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Table 3.

Diagnostic Clues from the Review of Systems Feature Condition Facial rash, photosensitivity Systemic lupus erythematosus Hair loss Systemic lupus erythematosus Uveitis Spondyloarthropathy, sarcoidosis, Behcet syndrome Conjunctivitis Reactive arthritis Dry eyes and/or mouth Sjogren syndrome Oral ulcers Systemic lupus erythematosus Nasal discharge, ulcers Wegener granulomatosis Diabetic stiff-hand syndrome, Dupuytren contractures, Diabetes reflex sympathetic dystrophy, carpal tunnel syndrome Thyroid problems Osteoporosis, myopathy Pleurisy Systemic lupus erythematosus, rheumatoid arthritis Hemoptysis Systemic lupus erythematosus, Wegener granulomatosis Abdominal pain, bowel Crohn disease, fibromyalgia (with irritable bowel dysfunction syndrome) Urethral burning or Reactive arthritis, septic arthritis discharge Kidney stones Gout Numbness or paresthesias Carpal tunnel syndrome, vasculitis Vaginal burning or Behcet syndrome, septic arthritis discharge Psoriasis Psoriatic arthritis Raynaud phenomenon and Scleroderma, systemic lupus erythematosus digital ulcer



Response Rate; Onset of Action

Magnitude Major Toxicities of Efficacy Bone marrow, immunosuppression, infection, cholestasis Kidney, hypertension, hypertrichosis, infection, immunosuppression Retinopathy, myopathy, hyperpigmentation Liver, teratogen, infection, immunosuppression, gastrointestinal, skin rash Liver, teratogen, hematologic, oral ulcers, alopecia Gastric and duodenal ulcer, renal Skin atrophy, cataracts, osteoporosis, avascular necrosis, infection, immunosuppresion Dyspepsia, hemolysis inglucose-6-phosphate dehydrogenase deficiency, liver



30-50%; 2++ 3 mo 30%; 2-3 mo ++

50-150 mg/day 2.5-5.0 mg/kg/day 200 mg b.i.d. 10-20 mg/day 7.5-25 mg/wk Varied

Cyclosporine Hydroxychloroquine Leflunomide Methotrexate NSAIDs

30-50%; 2++ 6 mo 50%; 2-3 mo +++

> 70%; 6+++ 12 wk > 75%; < 2 + wk > 90%; < 1 +++ wk


5-10 mg/day


> 30%; 2-3 ++ mo

1 g b.i.d. or t.i.d.

Table 4. Comparison of Various Antirheumatic TreatmentsBiologic Drugs Response Magnitude Drug Rate; Onset Major Toxicities of Efficacy of Action TNF blockers Etanercept Injection-site reactions or Infliximab 50-70%; 2infusion reactions, infections, +++ Adalimumab 12 wk immunosuppression, possible Golimumab lymphoma in children Certilizumab Infusion reactions, infections, IL-6 inhibitors 50-70%; 2immune surveillance, elevated +++ Tocilizumab 12 wk liver function tests, bowel perforations, lipid alterations IL-1 inhibitor 30%; 1-3 + Injection-site reactions, infection Anakinra mo B cell depleter Rituximab 50-70%; 4+++ 12 wk



4-8 mg/kg IV every 4 wk

T cell costimulation 50-70%; 4blocker +++ 12 wk Abatacept

100 mg/day SC 500-1,000 Infusion reactions, increased mg IV q. 2 infection wk 2 500-1,000 Injection-site reactions, mg IV q. 4 infections, immune surveillance wk

SS Reiter Syndrome (Reactive Arthritis) Male > female 20 Sudden

Ankylosing Spondylitis Sex distribution Age at onset (years) Mode of onset Male > female 20 Gradual

Psoriatic Arthritis Female > male Any age Gradual

Enteropathic Arthritis Female = male Any age Peripheral sudden Spinal gradual

Peripheral joints Enthesopathy Heel pain Spinal involvement Symmetry (sacroiliitis and syndesmophytes) Familial aggregation HLA-B27 positive Risk for B27-positive person Urethritis Skin involvement Nail involvement Mucous membrane involvement Cardiac involvement Self-limiting

Often lower limbs Asymmetrical + Occasional +++ (always) + ++ 90% 2% (20% when a relative) + -

Usually lower limbs Asymmetrical + Frequent + (20%) +/+ 63%-75% 20% (when infected) + + + ++ + +

Upper > lower limbs Asymmetrical + Occasional + (20%) +/-

Lower > upper limbs Symmetrical - Peripheral + Spinal Infrequent + (10%) +

++ ++ 20% (50% with 10% (50% with sacroiliitis) sacroiliitis) ? +++ +++ Rare ? + + Rare ++ Peripheral Spinal

Scleroderma aboratory and Other Studies for Scleroderma Test Notes Present in more than 95% of patients. The most common patterns Antinuclear antibodies are speckled, homogeneous, and nucleolar (1) One type of antinuclear antibody pattern that is most typically associated with limited cutaneous disease. Patients with anticentromere antibody tend to have a reduced frequency of Anticentromere antibody pulmonary (interstitial fibrosis), renal, and cardiac involvement (9). This antibody occurs in patients with pulmonary artery hypertension An antibody to topoisomerase I is most commonly seen in patients Anti-Scl-70 with diffuse cutaneous systemic sclerosis, and is associated with interstitial lung disease Associated with diffuse cutaneous skin disease and increased risk Anti-RNA polymerase III for scleroderma renal crisis. There is a reduced risk for interstitial antibody lung disease in patients with this autoantibody (10) Blood urea To monitor renal function, particularly in diffuse cutaneous


