illustrated in Table 6.2. Natural history of OA \200 Progression in the knee may take many years. Cohort studies ha ve found that radiographic deterioration occurs in one-third. Progression of hip disease is variable. A Danish study found that 66% of hips worsened radi ologically over 10 years, although symptomatic improvement was common. Hand disease is relapsing and remitting with episodic in \202 ammatory phases associated w ith redness and swelling. Flares then reduce in frequency, and pain also improves. Table 6.2 Secondary causes of OA Trauma In \202 ammatory arthritis Metabolic/endocrine Crystal deposition disease Hemochromatosis Calcium pyrophosphate Acromegaly Uric acid Hyperparathyroidism Hydroxyapatite Ochronosis (alkaptonuria) Neuropathic disorders Anatomical abnormalities Diabetes mellitus Bone dysplasia CHAPTER 6 Osteoarthritis (OA) 266 The investigation of OA \200 OA is a clinical and radiological diagnosis. There are no sp eci \201 c laboratory tests. Joint space narrowing may be dif \201 cult to appreciate in early OA; as the disease progr esses, other \201 ndings may appear, including osteophytes, subchondral bone sclerosis, a nd subchondral cysts. Radiographs correlate poorly with symptoms and clinical function. Many older patients will have radiographic changes consistent with OA, but will be asymptomatic. MRI may be better at identifying early loss of articular cartilage, but this and other imaging modalities have not been well validated for the evaluation of osteoa rthritis. Laboratory tests (including synovial \202 uid analysis) may be useful to exclude other causes of joint pain, such as pseudogout. There are potential markers of tissue destruction and in \202 ammation that may be of use clinically in the future. A pro \201 le of several markers with genetic analysis may in the future provide an individual assessment for disease development and re sponse to therapy. Examples of markers include: \200 cartilage oligomeric matrix protein (COMP) \200 pyridinoline and bone sialoprotein \200 metalloproteinases \200 hylaurona n. This page intentionally left blank CHAPTER 6 Osteoarthritis (OA) 268 The management of OA Successful management Successful management centers on: \200 A good history: symptoms and impact on life \200 functional disability \200 functional requirements \200 patient expectation \200 psychological factors. A good examination: extent of abnormality \200 origin of pain \200 degree of in \202 ammation \200 insta bility of joint \200 muscle condition \200 other medical, soft-tissue, and neurological disease. A multidisciplinary approach. Modalities for management \200 There are several resources that provide speci \201 c gui dance regarding the treatment of osteoarthritis. The Osteoarthritis Research Society International (OARSI) has developed evidence-based expert consensus guidelines regarding the management of osteoa rthritis of the hip and knee (http:// www.oarsi.org). In the United Kingdom, the National I nstitute for Health and Clinical Excellence (NICE) has published evidence-based guidelines for the cost-effective treatment of osteoarthritis (http://www.nice.org.uk/ CG59). Both of these guidelines include a discussion of pharmacologic and non-pharmacologic therapies, and may help with treatment decisions. Exercise is an important intervention, to build muscle strength, encourage weight loss, imp rove endurance and joint proprioception. Advice alone is not as good as a speci \201 c pro gram with follow-up. Evidence-based guidelines for exercise in hip and knee OA have been pu blished. 1 In more marked disease, support splints and walking aids may be necessary. Education has been shown in meta-analyzes to have a signi \201 cant effect on pain and fun ction, but only 20% as effective as NSAID treatment. \200 Topical preparations have minim al systemic absorption, and may help patients avoid cumulative toxicities associated with p olypharmacy. Topical 1% diclofenac gel (2 \200\2234 g every 6 hours) has been FDA approved for the treatment of osteoarthritis, and may be useful for treatment of symptomatic osteoar thritis in the hands and knees. Topical capsaicin (0.025% or 0.075% every 6 \200\2238 hours ) may also provide signi \201 cant pain relief. When topical therapies are not practical or ef \201 cacious, treatment often starts with a cetaminophen. That said, it is only modestly more effective than placebo, and chronic use i s associated with cardiovascular and gastrointestinal toxicity. Unintentional overdose is t he most common cause of liver failure in the United States, and patients must be counseled to avoid other medications that may contain acetaminophen. THE MANAGEMENT OF OA 269 NSAIDs are more effective than acetaminophen. Short-acting NSAIDs, such as ibuprofen (400 m g every 4 \200\2236 hours) are widely available, but patients may \201 nd