394 Neuroradiology Fast-moving technological advances in neurological imaging have revolu- tion ized neurological diagnosis and treatment, shedding light where there once was darkness \200\224but sometimes generating more heat than light. CT works by identifying x-ray attenu ation of materials, measured in Hounsfield units (HU) (e.g., bone +1,000, water 0, and air \200\2231,000 HU). The x-ray attenuation of a pixel is revealed as a shade of gray. At the extremes, high attenuation is white and low attenuation is black. The attenuation of biolo gical soft tissues is in a narrow range from about +80 for blood and muscle, to 0 for CSF, and down to \200\223100 for fat. IV contrast may be given, demonstrating initially an angi ographic effect, the high attenuation contrast in the vessels making them appear white. Lat er, if there is a defect in the blood \200\223brain barrier, as with neoplasms or infection , contrast will extravasate, giving an enhancing white area in the cerebrum or cerebellum. Some intracranial components do not have a blood \200\223brain barrier and thus will enhanc e (e.g., the pituitary gland and choroid plexus). Compared to MRI, CT is good at showing ac ute hemorrhage and fractures and is much easier to perform in ill or anesthetized patients \200\224so it is invalu- able in emergencies. Modern scanners can obtain a whole head view in seconds, and there are basically no contraindications to a noncontrast scan. Fresh blood is of higher attenuation (whiter) than brain tissue. Attenuation of hematomas declines as hem oglobin breaks down so that a subacute subdural hematoma at 2 wks may appear isodense to ad jacent brain, mak- ing it difficult to detect. A chronic subdural hematoma will be of relat ively low attenuation. CT is commonly performed in acute stroke to exclude hemorrhage (befo re giving thrombolytics). An area of ischemia will not show up distinctly for several hours or so, and will appear as low-attenuation cytotoxic edema (intracellular edema mainly conf ined to the gray matter). Tumors and abscesses may share radiographic features \200\224ring -enhancing mass, surrounding vasogenic edema, and mass effect. Vasogenic edema is extracell ular and spreads through the white matter. Mass effect can cause compression of the sulci a nd ipsilateral ventricle. It may also cause subfal- cine, transtentorial, or tonsillar hern iation. One indication for CT scan is acute, severe headache. If there is concern about sub arachnoid hemorrhage, a noncontrast CT may show acute blood. Even if it does not, it will s how if the basal cisterns are normal and therefore LP is probably safe. In MRI, an image is made by disturbing an atomic nucleus in a strong mag- netic field by using a radiofrequenc y pulse at the resonant frequency and detecting the signal as the nucleus (usually hydrogen ) returns to equilib- rium. The resulting noninvasively obtained anatomic and pathological infor- mation is unrivaled, but the technique has drawbacks as well (Table 10.26). The chie f clinically useful image sequences are: \212T1-weighted images: Give good anatomical deta il to which the T2 image can be compared/related. Fat is brightest ( \206\221 signal inten sity) other tissues are darker to varying degrees. Flowing blood appears black ( \200\234fl ow voids \200\235). Bone is dark. Gadolinium contrast agent can be given to \200\234enhance \200\235 vascu- lar lesions or areas of blood-brain barrier breakdown. y g o o r u e N l \212T2-weighted images: These provide the best detection of pathology, with most pathology having some edema fluid and therefore appearing white. Fat and fluid appear brightest. Aga in, fat is bright and bone is dark. \212FLAIR or TIRM: These sequences are similar to T2-weighted images and highlight patholo gy far better but remove the bright signal of CSF, which might otherwise obscure small lesi ons adjacent to sulci or ventricles. \212HEME, gradient echo, or susceptibility weighted i maging: All these sequences highlight blood products (or calcium deposits) as black. They a re very sen- sitive to the point of picking up previously asymptomatic \200\234microbleeds \200\235 in amyloidosis or mild head trauma but tend to \200\234overcall \200\235 the size of small lesions. 