systemic sclerosis as these patients are at risk for renal crisis Scleroderma renal crisis is a microangiopathic process resulting in Complete blood count anemia, schistocytes on peripheral blood smear, and with peripheral smear thrombocytopenia (see figure Peripheral Blood Smear) Urinalysis Proteinuria and erythrocytes occur in renal crisis 24-hour urine for protein Of baseline importance and for follow-up on renal function as a and creatinine marker for scleroderma renal crisis May reveal basilar pulmonary fibrosis (see figure Interstitial Chest radiograph Fibrosis) Reduced forced vital capacity occurs in interstitial lung disease. Reduced diffusion capacity occurs in either interstitial lung disease Pulmonary function tests or pulmonary hypertension. An isolated reduction of diffusion capacity may be indicative of pulmonary hypertension To assess need for home oxygen requirement. Also can be used to 6-minute walk test evaluated distance walked as a functional measure in patients treated for pulmonary hypertension Echocardiogram with A noninvasive method to evaluate for pulmonary hypertension Doppler Right-heart The gold standard for diagnosis of pulmonary hypertension catheterization An elevated level is predictive of cardiac involvement, including N-terminal pro-brain pulmonary hypertension, in patients with systemic sclerosis (11; natriuretic peptide 12) Wide-field magnification of the nailfold capillaries in patients with scleroderma shows characteristic changes (13). (See figures Nailfold capillaroscopy Nailfold Capillaroscopy (A), Nailfold Capillaroscopy (B), and Nailfold Capillaroscopy (C).) This procedure is best done by a specialist trained in its use

ifferential Diagnosis of Scleroderma Disease Notes Some patients may not meet Scleroderma diagnostic criteria; serology can be helpful in supporting diagnosis Primary Raynaud's Negative ANA and normal nailfold disease capillaroscopy The early stages of scleroderma may be characterized by Systemic lupus constitutional symptoms, and erythematosus patients may have a positive ANA, making a definitive diagnosis difficult Proximal myopathy can occur in Inflammation of muscle scleroderma. Patients with characterized by proximal muscle inflammatory myopathy may have Inflammatory weakness, elevated muscle enzymes arthralgias and/or arthritis, myopathy (creatine kinase, aldolase), Raynaud's phenomenon, abnormal electromyography, and a dysphagia, and interstitial lung positive ANA disease, making differentiation from scleroderma difficult Presence of Raynaud's phenomenon and characteristics of other connective-tissue diseases, such as Undifferentiated arthritis, serositis, pulmonary connective-tissue Often evolves into scleroderma fibrosis, dysphagia, etc., without disease meeting criteria for a specific connective-tissue disease. Often there is a positive ANA Features of SLE, inflammatory Mixed connectivemyopathy, scleroderma, Positive anti-RNP antibody tissue disease inflammatory arthritis Woody induration of the skin with Absence of Raynaud's thickening of the fascia often phenomenon, ANA, GI, and Eosinophilic fasciitis associated with a peripheral pulmonary symptoms. Fulleosinophilia. Typically spares the thickness skin to muscle biopsy is hands and feet helpful in making the diagnosis Absence of Raynaud's Confluence of plaques of morphea Generalized phenomenon and of internal organ (localized scleroderma) with morphea involvement. May be associated sparing of the hands and feet with a positive ANA Scleredema of Thickened skin typically involving Often seen in diabetes; absence of Bushke the upper back Raynaud's phenomenon or ANA Sclerodactyly in a patient with Absence of Raynaud's Diabetic cheiropathy diabetes. Has a positive "prayer phenomenon or ANA is associated sign" (inability to oppose the palms with poor glycemic control and Characteristics Two forms: limited systemic sclerosis (formerly termed CREST) or diffuse systemic sclerosis Cold-induced vasospasm without an associated underlying disease Autoimmune disease with autoantibodies produced against internal organs and cells. Among other disease characteristics, SLE patients have fatigue, arthralgias, and a positive ANA


Idiopathic pulmonary fibrosis

and phalanges) retinopathy Dermal inflammation with mucin Absence of Raynaud's deposition, may be associated with a phenomenon or ANA paraproteinemia Absence of Raynaud's phenomenon, GI, or Restrictive lung disease with musculoskeletal symptoms, as pathologic changes identical to well as an absence of both those seen in scleroderma scleroderma-specific serologies and nailfold capillary changes of scleroderma

able 2. Antinuclear Antibodies in Scleroderma Immunofluorescen t Pattern of Antigens Antinuclear Antibody Staining Nucleolar Nucleolar ribonucleoprotein s (nRNPs) RNA polymerases I, II, and III Clinical Pattern Approximat e Frequency Specificity (%) 50 23 Moderate High High for scleroderma and polymyositi s High

Diffuse or limited scleroderma Diffuse scleroderma

Nuclear proteins Sclerodermapolymyositi PM-1 (PM-Scl) and <5 s overlap Ku Fibrillarin (U3 snRNP) Centromere Centromeric (large proteins (CENP-A, speckles)* CENP-B, and CENP-C) DNA Diffuse (fine topoisomerase I speckles) (Scl-70) Diffuse scleroderma Usually in limited scleroderma (CREST syndrome) Diffuse scleroderma 12

50 (of patients with High CREST syndrome) 20-33 High

able 1. Classification of Scleroderma Form Syndrome Diffuse skin involvement Scleroderma (systemic Limited skin involvement (CREST syndrome) sclerosis) Overlapping features of mixed connective tissue disease

