed principally by dendritic cells, which bind to foreign and self antigens. This, in turn, acts upon cells of the adaptive system initi- ating auto-in \202 ammation. A localized rea ction then occurs with influx of inflammatory mediators via activated endothelial cells exp ressing various adhesion molecules. Arthritis associated antigens are subsequently presente d to T-helper 1 cell receptors via class II MHC molecules on antigen presenting cells (APCs ). The shared epitope allows binding of speci \201 c peptides and affects antigen presenta tion. T cell co-stimulation is then required for full activation occurring via CD80 and CD8 6 present on APCs binding to CD28 on T cells. Up-regulation of Th1 cells leads to secretion of various in \202 ammatory mediators, which in turn activate B cells, macrophages, \201 broblast-like synoviocytes and osteoclasts. Clinical features The most frequent presentation of RA is in \202 ammation of synovial joi nts. It is, however, a multisystem disorder and extra-articular features are common Key features in the history \200 Symmetrical polyarthritis predominantly affecting PIPs, MCPs, wrists and MTPs is the most c ommon presenta- tion, however, any synovial joint may be affected (the DIPs are classically spared) leading to pain, stiffness, swelling, and reduced manual dexterity. Joint pain ons et may be rapid or insidious. Joint symptoms are worse in the morning and after periods of immobility (gelling phenomenon). Fatigue is common. Palindromic rheumatism is a predominant ly large joint, migratory arthritis with attacks lasting hours to days. One-third of such p resentations eventually develop true RA. Classic symptoms of polymyalgia rheumatica (PMR) m ay herald the onset of RA by weeks to months. Neck pain and long tract symptoms may develop if there is signi \201 cant atlanto-axial subluxation though this is a late feature (C1/C 2 cervical spine involvement). Constitutional symptoms include fever, malaise, anorexia. \200 \200 B cells B cells are most likely involved in the in \202 ammatory process via several mecha nisms including: \200 \200 Autoantibody production (RFs, anti-CCP antibodies). Antigen presentation to T cells (a vici ous cycle may develop leading to perpetuation of the autoimmune response). T cell co-stimul ation, production of pro-in \202 ammatory cytokines. Development of immune complexes augme nts the pro-in \202 ammatory cytokine production via Fc-receptor and complement activation . Key features on examination Arthritis/musculoskeletal \200 Early joint signs: soft-tissue swelling, tenderness, pain on active and passive movement of joint. The piano key sign: damped depression of the ulnar head on pressure owing to surrou nding synovitis and laxity or disruption of distal radio-ulna ligament. Classic signs of lo ng-standing hand disease: swan- neck and boutonni re deformities of the \201 ngers, and Z deformity of the thumb, ulnar deviation, and subluxa- tion of the MCP and wrist joints. R heumatoid nodules occur in up to 20% especially over pressure areas. Patients are almost al ways serop- ositive for RF. The lesion consists of \201 brinoid necrosis with the center surrounded by pallisading histiocytes. Nodules may be exacerbated by MTX. Vasculitic skin l esions may occur especially in the hands (e.g. nail folds). Muscle weakness develops second ary to disuse atrophy and asthenia. General mobility may decline resulting in signi \201 c ant disability and handicap. Hoarseness and vocal cord collapse may develop with crico-aryt enoid cartilage involvement. Late signs in weight-bearing joints: knee valgus, hind- foot v algus with pes planus and posterior tibial tendon de \201 ciency. Cock-up, over-riding and hammer deformities of the toes may occur (relatively late signs). Synovial \201 broblasts Local proliferation of the \201 broblast-like type B synoviocyt es and migration of new macrophage-like type A synoviocytes from the bone marrow and blood into the joint leads to synovial hyperplasia. This mass of type B synoviocytes (pan- nus) p roduces pro-in \202 ammatory mediators including cyto- kines, prostaglandins and matrix me talloproteinases (MMPs), which in turn destroy cartilage and bone. Erosions Bone erosions are chie \202 y caused by osteoclasts. \200 Activation of receptor activator of nuclear factor kB (RANK) via its ligand (RANK-L), stimu lates osteoclast differentiation from monocyte and macrophage precur- sors, and leads to ma turation and survival of osteoclasts. The erosions are seen at the joint margins, where syn - ovium is re \202 