greater levels of relief with longer acting NSAIDs, such as diclofenac (50 mg every 8 hours), naproxen (50 0 mg every 12 hours), or nabumetone (500 \200\223750 mg every 8 \200\22312 hours); these ma y be of particular use for short periods during disease \202 ares. Long-term use of NSAIDs may be problematic, particularly among the elderly. The selective C OX-2 inhibitors are as ef \201 cacious as standard NSAIDs, but there remains concern over cardiovascular safety; they should be used with caution and avoided in patients with cardio vascular risk factors. Tramadol and duloxetine may also be useful for control of the pain associated with osteoart hritis. Narcotics are associated with a high rate of discontinuation due to side effects. Intra-articular injections of corticosteroids are very useful in treating in \202 ammatory disease \202 ares, and may result in sustained symptom improve ment, although response duration is variable. Many practitioners also add local anesthetic, although there is no clear evidence that this improves the ef \201 cacy of the treatment. Most data are available for knee OA. Infection is rare ( < 1 in 10,000 incidence), but car e should be taken to clean overlying skin, and injection through infected/psoriatic skin sh ould be avoided. Other side effects to warn patients about are skin depigmentation and fat atrophy. It is advised that patients receive no more than 2 or 3 injections per year. The ef \201 cacy of intra-articular injection of hyaluronic acid derivatives (visco-supple mentation) is controversial, although it may provide prolonged relief in some cases. Glucosamine and chondroitin sulfate are found in articular cartilage. Anecdotal evidence su ggests that when given as oral supplements, these agents have an analgesic effect in mild-t o-moderate OA of the knee, but this has been dif \201 cult to demonstrate consistently in controlled trials. There is little evidence for use in OA at other sites. \200 Acupunctur e has been shown in randomized controlled trials to be better than placebo acupuncture in improving symptoms. There is some evidence that avocado/soybean unsaponi \201 able (ASU) supplementation, even ing primrose oil, and omega-3 \201 sh oils improve pain. The clinician should also seek ways to reduce the impact of disability. Options include: 1 \200 occupational therapy: splints, tools, safe environment \200 tre at depression, anxiety, \201 bromyalgia \200 coping strategies \200\224behavioral thera py \200 patient education. For patients with activity-limiting osteoarthritis, joint replacement is effective at reducing pain, although function may not be restored. Arthroscopy and osteo tomy may be helpful in some cases. 1 Roddy E, Zhang W, Dohetry M et al . Evidence-based recommendations for the role of exerci se in the management of osteoarthritis of the hip or knee: the MOVE consensus. Rheumatology 2005; 44: 67 \200\22373. This page intentionally left blank 271 Chapter 7 The crystal arthropathies Gout and hyperuricemia 272 Calcium pyrophosphate dihydrate (CPPD) disease 278 Basic calcium phosphate (BCP) associated disease 281 Calcium oxalate arthritis 282 CHAPTER 7 The crystal arthropathies 272 The crystal arthropathies include gout, calcium pyrophosphate deposition disease (CPPD) or pseudogout, basic calcium phosphate (BCP) associ- ated syndromes, and calcium oxalate arthr itis. These conditions will be discussed in this chapter. Gout and hyperuricemia Epidemiology of gout \200 In its most general sense, gout is a gro up of conditions characterized by hyperuricemia and uric acid crystal formation. These clinical conditions include arthrit is, tophaceous gout, uric acid nephrolithiasis, and gouty nephropathy. In its more commonly assumed de \201 nition, gout refers to the acute in \202 ammatory arthropathy caused by uric acid crystal deposition. Gout is a relatively common condition, and is the most common form of in \202 ammatory art hritis. Prevalence data from the United States on self-reported disease show \201 gures o f 13.6 per 1000 persons in adult men and 6.4 per 1000 persons for women. It is more common in the middle aged and elderly, and its prevalence may be increasing due to changes in life style and diet. The risk factors for gout mirror those for hyperuricemia, and are shown in Table 7.1. The clinical features of gout \200 The \201 rst stage of the condition is usually asymp tomatic hyperuricemia. \200 Clinically, the \201 rst symptom is most often an acute, se lf-limiting, monoarticular in \202 ammatory arthritis; up to 60 \200\22370% of attacks \201 rst occur in the big toe ( \200\234podagra \200\235). Other frequently involved joints include the a nkle, foot, knee, wrist, elbow (olecranon bursa), and the small joints of the hands. The ax ial large joints and spine are rarely involved. Some 70 \200\22380% of individuals will hav e recurrent