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InternalMed_Harrison. For FMF patients who do not respond to colchicine or cannot tolerate therapeutic doses, injectable IL-1 inhibitors appear to be effective in preventing the acute attacks. In a small randomized placebo-controlled trial, weekly subcutaneous rilonacept, a recombinant IL-1 receptor fusion protein, significantly reduced the frequency of attacks. There is also substantial anecdotal experience with daily subcutaneous anakinra, a recombinant IL-1 receptor antagonist, in preventing the acute attacks of FMF, and in some cases reducing established amyloid deposits. Canakinumab, a monoclonal antibody to IL-1β, and tumor necrosis factor (TNF) inhibitors may also have a role in the treatment of colchicine-unresponsive or intolerant patients. Bone marrow transplantation has been suggested for refractory FMF, but the risk-benefit ratio is currently regarded as unacceptable.


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InternalMed_Harrison. Within 5 years of the discovery of the FMF gene, three additional genes causing five other hereditary recurrent fever syndromes were identified, catalyzing a paradigm shift in diagnosis and treatment of these disorders.


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InternalMed_Harrison. TRAPS is caused by dominantly inherited mutations in the extracellular domains of the 55-kDa TNF receptor (TNFR1, p55). Although originallydescribedinalargeIrishfamily(andhencethenamefamilial Hibernian fever), TRAPS has a broad ethnic distribution. TRAPS episodes often begin in childhood. The duration of attacks ranges from 1–2 days to as long as several weeks, and in severe cases symptoms maybe nearly continuous. Inadditionto peritoneal, pleural,and synovial attacks similar to FMF, TRAPS patients frequently have ocular inflammation (most often conjunctivitis and/or periorbital edema), and a distinctive migratory myalgia with overlying painful erythema may be present. TRAPS patients generally respond better to glucocorticoids than to prophylactic colchicine. Untreated, about 15% develop amyloidosis. The diagnosis of TRAPS is based on the demonstration of TNFRSF1A mutations in the presence of characteristic symptoms. Two particular variants, R92Q and P46L, are common in certain


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InternalMed_Harrison. amyloidosis. The diagnosis of TRAPS is based on the demonstration of TNFRSF1A mutations in the presence of characteristic symptoms. Two particular variants, R92Q and P46L, are common in certain populations and may act more as functional polymorphisms than as disease-causing mutations. In contrast, pathogenic TNFRSF1A mutations, including a number of substitutions at highly conserved cysteine residues, are associated with intracellular TNFR1 misfolding, aggregation, and retention, with consequent ligand-independent kinase activation,mitochondrialreactiveoxygenspeciesproduction,andproinflammatorycytokinerelease.Etanercept,aTNFinhibitor,ameliorates TRAPS attacks, but the long-term experience with this agent has been less favorable. Perhaps because of the ligand-independent signaling abnormalities in TRAPS, IL-1 inhibition has been beneficial in a large percentage of the patients in whom it has been used. Monoclonal antiTNFantibodiesshouldbeavoided,becausetheymayexacerbateTRAPS attacks.


InternalMed_Harrison

InternalMed_Harrison. HIDS is a recessively inherited recurrent fever syndrome found primarily in individuals of northern European ancestry. It is caused by mutations in mevalonate kinase (MVK), encoding an enzyme involved in the synthesis of cholesterol and nonsterol isoprenoids. Attacks usually begin in infancy and last 3–5 days. Clinically distinctive features include painful cervical adenopathy, a diffuse maculopapular rash sometimes affecting the palms and soles, and aphthous ulcers; pleurisy is rare, as is amyloidosis. Although originally defined by the persistent elevation of serum IgD, disease activity is not related to IgD levels, and some patients with FMF or TRAPS may have modestly increased serum IgD. Moreover, occasional patients with MVK mutations and recurrent fever have normal IgD levels. For these reasons, some have proposed renaming this disorder mevalonate kinase deficiency (MKD). All patients with mutations have markedly elevated urinary mevalonatelevels duringtheir febrileattacks,


InternalMed_Harrison

InternalMed_Harrison. these reasons, some have proposed renaming this disorder mevalonate kinase deficiency (MKD). All patients with mutations have markedly elevated urinary mevalonatelevels duringtheir febrileattacks, althoughtheinflammatorymanifestations are likely to be due to a deficiency of isoprenoids rather than an excess of mevalonate. There is currently no established treatment for HIDS/MKD, although intermittent or continuous IL-1 inhibition and TNF inhibitors have been effective in small series.


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InternalMed_Harrison. THE CrYOPYrINOPaTHIES, Or CrYOPYrIN-aSSOCIaTED PErIODIC SYNDrOMES (CaPS)


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InternalMed_Harrison. Three hereditary febrile syndromes, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), are all caused by mutations in NLRP3 (formerly known as CIAS1), the gene encoding cryopyrin (or NLRP3), and represent a clinical spectrum of disease. FCASpatientsdevelopchills,fever,headache,arthralgia,conjunctivitis, and an urticaria-like rash in response to generalized cold exposure. In MWS, an urticarial rash is noted, but it is not usually induced by cold; MWSpatientsalsodevelopfevers,abdominalpain,limbpain,arthritis, conjunctivitis, and, over time, sensorineural hearing loss. NOMID is the most severe of the three disorders, with chronic aseptic meningitis, a characteristic arthropathy, and rash. Like the FMF protein, pyrin, cryopyrin has an N-terminal PYRIN domain. Cryopyrin regulates IL-1βproductionthroughtheformationofamacromolecularcomplex 2215 termed the inflammasome. Peripheral blood leukocytes from


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InternalMed_Harrison. protein, pyrin, cryopyrin has an N-terminal PYRIN domain. Cryopyrin regulates IL-1βproductionthroughtheformationofamacromolecularcomplex 2215 termed the inflammasome. Peripheral blood leukocytes from patients with FCAS, MWS, and NOMID release increased amounts of IL-1β upon in vitro stimulation, relative to healthy controls. Macrophages from cryopyrin-deficient mice exhibit decreased IL-1β production in response to certain gram-positive bacteria, bacterial RNA, and mono-sodium urate crystals. Patients with all three cryopyrinopathies show a dramatic response to injections of IL-1 inhibitors. Approximately one-third of patients with clinical manifestations of NOMID do not have germline mutations in NLRP3, but have been found to be mosaic for somatic NLRP3 mutations. Such patients also respond dramatically to IL-1 inhibition. Similarly, somatic mosaicism in NLRP3 has been found in Schnitzler’s syndrome, which presents in middle age with recurrent fever, urticarial rash, elevated acute


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InternalMed_Harrison. dramatically to IL-1 inhibition. Similarly, somatic mosaicism in NLRP3 has been found in Schnitzler’s syndrome, which presents in middle age with recurrent fever, urticarial rash, elevated acute phase reactants, monoclonal IgM gammopathy, and abnormal bone remodeling. IL-1 inhibition is the treatment of choice for Schnitzler’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. There are a number of other Mendelian autoinflammatory diseases in which recurrent fevers are not a prominent clinical sign but that involve abnormalities of innate immunity. The syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) is a dominantly inherited disorder that presents with episodes of sterile pyogenic monoarthritis often induced by trauma, severe pyoderma gangrenosum, and severe cystic acne, usually beginning in puberty. It is caused by mutations in PSTPIP1, which encodes a pyrin-binding protein, and the arthritic manifestations often respond to IL-1 inhibition. Patients with the recessively inherited deficiency of the IL-1 receptor antagonist (DIRA) present with a generalized pustular rash and multifocal sterile osteomyelitis, and show dramatic clinical responses to anakinra, the recombinant form of the protein they lack. IL-36 is another member of the IL-1 family of cytokines that is regulated by an endogenous receptor antagonist. The recessively


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InternalMed_Harrison. responses to anakinra, the recombinant form of the protein they lack. IL-36 is another member of the IL-1 family of cytokines that is regulated by an endogenous receptor antagonist. The recessively inherited deficiency of the IL-36 receptor antagonist (DITRA) presents with episodes of generalized pustular psoriasis and dramatic systemic inflammation.


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InternalMed_Harrison. Whereas PAPA, DIRA, and DITRA all involve mutations in IL-1related molecules, other autoinflammatory diseases are caused by mutations in other components of innate immunity. Blau’s syndrome is caused by mutations in CARD15 (also known as NOD2), which regulates nuclear factor-κB activation. Blau’s syndrome is characterized by granulomatous dermatitis, uveitis, and arthritis; distinct CARD15 variants predispose to Crohn’s disease. Recessive mutations in one or more components of the proteasome lead to excessive interferon signaling and the syndrome of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), a severe form of generalized panniculitis. De novo gain-of-function mutations in TMEM173, encoding the stimulator of interferon genes (STING), cause severe vasculopathy and pulmonary fibrosis. Recessive loss-of-function mutations in CERCR1, encoding adenosine deaminase 2 (ADA2),causeavasculopathythatcanmanifestas livedoidrash,earlyonset lacunar


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InternalMed_Harrison. severe vasculopathy and pulmonary fibrosis. Recessive loss-of-function mutations in CERCR1, encoding adenosine deaminase 2 (ADA2),causeavasculopathythatcanmanifestas livedoidrash,earlyonset lacunar strokes, or polyarteritis nodosa.


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InternalMed_Harrison. Finally, it should be noted that a number of common, genetically complex disorders are now sometimes considered autoinflammatory, because of evidence that components of the innate immune system, such as the inflammasome, may play a role in the pathogenesis. Two prominent examples are gout and atherosclerosis. Large clinical trials of IL-1 inhibitors have been initiated in both conditions. 2216 approach to articular and Musculoskeletal Disorders John J. Cush Musculoskeletalcomplaintsaccountfor>315millionoutpatientvisitsperyearandover20%ofalloutpatientvisitsintheUnited393 SeC tIOn 3


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InternalMed_Harrison. States. The Centers for Disease Control and Prevention estimate that 22.7% (52.5 million) of the U.S. population has physician-diagnosed arthritis and 22 million have significant functional limitation. While many patients will have self-limited conditions requiring minimal evaluation and only symptomatic therapy and reassurance, specific musculoskeletal presentations or their persistence may herald a more serious condition that requires further evaluation or laboratory testing to establish a diagnosis. The goal of the musculoskeletal evaluation is to formulate a differential diagnosis that leads to an accurate diagnosis and timely therapy, while avoiding excessive diagnostic testing and unnecessary treatment (Table 393-1). There are several urgent conditions that must be diagnosed promptly to avoid significant morbid or mortal sequelae. These “red flag” diagnoses include septic arthritis, acute crystal-induced arthritis (e.g., gout), and fracture. Each may be suspected by its acute


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InternalMed_Harrison. to avoid significant morbid or mortal sequelae. These “red flag” diagnoses include septic arthritis, acute crystal-induced arthritis (e.g., gout), and fracture. Each may be suspected by its acute onset and monarticular or focal musculoskeletal pain (see below).