ected near the attachment of the capsule. The bone in this area is the so-called \200\230bare area \200\231, which is not protected by a layer of cartilage and i s directly attacked by the invading synovium and osteoclasts. Other factors Other factors at play in the destructive process include neovascularization, defective apoptosis of synovial cells, de \201 ciency of regulatory T cells, antibodies di rected at joint speci \201 c antigens such as a RA33. Duplication and redun- dancy in the in \202 ammatory process is evident as inhibition RHEUMATOID ARTHRITIS 200 \200 Acute phase response (elevated ESR, CRP). The usual iron indices are poorly specific for ir on de \201 ciency in the presence of systemic in \202 ammation. A low ferritin <25 g/l and elevated soluble transferrin receptor values are arguably the most reliable signs of ir on de \201 ciency and low erythropoiesis in RA patients. Baseline renal, bone biochemistry , and liver function tests (crucial to know baseline results prior to starting pharmacother apy especially DMARDs). Urinalysis is a useful screen for urinary infection and in \202 am matory renal lesions associated with RA or its therapies. Co-morbidities Bone Osteoporosis is common including generalized osteoporosis, periarticula r osteopaenia and bony erosions Haematologic/reticuloendothelial \200 \200 Anemia, leucopaenia, thrombocytosis may occur Lymphoma incidence is elevated in RA and is g enerally accepted to be increased 2-3 fold especially in long- standing disease. Lymphadeno pathy may occur. Felty \200\231s syndrome (RF positive RA, splenomegaly and pancytopaenia, most frequently neutropaenia) may lead to recurrent bacterial infections and chronic leg ul cers. Associated with autoimmune hepatitis. \200 Immunological tests \200 Rheumatoid factors are present in up to 85% of patients, but may be elevated in many other conditions. Anti-CCP (cyclic citrullinated protein) antibodies have similar sensitivity to RF (50 \200\22360%), but have higher speci \201 city (85 \200\22390%). Anti-CCP antibodies can be helpful in equivocal, especially RF negative, cases. CCP antibodies are more speci \201 c for RA than RF. CCP antibodies might in future be used preferentially for diagnosis . ANA is often positive, but usually in low titre. Complement levels are normal or high. Respiratory system (see also p. 54) Pulmonary involvement is common including interstitial lung disease, pleurisy, pleural effusions and bronchiectasis. \200 Symptoms of lung disea se include shortness of breath, wheeze, dry cough and possibly chest pain. Caplan \200\231s syndrome consists of pulmonary nodulosis and pneumoconiosis (especially coal dust exposure ) in patients with RA. \200 Cardiovascular involvement (see also p. 66) \200 Endothelial dysfunction results in cardiovascular disease (increased incidence of ischaemic heart disease and stroke). Rarely nodules can form in the heart. Pericardial effusion is r arely symptomatic. Imaging Radiographs \200 Radiographs of hands and feet are mandatory. Ball catcher views can show MCP joint erosions dif \201 cult to see on plain AP views. Features may include soft tissue swelling, loss o f joint space, periarticular osteopaenia and juxta-articular erosions, but radiographs are frequently normal at presentation. With radiographs, bony erosion can be seen, in up to 80% of patients within 2 years of symptom onset. (see Figure 6.1). CXR is essential to screen for evidence of RA lung disease especially prior to starting DMARDS (e.g. methotrexate). \200 Neurological (see also p. 90) \200 Signs of compressive neuropathies may develop, the commonest being carpal tunnel syndrome w ith an equivalent syndrome occurring in the feet (tarsal tunnel syndrome). Sensorimotor neu ropathy and mononeuritis multiplex is recognized especially when associated with vasculitis . Atlanto-axial subluxation may lead to long tract signs. Magnetic resonance (MR) imaging and ultrasound (US) Patients with subclinical disease may h ave erosions on presentation. Also radiographs can miss erosions. \200 Ophthalmologic involvement (see also p. 48) \200 Scleritis, episcleritis, and scleromalacia perforans (corneal melt) present with various oc ular symptoms including pain and blurred vision. Sicca symptoms are due to secondary Sj gr en \200\231s syndrome. MR scanning and high-resolution ultrasound (US) with color \202 ow Doppler are more sensi tive at detecting early erosive disease, subclinical synovitis and small joint effusions co mpared with radiographs. Other Amyloidosis may complicate longstanding