395 \212DWI and apparent diffusion coefficient (ADC): Most useful for revealing and dating acu te strokes. DWI imaging will reveal acute cytotoxic injury (ischemic infarction) as bright signal within minutes of onset, out to 14 d. ADC will reveal ischemic injury as dark signa l out to 7 d. \212Perfusion weighted imaging: Serial slices timed around injection of gado- linium contr ast medium reveal areas of the brain that are oligemic. In the setting of a stroke, an area of reduced blood flow without correspond- ing DWI brightness is \200\234at risk \200\235 b ut not yet infarcted and thus potentially salvageable. Often an \200\234ischemic penumbra \200\235 surrounds an area of acute stroke. \212MRA, MRV: MR scanners can reveal vasculature through various tech- niques, each with i ts own advantages and limitations. In general, images obtained from noncontrast studies are related to flow , rather than ana- tomic lumen size. MRV and neck MRA studies are best per formed with contrast enhancement, but MRA of the Circle of Willis is adequately obtained wi thout contrast. \212Other: A host of other specialized MR techniques have been developed that can highligh t specific anatomy and pathology. MR neurography can reveal peripheral nerves and plexus, d iffusion tensor imaging can high- light the integrity of white matter tracts, and morphomet ry and other volumetric imaging can reveal specific areas of atrophy or hypertrophy (often referenced to a standardized \200\234brain map \200\235). Novel sequences can reveal the ot herwise undetectable early gray matter involvement of MS, as well as clinically asymptomati c white matter lesions. MR spectroscopy can show us constituent molecular components of the brain in specific regions of interest (distinguishing, e.g., areas of demyelination from a reas of tumor or of cell death or of abscess). Functional MRI techniques can reveal regiona l brain activation in real time, by way of detecting changes in regional blood flow or bloo d oxygenation status. In PET and SPECT nuclear medicine techniques, images are created by detection of the decay of radioactive atoms attached to an injected molecu- lar label. PET has superior spatial an d far superior temporal resolution, but generally requires an on-site accelerator for gener ating isotopes. Areas of hypo- or hypermetabolism can reveal seizure foci, distinguish absc ess from tumors, or reveal patterns suggestive of specific types of dementia. Specific labe ls have been developed that bind amyloid- or dopamine-producing neu- rons, of potential use in Alzheimer \200\231s and Parkinson \200\231s diseases, respectively. Table 10.26 Advantages and disadvantages of MRI imaging Advantages of MRI Nonionizing radiation Shows vasculature without Disadvantages of MRI High cost Claustrophobia (in magnet tunnel for 15 \200\22360 min \200 \224sedation may be needed) contrast Images can easily be produced in any plane, e.g., sagittal or coronal Motion artifact and longer time for image acquisition Visualization of posterior fossa Unhelpful in imaging calcium Unsuitable for those with fer- romagnetic foreign bodies (pace makers, CNS vascular clips, cochlear implants, valves, shrapnel, etc.) and other areas prone to bony artifact on CT, e.g., at the cran- iocervical junction. MRI i mages the posterior fossa extremely well. 396 High inherent soft-tissue contrast Precise staging of malignancy, e.g., involvement of bone marrow Difficult in anesthetized patients Gadolinium may be harmful in patients with renal failure Imaging artifacts may be misinter- preted as abnormal findings This page intentionally left blank Rheumatology and musculoskeletal conditions Lanaya W. Smith M.D. and John A. Flynn , M.D., M.Ed., M.B.A. y g o o t a m u e h R l Contents Important points in assessing for rheumatic diseases 398 Synovial fluid analysis 400 Back p ain 401 Spondyloarthritis 402 Rheumatoid arthritis 404 Osteoarthritis 408 Fibromyalgia 408 Crystal-induced arthritis 408 Autoimmune connective tissue diseases 410 Systemic lupus eryt hematosus 410 Polymyositis and dermatomyositis 413 Vasculitis and polyarteritis nodosa 416 Polymyalgia rheumatica 417 Giant cell (temporal) arteritis 418 1 1 Important points in assessing for rheumatic disease Is there a history to suggest inflammat ion? \212 \212 \212 How many joints are involved? \212 \212 \212 Are there any extra- articular manifestations? Also consider age, gender, occupation, family history, ancestry ( e.g., sys- temic lupus erythematosus [SLE] is more common in women and African Americans). Morning stiffness (>30 min) Joint swelling, warmth, or redness Loss of function. One = monoarthritis Several (2 \200\2234) = oligoarthritis Many (>4) = polyarthritis 398 \212Presenting symptoms Joints \212Rheumatological and related diseases: E.g., Crohn \200\231s/ulcerative colitis (UC) in ankylosing spondylitis; psoriasis, gonorrhea, or reactive arthritis Morning stiffness Clinical synovitis (rheuma- toid arthritis [RA]) Pattern of distribution; mono vs. polyarticular Swelling; loss of function y g o o t a m u e h R Rashes, photosensitivity (SLE) Raynaud (SLE; scle- roderma poly- and dermatomyositis) Dry e yes or mouth (Sj gren \200\231s) Diarrhea/urethritis (Reactive arthritis) Red eyes, e.g. , ankylosing spondylitis, Nodules or nodes (RA, sarcoid, SLE, tuberculosis [TB], and gouty tophi) Mouth/genital ulcers (Beh et \200\231s)mouth ulcers also with SLE Weight loss (e. g., TB arthritis) Extra- articular \212 Current and past drugs: Disease modifying