InternalMed_Harrison

InternalMed_Harrison. Despite well-known links between certain disorders and laboratory testing, the majority of individuals with musculoskeletal complaints can be diagnosed with a thorough history and a comprehensive physical and musculoskeletal examination. The initial encounter should determine whether the musculoskeletal complaint signals a red flag condition (septic arthritis, gout, or fracture) or not. The evaluation should proceed to ascertain if the complaint is (1) articular or non-articular in origin, (2) inflammatory or noninflammatory in nature, (3) acute or chronic in duration, and (4) localized (monarticular) or widespread (polyarticular) in distribution.


InternalMed_Harrison

InternalMed_Harrison. With such an approach and an understanding of the pathophysiologic processes, the musculoskeletal complaint or presentation can be characterized (e.g., acute inflammatory monarthritis or a chronic noninflammatory, nonarticular widespread pain) to narrow the diagnostic possibilities. A diagnosis can be made in the vast majority of individuals. However, some patients will not fit immediately into an established diagnostic category. Many musculoskeletal disorders resemble each other at the outset, andsome may take weeks or months (but not years) to evolve into a recognizable diagnostic entity. This consideration should temper the desire to establish a definitive diagnosis at the first encounter. Timely provision of therapy Avoidance of unnecessary diagnostic testing Identification of acute, focal/monarticular “red flag” conditions Determination of chronology (acute vs chronic) Determination of the nature of the pathologic process (inflammatory vs noninflammatory)


InternalMed_Harrison

InternalMed_Harrison. Determination of chronology (acute vs chronic) Determination of the nature of the pathologic process (inflammatory vs noninflammatory) Determination of the extent of involvement (monarticular, polyarticular, focal, widespread) Anatomic localization of complaint (articular vs nonarticular) Consider the most common disorders first


InternalMed_Harrison

InternalMed_Harrison. The musculoskeletal evaluation must discriminate the anatomic origin(s) of the patient’s complaint. For example, ankle pain can result from a variety of pathologic conditions involving disparate anatomic structures, including gonococcal arthritis, calcaneal fracture, Achilles tendinitis, plantar fasciitis, cellulitis, and peripheral or entrapment neuropathy. Distinguishing between articular and nonarticular conditions requires a careful and detailed examination. Articular structures include the synovium, synovial fluid, articular cartilage, intraarticular ligaments, joint capsule, and juxtaarticular bone. Nonarticular (or periarticular) structures, such as supportive extraarticular ligaments, tendons, bursae, muscle, fascia, bone, nerve, and overlying skin, may be involved in the pathologic process. Although musculoskeletal complaints are often ascribed to the joints, nonarticular disorders more frequently underlie such complaints. Distinguishing between these potential sources of


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InternalMed_Harrison. process. Although musculoskeletal complaints are often ascribed to the joints, nonarticular disorders more frequently underlie such complaints. Distinguishing between these potential sources of pain may be challenging to the unskilled examiner. Articular disorders may be characterized by deep or diffuse pain, pain or limited range of motion on active and passive movement, and swelling (caused by synovial proliferation, effusion, or bony enlargement), crepitation, instability, “locking,” or deformity. By contrast, nonarticular disorders tend to be painful on active, but not passive (or assisted), range of motion. Periarticular conditions often demonstrate point orfocaltenderness in regionsadjacentto articular structures,are elicited with a specific movement or position, and have physical findings remote from the joint capsule. Moreover, nonarticular disorders seldom demonstrate swelling, crepitus, instability, or deformity of the joint itself.


InternalMed_Harrison

InternalMed_Harrison. In the course of a musculoskeletal evaluation, the examiner should determinethenatureoftheunderlyingpathologicprocessandwhether inflammatory or noninflammatory findings exist. Inflammatory disorders may be infectious (Neisseria gonorrhoeae or Mycobacterium tuberculosis), crystal-induced (gout, pseudogout), immune-related (rheumatoidarthritis[RA],systemiclupuserythematosus[SLE]),reactive (rheumatic fever, reactive arthritis), or idiopathic. Inflammatory disorders may be identified by any of the four cardinal signs of inflammation (erythema, warmth, pain, or swelling), systemic symptoms (fatigue, fever, rash, weight loss), or laboratory evidence of inflammation (elevated erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], thrombocytosis, anemia of chronic disease, or hypoalbuminemia). Articular stiffness commonly accompanies chronic musculoskeletaldisorders. Thedurationofstiffnessmaybeprolonged (hours) with inflammatory disorders (such as RA or polymyalgia rheumatica) and


InternalMed_Harrison

InternalMed_Harrison. Articular stiffness commonly accompanies chronic musculoskeletaldisorders. Thedurationofstiffnessmaybeprolonged (hours) with inflammatory disorders (such as RA or polymyalgia rheumatica) and may improve with activity. By contrast, intermittent stiffness (also known as gel phenomenon) is typical of noninflammatory conditions (such as osteoarthritis [OA]), shorter in duration (<60 min), and exacerbated by activity. Fatigue may accompany inflammation (as seen in RA and polymyalgia rheumatica) but may also be a consequence of fibromyalgia (a noninflammatory disorder), chronic pain, poor sleep, depression, anemia, cardiac failure, endocrinopathy, or malnutrition. Noninflammatory disorders may be related to trauma (rotator cuff tear), repetitive use (bursitis, tendinitis), degeneration or ineffective repair (OA), neoplasm (pigmented villonodular synovitis), or pain amplification (fibromyalgia). Noninflammatory disorders are often characterized by pain without synovial swelling or warmth,


InternalMed_Harrison

InternalMed_Harrison. repair (OA), neoplasm (pigmented villonodular synovitis), or pain amplification (fibromyalgia). Noninflammatory disorders are often characterized by pain without synovial swelling or warmth, absence of inflammatory or systemic features, daytime gel phenomena rather than morning stiffness, and normal (for age) or negative laboratory investigations.


InternalMed_Harrison

InternalMed_Harrison. Identification of the nature of the underlying process and the site of the complaint will enable the examiner to characterize the musculoskeletal presentation (e.g., acute inflammatory monarthritis, chronic noninflammatory, nonarticular widespread pain), narrow the diagnostic considerations, and assess the need for immediate diagnostic or Initial rheumatic history and physical exam to determine 1. Is it articular? 2. Is it acute or chronic? 3. Is inflammation present? 4. How many/which joints are involved?


InternalMed_Harrison

InternalMed_Harrison. Is it articular?Nonarticular condition Consider • Trauma/fracture • Fibromyalgia • Polymyalgia rheumatica • Bursitis • Tendinitis Is complaint > 6 wk? Acute Chronic Consider • Acute arthritis• Infectious arthritis • Gout • Pseudogout • Reactive arthritis • Initial presentation of chronic arthritis Chronic inflammatory arthritis How many joints involved? Are DIP, CMC1, hip or knee joints involved? Chronic inflammatory mono/oligoarthritis Consider • Indolent infection • Psoriatic arthritis • Reactive arthritis • Pauciarticular JIA Chronic inflammatory polyarthritis Is involvement symmetric? Are PIP, MCP, or MTP joints involved? Consider • Psoriatic arthritis • Reactive arthritis Rheumatoid arthritis Osteoarthritis No Yes Yes No No Yes No Yes No Yes No Yes >31– 3 Unlikely to be osteoarthritis Consider • Osteonecrosis • Charcot arthritis Chronic noninflammatory arthritis Unlikely to be rheumatoid arthritis Consider • SLE • Scleroderma • Polymyositis FIGUrE 393-1 Algorithm for the


InternalMed_Harrison

InternalMed_Harrison. Consider • Osteonecrosis • Charcot arthritis Chronic noninflammatory arthritis Unlikely to be rheumatoid arthritis Consider • SLE • Scleroderma • Polymyositis FIGUrE 393-1 Algorithm for the diagnosis of musculoskeletal complaints. Anapproachtoformulatingadifferentialdiagnosis(showninitalics).CMC,carpometacarpal;CRP,C-reactiveprotein;DIP,distalinterphalangeal;ESR,erythrocytesedimentationrate;JIA,juvenileidiopathicarthritis;MCP,metacarpophalangeal;MTP,metatarsophalangeal;PIP,proximalinterphalangeal;PMR,polymyalgiarheumatica;SLE,systemiclupuserythematosus.


InternalMed_Harrison

InternalMed_Harrison. Is inflammation present? 1. Is there prolonged morning stiffness? 2. Is there soft tissue swelling? 3. Are there systemic symptoms? 4. Is the ESR or CRP elevated? Approach to Articular and Musculoskeletal Disorders therapeutic intervention or for continued observation. Figure 393-1 presents an algorithmic approach to the evaluation of patients with musculoskeletal complaints. This approach relies on clinical and historic features, rather than laboratory testing, to diagnose many common rheumatic disorders.


InternalMed_Harrison

InternalMed_Harrison. Asimpler,alternativeapproachwouldconsiderthemostcommonly encountered complaints first, based on frequency in younger versus older populations. The most prevalent causes of musculoskeletal complaints are shown in Fig. 393-2. Because trauma, fracture, overuse syndromes, and fibromyalgia are among the most common causes of joint pain, these should be considered during the initial encounter. If these possibilities are excluded, other frequently occurring disorders should be considered according to the patient’s age. Hence, those younger than 60 years are commonly affected by repetitive use/ strain disorders, gout (men only), RA, spondyloarthritis, and uncommonly, infectious arthritis. Patients over age 60 years are frequently affected by OA, crystal (gout and pseudogout) arthritis, polymyalgia rheumatica, osteoporotic fracture, and uncommonly, septic arthritis.


InternalMed_Harrison

InternalMed_Harrison. Trauma/fracture Low back pain Age <60 years Age >60 years Repetitive strain injury (Tendinitis, Bursitis) Osteoarthritis Gout (males only) Gout Pseudogout Rheumatoid arthritis Polymyalgia rheumatica Osteoporotic fracture Infectious arthritis (GC, viral, bacterial, Lyme) Septic arthritis (bacterial) Fibromyalgia Orthopedic evaluation FREQUENCY More Less Psoriatic, Reactive arthritis, IBD arthritis FIGUrE 393-2 Algorithm for consideration of the most common musculoskeletal conditions. GC, gonococcal; IBD, inflammatory bowel disease. These conditions are between 10 and 100 times more prevalent than other serious autoimmune conditions, such as SLE, scleroderma, polymyositis, and vasculitis.


InternalMed_Harrison

InternalMed_Harrison. Additional historic features may reveal important clues to the diagnosis. Aspects of the patient profile, complaint chronology, extent of joint involvement, and precipitating factors can provide important information. Certain diagnoses are more frequent in different age groups. SLE and reactive arthritis occur more frequently in the young, whereas fibromyalgia and RA are frequent in middle age, and OA and polymyalgia rheumatica are more prevalent among the elderly. Diagnostic clustering is also evident when sex and race are considered. Gout, spondyloarthritis, and ankylosing spondylitis are more common in men, whereas RA, fibromyalgia, and lupus are more frequent in women. Racial predilections may be evident. Thus, polymyalgia rheumatica, giant cell arteritis, and granulomatosis with polyangiitis (GPA; formerly called Wegener’s granulomatosis) commonly affect whites, whereas sarcoidosis and SLE more commonly affect African Americans. Familial aggregation is most common with ankylosing


InternalMed_Harrison

InternalMed_Harrison. (GPA; formerly called Wegener’s granulomatosis) commonly affect whites, whereas sarcoidosis and SLE more commonly affect African Americans. Familial aggregation is most common with ankylosing spondylitis, gout, and Heberden’s nodes of OA.