attacks within 2 years. In the later stages of untreated disease, acute attacks are more often polyarticular (with shorter periods of remission), and are associated with joint damage and deformity; these la ter stages are associated with loss of mobility, chronic pain, and formation of tophi. Tophi are deposits of urate embedded in a matrix composed of lipids, proteins, and calci \201 c debris. Tophi are usually subcutaneous, but rarely can occur in bone and other organs such as the eye. The classic sites for tophi are the pinna o f the ear, bursa of the elbow and knee, Achilles tendon, and the dorsal surface of the MCP joints. Tophi are usually painless, but the overlying skin may ulcerate and become infected . Those most at risk of tophi are patients with prolonged severe hyperuricemia, polyarticul ar gout, and the elderly with primary nodal OA (see Chapter 6) on diuretics. Hyperuricemia by itself does not con \201 rm a diagnosis of gout. Some clinicians will treat asymptomatic hyperuricemia to prevent the onset of \200\234urate nep hropathy, \200\235 but this is controversial. GOUT AND HYPERURICEMIA 273 Table 7.1 The causes of hyperuricemia and risk factors for gout Primary gout Male gender Age <40 years Obesity Family history Alcohol use and purine rich foods Renal insuf \201 ciency Hypertension Inherited metabolic syndromes X-linked HPRT de \201 ciency (Lesch \200\223Nyhan) X-linked raised PRPP synthetase activit y Autosomal recessive G6P de \201 ciency (von Gierke \200\231s disease) Uric acid overproduction Cell lysis \200\224tumor lysis syndrome, myeloproliferative disease, hemolytic anemia, psor iasis, trauma; Drugs \200\224 alcohol, cytotoxic drugs, warfarin Uric acid underexcretion Renal failure Drugs \200\224alcohol, salicylates, diuretics, laxatives, cyclosporine, levodopa, ethambuto l, pyrazinamide Lead toxicity Renal impairment and altered purine turnover HPRT = hypoxanthine guanine phosphoribosyltransferase \200\224a salvage enzyme converting h ypoxanthine back to precursors and therefore competing with its conversion to xanthine and then uric acid. PRPP = phosphoribosylpyrophosphate synthetase \200\224a component enzyme in purine ring synthesis. G6P = glucose 6 phosphatase. G6P de \201 ciency leads to increased activity of amidophosphoribosyltransferase and purine formation. Diagnosis of gout \200 Synovial \202 uid analysis remains the single most important dia gnostic study. The diagnosis is made by the presence of typical, negatively birefringent, n eedle-shaped crystals seen with a polarized light microscope. The crystals may be extra- or intracellular. The absence of crystals does not rule out the diagnosis. Serum uric acid levels may be normal during an acute attack and may not re \202 ect pre-at tack levels. They cannot be used to exclude the diagnosis during an acute attack. Uric acid levels are of value in assessing the patient once the acute attack has subsided, either to establish the presence of hyperuricemia or to monitor the effectiveness of therapies that lower serum urate. Radiographs are often normal during the early phase of the disease, except for the presence of soft tissue swelling. They are, however, useful for excluding other conditions such as trauma or infection (see Table 7.2). Later in the disease, radiographs may demonstrate toph i near joints, tissue swelling, joint erosions, periosteal new bone formation, and joint de formity. Once these changes occur, gout may be misdiagnosed as RA (see Chapter 5) in some c ases. Dual-Energy Computed Tomography (DECT) can differentiate urate from calcium, and may be use ful to con \201 rm a diagnosis of gout when arthrocentesis is not practical. Causes of hyperuricemia should always be considered. CHAPTER 7 The crystal arthropathies 274 The management of gouty arthritis \200 The ef \201 cacy of any public health improvement measure for the prevention of gout has yet to be proven. It is reasonable to suggest that avoiding excess w eight gain and alcohol, controlling hypertension, and avoiding exposure to diuretics and le ad, may have some effect on decreasing the incidence of the condition. The management of gout otherwise should be seen as two phases: treatment of the acute attack, and treatment of chronic or tophaceous gout. The principal t herapies for acute gout are NSAIDs, colchicine, and steroids. Many treatments are empiric r ather than evidence based. Traditionally indomethacin has been the NSAID of choice in acute gout, but has no advantage over other NSAIDs. With treatment, symptoms should subside within 3 \200\2235 days. NSAIDs are contraindicated in renal insuf \201 ciency and should be used with caution in t he elderly (who are often also taking aspirin) or those with GI risk factors. Evidence show s that NSAIDs decrease pain, swelling, and duration of attack. There is no evidence for the use of