disease. Renal involvement is relatively rare , although membranous glo- merulonephritis (GN) is recognized. More common renal lesions in an RA patient might be GN or tubulointerstitial nephritis from the toxic effects of drugs. Investigations No pathognomonic test result exists for the diagnosis of RA; therefore, the investigation of polyarthritis is driven by clinical suspicion. Laboratory \200 FBC shows associated anemia (either normochromic normocytic or mildly hypochromic microcyti c) and thrombocytosis. Neutropaenia may point to a diagnosis of Felty \200\231s syndrome th ough isolated mild neutropaenia is not an uncommon \201 nding. Figure 6.1 Severe erosive rheumatoid arthritis. CHAPTER 6 Rheumatoid arthritis 201 Disease Activity Score (DAS), European League Against Rheumatism (EULAR responses), Health Assessment Questionnaire (HAQ), and the Medical Outcomes Study 36-Item Short Form (SF-36) MR with IV gadolinium contrast permits accurate assess- ment of synovial invasion though di scrimination of tissue from \202 uid can be dif \201 cult. Dual X-ray absorptiometry (DXA) and digital X-ray radiogrammetry (DXR) DXA software to allo w detection of periarticular osteopo- rosis about the small hand joints is available, but m ainly a research tool. DXR is a quantitative methodology for evaluating mineralization in p halanges in the hand and patterns of abnormality associated with RA are recognized compared with reference ranges. Differential diagnosis of in \202 ammatory polyarthropathy In \202 ammatory synovitis \200 Rheumatoid arthritis \200 Spondylarthropathy (incl. psoriatic polyarthritis) \200 Post-viral arthritis \200 Infectious (e.g. parvovirus B19, Lyme disease) \200 Crystal arthritides (e.g. gout and CPPDD) \200 In \202 ammatory osteoarthritis \200 Autoimmune Connective Tissue Diseases \200 Vasculitis, Sarcoidosis, Beh ets disease Synovial \202 uid analysis \200 Aspiration and analysis of synovial \202 uid is not particu- larly helpful for diagnosis, but analysis can help rule out infection (gram stain and culture), and crystal-induced art hritis (polarized light microscopy). Usually the \202 uid is straw colored and mildly tur bid, and predominantly comprised of neutrophils with the remainder being lymphocytes. The \202 uid glucose level is normal. Synovial biopsy can be helpful, but is not currently ava ilable in routine clinical practice. Metabolic \200 \200 \200 Hyperparathyroidism Thyroid disorders Haemachromatosis (secondary OA) \200 Chronic infection \200 \200 Other investigations If the diagnosis is unclear, investigation for other causes of polyart hritis is mandatory, such as gout (check urate level), CPPDD (requires metabolic screen, pa rticularly calcium and PTH), SLE (check ANA, ENAs, C3). \200 Infective endocarditis Hepatitis B, HIV Miscellaneous \200 \200 \200 \200 Paraneoplastic phenomenon Multiple myeloma Polymyalgia rheumatica (PMR onset of RA) Septic arthritis (usually monoarthrits) Other tests: thyroid function, creatine kinase, vasculitis screen, serum ACE, complement le vels, and infection screen (including parvovirus B19 and mycoplasma). Full pulmonary functi on tests (if suspicious of lung involvement) and high resolution CT scanning in the prone p osition (pulmonary disease). ECG and transthoracic ECHO (cardiovascular involvement \200 \223 particularly pericardial effusion). Nerve conduction studies (neuropathies, e.g. carpa l tunnel syndrome, ulna nerve irritation, vasculitis). DXA scan (osteoporosis, particularly in post-menopausal women or those who have had fractures). ACR response criteria \200 The ACR response criteria are categorical and allow assessment of improvement or change fro m baseline. ACR responses are expressed as ACR20, 50, 70, and 90 indicating 20%, 50%, 70%, and 90% improvement in the respective variables included in the criteria. They do not, howe ver, allow assessment of the actual state of disease activity at one time point. ACR respon ses are currently the most widely reported outcomes in clinical trials. Investigations to monitor drug therapy (see also p. 529) Monitoring of drug toxicity involv es regular FBC, LFTs, renal function, ESR, CRP, and urinalysis. Hepatitis B and C serology is advisable prior to B-cell depleting treatment. Disease Activity Score (DAS) Special case investigations \200 American College of Rheumatology response criteria for 20% improvement (ACR20) 20% reductio n in the number of tender and swollen joints, plus 20% improvement in 3 of the following 5 parameters: \200 \200 \200 \200 \200 Prior to starting biologic