Localized scleroderma

Morphea: single or multiple plaques or generalized lesions Linear scleroderma

OA: Differential Diagnosis of Osteoarthritis Disease Characteristics Differentiate from secondary causes, such as those due to systemic, Primary osteoarthritis metabolic, and inflammatory disorders Secondary osteoarthritis due to iron overload, predominantly men aged 40 to 60. Osteoarthritis in the second Hemochromatosis and third metacarpophalangeal joints with hook-like osteophytes are characteristic Early-onset lumbar spondylosis. Calcification and ossification of the lumbar intervertebral disks. Involves large joints and spares hands and feet Short stature, onset during teens to age 30; mainly affects hips, knees, elbows, ankles, and shoulders; initial radiographs show epiphyseal fragmentation and flattening of the femoral, metatarsal, and metacarpal heads. In SED, x-ray films also show flattening and wedging of the thoracic and lumbar spine Chondrocalcinosis in knees, triangular fibrocartilage of the wrist and symphysis pubis; attacks of pseudogout; osteoarthritis in the second and third metacarpophalangeal joints 60% of patients have joint symptoms (knees, hips, shoulders, elbows) and spine disease is common. Soft-tissue swelling, widened distal phalanx tufts seen in hands without radiographic osteoarthritis. Initial xray films may show widened joint space followed later by typical Notes Primary and secondary causes may be managed differently

Rare in premenopausal women


Deficiency of homogentisic acid oxidase causing excretion of excess homogentisic acid in the urine. When the urine stands or is alkalinized it turns dark (alkaptonuria)

Multiple epiphyseal and spondyloepiphyseal dysplasia

Autosomal dominant pattern of inheritance, spine not involved in MED

Calcium pyrophosphate deposition disease

CPPD crystals may be identified in synovial fluid


features of osteoarthritis. Increased size of hands, feet, nose and jaw; increased sweating and moist, coarsened skin; glucose intolerance occurs in 50% Synovial (soft-tissue swelling), not bony, enlargement of the proximal interphalangeal and metacarpophalangeal joints; rarely involves the distal interphalangeal Rheumatoid arthritis joints; inflammatory signs (fatigue, prolonged stiffness); rheumatoid nodules; inflammatory synovial fluid; marginal erosions and juxta-articular osteopenia seen on radiographs Synovial and entheseal swelling present; may involve distal Psoriatic arthritis interphalangeal joints; dactylitis (sausage digits) present; erosions and periostitis seen on x-ray films Pain and tenderness over the greater trochanter; pain may radiate down Trochanteric bursitis lateral aspect of thigh; in absence of hip disease, hip range of motion is normal Anserine bursitis

Rheumatoid arthritis and osteoarthritis may coexist

Psoriasis is prevalent, so osteoarthritis and psoriasis often coexist May be a confounding cause of hip-region pain in patients with hip osteoarthritis; responds to local glucocorticoid injection

De Quervain's tenosynovitis

Meniscal tear


May be a confounding cause of Pain and tenderness over the knee pain in patients with knee anteromedial aspect of the lower leg osteoarthritis; responds to local below the joint line of the knee glucocorticoid injection Finkelstein test (pain increases Pain over the radial styloid and at the when thumb is placed inside fist base of the thumb due to and the wrist is passively inflammation of the abductor pollicis deviated ulnarly) usually longus and extensor pollicis brevis. positive. Can be treated with Provoked by pinching with thumb splinting or local glucocorticoid while moving wrist injection Pain usually occurs acutely and is related to trauma, although this may be minor in some cases. Associated Positive McMurray test (clicking with buckling and locking of the felt when knee is compressed knee. Localized tenderness over the and rotated during valgus or affected joint line. Effusions are often varus stress) present and are usually hemarthroses Joint pain out of proportion to Usually involves hip or knee. radiographic changes. Suspect in Diagnosis confirmed by MRI patients at increased risk with acute

or subacute onset hip or knee pain with normal or minimally abnormal (areas of osteopenia or osteosclerosis) x-ray findings. Risk factors: high-dose corticosteroids, ethanol abuse, systemic lupus erythematosus, hemoglobinopathies History of acute attacks of monoarthritis with joint erythema. Bony enlargement of joints may be present. Tophi typically present on examination. X-ray films show large erosions with overhanging edges and occasionally soft-tissue calcification of the tophus. If gout is suspected, fluid from the involved joint(s) should be examined for crystals Chronic tophaceous gout may involve the distal interphalangeal and proximal interphalangeal joints and first metatarsophalangeal joint causing angulation deformities and bony enlargement akin to osteoarthritis. Gout may develop in preexisting Heberden's and Bouchard's nodes Loss of pain sensation and proprioception ranges from mild to severe. Other associated conditions include meningomyelocele, leprosy, amyloidosis, and hereditary sensory neuropathies. Syringomyelia most often affects the shoulder followed by the elbow, wrist, and C-spine. The knee is most commonly affected in tabes dorsalis. The tarsal and tarsometatarsal joints are most often involved in diabetes


May have unusually severe osteoarthritis. Most commonly associated conditions are syringomyelia, diabetes, tabes dorsalis due to syphilis. May have massive swelling and sometimes erythema. With progression there is Neuropathic (Charcot) marked crepitus, instability, and joint palpable loose bodies. Pain is less severe than would be expected from appearance of the joint. X-ray films show large unusually shaped osteophytes, transverse fractures, osteolysis, and large loose bodies. Synovial fluid is noninflammatory or bloody Polyarticular finger interphalangeal joint involvement with Heberden's and Bouchard's nodes. Usually affects perimenopausal women. There is usually a familial predisposition. Patients often Nodal generalized develop osteoarthritis in the knee, osteoarthritis hip and spine. Typically patients develop discomfort then swelling of a single finger interphalangeal joint that lasts from weeks to months. Another interphalangeal joint is affected similarly several months later. Heberden's and Bouchard's