InternalMed_Harrison

InternalMed_Harrison. The chronology of the complaint is an important diagnostic feature and can be divided into the onset, evolution, and duration. The onset of disorders such as septic arthritis or gout tends to be abrupt, whereas OA, RA, and fibromyalgia may have more indolent presentations. The patients’ complaints may evolve differently and be classified as chronic (OA), intermittent (crystal or Lyme arthritis), migratory (rheumatic fever, gonococcal or viral arthritis), or additive (RA, psoriatic arthritis). Musculoskeletal disorders are typically classified as acute or chronic based on a symptom duration that is either less than or greater than 6 weeks, respectively. Acute arthropathies tend to be infectious, crystal-induced, or reactive. Chronic conditions include noninflammatory or immunologic arthritides (e.g., OA, RA) and nonarticular disorders (e.g., fibromyalgia).


InternalMed_Harrison

InternalMed_Harrison. The extent or distribution of articular involvement is often informative. Articular disorders are classified based on the number of joints involved, as either monarticular (one joint), oligoarticular or pauciarticular (two or three joints), or polyarticular (four or more joints). Although crystal and infectious arthritis are often mono-or oligoarticular, OA and RA are polyarticular disorders. Nonarticular disorders may be classified as either focal or widespread. Complaints secondary to tendinitis or carpal tunnel syndrome are typically focal, whereas weakness and myalgia, caused by polymyositis or fibromyalgia, are more widespread in their presentation. Joint involvement in RA tends to be symmetric and polyarticular. By contrast, spondyloarthritis, reactive arthritis, gout, and sarcoid are often asymmetric and oligoarticular. OA and psoriatic arthritis may be either symmetric or asymmetric and oligo-or polyarticular. The upper extremities are frequently involved inRAandOA, whereas


InternalMed_Harrison

InternalMed_Harrison. are often asymmetric and oligoarticular. OA and psoriatic arthritis may be either symmetric or asymmetric and oligo-or polyarticular. The upper extremities are frequently involved inRAandOA, whereas lower extremityarthritis is characteristic of reactive arthritis and gout at their onset. Involvement of the axial skeleton is common in OA and ankylosing spondylitis but is infrequent in RA, with the notable exception of the cervical spine.


InternalMed_Harrison

InternalMed_Harrison. The clinical history should also identify precipitating events, such as trauma (osteonecrosis, meniscal tear), drug administration (Table 393-2), antecedent or intercurrent infection (rheumatic fever, reactive arthritis, hepatitis), or illnesses that may have contributed to the patient’s complaint. Certain comorbidities may have musculoskeletal consequences. This is especially so for diabetes mellitus (carpal tunnel syndrome), renal insufficiency (gout), depression or insomnia (fibromyalgia), myeloma (low back pain), cancer (myositis), and osteoporosis (fracture) or when using certain drugs such as glucocorticoids (osteonecrosis, septic arthritis) and diuretics or chemotherapy (gout) (Table 393-2).


InternalMed_Harrison

InternalMed_Harrison. Lastly, a thorough rheumatic review of systems may disclose useful diagnostic information. A variety of musculoskeletal disorders may be associated with systemic features such as fever (SLE, infection), rash (SLE, psoriatic arthritis), nail abnormalities (psoriatic or reactive arthritis), myalgias (fibromyalgia, statin-or drug-induced myopathy), Quinidine, cimetidine, beta blockers, quinolones, chronic acyclovir, interferons, IL-2, nicardipine, vaccines, rifabutin, aromatase and HIV protease inhibitors Glucocorticoids, penicillamine, hydroxychloroquine, AZT, lovastatin, simvastatin, atorvastatin, pravastatin, clofibrate, amiodarone, interferon, IL-2, alcohol, cocaine, paclitaxel, docetaxel, imatinib mesylate, colchicine, quinolones, cyclosporine, tacrolimus, protease inhibitors Quinolones, glucocorticoids, isotretinoin, statins, collagenase injections Diuretics, aspirin, cytotoxics, cyclosporine, alcohol, moonshine, ethambutol, fructose-containing soft drinks


InternalMed_Harrison

InternalMed_Harrison. Quinolones, glucocorticoids, isotretinoin, statins, collagenase injections Diuretics, aspirin, cytotoxics, cyclosporine, alcohol, moonshine, ethambutol, fructose-containing soft drinks Hydralazine, procainamide, quinidine, phenytoin, carbamazepine, methyl-dopa, isoniazid, chlorpromazine, lithium, penicillamine, tetracyclines, TNF inhibitors, ACE inhibitors, ticlopidine Proton pump inhibitors, calcium channel blockers (diltiazem), ACE inhibitors, TNF inhibitors, terbinafine, interferons (α and β-1a), paclitaxel, docetaxel, HCTZ Glucocorticoids, alcohol, radiation, bisphosphonates Glucocorticoids, chronic heparin, phenytoin Vinyl chloride, bleomycin, baricitinib, pentazocine, organic solvents, carbidopa, tryptophan, rapeseed oil Allopurinol, amphetamines, cocaine (often levamisole adulterated), thiazides, penicillamine, propylthiouracil, montelukast, TNF inhibitors, hepatitis B vaccine, trimethoprim/sulfamethoxazole, minocycline, hydralazine


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: ACE, angiotensin-converting enzyme; AZT, zidovudine; HCTZ, hydrochlorothiazide; IL-2, interleukin 2; TNF, tumor necrosis factor. or weakness (polymyositis, neuropathy). In addition, some conditions are associated with involvement of other organ systems including the eyes (Behçet’s disease, sarcoidosis, spondyloarthritis), gastrointestinal tract (scleroderma, inflammatory bowel disease), genitourinary tract (reactive arthritis, gonococcemia), or nervous system (Lyme disease, vasculitis).


InternalMed_Harrison

InternalMed_Harrison. The incidence of rheumatic diseases rises with age, such that 58% of those >65 years will have joint complaints. Musculoskeletal disorders inelderlypatientsareoftennotdiagnosed becausethesigns and symptoms may be insidious, overlooked, or overshadowed by comorbidities. These difficulties are compounded by the diminished reliability of laboratory testing in the elderly, who often manifest nonpathologic abnormal results. For example, the ESR may be misleadingly elevated, and low-titer positive tests for rheumatoid factor and antinuclear antibodies (ANAs) may be seen in up to 15% of elderly patients. Although nearly all rheumatic disorders afflict the elderly, geriatric patients are particularly prone to OA, osteoporosis, osteoporotic fractures, gout, pseudogout, polymyalgia rheumatica, vasculitis, and drug-induced disorders (Table 393-2). The elderly should be approached in the same manner as other patients with musculoskeletal complaints, but with an emphasis on identifying the


InternalMed_Harrison

InternalMed_Harrison. vasculitis, and drug-induced disorders (Table 393-2). The elderly should be approached in the same manner as other patients with musculoskeletal complaints, but with an emphasis on identifying the potential rheumatic consequences of medicalcomorbiditiesandtherapies.The physicalexaminationshould identify the nature of the musculoskeletal complaint as well as coexisting diseases that may influence diagnosis and choice of treatment.


InternalMed_Harrison

InternalMed_Harrison. Evaluation of a hospitalized patient with rheumatic complaints differs from that of an outpatient, owing to greater symptom severity, more acute presentations, and greater interplay of comorbidities. Patients with rheumatic disorders tend to be admitted for one of several reasons: (1) acute onset of inflammatory arthritis; (2) undiagnosed systemic or febrile illness; (3) musculoskeletal trauma; (4) exacerbation or deterioration of an existing autoimmune disorder (e.g., SLE); or (5) new medical comorbidities (e.g., thrombotic event, lymphoma, infection) arising in patients with an established rheumatic disorder. Notably, rheumatic patients are seldom if ever admitted because of widespread pain or serologic abnormalities or for the initiation of new therapies.


InternalMed_Harrison

InternalMed_Harrison. Acute monarticular inflammatory arthritis may be a “red flag” condition (e.g., septic arthritis, gout, pseudogout) that will require arthrocentesis and, on occasion, hospitalization if infection is suspected. However, new-onset inflammatory polyarthritis will have a wider differential diagnosis (e.g., RA, hepatitis-related arthritis, serum sickness, drug-induced lupus, polyarticular septic arthritis) and may require targeted laboratory investigations rather than synovial fluid analyses. Patients with febrile, multisystem disorders will require exclusion of crystal, infectious, or neoplastic etiologies and an evaluation driven by the dominant symptom/finding with the greatest specificity. Conditions worthy of consideration may include gout or pseudogout, vasculitis (giant cell arteritis in the elderly or polyarteritis nodosa in younger patients), adult-onset Still’s disease, SLE, antiphospholipid antibody syndrome, and sarcoidosis. Because the misdiagnosis of connective tissue


InternalMed_Harrison

InternalMed_Harrison. in the elderly or polyarteritis nodosa in younger patients), adult-onset Still’s disease, SLE, antiphospholipid antibody syndrome, and sarcoidosis. Because the misdiagnosis of connective tissue disorders is common, patients who present with a reported preexisting rheumatic condition (e.g., SLE, RA, ankylosing spondylitis) should have their diagnosis confirmed by careful history, physical and musculoskeletal examination, and review of their medical records. It is important to note that when established rheumatic disease patients are admitted to the hospital, it is usually not for a medical problem related to their autoimmune disease, but ratherbecauseofeitheracomorbid conditionorcomplicationofdrug therapy. Patients with chronic inflammatory disorders (e.g., RA, SLE, psoriasis) have an augmented risk of infection, cardiovascular events, and neoplasia.


InternalMed_Harrison

InternalMed_Harrison. Certain conditions, such as acute gout, can be precipitated in hospitalized patients by surgery, dehydration, or other events and should be consideredwhenhospitalizedpatientsareevaluatedfortheacuteonset ofamusculoskeletalcondition.Lastly,overlyaggressiveandunfocused 2219 laboratory testing will often yield abnormal findings that are better explained by the patient’s preexisting condition(s) rather than a new inflammatory or autoimmune disorder.


InternalMed_Harrison

InternalMed_Harrison. The goal of the physical examination is to ascertain the structures involved, the nature of the underlying pathology, the functional consequencesoftheprocess,andthepresence ofsystemicor extraarticular manifestations. A knowledge of topographic anatomy is necessary to identify the primary site(s) of involvement and differentiate articular from nonarticular disorders. The musculoskeletal examination depends largely on careful inspection, palpation, and a variety of specific physical maneuvers to elicit diagnostic signs (Table 393-3). Although most articulations of the appendicular skeleton can be examined in this manner, adequate inspection and palpation are not possible for many axial (e.g., zygapophyseal) and inaccessible (e.g., sacroiliac or hip) joints. For such joints, there is a greater reliance on specific maneuvers and imaging for assessment.