selective COX-2 inhibitors in gout. Colchicine can be very effective in acute gout, especially when treatment is started at the \201 rst sign of symptoms (i.e., a \200\234pill-in-the- pock et \200\235 strategy). Oral colchicine, given at 0.6 mg BID to TID for 5 days is very usefu l and can be well tolerated. It is often given in addition to NSAIDs (although there is no evidence to support this) or when NSAIDs are contraindicated. The 5-day dosage may be repea ted for an acute attack after 72 hours. IV colchicine is not used due to the potential for bone marrow suppression. There are no randomized controlled trials comparing colchicine to NSAIDs. Steroid regimens range from oral prednisone at tapering doses from 20 \200\22350 mg daily f or an average of 10 days, to IM triamcinolone 60 mg once only. A study comparing IM triamci nolone with indomethacin found no signi \201 cant difference in time to recovery. Intra-articular steroids are useful if only one or two joints are affected. In a case serie s from 1999, injection of triamcinolone acetonide into affected joints resolved all symptom s within 48 hours. Corticosteroids should not be used if there is a possibility of septic arthritis. Drugs that decrease serum uric acid levels are the standard therapy for prophylaxis against repeated gout attacks, but should not be started after just one isolated attack. Allopurin ol, a xanthine oxidase inhibitor, is the drug most commonly used, and the drug of choice in the presence of nephrolithiasis, or tophi. The drug should not be started during an acute attack of gout, as it is likely to make the situation worse. Allopurinol should be initiate d at 100 mg/d (or lower, in patients with renal insuf \201 ciency), and slowly titrated. P atients may require doses anywhere between 100 \200\223900 mg daily to achieve normal serum uric acid levels (i.e., < 5 mg/dL). The dose should be adjusted down in renal impairment. The onset of action of allopurinol is rapid, with effects seen as early as 4 days to 2 week s. GOUT AND HYPERURICEMIA 275 Table 7.2 Clinical conditions that can mimic gouty arthritis CPPD disease (pseudogout) BCP arthritis Cellulitis Infectious arthritis Trauma Rheumatoid arthritis Psoriatic arthritis Erythema nodosum Reactive arthritis Allopurinol can lead to a hypersensitivity reaction with rash and fever. Rarely a severe re action is seen with hepatitis, nephritis, and toxic epidermal necrolysis. In patients with mild to moderate intolerance, allopurinol can be reintroduced at very low levels, e.g. 100 mg, and built up slowly using desensitization regimens. Allopurinol can interfere with the metabolism of azathioprine and warfarin, augmenting their potential side effects. During it s introduction a patient may also experience an acute \202 are of gout. This may be treat ed with NSAIDs and/or low dose colchicine. Prior to treatment with allopurinol, Koreans, Ha n Chinese, and Thai patients should be screened for the presence of the HLA B*5801 allele, which is associated with an increased risk of hypersensitivity reactions. Some patients may respond to a combination of allopurinol and a uricosuric agent (such as p robenecid) when either alone has been ineffective. Uricosuric drugs should be avoided in pa tients with renal insuf \201 ciency or history of nephrolithiasis. Febuxostat (40 \200\22380 mg po QD) is a non-purine xanthine oxidase inhibitor that has been approved by the Food and Drug Administration in the United States f or the chronic management of hyperuricemia in patients with gout. Unlike allopurinol, febux ostat does not need to be adjusted based on renal function; it therefore may be especially appropriate for patients who are allergic to allopurinol or have severe renal insuf \201 c iency. Febuxostat 80 mg daily is more effective than allopurinol. Pegloticase (8 mg IV every 2 weeks) may be considered for patients who are refractory to co nventional therapies. Premedication with antihistamines and corticoisteroids is mandatory, and treatment must be discontinued if pre-infusion serum uric acid levels begin to increase , which indicates the presence of anti-pegloticase antibodies that are associated with infu sion reactions. Because of the importance of monitoring serum uric acid, this drug should n ot be combined with other urate-lowering agents. CHAPTER 7 The crystal arthropathies 276 In patients who are unable to take allopurinol or a uricosuric drug, daily low-dose oral co lchicine may be useful in preventing attacks. It is usually given in doses of 0.6 mg po BID . Serious side effects can still occur at this dose. This low-dose regimen may also be usef ul as prophylaxis against acute \202 ares during the introduction of allopurinol. Feno \201 brate is an established treatment for many lipid disorders. It also has the abil ity to decrease serum urate by increasing renal uric acid