May be mistaken for gout attacks, but in gout acute swelling only lasts for 7-10 days. Distal interphalangeal joint involvement is more common than proximal interphalangeal

nodes subsequently develop but these are usually asymptomatic. Xray films show typical osteoarthritis changes Clinically resembles nodal generalized osteoarthritis except inflammatory signs and symptoms are more prominent. Proximal Inflammatory interphalangeal and distal (erosive) interphalangeal joints are more osteoarthritis equally affected. There is a tendency for ankylosis of the joints. X-ray films show subchondral erosive changes causing a "gull-wing" appearance An injury to a joint may predispose it to develop osteoarthritis. This is especially true for intra-articular fractures but is also true for fractures at distant sites that result in altered joint loading: femoral shaft (hip), scaphoid (wrist), tibia (ankle), humerus (shoulder). Meniscal tear, meniscectomy, and ligament injuries increase the risk for knee osteoarthritis. Occupational trauma or overuse may predispose to osteoarthritis in atypical sites. Osteoarthritis due to Jackhammer or pneumatic tool trauma or mechanical operators develop wrist, elbow, and factors shoulder osteoarthritis. Cotton workers develop distal interphalangeal osteoarthritis. Farmers have an increased incidence of hip osteoarthritis. Conditions that cause alteration in the shape of the joint predispose to osteoarthritis. For the hip this includes Legg-CalvePerthes disease, slipped capital femoral epiphysis, and congenital hip dislocation. Osteochondritis dissecans may lead to knee osteoarthritis Pain at base of the thumb. Bony enlargement results in a squared Osteoarthritis of the appearance. Crepitus and pain first carpometacarpal elicited with passive circular motion joint of the joint ("grind test"). Often coexists with osteoarthritis of the

May be a severe form of nodal generalized osteoarthritis, although there does not seem to be a familial tendency

Must distinguish from de Quervain's tenosynovitis

distal interphalangeal and proximal interphalangeal joints but it may be an isolated finding

boratory and Other Studies for Osteoarthritis of the Hand, Hip, and Knee Likelihood Likelihood Sensitivity Specificity Ratio Ratio Notes (%) (%) Positive Negative Component of the ACR classification criteria for hip osteoarthritis; the ESR must be used in ESR <20 mm/hr 58 64 1.6 0.65 conjunction with the other clinical and radiographic criteria to provide useful diagnostic information Radiographic Component of the ACR femoral or 89 90 8.9 0.12 classification criteria for acetabular hip osteoarthritis osteophytes Radiographic joint space Component of the ACR narrowing 91 60 2.3 0.15 classification criteria for (superior, axial, hip osteoarthritis or medial) Knee clinical and See ACR classification radiographic 91 86 6.5 0.10 criteria for knee criteria osteoarthritis Knee clinical and See ACR classification laboratory 92 75 3.7 0.11 criteria for knee criteria osteoarthritis Synovial fluid from osteoarthritis joints is usually clear, viscous, Synovial fluid and noninflammatory. leukocyte count Synovial fluid is usually 3 <2000/mm not obtained from the Unknown Unknown Unknown Unknown (only listed in finger joints unless there the knee is concern about criteria) infection or crystalinduced disease. Fluid is usually not obtained from hip joints unless Test

there is concern that the joint is infected and is usually aspirated by a radiologist. Synovial fluid analysis is not necessary to diagnose osteoarthritis, but it supports the diagnosis especially if it is uncertain

Step 2. Indentify the criteria that are present: 1. Symmetric, often progressive, proximal muscle weakness 2. Characteristic electromyographic triad Short-duration, small, low-amplitude polyphasic potentials Fibrillation potentials, seen even at rest Bizarre, high-frequency, repetitive discharges 3. Elevations of serum levels of muscle-associated enzymes Creatine kinase Aldolase Lactate dehydrogenase Transaminases (ALT and AST) 4. Evidence of chronic inflammation in muscle biopsy Necrosis of type I and type II muscle fibers Degeneration and regeneration of myofibers with variation in myofiber size Focal collections of interstitial or perivascular mononuclear cells 5. Characteristic rashes of dermatomyositis Scaly erythematous palpable eruptions over the metacarpophalangeal or interphalangeal joints, knees, elbows or medial malleoli (Gottron papules) Erythematous macules over the metacarpophalangeal or interphalangeal joints, knees, elbows or medial malleoli (Gottron sign) Periorbital or upper eyelid purplish discoloration (heliotrope rash)

Criteria for Classification of Polymyositis and Dermatomyositis Classification criteria* Symmetric proximal muscle weakness Muscle biopsy evidence of myositis Increase in serum muscle enzymes Characteristic electromyographic pattern Rash of dermatomyositis Differential Diagnosis of Dermatomyositis and Polymyositis Disease Polymyositis and dermatomyositis Characteristics Notes Truncal and bilateral muscle weakness is suggestive of polymyositis. Dermatomyositis has a characteristic rash of face and arms Weakness, stiffness, CK Screen all patients with TSH elevation Screen for hypercalcemia. Consider Fatigue, generalized muscle tests for hyperthyroidism, weakness hypercortisolism. Diabetes causes neuropathies and plexopathies Can cause weakness, pain, and elevated CK See table Drugs That Cause Myopathy and Myositis