InternalMed_Harrison

InternalMed_Harrison. Examination of involved and uninvolved joints will determine whether pain, warmth, erythema, or swelling is present. The locale and level of pain elicited by palpation or movement should be quantified. One standard would be to count the number of tender joints on palpation of 28 easily examined joints (proximal interphalangeals, metacarpophalangeals, wrists, elbows, shoulders, and knees). Similarly, the number of swollen joints (0–28) can be counted and recorded. Careful examination should distinguish between true articular swelling (caused by bony hypertrophy, synovial effusion or proliferation) and nonarticular (or periarticular) involvement, which usually extends beyond the normal joint margins. Synovial effusion can be distinguished from synovial hypertrophy or bony hypertrophy by palpation or specific maneuvers. For example, small to moderate knee effusions may be identified by the “bulge sign” or “ballottement of the patellae.” Bursal effusions (e.g., effusions of the olecranon


InternalMed_Harrison

InternalMed_Harrison. or specific maneuvers. For example, small to moderate knee effusions may be identified by the “bulge sign” or “ballottement of the patellae.” Bursal effusions (e.g., effusions of the olecranon or prepatellar bursa) are often focal, periarticular, overlie bony prominences, and are fluctuant with sharply defined borders. Joint stability can be assessed by stabilizing the proximal joint, by palpation, and by the application of manual stress to the distal appendage. Subluxation or dislocation, which may be secondary to traumatic, mechanical, or inflammatory


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InternalMed_Harrison. A palpable (less commonly audible) vibratory or crackling sensation elicited with joint motion; fine joint crepitus is common and often insignificant in large joints; coarse joint crepitus indicates advanced cartilaginous and degenerative changes (as in osteoarthritis) Alteration of joint alignment such that articulating surfaces incompletely approximate each other Abnormal displacement of articulating surfaces such that the surfaces are not in contact Range of motion For diarthrodial joints, the arc of measurable movement through which the joint moves in a single plane Loss of full movement resulting from a fixed resistance caused either by tonic spasm of muscle (reversible) or by fibrosis of periarticular structures (permanent) Abnormal shape or size resulting from bony hypertrophy, malalignment of articulating structures, or damage to periarticular supportive structures Inflammation of the entheses (tendinous or ligamentous insertions on


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InternalMed_Harrison. Approach to Articular and Musculoskeletal Disorders 2220 causes, can be assessed by inspection and palpation. Joint swelling or volume can be assessed by palpation. Distention of the articular capsule usually causes pain and evident enlargement or fluctuance. The patient will attempt to minimize the pain by maintaining the joint in the position of least intraarticular pressure and greatest volume, usually partial flexion. For this reason, inflammatory effusions may give rise to flexion contractures. Clinically, this may be detected as fluctuant or “squishy” swelling in larger joints and grape-like compressibility in smaller joints. Inflammation may result in fixed flexion deformities or diminished range of motion—especially on extension, when intraarticular pressure is increased. Active and passive range of motion should be assessed in all planes, with contralateral comparison. A goniometer may be used to quantify the arc of movement. Each joint should be passively manipulated through


InternalMed_Harrison

InternalMed_Harrison. passive range of motion should be assessed in all planes, with contralateral comparison. A goniometer may be used to quantify the arc of movement. Each joint should be passively manipulated through its full range of motion (including, as appropriate, flexion, extension, rotation, abduction, adduction, lateral bending, inversion, eversion, supination, pronation, medial/lateral deviation, and plantar-or dorsiflexion). Extreme range of motion may be seen with hypermobility syndrome, with joint pain and connective tissue laxity, often associated with Ehlers-Danlos or Marfan’s syndrome. Limitation of motion is frequently caused by inflammation, effusion, pain, deformity, contracture, or restriction from neuromyopathic causes. If passivemotion exceeds active motion, a periarticular process (e.g., tendinitis, tendon rupture, or myopathy) should be considered. Contractures may reflect antecedent synovial inflammation or trauma. Minor joint crepitus is common during joint palpation and


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InternalMed_Harrison. (e.g., tendinitis, tendon rupture, or myopathy) should be considered. Contractures may reflect antecedent synovial inflammation or trauma. Minor joint crepitus is common during joint palpation and maneuvers but only indicates significant cartilage degeneration as it becomes coarser (e.g., OA). Joint deformity usually indicatesalong-standingoraggressivepathologicprocess.Deformities may result from ligamentous destruction, soft tissue contracture, bony enlargement, ankylosis, erosive disease, subluxation, trauma, or loss of proprioception. Examination of the musculature will document strength, atrophy, pain, or spasm. Appendicular muscle weakness should be characterized as proximal or distal. Muscle strength should be assessed by observing the patient’s performance (e.g., walking, rising from a chair, grasping, writing). Strength may also be graded on a 5-point scale: 0 for no movement; 1 for trace movement or twitch; 2 for movement with gravity eliminated; 3 for movement against


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InternalMed_Harrison. from a chair, grasping, writing). Strength may also be graded on a 5-point scale: 0 for no movement; 1 for trace movement or twitch; 2 for movement with gravity eliminated; 3 for movement against gravity only; 4 for movement against gravity and resistance; and 5 for normal strength. The examiner should assess for often-overlooked nonarticular or periarticular involvement, especially when articular complaints are not supported by objective findings referable to the joint capsule. The identification of soft tissue/nonarticular pain will prevent unwarranted and often expensive additional evaluations. Specific maneuvers may reveal common nonarticular abnormalities, such as a carpal tunnel syndrome (which can be identified by Tinel’s or Phalen’s sign). Other examples of soft tissue abnormalities include olecranon bursitis, epicondylitis (e.g., tennis elbow), enthesitis (e.g., Achilles tendinitis), and tender trigger points associated with fibromyalgia.


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InternalMed_Harrison. Although all patients should be evaluated in a logical and thorough manner, many cases with focal musculoskeletal complaints are caused by commonly encountered disorders that exhibit a predictable pattern of onset, evolution, and localization; they can often be diagnosed immediately on the basis of limited historic information and selected maneuvers or tests. Although nearly every joint could be approached in this manner, the evaluation of four common involved anatomic regions—the hand, shoulder, hip, and knee—are reviewed here.


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InternalMed_Harrison. Focal or unilateral hand pain may result from trauma, overuse, infection, or a reactive or crystal-induced arthritis. By contrast, bilateral hand complaints commonly suggest a degenerative (e.g., OA), systemic, or inflammatory/immune (e.g., RA) etiology. The distribution orpattern of joint involvement is highly suggestive of certain disorders (Fig. 393-3). Thus, OA (or degenerative arthritis) may manifest as distal interphalangeal (DIP) and proximal interphalangeal (PIP) joint pain with bony hypertrophy sufficient to produce Heberden’s and Bouchard’s nodes, respectively. Pain, with or without bony swelling, 1st CMC: OA de Quervain's tenosynovitis Wrist: RA, pseudogout, gonococcal arthritis, juvenile arthritis, carpal tunnel syndrome FIGUrE 393-3 Sites of hand or wrist involvement and their poten- DIP: OA, psoriatic or reactive arthritis PIP: OA, SLE, RA, psoriatic arthritis


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InternalMed_Harrison. MCP: RA, pseudogout, hemochromatosis tial disease associations. CMC, carpometacarpal; DIP, distal interphalangeal; MCP, metacarpophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. (From JJ Cush et al: Evaluation of musculoskeletal complaints, in Rheumatology: Diagnosis and Therapeutics, 2nd ed, JJ Cush et al [eds]. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 3–20. Used with permission from Dr. John J. Cush.) involving the base of the thumb (first carpometacarpal joint) is also highly suggestive of OA. By contrast, RA tends to cause symmetric, polyarticular involvement of the PIP, metacarpophalangeal (MCP), intercarpal, and carpometacarpal joints (wrist) with pain and palpable synovial tissue hypertrophy. Psoriatic arthritis may mimic the pattern of joint involvement seen in OA (DIP and PIP joints), but can be distinguished by the presence of inflammatory signs (erythema, warmth, synovial swelling), with


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InternalMed_Harrison. arthritis may mimic the pattern of joint involvement seen in OA (DIP and PIP joints), but can be distinguished by the presence of inflammatory signs (erythema, warmth, synovial swelling), with or without carpal involvement, nail pitting, or onycholysis. Whereas lateral or medial subluxations at the PIP or DIP joints are most likely due to inflammatory OA or psoriatic arthritis, dorsal or ventral deformities (swan neck or boutonnière deformities) are typical of RA. Hemochromatosis should be considered when degenerative changes (bony hypertrophy) are seen at the second and third MCP joints with associated radiographic chondrocalcinosis or episodic, inflammatory wrist arthritis.


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InternalMed_Harrison. Dactylitis manifests as soft tissue swelling of the whole digit and may have a sausage-like appearance. Common causes of dactylitis include psoriatic arthritis, spondyloarthritis, juvenile spondylitis, mixed connective tissue disease, scleroderma, sarcoidosis, and sickle cell disease. Soft tissue swelling over the dorsum of the hand and wrist may suggest an inflammatory extensor tendon tenosynovitis possibly caused by gonococcal infection, gout, or inflammatory arthritis (e.g., RA). Tenosynovitis is suggested by localized warmth, swelling, or pitting edema and may be confirmed when the soft tissue swelling tracks with tendon movement, such as flexion and extension of fingers, or when pain is induced while stretching the extensor tendon sheaths (flexing the digits distal to the MCP joints and maintaining the wrist in a fixed, neutral position).


InternalMed_Harrison

InternalMed_Harrison. Focal wrist pain localized to the radial aspect may be caused by de Quervain’s tenosynovitis resulting from inflammation of the tendon sheath(s) involving the abductor pollicis longus or extensor pollicis brevis (Fig. 393-3). This commonly results from overuse or follows pregnancy and may be diagnosed with Finkelstein’s test. A positive result is present when radial wrist pain is induced after the thumb is flexed and placed inside a clenched fist and the patient actively deviates the hand downward with ulnar deviation at the wrist. Carpal tunnel syndrome is another common disorder of the upper extremity and results from compression of the median nerve within the carpal tunnel. Manifestations include pain in the wrist that may radiate with paresthesia to the thumb, second and third fingers, and radial half of the fourth finger and, at times, atrophy of thenar musculature. Carpal tunnel syndrome is commonly associated with pregnancy, edema, trauma, OA, inflammatory arthritis, and


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InternalMed_Harrison. and radial half of the fourth finger and, at times, atrophy of thenar musculature. Carpal tunnel syndrome is commonly associated with pregnancy, edema, trauma, OA, inflammatory arthritis, and infiltrative disorders (e.g., amyloidosis). The diagnosis may be suggested by a positive Tinel’s or Phalen’s sign. With each test, paresthesia in a median nerve distribution is induced or increased by either “thumping” the volar aspect of the wrist (Tinel’s sign) or pressing the extensor surfaces of both flexed wrists against each other (Phalen’s sign). The low sensitivity and moderate specificity of these tests may require nerve conduction velocity testing to confirm a suspected diagnosis.