clearance. It may have a role (of f label) in patients resistant or intolerant to other agents. It should be avoided in hepat ic and biliary disease, hypothyroidism and pregnancy. Side effects may include arthralgias and myalgias. Increasing intake of (low-fat) dairy, and decreasing intake of organ meats and alcohol, may help reduce the risk of gout attacks. \200 Patients with uric acid stones are best managed with adequate hydration, urinary alkalization, and allopurinol. This regimen is also effective in prevent ing calcium oxalate stones. Finally, gouty tophi may be amenable to surgical removal. Khanna D. et al., \200\2342012 American College of Rheumatology Guidelines for the Managem ent of Gout. Part 1. Systemic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia \200\235 Arthritis Care Res 2012; 64 (10): 1431 \200\2231446. This page intentionally left blank CHAPTER 7 The crystal arthropathies 278 Calcium pyrophosphate dihydrate (CPPD) disease \200 CPPD disease is the second most commo n form of crystal arthropathy. Our understanding of the pathophysiology of CPPD remains rudimentary, and cons equently no speci \201 c therapies for this arthropathy exist. Several clinical syndromes are associated with CPPD the features of the condition are heter ogeneous, sometimes mimicking other rheumatic conditions. De \201 nite associations with C PPD and chondrocalcinosis (i.e., calci \201 cation of \201 bro- and hyaline cartilage ty pically at the knee and wrist) include: \200 hypomagnesemia \200 hypophosphatasia \200 hemochromatosis \200 Wilson \200\231s disease \200 hyperparathyroidism. \200 Possib le associations include: gout \200 ochronosis \200 hypocalciuric hypercalcemia \200 diabetes mellitus \200 X -linked hypophosphatemic rickets. These crystals are also found in the synovial \202 uid of patients with both acute and chronic arthritis. They are associated with advanced age, chondrocalcinosis, and a characteristic pattern of severe joint degeneration. There are several presentations of CPPD that afford at least some form of classi \201 cati on based on clinical features. It is not easy to categorize all cases, but the classi \201 cation serves to point out the heterogeneity of the condition in acute, chronic, in \202 ammatory, and nonin \202 ammatory arthritis (see Tables 7.3, 7.4). Laboratory tests \200 CPPD disease is de \201 ned by the presence of positively birefrin gent, rhomboid crystals on examination of synovial \202 uid under polarized light microsc opy. The crystals may be intra- or extracellular. These crystals may be dif \201 cult to v isualize; therefore, the absence of CPPD crystals in synovial \202 uid does not necessari ly rule out CPPD disease. \200 Radiographs of the affected joints may not be helpful in e stablishing the diagnosis. The presence of chondrocalcinosis increases the likelihood of CP PD disease. Radiographic clues that may help to distinguish CPPD from OA include: \200 ax ial involvement \200 sacroiliac erosions \200 cortical erosions of the femur \200 ost eonecrosis of the medial femoral condyle. C A L C U M P Y R O P H O S P H A T E Table 7.3 The clinical presentations of CPPD disease I Type Description Frequency Features A Pseudogout 25% Acute pain and swelling, often amonoarthropathy of the knee, wrist or shoulder.Rare in smal l joints B Pseudorheumatoid 5% Polyarthritis. Synovitis. Joint \202 ares out of phase with each other C and D Pseudo-osteoarthritis: C with attacks D without acute attacks 50% Acute attacks on chronic symptoms E Asymptomatic ? Incidental chondrocalcinosis D H Y D R A T E I F Pseudoneurotrophic Rare Severe joint destruction and neuropathy Others Tophaceous CPPD deposits Spinal CPPD: \200\230Crowned dens syndrome \200\231 deposits around the atlantoaxial joint . Spinal stenosis. Cervical myelopathy Tendon and bursa deposits ( C P P D ) D I S E A S E 2 7 9 CHAPTER 7 The crystal arthropathies 280 Patients under the age of 60 years should be screened for secondary CPPD disease, i.e. seru m calcium, magnesium, alkaline phosphatase, ferritin, iron, and iron binding capacity. Management of CPPD disease \200 NSAIDs are the most commonly used therapy, but must be us ed with caution as the majority of affected patients are elderly. Joint aspiration and intra-articular corticosteroids are of bene \201 t in acute \202 ares of pseudogout. The role of oral steroids remains unclear. \200 Low-dose oral colchicine (0.6 mg QD-BID) may reduce the frequency of acute attacks in pseudogout. Rest, splinting, and eventual joint replacement may be helpful. \200 Other therapies that have been tried include: oral magnesium carbonate \200 intra-articular glycosaminoglycan polysulfate \200 intra- articular corticosteroids \200 IM gold or hydroxychloroquine for type B ( \200\234pseudor heumatoid \200\235) disease. Table 7.4 Factors that may trigger acute pseudogout