Hypothyroidism Other endocrine disorders Drug- and alcoholinduced muscle disease

Inclusion body myositis

Has a combination of proximal and distal weakness and is asymmetric Sensory losses, focal deficits, tremor, fasciculations, atrophy, spasticity, cranial nerve and central abnormalities Viruses often cause pain and may cause frank myositis. HIV can cause myositis Periodic weakness, pain, and cramping with exercise and rhabdomyolysis

More common in older people than polymyositis and does not respond well to steroids and immunosuppressants. A properly prepared biopsy is essential to make the diagnosis (38 Neurology consultation is indicated to classify and diagnose causes of weakness Consider bacterial, Trichinella, and other parasitic infections Require specific tests and specific preparations of muscle tissue for diagnosis (29) See modules on Systemic Lupus Erythematosus, Scleroderma, Amyloidosis, Vasculitis, Sarcoidosis, and Rheumatoid Arthritis for guidance in diagnosing these diseases. When two or more connective-tissue diseases are present, the patient is said to have an overlap syndrome. When the combined disease is associated with high titers of anti-RNP antibodies, it is classifed as mixed connectivetissue disease

Other neurologic disease

Infections Metabolic muscle disorders

SLE, scleroderma, Sjogren's syndrome, May mimic myositis, have an amyloidosis, element of myositis, or coexist vasculitis, independently of polymyositis sarcoidosis, and rheumatoid arthritis

Profound generalized weakness Electromyographic studies indicate Critical illness following prolonged combinations of muscle and nerve neuromyopathy therapeutic paralysis in an dysfunction (39) intensive care unit Acute muscle necrosis with Caused by drugs, alcohol, trauma, Rhabdomyolysis myoglobinuria leading to renal seizures, and muscle disease. CPK is failure usually >10,000 CK = creatine kinase; CPK = creatine phosphokinase; HIV = human immunodeficiency virus; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus; TSH = thyrotropin.


Diagnostic Studies for Gout Test Serum uric acid (level >7 mg/dL) Synovial fluid MSU crystals on polarized microscopy MSU crystals in tophi Sensitivity (%) 55 Specificity (%) 93 Notes The higher and more prolonged the elevated uric acid level, the more likely that gout and tophi will develop (29) Sensitivity may be operator dependent (15) Sensitivity may be operator dependent (15) Diagnostic accuracy was measured in a primary care population (23) From the European League Against Rheumatism guideline (19) From the European League Against Rheumatism guideline (19) From the European League Against Rheumatism guideline (19)

84.4 30

100 100 64 24 71 48

ACR diagnostic criteria 80 Overlying erythema on 89 exam Unilateral first MTP 77 joint attack Symptom onset at night 90

Differential Diagnosis of Gout Disease Gout Characteristics Acute, rapid onset of painful monarticular arthritis, commonly in Notes Monosodium urate crystals typically seen in synovial fluid.

the great toe

More common in men than women; incidence rises with patient age

Rheumatoid arthritis (see module Rheumatoid Arthritis)

Septic arthritis

Cellulitis (see module Cellulitis and Soft Tissue Infections)

Reactive arthritis (as in Reiter's syndrome; see module Reactive Arthritis)

Fracture or trauma

Symmetrical polyarthritis that preferentially affects small joints of hands and feet, often with subcutaneous rheumatoid nodules. About 20% of these patients have subcutaneous rheumatoid nodules. Radiographic changes include softtissue swelling, diffuse joint-space narrowing (within a joint), marginal erosions of small joints, and symmetrical multiple joint involvement. Usually is osteopenic and without signs of repair (osteophytes) Fever, arthritis, great tenderness. Joint sepsis usually occurs in previously abnormal joints; up to half of patients have RA. Radiographs generally show presence of swelling and effusion; if not treated promptly, damage occurs, with diffuse jointspace narrowing Erythema and swelling of extremity that is very tender; is often febrile. Soft-tissue lymphatic drainage often abnormal. Radiography shows softtissue swelling but no joint changes due to the cellulitis Inflammatory oligoarthritis, weightbearing joints most often affected, may have tendon insertion inflammation. Swollen fingers and toes may resemble sausages (dactylitis). Extraarticular manifestations include conjunctivitis, urethritis, stomatitis, and psoriaform skin changes. Radiography may show soft-tissue swelling; the only acute bony change is dactylitis Tenderness is generally along the affected bony surface. History of trauma, except when stress fractures occur. Radiography should show disruption of the cortex where

Acute RA synovitis sometimes mimics gout. The greater the number of joints involved, the more likely that RA is the diagnosis. RA is much more likely than gout to involve the hands

Must be diagnosed early to avoid the long-term sequelae of joint destruction

Infection often due to Staphylococcus or Streptococcus infection. Joint exam may be difficult

Patient usually has had infection with an appropriate organism (Salmonella, Shigella, Yersinia, Campylobacter, or Chlamydia species or intravesicular bacilli CalmetteGuerin) within the 3 weeks before onset of initial attack

Radiography should demonstrate fracture (more than one view may be required)

fracture has occurred Bony enlargement, no acute signs of inflammation; patient may have acute exacerbation of joint symptoms, Osteoarthritis (see especially after use. Radiographs may module show focal joint-space loss within the Osteoarthritis) joint, bony repair with osteophytes, subchondral sclerosis. Osteoarthritis in fingers is sometimes associated with central erosions Joint distribution and appearance similar to reactive arthritis. Predilection for distal interphalangeal joints of fingers, often with nail changes. Radiographic findings similar to those seen with Reiter's Psoriatic arthritis syndrome, with soft-tissue swelling (see module Psoriatic and possible dactylitis. If the arthritis Arthritis) is long-standing, the patient may have diffuse joint-space narrowing; small joints of hands may also have central erosions. Some tendency to have subchondral sclerosis and other signs of bony repair Generally involves ankles, sometimes with erythema nodosum or Sarcoidosis (see subcutaneous nodules. Radiography module Sarcoidosis) may show subcutaneous nodules and soft-tissue swelling Multiple presentations, including osteoarthritis and gout-like inflammation, or may be asymptomatic. May resemble osteoarthritis or RA on radiography, but usually shows some evidence of Pseudogout (see bony repair (osteophytes or lack of module Calcium osteopenia). Cartilage calcification, Pyrophosphate especially in fibrocartilage of knee Dihydrate Deposition meniscus, symphysis pubis, glenoid Disease) and acetabular labrum, and triangular cartilage of wrist are pathognomonic for CPPD. Osteoarthritis in unusual places (wrist, elbow, metacarpophalangeal joints, or shoulder) without a history of trauma should suggest CPPD