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InternalMed_Harrison. During the evaluation of shoulder disorders, the examiner should carefully note any history of trauma, fibromyalgia, infection, inflammatory disease, occupational hazards, or previous cervical disease. In addition, the patient should be questioned as to the activities or movement(s) that elicit shoulder pain. While arthritis is suggested by pain on movement in all planes, pain with specific active motion suggests a periarticular (nonarticular) process. Shoulder pain may originateintheglenohumeral oracromioclavicularjoints,subacromial (subdeltoid) bursa, periarticular soft tissues (e.g., fibromyalgia, rotator cuff tear/tendinitis), or cervical spine (Fig. 393-4). Shoulder pain is referred frequently from the cervical spine but may also be referred from intrathoracic lesions (e.g., a Pancoast tumor) or from gallbladder, hepatic, or diaphragmatic disease. These same visceral causes may also manifest as focal scapular pain. Fibromyalgia should be suspected


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InternalMed_Harrison. FIGUrE 393-4 Origins of shoulder pain. The schematic diagram of the shoulder indicates with arrows the anatomic origins of shoulder pain.


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InternalMed_Harrison. when glenohumeral pain is accompanied by diffuse periarticular (i.e., 2221 subacromial, bicipital) pain and tender points (i.e., trapezius or supraspinatus). The shoulder should be put through its full range of motion bothactivelyandpassively(withexaminerassistance):forwardflexion, extension, abduction, adduction, and internal and external rotation. Manual inspection of the periarticular structures will often provide important diagnostic information. Glenohumeral involvement is best detected by placing the thumb over the glenohumeral joint just medial and inferior to the coracoid process and applying pressure anteriorly while internally and externally rotating the humeral head. Pain localized to this region is indicative of glenohumeral pathology. Synovial effusion or tissue is seldom palpable but, if present, may suggest infection, RA, amyloidosis, or an acute tear of the rotator cuff. The examiner should apply direct manual pressure over the subacromial bursa that lies lateral to


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InternalMed_Harrison. but, if present, may suggest infection, RA, amyloidosis, or an acute tear of the rotator cuff. The examiner should apply direct manual pressure over the subacromial bursa that lies lateral to and immediately beneath the acromion (Fig. 393-4). Subacromial bursitis is a frequent cause of shoulder pain. Anterior to the subacromial bursa, the bicipital tendon traverses the bicipital groove. This tendon is best identified by palpating it in its groove as the patient rotates the humerus internally and externally. Direct pressure over the tendon may reveal pain indicative of bicipital tendinitis. Palpation of the acromioclavicular joint may disclose local pain, bony hypertrophy,or,uncommonly,synovialswelling.WhereasOAandRA commonly affect the acromioclavicular joint, OA seldom involves the glenohumeral joint, unless there is a traumatic or occupational cause.


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InternalMed_Harrison. Rotator cuff tendinitis or tear is a very common cause of shoulder pain. Nearly 30 percent of the elderly will have shoulder pain, with rotator cuff tendinitis or tear as the primary cause. The rotator cuff is formed by four tendons that attach the scapula to the proximal humerus (supraspinatus, infraspinatus, teres minor, and subscapularis tendons). Of these, the supraspinatus muscle is the most commonly damaged. Rotator cuff tendinitis is suggested by pain on active abduction (but not passive abduction), pain over the lateral deltoid muscle, nightpain,andevidenceoftheimpingementsigns(painwithoverhead arm activities). The Neer test for impingement is performed by the examiner raising the patient’s arm into forced flexion while stabilizing and preventing rotation of the scapula. A positive sign is present if pain develops before 180° of forward flexion. Tear of the rotator cuff is common in the elderly and often results from trauma; it may manifest in the same manner as tendinitis.


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InternalMed_Harrison. sign is present if pain develops before 180° of forward flexion. Tear of the rotator cuff is common in the elderly and often results from trauma; it may manifest in the same manner as tendinitis. The drop arm test is abnormal with supraspinatus pathology and is demonstrated by passive abduction of the arm to 90° by the examiner. If the patient is unable to hold the arm up actively or unable to lower the arm slowly without dropping, the test is positive. Tendinitis or tear of the rotator cuff is best confirmed by magnetic resonance imaging (MRI) or ultrasound.


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InternalMed_Harrison. Knee pain may result from intraarticular (OA, RA) or periarticular (anserine bursitis, collateral ligament strain) processes or be referred from hip pathology. A careful history should delineate the chronology of the knee complaint and whether there are predisposing conditions, trauma, or medications that might underlie the complaint. For example, patellofemoral disease (e.g., OA) may cause anterior knee pain that worsens with climbing stairs. Observation of the patient’s gait is also important. The knee should be carefully inspected in the upright (weight-bearing) and supine positions for swelling, erythema, malalignment, visible trauma, muscle wasting, and leg length discrepancy. The most common malalignment in the knee is genu varum (bowlegs) or genu valgum (knock-knees) resulting from asymmetric cartilage loss medially or laterally. Bony swelling of the knee joint commonly results from hypertrophic osseous changes seen with disorders such as OA and neuropathic arthropathy.


InternalMed_Harrison

InternalMed_Harrison. from asymmetric cartilage loss medially or laterally. Bony swelling of the knee joint commonly results from hypertrophic osseous changes seen with disorders such as OA and neuropathic arthropathy. Swelling caused by hypertrophy of the synovium or synovial effusion may manifest as a fluctuant, ballotable, or soft tissue enlargement in the suprapatellar pouch (suprapatellar reflection of the synovial cavity) or regions lateral and medial to the patella. Synovial effusions may also be detected by balloting the patella downward toward the femoral groove or by eliciting a “bulge sign.” With the knee extended, the examiner should manually compress, or “milk,” synovial fluid down from the suprapatellar pouch and lateral to the patellae. The


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InternalMed_Harrison. Approach to Articular and Musculoskeletal Disorders 2222 application of manual pressure lateral to the patella may cause an observable shift in synovial fluid (bulge) to the medial aspect. The examiner should note that this maneuver is only effective in detecting small to moderate effusions (<100 mL). Inflammatory disorders such as RA, gout, pseudogout, and psoriatic arthritis may involve the knee joint and produce significant pain, stiffness, swelling, or warmth. A popliteal or Baker’s cyst may be palpated with the knee partially flexed and is best viewed posteriorly with the patient standing and knees fully extended to visualize isolated or unilateral popliteal swelling or fullness. Anserine bursitis is an often missed periarticular cause of knee pain in adults. The pes anserine bursa underlies the insertion of the conjoined tendons (sartorius, gracilis, semitendinosus) on the anteromedial proximal tibia and may be painful following trauma, overuse, or inflammation. It is often


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InternalMed_Harrison. underlies the insertion of the conjoined tendons (sartorius, gracilis, semitendinosus) on the anteromedial proximal tibia and may be painful following trauma, overuse, or inflammation. It is often tender in patients with fibromyalgia, obesity, and knee OA. Other forms of bursitis may also present as knee pain. The prepatellar bursa is superficial and is located over the inferior portion of the patella. The infrapatellar bursa is deeper and lies beneath the patellar ligament before its insertion on the tibial tubercle. Internal derangement of the knee may result from trauma or degenerative processes. Damage to the meniscal cartilage (medial or lateral) frequently presents as chronic or intermittent knee pain. Such an injury should be suspected when there is a history of trauma, athletic activity, or chronic knee arthritis, and when the patient relates symptoms of “locking” or “giving way” of the knee. With the knee flexed 90° and the patient’s foot on the table, pain elicited during


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InternalMed_Harrison. activity, or chronic knee arthritis, and when the patient relates symptoms of “locking” or “giving way” of the knee. With the knee flexed 90° and the patient’s foot on the table, pain elicited during palpation over the joint line or when the knee is stressed laterally or medially may suggest a meniscal tear. A positive McMurray test may also indicate a meniscal tear.Toperformthistest,thekneeisfirstflexedat90°,andthelegisthen extended while the lower extremity is simultaneously torqued medially or laterally. A painful click during inward rotation may indicate a lateral meniscus tear, and pain during outward rotation may indicate a tear in the medial meniscus. Lastly, damage to the cruciate ligaments should be suspected with acute onset of pain, possibly with swelling, a history of trauma, or a synovial fluid aspirate that is grossly bloody. Examination of the cruciate ligaments is best accomplished by eliciting a drawer sign. With the patient recumbent, the knee should be partially


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InternalMed_Harrison. or a synovial fluid aspirate that is grossly bloody. Examination of the cruciate ligaments is best accomplished by eliciting a drawer sign. With the patient recumbent, the knee should be partially flexed and the footstabilizedon the examining surface. Theexaminer shouldmanually attempt to displace the tibia anteriorly or posteriorly with respect to the femur. If anterior movement is detected, then anterior cruciate ligament damage is likely. Conversely, significant posterior movement may indicate posterior cruciate damage. Contralateral comparison will assist the examiner in detecting significant anterior or posterior movement.


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InternalMed_Harrison. The hip is best evaluated by observing the patient’s gait and assessing range of motion. The vast majority of patients reporting “hip pain” localize their pain unilaterally to the posterior Enthesitis gluteal musculature (Fig. 393-5). Such pain tends to radiate down the posterolateral aspect of the thigh and may or may not be associated


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InternalMed_Harrison. True hip pain, with complaints of low back pain. This pre sentation frequently results from degenerative arthritis of the lumbosacral spine or disks and commonly follows a dermatomal distribution Meralgia with involvement of nerve roots between L4 and S1. Sciatica is caused by impingement of the L4, L5, or S1 nerve (i.e., from a herniated disk) and manifests as unilateral neuropathic pain extending from the gluteal region down the posterolateral leg to the foot. Some individuals instead localize their “hip pain” laterally to the area overlying the trochanteric bursa. Because of the depth of this bursa, swelling and warmth are FIGUrE 393-5 Origins of hip pain and dysesthesias. (From JJ Cush et al: Evaluation of mus-usually absent. Diagnosis of trochanteric bursitis culoskeletal complaints, in Rheumatology: Diagnosis and Therapeutics, 2nd ed, JJ Cush et al [eds]. or enthesitis can be confirmed by inducing point Philadelphia, Lippincott Williams & Wilkins, 2005, pp 3–20. Used with


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InternalMed_Harrison. in Rheumatology: Diagnosis and Therapeutics, 2nd ed, JJ Cush et al [eds]. or enthesitis can be confirmed by inducing point Philadelphia, Lippincott Williams & Wilkins, 2005, pp 3–20. Used with permission from Dr. John tenderness over the trochanteric bursa. Gluteal J. Cush.) and trochanteric pain are common findings in fibromyalgia. Range of movement may be limited by pain. Pain in the hip joint is less common and tends to be located anteriorly, over the inguinal ligament; it may radiate medially to the groin. Uncommonly, iliopsoas bursitis may mimic true hip joint pain. Diagnosis of iliopsoas bursitis may be suggestedbyahistoryoftraumaorinflammatoryarthritis.Painassociated with iliopsoas bursitis is localized to the groin or anterior thigh and tends to worsen with hyperextension of the hip; many patients prefer to flex and externally rotate the hip to reduce the pain from a distended bursa.