Intercurrent illness, e.g., chest infection Direct trauma to the joint Surgery, especially parathyroidectomy Blood transfusion and parenteral \202 uids Institution of thyroxine replacement therapy Joint lavage BASIC CALCIUM PHOSPHATE (BCP) ASSOCIATED DISEASE 281 Basic calcium phosphate (BCP) associated disease \200 BCP crystals include hydroxyapatite , octacalcium phosphate, and tricalcium phosphate. These crystals are associated with several rheumatic conditions as shown in Table 7.5. The treatment of these conditions is as per CPPD disease (see previous section), with NSAIDs and colchicine principally. \200 Calcium hydroxyapetitie c rystals are not visible under plain or polarized light microscopy, but may be visualized by staining with alizarin red. Table 7.5 BCP associated conditions Articular disease Milwaukee shoulder syndrome (severe degenerative arthropathy, more common on the dominant s ide and in elderly women) Osteoarthritis (synovial \202 uid crystals found in up to 60% of OA patients) Erosive arthritis Mixed crystal deposition Periarticular Pseudopodagra. Calci \201 c tendonitis and bursitis CHAPTER 7 The crystal arthropathies 282 Calcium oxalate arthritis \200 This is an unusual form of arthritis. The crystals are pos itively birefringent and bipyramidal on polarized light microscopy. Radiographs and laboratory tests are not diagnostic. \200 Treatment is as for CPPD diseas e. \200 Several conditions are associated with calcium oxalate arthritis (Table 7.6). Table 7.6 Conditions associated with calcium oxalate arthritis End-stage renal disease on dialysis Short bowel syndrome Diet rich in rhubarb, spinach, ascorbic acid Thiamine de \201 ciency Pyridoxine de \201 ciency Primary oxalosis: recessive trait Early renal failure (age 20s) Arthritis Tendonitis 283 Chapter 8 The spondyloarthridities Introduction 284 Diagnostic criteria and clinical subsets 286 Ankylosing spondylitis 290 Ps oriatic arthritis 296 Reactive arthropathy 300 Enteric arthropathy 302 Undifferentiated spo ndyloarthritis 303 SAPHO 304 Spondyloarthridities in childhood 306 CHAPTER 8 The spondyloarthridities 284 Introduction \200 This set of diseases is also referred to as the \200\234spondyloarthro pathies \200\235. Using the name \200\234spondyloarthritis \200\235 emphasizes the in \202 ammatory nature of these syndromes. The seronegative spondyloarthridities are classically characterized by some combination of axial and peripheral joint manifestations: \200 Axial: sacroiliitis a nd in \202 ammatory back pain \200 Peripheral: asymmetric arthritis, enthesitis, dactyli tis These diseases may also be accompanied by: extra-articular disease \200 anterior uveitis The group is made up of several conditions that often overlap. Five major diseases are recognized by the European Spondyloarthropathy Study Group (ESSG). These are: \200 ankylosing spondylitis \200 psoriatic arthritis \200 reactive arthropathy \200 enteropathic arthritis \200 undifferentiated spondyloarthritis. The diagnosis \200\234undifferentiated spondyloarthritis \200\235 includes subsets of case s in which features such as dactylitis, uveitis, or sacroiliitis exist without the full cri teria for a diagnosis. In addition, we recognize a juvenile enthesitis related arthritis. \200 Some physicians s uggest that other diseases that may be associated with sacroiliitis should also be classi \201 ed as a spondyloarthritis. These diseases include Beh et \200\231s disease, Whipple \200\231s disease, and SAPHO (Synovitis-Acne-Pustulosis-Hyperostosis-Osteitis) syndrome. \200 Pathological changes are mainly at the insertion of tendons and ligaments into bone (i.e., enthesitis ), and extra-articular changes may also develop in th e eye, aortic valve, lung, and skin. This page intentionally left blank CHAPTER 8 The spondyloarthridities 286 Diagnostic criteria and clinical subsets \200 There is a general consensus that most crit eria are too restricted given the wide spectrum of disease. For example, radiographic evide nce of sacroiliitis in the absence of symptoms, or unilateral sacroiliitis with only dactyl itis or uveitis, would be excluded by most criteria and yet could be part of the spondyloar thritis spectrum. Most clinical criteria require the presence of radiographic sacroiliitis, which make them less sensitive for detecting early disease. To address these shortcomings, the Assessment of Spondyloarthritis International Society (A SAS) classi \201 cation criteria were developed (Table 8.1 and 8.2). The ASAS criteria allow patients to be classi \201 ed as having spondyloarthritis before the onset of radiographic sacroiliitis, and solidify the use of MR I as the standard-of-care modality for detecting sacroiliitis. \200 A variety of symptoms and signs are present, and Table 8.3 highlights the differences between these conditions. The speci \201 c expression of