Hallux valgus (bunion) is very common and is the most commonly affected joint (as in gout). Concomitant crystal disease (calcium pyrophosphate dihydrate deposition, hydroxyapatite) is increasingly common with age, particularly in knees

Patients with psoriasis often have elevated uric acid levels proportional to proliferative state of skin

Parotitis, uveitis, or lung involvement are features of sarcoidosis but not gout

Defined by finding CPPD crystals in synovial fluid and by chondrocalcinosis on radiography (most commonly in fibrocartilage)

aboratory and Other Studies for CPPD Disease Test Notes Look for chondrocalcinosis on radiographs of knees, anteroposterior pelvis, and hands; joint space narrowing, subchondral sclerosis, osteophytes of metacarpophalangeal joints on radiographs of hands; and joint space narrowing, subchondral sclerosis, osteophytes of the patellofemoral compartment out of proportion to the tibiofemoral compartments and geodes on radiographs of knees. Primary Joint x-rays hand osteoarthritis does not involve metacarpophalangeal joints except with coexisting CPPD disease, hemochromatosis, or both. Knee osteoarthritic changes on radiographs that involve a patellofemoral compartment out of proportion to other knee compartments are usually seen in osteoarthritis with CPPD disease. If radiographs of the shoulders, wrists, hips and knees are negative, more extensive screening is unlikely to be helpful Definitive diagnosis can be established with identification of weakly positively birefringent crystals, but sensitivity of this Synovial fluid analysis examination is not established. If monarticular arthritis is present, consider infectious arthritis as part of the differential diagnosis or as a coexisting disease process Marked leukocytosis may be seen in patients with septic CBC arthritis Baseline studies of renal function are helpful in choosing BUN/creatinine therapy, especially when use of NSAIDs is contemplated Useful in patients with suspected coexisting gout as suggested by negatively birefringent crystals on synovial fluid analysis. Serum uric acid Elevated uric acid level is not diagnostic of gout, and normal uric acid level does not exclude gout Serum iron studies (iron, total If signs of CHF, hepatic disease, male impotence, or skin iron-binding capacity, and pigmentation are noted, consider screening for ferritin) hemochromatosis Serum calcium and PTH To look for coexisting hyperparathyroidism Thyroid function tests (TSH, To look for associated hyperthyroidism and hypothyroidism free T4) Obtain if rheumatoid arthritis is suspected. The sensitivity ranges from 66%-80%. Anti-CCP has similar sensitivity for rheumatoid arthritis and may be present in rheumatoid Rheumatoid factor arthritis patients when rheumatoid factor is negative. Specificity is a problem because 30% of women > age 70 have positivity for rheumatoid factor. This test is not diagnostic for rheumatoid arthritis

ifferential Diagnosis of CPPD Disease Disease Characteristics Diseases that may underlie CPPD disease with other joint manifestations Notes


Hypomagnesemia Hypothyroidism

Osteoarthritis in the second and third metacarpophalangeal joints Secondary osteoarthritis due to with hook-like osteophytes are iron overload, predominantly men characteristic. Rare in aged 40 to 60 years premenopausal women. Can be seen in association with CPPD disease Magnesium deficiency 60% of patients have joint symptoms involving shoulders, elbows, hips, and knees; spine disease is common. Increased size of nose, jaw, hands, and feet; increased sweating and moist coarsened skin; glucose intolerance occurs in 50% of patients Early onset lumbar spondylosis. Sclera and ear cartilage may become blackened. Deficiency of homogentisic acid oxidase causing excretion of excess homogentisic acid in the urine. Urine turns dark (alkaptonuria) when the urine stands


Initial radiographs may show widened joint space followed by typical osteoarthritis features. Can be seen in association with CPPD disease


Calcification and ossification of the lumbar intervertebral disks involving large joints and sparing hands and feet. Can be seen in association with CPPD disease

Diseases that mimic or coexist with CPPD disease Radiographs often show large History of acute attacks of erosions with overhanging edges monoarthritis with joint erythema. and occasionally soft tissue Bony enlargement of joints may be calcification of tophi. If gout is present. Tophi typically present on suspected, fluid from the involved examination in patients with joint should be examined for disease greater than 5-10 years monourate sodium crystals. Gout and CPPD disease may coexist Usually presents with Synovial fluid analysis for crystals monarticular arthritis or in and cell count; Gram stain and patients with existing culture should be obtained in any


Septic arthritis

inflammatory arthritis who develop exacerbation of arthritis predominantly involving just one joint Symmetrical synovial, not bony, enlargement of the proximal interphalangeal and metacarpophalangeal joints with Rheumatoid arthritis rare involvement of distal interphalangeal joints. Inflammatory signs including prolonged morning stiffness History of acute attacks of monoarthritis in patient with Acute seronegative known underlying seronegative monarticular spondyloarthropathy, i.e., psoriatic arthritis arthritis, Reiter's disease, inflammatory bowel diseaseassociated arthritis CPPD = calcium pyrophosphate dihydrate.