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InternalMed_Harrison. The vast majority of musculoskeletal disorders can be easily diagnosed by a complete history and physical examination. An additional objective of the initial encounter is to determine whether additional investigations or immediate therapy is required. Additional evaluation is indicated with: (1) monarticular conditions; (2) traumatic or inflammatory conditions; (3) the presence of neurologic findings; (4) systemic manifestations; or (5) chronic symptoms (>6 weeks) and a lack of response to symptomatic measures. The extent and nature of the additional investigation should be dictated by the clinical features and suspected pathologic process. Laboratory tests should be used to confirm a specific clinical diagnosis and not be used to screen or evaluate patients with vague rheumatic complaints. Indiscriminate use of broad batteries of diagnostic tests and radiographic procedures is rarely a useful or cost-effective means to establish a diagnosis.


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InternalMed_Harrison. Besidesacomplete bloodcount,includingawhitebloodcell(WBC) and differential count, the routine evaluation should include a determination of an acute-phase reactant such as the ESR or CRP, which can be useful in discriminating inflammatory from noninflammatory disorders. Both are inexpensive, easily obtained, and may be elevated with infection, inflammation, autoimmune disorders, neoplasia, pregnancy, renal insufficiency, advanced age, or hyperlipidemia. Extreme elevation of the acute-phase reactants (CRP, ESR) is seldom seen without evidence of serious illness (e.g., sepsis, pleuropericarditis, polymyalgia rheumatica, giant cell arteritis, adult Still’s disease).


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InternalMed_Harrison. Serum uric acid determinations are useful in the diagnosis of gout and in monitoring the response to urate-lowering therapy. Uric acid, the end product of purine metabolism, is primarily excreted in the urine. Serum values range from 238 to 516 μmol/L (4.0–8.6 mg/dL) in men; the lower values (178–351 μmol/L [3.0–5.9 mg/dL]) seen in women are caused by the uricosuric effects of estrogen. Urinary uric acid levels are normally <750 mg per 24 h. Although hyperuricemia (especiallylevels>535μmol/L[9mg/dL])isassociatedwithanincreased incidence of gout and nephrolithiasis, levels may not correlate with the severity of articular disease. Uric acid levels (and the risk of gout) may be increased by inborn errors of metabolism (Lesch-Nyhan syndrome), disease states (renal insufficiency, myeloproliferative disease, psoriasis), or drugs (alcohol, cytotoxic therapy, thiazides). Although nearly all patients with gout will demonstrate hyperuricemia at some time during their illness, up to 50% of


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InternalMed_Harrison. disease, psoriasis), or drugs (alcohol, cytotoxic therapy, thiazides). Although nearly all patients with gout will demonstrate hyperuricemia at some time during their illness, up to 50% of patients with an acute gouty attack will have normal serum uric acid levels. Monitoring serum uric acid may be useful in assessing the response to urate-lowering therapy or chemotherapy, with the target goal being a serum urate <6 mg/dL.


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InternalMed_Harrison. Serologic tests for rheumatoid factor (RF), cyclic anticitrullinated peptide (CCP or ACPA) antibodies, ANAs, complement levels, Lyme and antineutrophil cytoplasmic antibodies (ANCA), or antistreptolysin O (ASO) titer should be carried out only when there is clinical evidence to specifically suggest an associated diagnosis, because these have poor predictive value when used for screening, especially when the pretest probability is low. For most of these, there is no value to repeated or serial serologic testing. Although 4–5% of a healthy population will have positive tests for RF and ANAs, only 1% and <0.4% of the population will haveRA orSLE, respectively. IgM RF(autoantibodies against theFc portionofIgG)isfoundin80%ofpatientswithRAandmayalsobeseen in low titers in patients with chronic infections (tuberculosis, leprosy, hepatitis); other autoimmune diseases (SLE, Sjögren’s syndrome); and chronic pulmonary, hepatic, or renal diseases. When considering RA, both serum RF and anti-CCP


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InternalMed_Harrison. infections (tuberculosis, leprosy, hepatitis); other autoimmune diseases (SLE, Sjögren’s syndrome); and chronic pulmonary, hepatic, or renal diseases. When considering RA, both serum RF and anti-CCP antibodies should be obtained as these are complementary. Both are comparably sensitive, but CCP antibodies are more specific than RF. In RA, the presence of anti-CCP and RF antibodies may indicate a greater risk for more severe, erosive polyarthritis. ANAs are found in nearly all patients with SLE and may also be seen in patients with other autoimmune diseases (polymyositis, scleroderma, antiphospholipid syndrome, Sjögren’s syndrome), drug-induced lupus (Table 393-2), chronic liver or renal disorders, and advanced age. Positive ANAs are found in 5% of adults and in up to 14% of elderly or chronically ill individuals. The ANA test is very sensitive but poorly specific for lupus, as only 1–2% of all positive results will be caused by lupus alone. The interpretation of a positive ANA test


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InternalMed_Harrison. ill individuals. The ANA test is very sensitive but poorly specific for lupus, as only 1–2% of all positive results will be caused by lupus alone. The interpretation of a positive ANA test may depend on the magnitude of the titer and the pattern observed by immunofluorescence microscopy (Table 393-4). Diffuse and speckled patterns are least specific, whereas a peripheral, or rim, pattern (related to autoantibodies against double-strand [native] DNA) is highly specific and suggestive of lupus. Centromeric patterns are seen in patients with limited


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InternalMed_Harrison. Abbreviations: ANA, antinuclear antibody; CREST, calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia; MCTD, mixed connective tissue disease; PSS, progressive systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus. scleroderma (calcinosis, Raynaud’s phenomenon, esophageal involve-2223 ment, sclerodactyly, telangiectasia [CREST] syndrome) or primary biliary sclerosis, and nucleolar patterns may be seen in patients with diffuse systemic sclerosis or inflammatory myositis.


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InternalMed_Harrison. Aspiration and analysis of synovial fluid are always indicated in acute monarthritis or when an infectious or crystal-induced arthropathy is suspected. Synovial fluid may distinguish between noninflammatory and inflammatory processes by analysis of the appearance, viscosity,andcellcount.Testsforsynovialfluidglucose,protein,lactate dehydrogenase, lactic acid, or autoantibodies are not recommended because they have no diagnostic value. Normal synovial fluid is clear or a pale straw color and is viscous, primarily because of the high levels of hyaluronate. Noninflammatory synovial fluid is clear, viscous, and amber-colored, with a WBC count of <2000/μL and a predominance of mononuclear cells. The viscosity of synovial fluid is assessed by expressing fluid from the syringe one drop at a time. Normally, there is a stringing effect, with a long tail behind each synovial drop. Effusions caused by OAor traumawillhavenormalviscosity. Inflammatoryfluid is turbid and yellow, with an increased


InternalMed_Harrison

InternalMed_Harrison. Normally, there is a stringing effect, with a long tail behind each synovial drop. Effusions caused by OAor traumawillhavenormalviscosity. Inflammatoryfluid is turbid and yellow, with an increased WBC count (2000–50,000/μL) and a polymorphonuclear leukocyte predominance. Inflammatory fluid has reduced viscosity, diminished hyaluronate, and little or no tail following each drop of synovial fluid. Such effusions are found in RA, gout, andotherinflammatoryarthritides.Septicfluidisopaqueandpurulent, with a WBC count usually >50,000/μL, a predominance of polymorphonuclear leukocytes (>75%), and low viscosity. Such effusions are typical of septic arthritis but may also occur with RA or gout. In addition, hemorrhagic synovial fluid may be seen with trauma, hemarthro sis, or neuropathic arthritis. An algorithm for synovial fluid aspiration and analysis is shown in Fig. 393-6. Synovial fluid should be analyzed immediately for appearance, viscosity, and cell count. Monosodium urate crystals


InternalMed_Harrison

InternalMed_Harrison. An algorithm for synovial fluid aspiration and analysis is shown in Fig. 393-6. Synovial fluid should be analyzed immediately for appearance, viscosity, and cell count. Monosodium urate crystals (observed in gout) are seen by polarized microscopy and arelong,needle-shaped,negativelybirefringent,andusuallyintracellular. In chondrocalcinosis and pseudogout, calcium pyrophosphate dihydrate crystals are usually short, rhomboid-shaped, and positively birefringent. Whenever infection is suspected, synovial fluid should be Gram stained and cultured appropriately. If gonococcal arthritis is suspected, nucleic acid amplification tests should be used to detect either Chlamydia trachomatis or N. gonorrhoeae infection. Synovial fluid from patients withchronicmonarthritisshouldalsobeculturedfor M. tuberculosis and fungi. Last, it should be noted that crystal-induced arthritis and septic arthritis occasionally occur together in the same joint.


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InternalMed_Harrison. Conventional radiography has been a valuable tool in the diagnosis and staging of articular disorders. Plain x-rays are most appropriate and cost effective when there is a history of trauma, suspected chronic infection, progressive disability, or monarticular involvement; when therapeutic alterations are considered; or when a baseline assessment is desired for what appears to be a chronic process. However, in acute inflammatory arthritis, early radiography is rarely helpful in establishinga diagnosisand may only reveal soft tissueswelling or juxtaarticular demineralization.Asthediseaseprogresses,calcification(ofsofttissues, cartilage,orbone),jointspacenarrowing,erosions,bonyankylosis,new bone formation (sclerosis, osteophytes, or periostitis), or subchondral cysts may develop and suggest specific clinical entities. Consultation with a radiologist will help define the optimal imaging modality, technique, or positioning and prevent the need for further studies.


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InternalMed_Harrison. Additional imaging techniques may possess greater diagnostic sensitivity and facilitate early diagnosis in a limited number of articular disorders and in selected circumstances and are indicated when conventional radiography is inadequate or nondiagnostic (Table 393-5). Ultrasonography is useful in the detection of soft tissue abnormalities, such as tendinitis, tenosynovitis, enthesitis, bursitis, and entrapment neuropathies. Wider use, lower cost, better technology, and enhanced site-specific transducers now allow for routine use in outpatient care. Owing to low cost, portability, and wider use, ultrasound use has grown and is the preferred method for the evaluation of synovial (Baker’s) cysts, rotator cuff tears, tendinitis and tendon injury, and Approach to Articular and Musculoskeletal Disorders Strongly consider synovial fluid aspiration and analysis if there is Trauma with joint effusion Monarthritis in a patient with chronic polyarthritis


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InternalMed_Harrison. Strongly consider synovial fluid aspiration and analysis if there is Trauma with joint effusion Monarthritis in a patient with chronic polyarthritis Suspicion of joint infection, crystal-induced arthritis, or hemarthrosis


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InternalMed_Harrison. Analyze fluid for • Appearance, viscosity• WBC count, differential• Gram stain, culture, and sensitivity (if indicated)• Crystal identification by polarized microscopyInflammatory ornoninflammatoryarticular condition Consider• Trauma or mechanical derangement• Coagulopathy• Neuropathic arthropathy• OtherIs the WBC > 2000/˜L? Consider otherinflammatoryor septic arthritides • Gram stain, culture mandatoryIs the % PMNs > 75%? Are crystals present? Considernoninflammatoryarticular conditions • Osteoarthritis• Trauma• OtherIs the WBC > 50,000/˜L? Crystal identification for specific diagnosis • Gout• PseudogoutProbable inflammatory arthritisPossible septic arthritis Consider inflammatoryor septic arthritis Is the effusion hemorrhagic? NoYes NoYes NoYes Yes NoYes NoFIGUrE 393-6 Algorithmic approach to the use and interpretation of synovial fluid aspiration and analysis. PMNs,polymorphonucle-ar(leukocytes);WBC,whitebloodcell(count).