disease is a product of inter related genetic and environme ntal factors. The precise link between triggers such as infection and pathogenesis, and ind eed the exact role of the HLA B27 molecule remains a mystery. The HLA B27 molecule has an association with the spondylo- arthropathies ranging between 50 \200\22395%. Interpretation of a positive result is compli cated by the presence of this allele of the HLA B gene in up to 5 \200\22310% of the normal population. It may be useful to assess symptomatic \201 rst-degree relatives of HLA B27+ probands with ankylosing spondylitis (AS), for whom the risk of developing the same diseas e is approximately 1 in 3. There are a number of interesting observations in the study of HLA B27, which include the following: \200 HLA B27 is inherited as an autosomal co-dominant c haracteristic: 50% of \201 rst-degree relatives of probands with HLA B27 possess the antigen. 5 \200\22310% of HLA B27 positive individuals develop AS over time and 20% of individuals w ith B27 develop a reactive arthropathy after contact with agents such as chlamydia or salmo nella. Only 50% of patients with psoriatic or enteropathic spondylitis are HLA B27 positive. Only 50% of non-Caucasians with AS are HLA B27 positive. This is considerably less than the prevalence of HLA B27 among Caucasians with AS (95%). Relatives of probands with both sacroiliitis and HLA B27 frequently remain disease free. Concordance in identical twins is 70% vs 13% in non-identical twins. \200 Uveitis is a co mmon accompaniment of AS. HLA B27 is found in up to 40% of cases of uveitis, even in the ab sence of underlying rheumatic disease. DIAGNOSTIC CRITERIA AND CLINICAL SUBSETS 287 Table 8.1 Assessment of Spondyloarthritis International Society (ASAS) classi \201 cation criteria for axial spondyloarthritis Classi \201 cation requires the following: 1. Chronic back pain ( (cid:4) 3 months) 2. Age of onset < 45 years 3. Sacroiliitis on imaging + 1 clinical feature, OR HLA-B27 + 2 clinic al features Clinical features 1. In \202 ammatory back pain 2. Arthritis 3. Enthesitis 4. Dactylitis \200\224sausage-like \201 ngers 5. Uveitis 6. Psoriasis 7. Crohn \200\231s disease/ ulcerative colitis 8. Good response to NSAIDs 9. Family history of spondyloarthritis 10. HLA-B27-positive 11. Elevated C-reactive protein Radiological features of sacroiliitis: 1. MRI features of sacroiliitis (i.e., bone marrow edema) 2. Radiographic sacroiliitis The ASAS classi \201 cation criteria have a sensitivity of 82.9%, and a speci \201 city o f 84.4% Rudwaleit M, et al. Ann rheum Dis 2009; 68: 777 \200\223783. CHAPTER 8 The spondyloarthridities 288 Table 8.2 Assessment of Spondyloarthritis International Society (ASAS) classi \201 cation criteria for peripheral spondyloarthritis Classi \201 cation requires the following: 1 clinical feature + 1 associated feature, OR 2 clinical features In either case, at least one clinical feature must be arthritis, ethesitis, or dactylitis. Clinical features 1. Arthritis (typically asymmetric, affecting predominantly the lower extremities) 2. Enthesitis 3. Dactylitis 4. In \202 ammatory back pain 5. Family history of spondyloarthritis Associated features: 1. Uveitis 2. HLA-B27 2. Preceeding genitourinary or gastrointestinal infection 3. Psoriasis 4. In \202 ammatory bowedl disease 5. Sacroiliitis on imaging The ASAS classi \201 cation criteria have a sensitivity of 77.8%, and a speci \201 city o f 82.8% for peripheral spondyloarthritis Rudwaleit M, Curr Opin Rheumatol 2010; 22: 375 \200\22380. DIAGNOSTIC CRITERIA AND CLINICAL SUBSETS 289 Table 8.3 Comparison of the seronegative spondyloarthridities Feature AS REA PA EA More 4 20 \200\22330 4 = 5 Any age 4 = 5 Any age 4 = 5 Any age Sex Age onset (years) Onset Gradual Sudden Variable Gradual % HLA B27 positive 95 20 (50 if sacroiliac disease is present) Sacroiliitis Always Often Often Often Peripheral joint disease Lower limb > upper Usually lower limb Usually lower limb Usually lower limb Enthesitis Present Present Present Present Uveitis Common Not common Not common Not common Conjunctivitis Not seen Not common Not seen Not seen Urethritis Not seen Rare Not seen Not seen Skin disease Not seen Rare Very common Rare Mucosal disease Not seen Not seen Not seen Not common AS, ankylosing spondylitis; REA, reactive arthritis; PA, psoriatic arthritis; EA, enteropat hic arthropathy. CHAPTER 8 The spondyloarthridities 290 Ankylosing spondylitis Epidemiology \200 Few clinicians rely solely on the criteria; most would consider the diagnosis of ankylosing spondylitis (AS) in any case of symptomatic in \202 ammatory back pain with radiographic evidence of sacroiliitis. The modi \201 ed New York criteria for AS, shown in Table 8.4, are better at capturing well-established disease; many patients with early AS would not meet the radio logic criteria, which requires unequivocal