patient with monarticular arthritis either at initial presentation or during the course of established CPPD disease Marginal erosions and juxtaarticular osteopenia seen on radiographs. It is rarer that rheumatoid arthritis and CPPD disease coexist compared with the coexistence of rheumatoid arthritis and osteoarthritis

Synovial fluid analysis for crystals; Gram stain and culture are negative in these patients

istory and Physical Examination Elements for CPPD Disease Category Element Notes Common to all types of CPPD disease and can involve the Joint pain and knee, wrist, shoulder, ankle, elbow, hand, and first History swelling metatarsophalangeal joint. Pain can be constant, unlike in osteoarthritis, in which pain during rest is rare History Morning stiffness Stiffness usually lasts for more than 30 minutes Fever can be seen in association with acute CPPD disease Physical exam Temperature but also can occur with infectious arthritis Either intermittent monoarthritis typically involving Joint exam for wrists or knees, or symmetrical arthritis involving Physical exam swelling and wrists, metacarpophalangeal joints, hips, or knees. Can inflammation also be seen in hand osteoarthritis that also involves metacarpophalangeal joints

SLU e 8. Commonly Abnormal Tests on Body Fluids in Systemic Lupus Erythematosus Test Abnormality Interpretation Normochromic anemia, CBC leukopenia (WBCs Active SLE 3 3,000/mm ,

ESR and CRP Urinalysis Coombs and reticulocyte count APTT, dRVVT Antinuclear antibody Anti-dsDNA antibody Anti-Sm antibody Anti-SS-A, anti-SS-B, and anti-RNP antibodies Anticardiolipin antibody Complement C3, C4, and CH50 Cryoglobulin BUN and serum creatinine Liver function tests CSF protein and cells Synovial fluid

thrombocytopenia) Elevated Active SLE Proteinuria, hematuria, Active lupus nephritis leukocyturia, cylindruria Positive, high High Strongly positive Strongly positive Positive Positive Positive Low Present Elevated Elevated Elevated WBCs 5,00010,000/mm3, normal glucose level WBCs 5,00010,000/mm3, normal glucose level, low complement, LE cells present Hemolytic anemia If confirmed with mixing test, lupus anticoagulant Positive in almost all patients during active disease; not specific for lupus Positive in two thirds to three quarters of patients during active disease, diagnostic of lupus Positive in one quarter to one third of patients; diagnostic of lupus Positive in one third of patients; nonspecific Antiphospholipid syndrome Lupus nephritis likely; also hemolytic anemia and cryoglobulinemia Active SLE Severe lupus nephritis, drug toxicity Drug toxicity (rarely, active SLE) Present in a minority of patients with CNS SLE Lupus arthritis

Pleural fluid, pericardial fluid

Lupus serositis

Differential Diagnosis of Psoriatic Arthritis Disease Rheumatoid arthritis Characteristics Notes Symmetric small-joint inflammatory Psoriatic arthritis tends to be arthritis, affecting women three times asymmetric and affects both

more than men Proximal joint involvement Very tender joints Dactylitis uncommon Rheumatoid nodules present in 20% of patients Rheumatoid factor positive in 80% of patients No axial involvement Osteoarthritis Gout Noninflammatory arthritis Usually toes (podagra), often selflimited Mainly spinal involvement that tends to be symmetric. Overall spondyloarthropathy more severe with more marked limitation of movement than in psoriatic arthritis Absence of psoriasis Similar clinical presentation with asymmetric, often large joint, arthritis with spondyloarthropathy. The rash of Reiter's/reactive arthritis occurs primarily on palms and soles (keratodermia blenorrhagica) and not on the extensor surfaces as with psoriasis

genders equally Distal joint involvement Not as tender joints Dactylitis common No rheumatoid nodules Rheumatoid factor in only 15% of patients, usually low titer Axial involvement Psoriatic arthritis is inflammatory Psoriatic arthritis involves many joints. Usually chronic

Ankylosing spondylitis

Axial involvement tends to be asymmetric in psoriatic arthritis

Reiter's/reactive arthritis

Urethritis less common in psoriatic arthritis Eye involvement in Reiter's/reactive arthritis includes conjunctivitis which is rare in psoriatic arthritis

ifferential Diagnosis of Ankylosing Spondylitis Disease Common Characteristics Notes

Nonspecific musculoskeletal back pain

Most (approximately 80%) individuals will experience at Usually localized to low back, least one episode of back pain tends to worsen on physical during their lifetimes; most of activity, and is alleviated with rest. these episodes, however, are May radiate into buttocks and/or self-limited, can be related to thigh. Patient may have specific activity or exertion, paravertebral muscle spasm and and can be recurrent. Acute or tenderness, with loss of the recurrent and sometimes normal lumbar lordosis during the chronic low-back pain is back pain episode, but the usually localized to the low neurologic exam is normal back, does not radiate, and responds to conservative therapy (89)