drugs, e.g., methotrex- ate etc. l \212Family history: Arthritis; psoriasis (psoriatic arthritis, ankylosing spondylitis) \212Social history: Functioning, e.g., dress- ing, writing, walking, activities of daily living (ADLs), social support, home adaptations Features of inflammatory arthritis Pain, stiffness (especially morning), synovitis, destruc tion of the joint on x-ray, loss of function. Causes \200\224Monoarthritis Septic arthriti s (e.g., staph, strep, Gram-negative bacilli, gonococci, TB) Psoriatic and reactive Polyarthritis (e.g., >4 swollen painful joints) Viruses, e.g., mumps, rubella, parvovi- rus B19, Chikungunya, EBV, hepatitis B, enteroviruses, HIV, \227 -viral arthropathy arthritis Trauma (hemarthrosis) Calcium pyrophosphate Rheumatoid (RA) or osteoarthritis (OA) Spondyloarthritis Connective tissue diseases (e.g., sclero- dihydrate (CPPD) crys- tals; gout Osteoarthritis Monoarthritic presentation of a polyarticu lar disease (e.g., RA) derma, SLE) Crystal arthropathies (gout, CPPD) Poststreptococcal reactive arthritis Sarcoidosis 399 Assessment Assess extent of joint involvement (include spine), symmetry, disruption of join t involvement, limitation of movement, effusions and periarticular involvement. Associated features : Dysuria or genital ulcers, skin or eye involvement, lungs, kidneys, heart, GI (e .g., mouth ulcers, bloody diarrhea), and central nervous system (CNS). Urine: Urine protein /creatinine (or 24 h urine protein) representing at least 500 mg of protein/24 h or red blo od cell casts. Adjunct therapy for proteinuria (angiotensin-converting enzyme [ACE]- inhibi tors or angiotensin receptor blocker [ARB]) Radiology: Look for erosions, calcification, lo ss of joint space, changes in un- derlying bone (e.g., periarticular osteoporosis, scleroti c areas, osteophytes) of affected joints. Image sacroiliac joints if considering a spondylo arthritis (irregularity of lower third); chest x-ray (CXR) in RA, SLE, vasculitis, and TB. In septic arthritis, x-rays may be normal, as may be erythrocyte sedi- mentation rate (ESR) and c-reactive protein (CRP; if CRP \206\221 , expect it to fall with treatment). Septic arthritis Consider septic arthritis in any acute monoarthritis. Feature s may be less overt if immunosuppressed or if underlying joint disease. Aspirate the joint. Look for blood, crystals, and pus (polarized light microscopy, culture, Gram stain). Sepsi s may damage a joint within 24 h. If in doubt, treat initially for sepsis, as described bel ow. Joint aspiration: Microscopy (+culture): Any blood, crystals, or pus? Do polarized ligh t microscopy for urate or CPPD crystals (p. 409). Blood: Culture if sepsis is possible. CBC , ESR, uric acid, urea, and creatinine if systemic disease. Rheumatoid factor, antinuclear antibody, and other au- toantibodies (p. 414). Consider HIV serology. Treatment is determin ed by the cause. If septic arthritis is suspected, provide analgesia, immediate antibiotics , imaging, and surgical intervention (washing) if necessary. Oxacillin or cefazolin for met h-sensitive staph; vancomycin if meth resistance is suspected, third-generation cephalospor in if gram-negative organisms are suspected, until sensitivities are known. Look for atypic al mycobacteria and fungi if HIV +ve. Request infectious disease consultant for how long to continue treatment (e.g., 2 wks IV, then 3 wks PO). Repeat aspiration (arthrocentesis) if no improvement (falling joint white blood cells [WBCs] and culture becoming sterile), then consider lavage and arthroscopic debridement(e.g., for knee) or open (e.g., for hip or shou lder; this allows biopsy; helpful for TB). Ask for orthopedic consult. If a joint prosthesi s is in situ , get orthopedic consult before aspiration. Try to determine the source of inf ection. Is there immunosuppression or a focus of infection (e.g., pneumonia, as in 50% of t hose with pneumococcal arthritis)? Synovial fluid analysis Table 11.1 Synovial fluid analysis Aspiration of synovial fluid is primarily used to look for infection or crystals (gout and CPPD crystal arthritis. 400 Appearance Viscosity WBC/mm 3 Neutrophils (%) None 25 50 Clear, colorless Clear, straw Bloody, 200 5000 10,000 Normal Noninflammatory a Hemorrhagic b \206\221 \206\221 Varies xanthochromic Acutely inflamed c \212 \212 RA \212 Septic TB \212 \212 \212 Turbid, yellow \206\223 Crystal Rheumatic fever 14,000 18,000 16,000 80 50 Varies Turbid, yellow \206\223 20,000 10,000 50,000 70 60 95 Gonorrheal Septic (nongonococcal) d a E.g., degenerative joint disease b E.g., tumors, hemophilia, trauma c E.g., Reactive arth ritis, CPPD crystals, SLE d Includes staphs, streps, and Pseudomonas (e.g., postop) Back pain This is very common and often self-limiting; but be alert to \200\234red flags \200\235 that may indicate serious underlying causes (see Table 11.2). Key points in the hi story: (1) Onset : Sudden (related to trauma?) or gradual? (2) Are there motor or sensory s ymptoms? (3) Is bladder or bowel affected? Pain that is worse with movement and relieved by rest is often mechanical. If it is worse after rest, an inflammatory cause should be consi dered, such as ankylosing spondylitis. (4) Constitutional symptoms (fever, weight loss, nig ht sweats). Examination (1) With the patient standing (legs straight), gauge the extent and smoothness of lumbar forward/lateral flexion and extension. (2) Neurological de \201 cits : Perianal sensation; upper and lower motor neuron (UMN and LMN) signs in legs (p. 392); ( 3) signs of generalized disease suggest malignancy. Nerve root impingement causes pain in r elevant dermatomes and can be worsened by bending forward. A positive straight leg raising sign occurs when a supine patient experiences pain in buttock/back/other leg when lifting l eg to <45 degrees. It suggests lumbar disc herniation impinging on nerve roots. (Its sensit ivity is 0.9 and its specificity is 0.2.) y g o o t a m u e h R l Neurosurgical emergencies Acute cauda equina compression: Alternating or bilateral root pai n in legs, saddle anesthesia (i.e., bilaterally around anus) and disturbance of bladder or bowel function Acute cord compression: Bilateral pain, LMN signs at level of compression, U MN and sensory signs below, sphincter disturbance. Causes (same for both types of compressi on): Bony metastasis (look for missing pedicle on x-ray), myeloma, cord or paraspinal tumor , TB (p. 552), abscess. Urgent treatment needed to prevent irreversible loss : Laminectomy for disc protru- sions; decompression for abscess; radiotherapy for tumors. Tests Magnetic resonance imaging (MRI) is the best way to image cord compression, myelopathy, spinal neopl asms, cysts, hemorrhages, and abscesses. CBC, ESR ( \206\221 in myeloma, infections, tumor s), prostate specific antigen (PSA), and bone scan \200\234hot spot \200\235 suggest neopl astic diagnoses. Causes Age determines the most likely causes. \212 Herniated disc, trauma, fractures, ankylosing spondylitis (AS) 15 \200\22330 yrs: (p. 402), spondylolisthesis (e.g., L5 shifts forward on S1) 30 \200\2235 0 yrs breast, prostate) Degenerative, osteoporosis compression fracture, Paget \200\231s, m alig- >50 yrs: nancy, myeloma (request serum electrophoresis), lumbar spinal stenosis Rarer causes: Cauda equina tumors, spinal infection (usually staphylococcal, also TB). Treatment Specific causes need specific treatment. For most back pain, a specific cause is not found , so treat empirically. Avoid precipitants; arrange physical therapy. Analgesia and normal activities are better than bed rest. In certain patients there are roles for disc, epidural , or nerve root 401 \212 : Degenerative spinal disease, herniated disc, malignancy (lung, \212 injections and surgical procedures, such as foraminotomy, stabilization, or laminectomy. Fe atures of serious causes of back pain \212 Young (<20 yrs) or old (>55 yrs) Trauma Alternating sciatica Bilateral sciatica Weak legs W eight loss Fever of unknown origin (FUO); ESR \206\221 (>25 mm/h) Systemic steroids or imm unosuppressive use \212 Progressive, continuous, nonmechani- cal pain Constitutionally ill; drug abuse; HIV +ve Spi ne pain in all directions of movement Localized bony tenderness CNS deficit at more than on e root level Pain or tenderness of thoracic spine Bilateral nerve impingement \212 \212 \212 \212 \212 \212 \212 \212 \212 \212 \212 \212 \212 \212 Past history of malignancy Table 11.2 Inflammatory versus mechanical back pain Inflammatory back pain is associated with ankylosing spondylitis and other forms of spondyl oarthritis (psoriatic, inflammatory bowel disease [IBD], and reactive arthritis). When dete rmining if the back pain is inflammatory in nature, the follow- ing features should be soug ht: \212 \212 \212 Onset of pain is usually <40 years of age and is insidious. Pain persists for >3 months (i. e., it is chronic). The back pain and stiffness worsen with immobility, especially at night and early morning. The back pain can be alternating in nature: \200\234buttock to buttock . \200\235 The back pain and stiffness tend to ease with physical activity and exercise. NS AIDs are effective in relieving pain and stiffness in most patients. \212 \212 \212 402 Spondyloarthritis Investigations Diagnosis of spondyloarthritis (SPA) is clinical, supporte d by radiology findings (may be normal in early disease). Look for irregu- larities, erosio ns, or sclerosis affecting both sides of the lower third of the sacroiliac joints. See Tabl e 11.3. Later: Squaring of the vertebra, \200\234bamboo spine, \200\235 erosions of the ap ophyseal joints, obliteration of the sacroiliac joints (sacroiliitis also occurs in reactiv e arthritis, Crohn \200\231s disease, psoriatic arthri- tis, Brucella arthritis). Other tes ts : CBC (normochromic anemia), ESR \206\221 , \206\221 CRP. A new classification criteri on has been developed for SPA. Ankylosing spondylitis (AS) Prevalence: 0.25 \200\2231%. Men present earlier : : 6:1 at 16 yrs and 2:1 at 30 yrs. >85% are human leukocyte a ntigen (HLA) B27 +ve. Symptoms: The typical patient is a young man presenting with low back pain, spinal morning stiffness, and progressive loss of spinal movement (spinal ankylosis) who later develops kyphosis and cervical ankylosis. Other features and a ssociations: y g o o t a m u e h R l \212 Chest wall expan- sion \206\223 Chest pain \212 Enthesitis of calcaneal, tibial or ischial tuberosities, or plantar fascia Crohn \200\231s/ UC Amyloid \212 Carditis; iritis; recur- rent sterile urethritis Aortic valve disease Psoriaform rashes \212 \212 \212 \212 \212 Hip involvement Knee involvement \212 \212 Osteoporosis \212 Treatment: Exercise, not rest, for backache; physical therapy regimens to maintain posture and mobility. Trial NSAIDs 4 \200\2236 wks; if unsuccessful, change to another class before moving to anti-tumor necrosis factor (TNF) therapy. Sulfasalazine and methotrexate help pe ripheral arthritis and en- thesitis but not spinal inflammation. Efficacy is proved with an ti-TNF thera- pies. Rarely, spinal osteotomy is useful. Difficult-to-fix osteoporotic spina l fractures can occur. Enteropathic spondyloarthritis Inflammatory bowel disease (Crohn \200\231s and UC) are associated with spondyloarthritis. Avoid etanercept. Psoriatic arthri tis Often asymmetrical, involves distal interphalangeal (DIP) joints, spine, typically caus ing dactylitis (sausage digits). X-ray changes can be misinterpreted as OA. Associated with synovitis, acneiform rashes, palmoplantar pustulosis, hyperostoses, and (sterile) osteomye litis (SAPHO). Responds to NSAIDs, methotrexate, cyclosporin, and anti-TNF- therapy (p. 406). Reactive arthritis Presentation: Secondary to Chlamydia trachomatis urethritis, Campy lobacter jejuni, Salmonella, Shigella, and Yersinia species. Typically, a young man with re cent nonspecific urethritis, which may be asymptomatic; it may also follow dysentery. Often large joint, lower limb mono- or oligoarthritis or enthesitis; it may be chronic or relaps ing. Also: Iritis, keratoderma blenorrhagica (brown, aseptic abscesses on soles and palms), and circinate balanitis \200\224painless serpiginous penile rash; mouth ulcers; enthesitis (plantar fasciitis, Achilles tendonitis) and aortic regurgitation. Tests: ESR and CRP \206\221 or normal. Culture stool if diarrhea. Obtain sexual history. X-rays : Periostitis at ligamentous entheses; enthesopathic erosions. Management: Rest; splint affected joints; NSAIDs or steroids. Consider sulfasalazine or methotrexate. Rarely, TNF inhibitor. 403 Table 11.3 Features common to spondyloarthritis 1 Seronegativity (rheumatoid factor \200\223ve) 2 Pathology in spine (spondylo-) and sacro iliac (SI) joints; i.e., \200\234axial arthritis. \200\235 3 Asymmetrical monoarthritis large-joint oligoarthritis (i.e. few joints) or 4 Inflamed tendon ligament union sites (enthesitis); e.g., plantar fasciitis, Achilles tend onitis, costochondritis, or digit (finger and toe) tendon sheaths (dactylitis) 5 Extra-articular manifestations; e.g., uveitis, psoriaform rashes, Crohn \200\231s, UC 6 HLA B27 association (84 \200\22396% of those with AS) Different forms of spondyloarthriti s show much overlap with one another. They are treated with physical and occupational thera py, advice on posture, NSAIDs, sulfasalazine, methotrexate, and TNF inhibitors. Rheumatoid arthritis Typically, RA has a persistent, symmetrical distribution but does not have to be symmetric! Persistent symptoms >6 months. To recognize early disease, look for m orning stiffness >30 min, + antibodies, + squeeze test across metacarpophalangeal/metatarsa l Deforming, polyarthritis often affecting hands and feet. Peak onset : Fifth decade. : > 2:1. Prevalence: 0.5 \200\2231% (higher in smokers). Genetics: H LA DR4 linked in Cauc asians. Presentation Typically swollen, painful, and stiff hands and feet, especially in th e morning. This can fluctuate and larger joints become involved. Less common presentations are: \212 \212 \212 (MCP/MTP)joints. Later: Recurring monoarthritis of various joints Persistent monoarthritis (often of one knee) Syst emic illness (pericarditis, pleurisy, weight lems at first (more common in men) Sudden onse t of widespread arthritis \206\223 ) with minimal joint prob- \212 Palindromic RA : The onset of RA is episodic, with one to several joints being affect ed sequentially for hours to days, with symptom-free periods in between Signs At first, swo llen fingers and MCP joint swelling or pain and swelling of the feet \200\234positive sque eze test. \200\235 The first site for erosive change can be the metatarsals. Later, ulnar d eviation at MCPs and dorsal