DMARD therapy, especially anti-TNFA agents, Mycobacterium tuberc ulosis (MTB) should be excluded by thorough history and physical examination, CXR tuberc ulin skin test (see p. 566). Patients should be asked about immunity to Varicella zoster an d tested for antibodies if necessary. Physician global assessment of disease Patient global assessment of disease Patient assessm ent of physical function Patient assessment of pain ESR or CRP Differential diagnosis The main differential diagnoses will be psoriatic polyarthritis, in \202 ammatory osteoarthritis, SLE, post-infectious arthritis, and in the elderly, polyarti cular CPPDD or gout. Disease activity assessment Measurement of different aspects of disease in RA has be- come important, particularly the assessment of disease activity and the response to treatment. O wing to the het- erogeneous nature of RA, various composite indices have been developed to assess disease including the American College of Rheumatology (ACR) Response Criteria, The DAS is a composite index of disease activity \200 The DAS is used in clinical trials and is also useful in daily practice as it allows assess ment of the actual state of disease activity at any time point. DAS-CRP may be used as an a lternative to ESR in the calculation of the DAS. RHEUMATOID ARTHRITIS 202 EULAR response criteria have also been developed, based on the DAS and when measured at two time points the patients clinical response can be assessed. EULAR criteria for disease act ivity are based on the DAS28, allowing a continuous measurement of disease activity. Other scores have also been developed that are easier to calculate, such as the simpli \201 ed d isease activity index (SDAI) and the clinical disease activity index (CDAI). The Disease Activity Score (DAS) To calculate the DAS28 one requires: \200 \200 \200 \200 The number of swollen joints out of 28 (SJC28) The number of tender joints out of 28 (TJC28 ) The ESR (measured in mm/hour). An assessment of the patient \200\231s general health (GH) measured on a Visual Analog Scale (VAS) of 100 mm Using these data, the DAS28 can be calcu lated using the following formula: DAS28 = (0.56 \227 sqrt [TJC28]) + (0.28 \227 sqrt [SJ C28]) + Health status and quality of life measures Assessment of disability and overall health stat us is critical in patients with RA. Patient-reported outcomes provide intrinsic knowledge a bout a patient \200\231s symptoms, general health, functional status, satisfaction, prefere nces for treat- ment, and quality of life. (0.70 \227 ln[ESR]) + (0.014 \227 GH) This is not simple, but can easily be calculated using a pre-programmed calculator: \200 The DAS28 provides a number on a scale from 0 to 10 indicating the current activity of dise ase. A DAS28 >5.1 means high disease activity. DAS28 <3.2 indicates low disease activity. R emission is achieved by a DAS28 <2.6. Health Assessment Questionnaire (HAQ) \200 \200 \200 The HAQ is the most frequently used method to measure functional impairment. The HAQ was on e of the \201 rst self-reported functional status measures and is based on \201 ve pati ent-centered dimensions: disability, pain, medication effects, costs of care, mortality. Ty pically, one of two HAQ versions is used: The Full HAQ, which assesses all \201 ve dimens ions, and the Short or 2-page HAQ, which contains only the HAQ disability index (HAQ-DI) an d the HAQ s patient global and pain visual analog scales (VAS). Medical Outcomes Study 36-Item Short Form (SF-36) \200 \200 \200 The SF-36 is a health-based survey of quality of life. Like the HAQ is it patient-derived a nd objective. The SF-36 has been implemented to define disease conditions, to determine the effect of treatment, to differentiate the effect of different treatments, and to compare a cross conditions. SF36 comprises 8 individual subscale scores and physical and mental summa ry scores. Physical component summary includes physical functioning, role-physical, bodily pain and general health. Mental component summary includes vitality, social functioning, ro le-emotional and mental health. Figure 6.2 Joints utilized in a DAS28 joint count. Table 6.2 The EULAR response criteria using the DAS28 Current DAS28 DAS28 improvement >1.2 0.6 \200\2231.2 <0.6 <3.2 Good Moderate No response response response 3.2 \200\2235.1 Moderate Moderate No response response response >5.1 Moderate No No response response response Comparing the DAS28 from one patient on two different time points it is possible to de \201 ne improvement or response. CHAPTER 6 Rheumatoid arthritis 203