Pain is often acute, radicular, severe, and exacerbated by physical activity, trauma, or exercise; it abates when the patient is resting. Look for paravertebral muscle spasm and Degenerative disk disease tenderness, and signs of radicular neuropathy. Characteristic radiographic changes are evident at disco-vertebral junctions and apophyseal joints with adjacent osteophytes Usually seen in patients with degenerative disk disease and in older age groups. Varying degrees of pain, worsened by standing erect, walking downhill, or lying on the back, and eased on forward stooping or lying on the side with Spinal stenosis the hip flexed. There is pseudoclaudication often involving the L4 nerve root. Neurologic findings are variable. Elderly patients with spinal stenosis may resemble individuals with ankylosing spondylitis, as far as posture is concerned Compression fractures that may or may not be symptomatic. May involve spine or pelvis. Pain from acute spinal fractures can be severe, and movement may Osteoporotic stress exacerbate it. The posture and fracture stiffness of elderly patients with kyphosis due to multiple compression fractures of the vertebral bodies resembles that of ankylosing spondylitis Less Common Includes diskitis, osteomyelitis, and epidural and paravertebral abscesses. Unremitting or progressive pain at rest. Infections Sometimes there is tenderness over spinous process at involved level. Look for history of diabetes, drug abuse, immunosuppression, previous spinal surgery. Variable

Intervertebral disk prolapse can best be visualized with CT or MRI (89)

Imaging with CT or MRI supports diagnosis (89)

Difficult to differentiate new from former stress fractures on imaging studies

Radiographs may show destructive lesion. MRI is best imaging modality (89)

Myeloma and other neoplasms

Other spondyloarthropathies

Referred pain from viscera

neurologic findings. These infections also include localized infections with brucellosis and mycobacteria, which may result in spinal fusion, usually localized, or sacroiliac joint changes Similar presentation to that of spinal infections The chronic back pain and stiffness due to sacroiliitis/spondylitis is similar to that of ankylosing spondylitis. Look for history of rash, urethritis, colitis, and signs of psoriasis or skin findings seen in reactive arthritis Usually accompanied by systemic and abdominal findings. Etiologies include: aortic dissection or aneurysm, tumor, pancreatitis, peptic ulcer disease, cholecystitis, pyelonephritis, perinephric abscess, retroperitoneal fibrosis, nephrolithiasis, pelvic infection, endometriosis, prostatitis, and herpes zoster


Evaluation similar to that of ankylosing spondylitis with additional studies as dictated by systemic picture (7; 12; 20; 81; 82)

Evaluation dependent upon likely etiology (89)

Severe degenerative and hyperostotic changes of the Usually seen in elderly people and sacroiliac joints (joint space characterized by hyperostosis narrowing, subchondral bone Ankylosing hyperostosis affecting the anterior longitudinal sclerosis, and capsular (Forestier's disease or ligament and skeletal attachments ossification); may resemble the Diffuse Idiopathic Skeletal of tendons and ligaments. The sacroiliitis of ankylosing Hyperostosis [DISH]) posture and spinal stiffness may spondylitis on anteroposterior resemble ankylosing spondylitis view on radiography (54; 55; (180; 181) 56). It shows no association with HLA-B27 Least Common Confirmed by means of Spondylolysis/ May or may not be present in radiography (in particular spondylolisthesis patients with low-back pain oblique lateral view of the spine) May or may not be symptomatic. May result in spinal and/or Bony lesions can cause nerve root sacroiliac joint changes that Paget's disease impingement and radicular signs can resemble and symptoms spondyloarthropathies Osteitis condensans ilii Seen primarily in young A self-limited condition with no

multiparous women, often association with HLA-B27 and symptomatic, characterized by no evidence to indicate that it radiographic evidence of a is a form of ankylosing triangular area of dense sclerotic spondylitis (57) bone in the iliac bones of the pelvis adjacent to the lower half of the sacroiliac joints, which themselves are normal Inflammatory condition that can cause spinal and/or SAPHO (Synovitis, Acne, Syndrome consisting of Synovitis, sacroiliac joint changes Pustulosis, Hyperostosis, Acne, Pustulosis, Hyperostosis, resembling and Osteitis) syndrome and Osteitis spondyloarthropathies (56; 182) Paraplegia or In long-standing quadriplegia Neurologic findings predominate, quadriplegia causing or paraplegia, changes may depending upon level of sacroiliac and spinal resemble those of sacroiliitis or involvement changes spondylitis (58; 59) A disorder of the anterior section of the thoracic vertebral bodies in children, with resultant thoracic Can cause spinal changes that Scheuermann's disease kyphosis that may be confused may resemble those of the (juvenile kyphosis) with ankylosing spondylitis. It is spondyloarthropathies (57) osteochondrosis of the secondary ossification centers of the vertebral bodies Metabolic diseases (including chondrocalcinosis, osteofluorosis, axial In elderly patients with osteomalacia, ochronosis Parkinson's syndrome, posture and and stiffness resemble what is hyperparathyroidism) seen in ankylosing spondylitis and rare disorders (such as congenital kyphoscoliosis)

Differential Diagnosis of Reactive Arthritis Disease Characteristics Septic arthritis (including possible Usually monoarthritis gonococcal septic arthritis) Gout, pseudogout Asymmetric oligoarthritis in

Notes Synovial fluid culture positive for certain bacteria Crystals may be found on synovial fluid

older patients

Rheumatoid arthritis

Symmetric polyarthritis

microscopy Rheumatoid arthritis is usually a symmetric polyarthritis of the small joints in the hands and feet; however, rheumatoid arthritis may begin as oligoarthritis, and an accurate diagnosis may be revealed only by observation over time Typical radiographic changes of sacroiliitis

Ankylosing spondylitis

Back pain with inflammation in 1 or both sacroiliac joints presented as tenderness and pain with motion

Psoriasis and nail changes may emerge Psoriasis and typical nail years after the joint disease, and accurate Psoriatic arthritis changes may be found diagnosis may be revealed only by observation over time (29) Rheumatic fever Migrating polyarthritis Recent tonsillitis or pharyngitis Copyright 2013 by the American College of Physicians. All rights reserved.