wrist subluxation. Boutonni re and swan-neck deformities of fingers (see Figure 11.1) or Z-deformity of thumbs. Hand extensor tendons may rupture and a djacent muscles waste. Foot changes are similar. Larger joints may be involved. Atlantoaxia l joint subluxation may threaten the cervical spinal cord. (See Plate 20.) Extra-articular Anemia, nodules, lymphadenopathy, vasculitis, carpal tunnel syndrome, multifocal neuropathi es, splenomegaly (5%, but only 1% have Felty syndrome : Splenomegaly and granulocytopenia). Eyes : Episcleritis, scleritis, keratoconjunctivitis sicca. Other signs : Pleurisy, perica rditis, pulmonary fibrosis, osteoporosis, amyloidosis. Associated with increased risk of is chemic heart disease and lymphomas. Diagnosis New international criteria have been develope d with the purpose of establishing an earlier diagnosis of RA. A scoring system is based on joint distribution, symptom duration, and the presence of serologies and acute-phase react ants. See: Http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp X-ra ys Increased soft tissue, juxta-articular osteoporosis, widened joint space. Later : Bony e rosions subluxation complete carpal destruction. Blood tests ESR \206\221 ; hemoglob in (Hb) \206\223 ; mean cellular volume (MCV) ; WBC \206\223 ; platelets \206\221 . R heumatoid factor often \200\223ve at start, becoming +ve in 80% (also +ve in: Sj gren \200\231s syndrome (80%), SLE (30%), systemic sclerosis (30%); antinuclear antibodies (ANA) +ve in 30%. Anti-CCP (cyclic citrullinated peptide) can be seen in early polyarthritis whe n RF negative, indicating early RA. This has a high specificity and a high positive predict ive value for RA. Treatment Encourage regular exercise, physio- and occupational therapy. T reat to target! The goal is to achieve very low disease activity or remission: \212 \212E arly disease recognition \212 \212 404 Prevent joint damage and deformity Fewer swollen and tender joints Normal acute-phase reactants \212Early start of disease-modifying therapy and control of the disease \212 Most erosion s happen within the first few years of the disease. \212 Assistive devices and appropriate orthotics (e.g., wrist splints) \212 Intra-articular steroids : If no contraindication (a sthma, active peptic ulcer) start an \212 Oral drugs NSAID. Often, NSAIDs, such as ibuprof en 400 mg/8 h after food, do not control symptoms or are not tolerated (GI bleeds). Patient s who need low-dose aspirin prednisone may also need regular proton pump inhibi- tor. On e cannot predict which NSAID a patient will respond to: Different ones can be tried. Diseas e-modifying antirheumatic drugs (DMARDs) should be considered early (see Table 11.4). Regul ar monitoring is vital. Steroids may reduce joint damage and control difficult symptoms (e. g., prednisone 5 mg/d PO), but place in treatment schema is controversial. One problem is r educed bone density over long periods. Manage cardiovascular risk factors ( accelerated. Su rgery to relieve pain, improve function, and to prevent disease compli- cations (e.g., radi al-carpal fusion, joint replacements) y g o o t a m u e h R l \212 \212 p. 89) because atherosclerosis is \212 Adult-onset Still \200\231s disease (AOSD) is a systemic inflammatory disorder characterize d by fever, skin rash, polyarthralgias or polyarthritis, sore throat, hepatosplenomegaly, l ymphadenopathy, leukocytosis, liver enzyme elevation, and high serum level of ferritin. No specific diagnostic test is available. The clinical diagnosis is based on pattern recogniti on and exclusion of other conditions. Treatment requires suppression of inflammation: NSAID s, IL-1 inhibition (Anakinra). See Table 11.5 for forms of arthritis not associated with rh eumatoid factor. Figure 11.1 405 Table 11.4 Influencing biological events in RA The chief biological event is inflammation. Monocytes traffic into joints, cytokines are pr oduced, fibroblasts and endothelial cells are activated, and tissue proliferates. Inflammat ory fluid is generated (synovial effu- sion), and cytokines and cellular processes erode ca rtilage and bone. Cytokines also produce systemic effects: Fatigue, accelerated atheroscle- rosis, and accelerated bone turnover. Disease-modifying drugs (DMARDs) Drugs that alter th e course of disease and slow joint destruction. Traditional DMARDs Methotrexate (MTX), sulf asalazine, leflunomide, and hydroxy- chloroquine First-line therapy is commonly MTX. \212S ulfasalazine: Common side effects (SE): Nausea, headaches, diar- rhea, marrow \206\223 , r eversible sperm count \206\223 , rash, G6PD deficiency, oral ulcers. \212Methotrexate: Avoid in liver disease, pregnancy, and excessive alcohol consumption; ca ution if preexisting lung disease. SE : Mucositis, nausea, fatigue/lethargy, pneumonitis (r are; can be life-threatening), aspartate aminotransferase/alanine aminotransferase (AST/ALT ) \206\221 . Give concur- rent folate supplements (e.g., folic acid 1 mg/d, PO). \212Cyclosporin: SE: Nausea, tremor, gingival hypertrophy, hypertension, renal impairment/hypertension \212Leflunomide: Reduces autoimmune effects (takes months to work). For first 6 months, do CBC and chemistry monthly. Stop if platelets < 150 \236 \227 10 9 /L; WBC < 4 \236 \227 10 9 /L, or AST \206\221 by >3-fold or rashes. SE : liver function tests (LFT) \206 \221 , alopecia, diarrhea, infections \212Azathioprine: S E: Marrow \206\223 , nausea, LFT \206\221 , oncogenic (do TPMT 1 tes t first). \212Hydroxychloroquine (HCQ): S E: Rash, diarrhea, While on HCQ, oph- thalmic evaluation s hould occur every year. After 5 years, 1 in 5,000 patients can experience retinopathy. Anticytokine therapy Tumor necrosis factor- (TNF) is a key cytokine overproduced in RA s ynovium. Infliximab (chimeric murine/human anti- TNF antibody given IV every 8 wks), etaner cept (TNF- receptor/Ig Fc fusion protein given 25 mg SC twice weekly or 50 mg weekly), a nd adali- mumab (fully human anti-TNF monoclonal given as 40 mg SC every 2 wks). SE: Rashes , nausea, diarrhea, and infections (e.g., reactivation of TB). ANA and even SLE-type illnes s can evolve. Long-term safety issues are unclear (?increased risk of cancer, multiple scle rosis) but responses can be striking compared with other DMARDs. Immune modulator therapy A batacept (binds to CD86 and CD80 receptors on antigen presenting cells with down-regulation of T cell acti- vation; given IV every 4 wks). SE : Exacerbation of COPD, headaches, nause a. Rituximab (a monoclonal antibody that binds to CD20 anti- gen on B lymphocytes reducing B cell function). Given in combination with methotrexate and prednisone as two separate IVs 2 wks apart. SE : Fevers, chills, headache, rash, nausea, hepatitis B reactivation, and pr o- gressive multifocal leukoencephalopathy (PML) reported. 406 (Continued) 1 Thiopurine methyl transferase \200\224deficiency of this enzyme can lead to bone marrow s uppression in the setting of azathioprine use. y g o o t a m u e h R Table 11.4 (Continued) l TNF Antagonists Adalimumab Etanercept Infliximab Golimumab Certolizumab Pegol IL-1 antagoni st Anakinra Janus kinase inhibitor Tofacitinib T-cell modulators: Abatacept B-cell depletion Rituximab IL-6 antagonist Tocilizumab Table 11.5 Forms of arthritis not associated with rheuma- toid factor (sero \200\223ve) Lyme disease, Beh et \200\231s, leukemia, pulmonary osteoarthropathy, endo- carditis, ac romegaly, Wilson \200\231s disease, familial Mediterranean fever, sar- coid, hemophilia, si ckle-cell, hemochromatosis, and infections, as from: Poststreptococcal Parvovirus B19 Vibri o parahaemolyticus Borrelia burgdorferi Chronic arthritis in children (i.e., before 16 yrs) takes several forms and is classified into juvenile idiopathic arthritis (JIA) subforms: \212 Hepatitis B Chl. pneumoniae Rubella Ureaplasma; HIV Clostridium difficile Systemic arthritis (or Still \200\231s disease) Oligoarthritis (1 \200\2234 joints affected in first 6 months) \212 \212 \212 \212 Polyarthritis (RhF \200\223ve, ANA +ve) Polyarthritis (RhF +ve) Psoriatic arthritis Enthes itis-related arthritis at ligament/tendon insertion into bone. \212 NB: JIA shares only some features with RA: JIA shares these in com- JIA and RA differ in these ways: mon with RA: Both display destruc- tive arthritis Autoimmune with autoantibodies Both have HLA associations Children with chronic arthritis need regular ophthalmic review to detect o ccult uveitis, as well as regular monitoring of growth and development. RA is more likely to run in families RA is more homogeneous than JIA RA has poorer outcomes than JIA 407 Osteoarthritis OA is the commonest joint condition. Women are prone to symptom- atic OA ( : 3:1). Mean age at onset : 50 yrs. OA is usually primary, but may be secondary to any joint disease/injury or some diseases (e.g., hemochromatosis). Signs and symptoms In si ngle joints, pain on movement, worse at end of day; background pain at rest; minimal stiffn ess; joint instability. In polyarticular OA with Heberden nodes ( \200\234nodal OA \200\235 ), the most commonly affected joints are DIP, thumb metacarpophalangeal joints, cervical an d lumbar spine, and knee. There may be joint tenderness, derangement bony swelling (e.g. , Heberden nodes; i.e. bony lumps at DIP joints), poor range of movement, and some (usually limited) synovitis. Imaging/tests Radiology: Loss of joint space, subchondral sclerosis an d cysts, osteophytes. CRP usually normal. Treatment Acetaminophen for pain. If ineffective, try NSAIDs. Reduce weight; use walking aids, supportive footwear; physical therapy. Do exe rcises (e.g., regular quadriceps exercises in knee OA) and keep active. Joint replacement f or end-stage OA. Fibromyalgia Fibromyalgia is a chronic, widespread pain disorder. Fibromyalgia