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InternalMed_Harrison. crystal deposition on cartilage. Use of power Doppler allows for early detection of synovitis and bony erosions. Radionuclide scintigraphy is a very sensitive, but poorly specific, means of detecting inflammatory or metabolic alterations in bone or periarticular soft tissue structures. Scintigraphy is best suited for total-body assessment (extent and distribution) of skeletal involvement (neoplasia, Paget’s disease) and the assessment of patients with undiagnosed polyarthralgias, looking for occult arthritis. The use of scintigraphy has declined with greater use and declining cost of ultrasound and MRI. The limited tissue contrast resolution of scintigraphy may obscure the distinction between a bony or periarticular process and may necessitate the additional use of MRI. Scintigraphy using 99mTc, 67Ga, or 111In-labeled WBCs has been applied to a variety of articular disorders with variable success (Table 393-5). Although [99mTc] diphosphate scintigraphy may be useful in identifying


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InternalMed_Harrison. 99mTc, 67Ga, or 111In-labeled WBCs has been applied to a variety of articular disorders with variable success (Table 393-5). Although [99mTc] diphosphate scintigraphy may be useful in identifying osseous infection, neoplasia, inflammation, increasedbloodflow,boneremodeling,heterotopicboneformation,or avascular necrosis, MRI is preferred in most instances. Gallium scanning uses 67Ga, which binds serum and cellular transferrin and lactoferrin and is preferentially taken up by neutrophils, macrophages,


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InternalMed_Harrison. Imaging Method Time, h Costa Current Indications aRelative cost for imaging study. Abbreviations: NA, not commercially available; WBC, white blood cell. bacteria, and tumor tissue (e.g., lymphoma). As such, it is primarily used in the identification of occult infection or malignancy. Scanning with 111In-labeled WBCs has been used to detect osteomyelitis and infectious or inflammatory arthritis. Despite their utility, 111In-labeled WBC or 67Ga scanning has largely been replaced by MRI, except when there is a suspicion of septic joint or prosthetic joint infections.


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InternalMed_Harrison. Computed tomography (CT) provides detailed visualization of the axial skeleton. Articulationspreviously considered difficult to visualize by radiography (e.g., zygapophyseal, sacroiliac, sternoclavicular, hip joints) can be effectively evaluated using CT. CT has been demonstrated to be useful in the diagnosis of low back pain syndromes (e.g., spinal stenosis vs herniated disk), sacroiliitis, osteoid osteoma, and stress fractures. Helical or spiral CT (with or without contrast angiography) is a novel technique that is rapid, cost effective, and sensitive in diagnosing pulmonary embolism or obscure fractures, often in the setting of initially equivocalfindings. High-resolutionCTcan beadvocated in the evaluation of suspected or established infiltrative lung disease (e.g., scleroderma or rheumatoid lung). The recent use of hybrid (positron emission tomography [PET] or single-photon emission CT [SPECT]) CT scans in metastatic evaluations has incorporated CT to provide better anatomic


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InternalMed_Harrison. rheumatoid lung). The recent use of hybrid (positron emission tomography [PET] or single-photon emission CT [SPECT]) CT scans in metastatic evaluations has incorporated CT to provide better anatomic localization of scintigraphic abnormalities.


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InternalMed_Harrison. FIGUrE 393-7 Dual-energy computed tomography (DECT) scan from a 45-year-old woman with right ankle swelling around the lateral malleolus. Three-dimensionalvolume-renderedcoronalreformattedDECTimageshowsthatthemassiscomposedofmonosodiumurate(red)inkeepingwithtophus(arrow).(Used with permission from S Nicolaou et al: AJR 194:1072, 2010.) 18F-Fluorodeoxyglucose (FDG) is the most commonly used radio-pharmaceutical in PET scanning. FDG-PET/CT scans have been seldom used in the evaluation of septic or inflammatory arthritis. Dual-energy CT (DECT) scanning, developed in urology to identify urinary calculi, has been a highly sensitive and specific method used to identify and quantify uric acid deposition in tissues (Fig. 393-7).


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InternalMed_Harrison. MRI has significantly advanced the ability to image musculoskeletal structures. MRI has the advantages of providing multiplanar images with fine anatomic detail and contrast resolution (Fig. 393-8) that allows for the superior ability to visualize bone marrow and soft tissue periarticular structures. Although more costly with a longer proceduraltimethanCT,theMRIhasbecomethepreferredtechniquewhen evaluating complex musculoskeletal disorders.


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InternalMed_Harrison. MRI can image fascia, vessels, nerve, muscle, cartilage, ligaments, tendons, pannus, synovial effusions, and bone marrow. Visualization of particular structures can be enhanced by altering the pulse sequence to produce either T1-or T2-weighted spin echo, gradient echo, or inversion recovery (including short tau inversion recovery [STIR]) images. Because of its sensitivity to changes in marrow fat, MRI is a sensitivebutnonspecificmeansofdetectingosteonecrosis,osteomyelitis, and marrow inflammation indicating overlying synovitis or osteitis (Fig. 393-8). Because of its enhanced soft tissue resolution, MRI is more sensitive than arthrography or CT in the diagnosis of soft tissue injuries (e.g., meniscal and rotator cuff tears); intraarticular derangements; marrow abnormalities (osteonecrosis, myeloma); and spinal cord or nerve root damage, synovitis, or cartilage damage or loss. The author acknowledges the contributions of Dr. Peter E. Lipsky to this chapter in previous editions.


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InternalMed_Harrison. The author acknowledges the contributions of Dr. Peter E. Lipsky to this chapter in previous editions. Approach to Articular and Musculoskeletal Disorders FIGUrE 393-8 Superior sensitivity of magnetic resonance imaging (MRI) in the diagnosis of osteonecrosis of the femoral head. A 45-year-old woman receiving high-dose glucocorticoids developed right hip pain. Conventional x-rays (top) demonstrated only mild sclerosis of the right femoral head. T1-weighted MRI (bottom) demonstrated low-density signal in the right femoral head, diagnostic of osteonecrosis. 2226 Osteoarthritis David T. Felson Osteoarthritis(OA)isthemostcommontypeofarthritis.Itshighprevalence,especiallyintheelderly,andthehighrateofdisabilityrelatedtodiseasemakeitaleadingcauseofdisabilityintheelderly.BecauseoftheagingofWesternpopulationsandbecauseobesity,a394


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InternalMed_Harrison. FIGUrE 394-2 Severe osteoarthritis of the hands affectingthedis-talinterphalangealjoints(Heberden’snodes)andtheproximalinter-phalangealjoints(Bouchard’snodes).Thereisnoclearbonyenlarge-mentoftheothercommonsiteinthehands,thethumbbase. major risk factor, is increasing in prevalence, the occurrence of OA is on the rise. In the United States, OA prevalence will increase by 66–100% by 2020.


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InternalMed_Harrison. major risk factor, is increasing in prevalence, the occurrence of OA is on the rise. In the United States, OA prevalence will increase by 66–100% by 2020. OA affects certain joints, yet spares others (Fig. 394-1). Commonly affected joints include the cervical and lumbosacral spine, hip, knee, and first metatarsal phalangeal joint (MTP). In the hands, the distal and proximal interphalangeal joints and the base of the thumb are often affected. Usually spared are the wrist, elbow, and ankle. Our joints were designed, in an evolutionary sense, for brachiating apes, animals that still walked on four limbs. We thus develop OA in joints that were ill designed for human tasks such as pincer grip (OA in the thumb base) and walking upright (OA in knees and hips). Some joints, like the ankles, may be spared because their articular cartilage may be uniquely resistant to loading stresses.


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InternalMed_Harrison. OA can be diagnosed based on structural abnormalities or on the symptoms these abnormalities evoke. According to cadaveric studies, by elderly years, structural changes of OA are nearly universal. These include cartilage loss (seen as joint space loss on x-rays) and osteophytes. Many persons with x-ray evidence of OA have no joint symptoms, and although the prevalence of structural abnormalities is of interest in understanding disease pathogenesis, what matters more from a clinical perspective is the prevalence of symptomatic OA. Symptoms, usually joint pain, determine disability, visits to clinicians, and disease costs.


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InternalMed_Harrison. SymptomaticOAoftheknee(painonmostdaysofarecentmonthin akneeplusx-rayevidenceofOAinthatknee)occursin~12%ofpersons age ≥60 in the United States and 6% of all adults age ≥30. Symptomatic hipOAisroughlyone-thirdascommonasdiseaseintheknee.Although radiographically evident hand OA and the appearance of bony enlargementinaffectedhandjoints(Fig. 394-2) areextremelycommoninolder persons, most cases are often not symptomatic. Even so, symptomatic FIGUrE 394-1 Joints commonly affected by osteoarthritis. hand OA occurs in ~10% of elderly individuals and often produces measurable limitation in function. The prevalence of OA rises strikingly with age. Regardless of how it is defined, OA is uncommon in adults under age 40 and highly prevalent inthoseoverage 60.Itisalsoa disease that, atleast inmiddle-aged and elderly persons, is much more common in women than in men, and sex differences in prevalence increase with age.


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InternalMed_Harrison. X-ray evidence of OA is common in the lower back and neck, but backpain and neck pain have not been tied to findings of OA on x-ray. Thus, back pain and neck pain are treated separately (Chap. 22). OA is joint failure, a disease in which all structures of the joint have undergone pathologic change, often in concert. The pathologic sine qua non of disease is hyaline articular cartilage loss, present in a focal and, initially, nonuniform manner. This is accompanied by increasing thickness and sclerosis of the subchondral bony plate, by outgrowth of osteophytes at the joint margin, by stretching of the articular capsule, by mild synovitis in many affected joints, and by weakness of muscles bridging the joint. In knees, meniscal degeneration is part of the disease. There are numerous pathways that lead to joint failure, but the initial step is often joint injury in the setting of a failure of protective mechanisms.


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InternalMed_Harrison. Joint protectors include joint capsule and ligaments, muscle, sensory afferents, and underlying bone. Joint capsule and ligaments serve as joint protectors by providing a limit to excursion, thereby fixing the range of joint motion. Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving as a protector against friction-induced cartilage wear. This lubrication function depends on hyaluronic acid and on lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose concentration diminishes after joint injury and in the face of synovial inflammation.


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InternalMed_Harrison. The ligaments, along with overlying skin and tendons, contain mechanoreceptor sensory afferent nerves. These mechanoreceptors fire at different frequencies throughout a joint’s range of motion, providing feedback by way of the spinal cord to muscles andtendons. As a consequence, these muscles and tendons can assume the right tension at appropriate points in joint excursion to act as optimal joint protectors, anticipating joint loading. Muscles and tendons that bridge the joint are key joint protectors. Their coordinated contractions at the appropriate time in joint movement provide the appropriate power and acceleration for the limb to accomplish its tasks. Focal stress across the joint is minimized by muscle contractionthatdeceleratesthejointbeforeimpactandassuresthatwhen joint impact arrives, it is distributed broadly across the joint surface.