evidence of sacroiliitis on a plain radiograph. The dif \201 culty comes in recognizing early disease or subtle radiological change. There is often an insidious onset of back pain and morning stiffness that tends to improve with exercise. MRI is more sensitive than plain radiographs for detecting sacroiliiits, but occa sionally, sacroiliitis is a chance \201 nding in the absence of pain. Patients are typically <40 years of age with a male to female ratio of approximately 3:1. The condition occurs more frequently in Caucasian populations. In American Indians, where HLA B27 prevalence is high, AS is particularly frequent, whereas th e condition is less common in African-Americans, and rarer still in Sub-Saharan Africans, r e \202 ecting the declining prevalence of HLA B27 in these groups. Prevalence estimates in Caucasians range from 0.05 \200\2230.23% in adults. This may be an underestimate as people with mild symptoms may not seek medical advice. As previously stated, HLA B27 typing has led to greater understanding of the spondyloarthropathies, but should not be considered a diagnostic test or necessary f or the diagnosis of AS. Up to 5% of Caucasian patients with AS are negative for HLA B27. Clinical features of AS \200 The principal feature of the condition and allied diseases i s enthesitis , i.e., \201 brosis and ossi \201 cation of ligament, tendon, and capsule insertions into bone (the entheses), mainly in the region of the disks and sacroiliac joints. Synovitis also occurs, typically in the larger peripheral joints (hips and knees in particu lar). 20 \200\22340% of patients have some degree of peripheral joint disease at some stage during their illness, moreso in women than in men. Approximately 50% of patients with adul t AS will develop hip arthritis and some of these will need surgery. The standardized mortality ratio is 1.5; this increased mortality is due to cardiac valve a nd respiratory disease, amyloidosis, and fractures. \200 Like other forms of chronic dise ase, AS patients have a signi \201 cant risk of having to alter or give up work. Although recognized as typical of as, few patients progress to the classical late \200\234 bamboo spine. \200\235 When the spine does fuse (with \200\234syndesmophytes \200\235 brid ging the gap between vertebral bodies) microfractures can occur leading to acute episodes o f severe pain and ANKYLOSING SPONDYLITIS 291 Table 8.4 Diagnostic criteria: Modi \201 ed New York Criteria Clinical criteria: Low back pain and stiffness for >3 months improving with exercise but no t relieved by rest Limitation of lumbar spine movements in sagittal and frontal planes Limi tation of chest expansion relative to normal values for age and sex Radiological criteria: Greater than or equal to Grade II bilateral sacroiliitis Grade III or IV unilateral sacroiliitis Combined diagnostic criteria: De \201 nite AS if 1 radiological and 1 clinical criterion Probable AS if 3 clinical criteria or a radiological criterion without signs or symptoms sa tisfying the clinical criteria Van der Linden et al. Evaluation of diagnostic criteria for ankylosing spondylitis: a propo sal for modi \201 cation of the New York Criteria. Arthritis Rheum, 1984; 27: 361 \200\223 8. spondylodiscitis, a term given to collapse of the vertebral end-plate and destruction of th e disc \200\223bone border. This process is usually self-limiting, requiring rest and analgesia for up to 3 weeks. Most spinal disease is limited to chronic low-grade pain and stiffness with clinical evidence o f a symmetrical reduction in spinal mobility. Patients may have insertional tendonitis at several other common sites including the Achill es tendon, intercostal muscles, plantar fascia, and dactylitis of the hands and feet. Extra-articular disease in AS \200 Constitutional features of fatigue, weight loss, low-g rade fever, and anemia are common. Fatigue as opposed to pain or stiffness can be the most troublesome symp tom for many patients. Iritis occurs in up to 40% of cases but has little correlation with disease activity in the spine. There are no known triggers for this condition and although self-limiting, topical or systemic steroids may be required in severe cases. Iritis is usually unilateral. Upper lobe, bilateral pulmonary \201 brosis is a recognized feature of the disease. Occas ionally the \201 brotic area is invaded by aspergillus with changes mimicking tuberculosi s. Treatment of the \201 brosis is of not effective. Pleuritis can occur as a consequence of insertional tendonitis of the costosternal and costovertebral muscles. Fusion of the th oracic wall leads to rigidity and reduction in chest expansion. Ventilation is maintained b y the diaphragm; however, there is a threefold increased risk of death from a respiratory c ause compared with a normal population. CHAPTER 8 The spondyloarthridities 292