is not due t o inflammation but to abnormal nerve conduction that causes pain. Tai Chi twice daily has b een shown to be beneficial in reducing pain. 2 Three medications have been FDA-approved for fibromyalgia: pregabalin, dulox- etine, and milnacipran. Narcotics are of no benefit in fi bromyalgia and can paradoxically increase pain. Crystal-induced arthritis Gout In the acute stage, there is severe pain, redness, and swell ing of the joint \200\224often the metatarsophalangeal joint of the big toe (podagra). Atta cks are due to the deposition of monosodium urate crystals in and around joints and may be precipitated by trauma, surgery, starvation, infection, or diuretics. With long-term hyperu ricemia, after repeated attacks, urate deposits (tophi) develop (e.g., finger pads, tendons , joints, pinna). \200\234Secondary \200\235 causes : Polycythemia, psoriasis, leukemia, c ytotoxics, renal impairment, long-term alcohol excess. Diagnosis depends on finding urate c rystals in tissues and synovial fluid (serum urate not always \206\221 ). Synovial \202 uid microscopy : Negatively birefringent crystals; neutrophils (+ingested crystals). X-rays may show only soft-tissue swelling in the early stages. Later, well-defined \200\234punch ed out \200\235 lesions are seen in juxta-articular bone. Sclerotic reaction develops later creating an \200\234overhanging edge \200\235 or \200\234rat-bite \200\235 erosion. Join t spaces are preserved until late. Prevalence: 0.5 \200\2231%. : 5:1. (See PLATE 16.) Treating acute gout Use an NSAID unless contraindicated (e.g., peptic ulcer, renal ins ufficiency). Steroids are effective (prednisone 30 \200\22340 mg PO with rapid taper over 6 \200\22310 d). Oral colchicine for acute gout flare treatment; use low-dose colchicine 1.2 mg followed by 0.6 mg in 1 h (1.8 mg total). Low-dose colchicine has both maximum plasma c oncentration and early gout flare efficacy comparable with that of high-dose colchicine, wi th a better safety profile. 3 408 2 Zhang F, et al. A randomized trial of tai chi for fibromyalgia. N Engl J Med . 2010;363:2 265 \200\22367. Preventing attacks The goal is to lower uric acid levels: Avoid prolonged fasts, alcohol ex cess, and high purine food. Lose weight. Allopurinol inhibits xanthine oxidase, metabolized by the kidney. Consider reducing serum urate with long-term allopurinol, but not until 3 w ks after an attack. Start with regular NSAID or colchicine cover (0.6 mg/d PO) as introduct ion of allopurinol may cause gout attack. Allopurinol dose: Start at low dose (100 mg/24 h PO), adjust monthly in light of serum urate levels to achieve <6 mg/dL or <5 mg/dL for toph aceous gout. Haste makes waste! Typically 300 \200\223400 mg/24 h for mild disease; up to 4 00 \200\223600/d for severe disease. SE : Rash, fever, WBC \206\223 . If simple treatment fails, refer to a rheumatologist. Febuxostat: 40 mg/d metabolized by the liver, PO administ ration. This is a therapeutic alternative when allopurinol is not tolerated (monitor for cy topenias and monitor liver function). Uricase : A recombinant mammalian uricase, reduces nu mber of tophi. Acute- ly lowers uric acid levels in patients refractory to conventional the rapy. Must check for G6PD deficiency. Dose : IV 8 mg/mL (2 mL) infuse over 2 h every 2 wks. SE : Gout flare, infusion reaction, antibody formation (anti-PEG anti- bodies). Uric acid increase after infusion may indicate antibody formation. Calcium pyrophosphate dihydrate ar thritis Risk factors : \212 y g o o t a m u e h R l Dehydration \212 Intercurrent illness Osteoarthritis \212 Hyper- parathyroidism Hemo- chromatosis \212 Myxedema \212 \212 \212 Acromegaly \212 PO 4 3 \200\223 \206\223 ; Mg 2+ \206\223 Acute CPPD monoarthritis (pseudogout): Similar to gout; affects different joints (mainly wr ist, knee, ankles). Chronic CPPD: Destructive changes like OA, but more severe; affects kne es (also wrists, shoulders, hips). Can pres- ent as polyarthritis (pseudorheumatoid). See F igure 11.2. Tests: Polarized light microscopy of joint fluid; crystals are weakly positivel y birefringent. Associated with soft-tissue calcium deposition on x-ray; e.g., triangular l igament in wrist or in knee cartilage (chondrocalcinosis). If ar- throcentesis is performed , it can be blood tinged. Treatment: NSAIDs help but are rarely sufficient and often contra indicated in the elderly; consider steroid joint injection for mono-arthritis, oral or pare nteral administration for >2 joints with taper over 1 \200\2232 wks. For chronic disease, c onsider colchi- cine 0.6 mg/d to prevent flares. See Table 11.6. 409 Table 11.6 Prescribing NSAIDs: Patient education Most patients prescribed NSAIDs do not need them all the time, but some patients obediently take them continuously, as prescribed, with potential serious side effects, such as GI ble eding. Explain to your patients that: \212 \212