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InternalMed_Harrison. Failure of these joint protectors increases the risk of joint injury and OA.Forexample,inanimals,OAdevelopsrapidlywhenasensorynerve to the joint is sectioned and joint injury induced. Similarly, in humans, Charcot’s arthropathy, a severe and rapidly progressive OA, develops when minor joint injury occurs in the presence of posterior column peripheral neuropathy. Another example of joint protector failure is rupture of ligaments, a well-known cause of the early development of OA. In addition to being a primary target tissue for disease, cartilage also functions as a joint protector. A thin rim of tissue at the ends of two opposing bones, cartilage is lubricated by synovial fluid to provide an almost frictionless surface across which these two bones move. The compressible stiffness of cartilage compared to bone provides the joint with impact-absorbing capacity.


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InternalMed_Harrison. The earliest changes of OA may occur in cartilage, and abnormalities there can accelerate disease development. The two major macromolecules in cartilage are type 2 collagen, which provides cartilage its tensile strength, and aggrecan, a proteoglycan macromolecule linked with hyaluronic acid, which consists of highly negatively charged glycosaminoglycans. In normal cartilage, type 2 collagen is woven tightly, constraining the aggrecan molecules in the interstices between collagen strands, forcing these highly negatively charged molecules into close proximity with one another. The aggrecan molecule, through electrostatic repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize all elements of the matrix and produce enzymes that break down the matrix. Synovium and chondrocytes synthesize and release cytokines and growth factors, which provide feedback that modulates synthesis of matrix molecules (Fig.


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InternalMed_Harrison. produce enzymes that break down the matrix. Synovium and chondrocytes synthesize and release cytokines and growth factors, which provide feedback that modulates synthesis of matrix molecules (Fig. 394-3). Cartilage matrix synthesis and catabolism are in a dynamic equilibrium influenced by the cytokine and growth factor environment. Mechanical and osmotic stress on chondrocytes induces these cells to alter gene expression and increase production of inflammatory cytokines and matrix-degrading enzymes. While chondrocytes synthesize numerous enzymes, matrix metalloproteinases (MMP) (especially collagenases and ADAMTS-5) arecriticalenzymesinthebreakdownofcartilagematrix.Bothcollagenase and aggrecanases act primarily in the territorial matrix surrounding chondrocytes; however, as the osteoarthritic process develops, their activities and effects spread throughout the matrix, especially in the superficial layers of cartilage.


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InternalMed_Harrison. The synovium, cartilage, and bone all influence disease develop-2227 ment through cytokines, chemokines, and even complement activation (Fig. 394-3). These act on chondrocyte cell surface receptors and ultimately have transcriptional effects. Matrix fragments released from cartilage stimulate synovitis. Among the most important cytokines are interleukin (IL) 1β, which exerts transcriptional effects on chondrocytes, stimulating production of proteinases and suppressing cartilage matrix synthesis. Tumor necrosis factor (TNF) α may play a similar role to that of IL-1. These cytokines also induce chondrocytes to synthesize prostaglandin E2 and nitric oxide, which have complex effects on matrix synthesis and degradation. At early stages in the matrix response to injury and in the healthy response to loading, the net effect of cytokine stimulation may be matrix synthesis, but ultimately, the combination of effects on chondrocytes triggers matrix degradation. Enzymes in the matrix are held


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InternalMed_Harrison. to loading, the net effect of cytokine stimulation may be matrix synthesis, but ultimately, the combination of effects on chondrocytes triggers matrix degradation. Enzymes in the matrix are held in check by activation inhibitors, including tissue inhibitor of metalloproteinase (TIMP). Growth factors are also part of this complex network, with BMP-2 and transforming growth factor β playing prominent roles in stimulating the development of osteophytes. Whereas healthy articular cartilage is avascular in part due to angiogenesis inhibitors present in cartilage, disease is characterized by the invasion of blood vessels into cartilage from underlying bone and proliferation of vessels within synovium. This is influenced by vascular endothelial growth factor (VEGF) synthesis in the cartilage and bone. With these blood vessels come nerves that may bring nociceptive innervation.


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InternalMed_Harrison. Probably as a result of chronic oxidative damage, articular chondrocytes exhibit an age-related decline in synthetic capacity while maintaining the ability to produce proinflammatory mediators and matrix-degrading enzymes, findings characteristic of a senescent secretory phenotype. These chondrocytes are unable to maintain tissue homeostasis (such as after insults of a mechanical or inflammatory nature). Thus, with age, cartilage is easily damaged by minor sometimesunnoticedinjuries,includingthosethatarepartofdailyactivities. OA cartilage is characterized by gradual depletion of aggrecan, an unfurling of the tightly woven collagen matrix, and loss of type 2 collagen. With these changes comes increasing vulnerability of cartilage, which loses its compressive stiffness. Joint vulnerability and joint loading are the two major factors contributing to the development of OA. On the one hand, a vulnerable joint whose protectors are dysfunctional can develop OA with minimal


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InternalMed_Harrison. Hyalinecartilage(non-calcified)RANKL,OPG, uPAMMPs, IL-5,IL-8OsteocyteVEGFSclerostinVascularinvasionMatrix fragmentseophyt formation CalcifiedcartilageVEGFBONE REMODELINGSYNOVITISCell surface receptors on chondrocytesactivated by complement attack complex,DAMPS, cytokines and chemokines, WNTs(frizzled), fibronectin fragments and others SYNOVITIS mmentents BONBONBONBONBONBONERERERERERERE REMOEMOEMOEMOEMOEMOEMODELDELDELDELDELDELDELINGNGINGINGINGINGINGINGING titititit nnn ininvasiasionon˜BMPGFVascularGFGGGOstevOstOsteopeophhyteformatmationionHyaline cartilage (non-calcified) S100 proteins (alarmins), DAMPs, complements, IL-1˜, TNF°, IL-15, CCL 19, MCP-1, MIP-1˜RANKL, OPG, uPA MMPs, IL-5, IL-8 TGF--2 OsteocyteVESclerostin invasion Matrix fragments Osteophyte formationCalcified cartilage VEBONE REMODELING SYNOVITIS OOOOsOsststtOOOOOstt TGF-˜BMP-2 ooststststoostst BBBBBBBB tteeeeootteeo llclcl oeroerolcl roero oococcoco yytyteeyoococyte SSScScSSc EEEVEVEVEEEVEVE VascularVascular


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InternalMed_Harrison. VEBONE REMODELING SYNOVITIS OOOOsOsststtOOOOOstt TGF-˜BMP-2 ooststststoostst BBBBBBBB tteeeeootteeo llclcl oeroerolcl roero oococcoco yytyteeyoococyte SSScScSSc EEEVEVEVEEEVEVE VascularVascular inviasioninvasion FGGFGFGGGGGFFFFFGGG FFF EGEGEGGFG F EGEGEGEGEGEGVEVEVEVVEVEVE EGEG TGF-˜BMP-2 xfrmagmexfr magme agag T BB VascularVascular MatrixfMatrixf MM Cell surface receptorbyDAMPSreceptory t b pp yy ememe tnt att kack co lod hssbbanthethers Cell surface receptors on chondrocytes activated by complement attack complex, DAMPS, cytokines and chemokines, WNTs (frizzled), fibronectin fragments and others


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InternalMed_Harrison. FIGUrE 394-3 Selected factors involved in the osteoarthritic process including chondrocytes, bone, and synovium. Synovitis causes release of cytokines, alarmins, damage-associated molecular pattern (DAMP) molecules, and complement, which activate chondrocytes through cell surface receptors. Chondrocytes produce matrix molecules (collagen type 2, aggrecan) and the enzymes responsible for the degradation of the matrix (e.g., ADAMTS-5 and matrix metalloproteinases [MMPs]). Bone invasion occurs through the calcified cartilage, triggered by vascular endothelial growth factor (VEGF) and other molecules. IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor. (From RF Loeser et al: Arthritis Rheum 64:1697, 2012.) Previous damage (e.g., meniscectomy) Bridging muscle weakness Increasing bone density Malalignment Proprioceptive deficiences Susceptibility to OA


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InternalMed_Harrison. Previous damage (e.g., meniscectomy) Bridging muscle weakness Increasing bone density Malalignment Proprioceptive deficiences Susceptibility to OA FIGUrE 394-4 Risk factors for osteoarthritis (OA) either contribute to the susceptibility of the joint (systemic factors or factors in the local joint environment) or increase risk by the load they put on the joint. Usually a combination of loading and susceptibility factors is required to cause disease or its progression. levels of loading, perhaps even levels encountered during everyday activities. On the other hand, in a young joint with competent protectors, a major acute injury or long-term overloading is necessary to precipitate disease. Risk factors for OA can be understood in terms of their effect either on joint vulnerability or on loading (Fig. 394-4).


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InternalMed_Harrison. Age is the most potent risk factor for OA. Radiographic evidence of OA is rare in individuals under age 40; however, in some joints, such as the hands, OA occurs in >50% of persons over age 70. Aging increases joint vulnerability through several mechanisms. Whereas dynamic loading of joints stimulates cartilage matrix synthesis by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. Partly because of this failure to synthesize matrix with loading, cartilage thins with age, and thinner cartilage experiences higher shear stress at basal layers and is at greater risk of cartilage damage. Also, joint protectors fail more often with age. Muscles that bridge the joint become weaker with age and also respond less quickly to oncoming impulses. Sensory nerve input slows with age, retarding the feedback loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less


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InternalMed_Harrison. loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less able to absorb impulses. These factors work in concert to increase the vulnerability of older joints to OA.


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InternalMed_Harrison. Older women are at high risk of OA in all joints, a risk that emerges as women reach their sixth decade. Although hormone loss with menopause may contribute to this risk, there is little understanding of the unique vulnerability of older women versus men to OA. OA is a highly heritable disease, but its heritability is joint specific. Fifty percent of the hand and hip OA in the community is attributable to inheritance, i.e., to disease present in other members of the family. However, the heritable proportion of knee OA is at most 30%, with some studies suggesting no heritability at all. Whereas many people with OA have disease in multiple joints, this “generalized OA” phenotype is rarely inherited and is more often a consequence of aging.


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InternalMed_Harrison. Emerging evidence has identified genetic mutations that confer a high risk of OA, the best replicated is a polymorphism within the growth differentiation factor 5 gene. This polymorphism diminishes the quantity of GDF5; GDF5 has its main influence on joint shape, and genes predisposing to OA are likely to increase risk of disease based on their effects on joint development and shape. United States. However, OA in the knees is at least as com mon, if not more so, in Chinese than in whites from the United States, and knee OA represents a major cause of disability in China, especially in rural areas. Anatomic differences between Chinese and white hips may account for much of the difference in hip OA prevalence, with white hips having a higher prevalence of anatomic predispositions to the development of OA. Persons from Africa, but not African Americans, may also have a very low rate of hip OA.