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joint pain

Jan 22, 202354 min read

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🌱 來自: sxtodx

joint pain🚧 施工中

joint pain

Adam S. Cifu, MD

CHIEF COMPLAINT

PATIENT

Mrs. K is a 75-year-old woman who complains of a painful left knee.

What is the differential diagnosis of joint pain? How would you frame the differential?

CONSTRUCTING A DIFFERENTIAL DIAGNOSIS

The causes of joint pain range from common to rare and from bothersome to life-threatening. Even the most benign causes of joint pain can lead to serious disability. The evaluation of a patient with joint pain calls for a detailed history and physical exam (often focusing on extra-articular findings) and occasionally the analysis of joint fluid, serologies, and radiologic tests.

The differential diagnosis of joint pain can be framed with the use of 3 pivotal questions. First, is a single joint or are multiple joints involved (is the joint pain monoarticular or polyarticular)? If the pain involves just 1 joint, the next question is, is the pain monoarticular or extra-articular? Although this distinction may seem obvious, abnormalities of periarticular structures can mimic articular disease. Finally, are the involved joints inflamed or not? Further down the differential, the acuity of the pain may also be important.

Figure 27-1 shows a useful algorithm organized according to these pivotal points. Because periarticular joint pain is almost always monoarticular, the first pivotal point differentiates monoarticular from polyarticular pain. Periarticular syndromes are discussed briefly at the end of the chapter.

Figure 27-1. Diagnostic approach: joint pain.

The differential diagnosis below is organized by these 3 pivotal points as well. When considering both the algorithm and the differential diagnosis, recognize that all of the monoarticular arthritides can present in a polyarticular distribution, and classically polyarticular diseases may occasionally only affect a single joint. Thus, this organization is useful to organize your thinking but should never be used to exclude diagnoses from consideration.

A.  Monoarticular arthritis

1.  Inflammatory

a.  Infectious

(1)  Nongonococcal septic arthritis

(2)  Gonococcal arthritis

(3)  Lyme disease

b.  Crystalline

(1)  Monosodium urate (gout)

(2)  Calcium pyrophosphate dihydrate deposition disease (CPPD or pseudogout)

2.  Noninflammatory

a.  Osteoarthritis (OA)

b.  Traumatic

c.  Avascular necrosis

B.  Polyarticular arthritis

1.  Inflammatory

a.  Rheumatologic

(1)  Rheumatoid arthritis (RA)

(2)  Systemic lupus erythematosus (SLE)

(3)  Psoriatic arthritis

(4)  Other rheumatic diseases

b.  Infectious

(1)  Bacterial

(a)  Bacterial endocarditis

(b)  Lyme disease

(c)  Gonococcal arthritis

(2)  Viral

(a)  Rubella

(b)  Hepatitis B

(c)  HIV

(d)  Parvovirus

(3)  Postinfectious

(a)  Enteric

(b)  Urogenital

(c)  Rheumatic fever

2.  Noninflammatory: OA

Mrs. K’s symptoms started after she stepped down from a bus with unusual force. The pain became intolerable within about 6 hours of onset and has been present for 3 days now. She otherwise feels well. She reports no fevers, chills, dietary changes, or sick contacts.

On physical exam she is in obvious pain, limping into the exam room on a cane. Her vital signs are temperature, 37.0°C; RR, 12 breaths per minute; BP, 110/70 mm Hg; pulse, 80 bpm. The only abnormality on exam is the left knee. It is red, warm to the touch, and tender to palpation. The range of motion is limited to only about 20 degrees.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

The patient’s symptoms and physical exam clearly localize the problem to articular rather than periarticular structures as the exam reveals an inflamed joint with limited range of motion. Considering the pivotal points in this case, we can limit the differential diagnosis to those diseases that cause acute, monoarticular, inflammatory joint pain. These include septic arthritis, gout, and pseudogout. Traumatic injury to the knee such as a meniscal injury or intra-articular fracture, although suggested by the history, are probably less likely given the mild nature of the injury and the inflammation of the joint.

Salient points of the patient’s presentation are the rapid onset of the pain; the mild, antecedent trauma; and the lack of systemic symptoms, such as fever, fatigue, or weight loss.

Gout is the leading hypothesis given its high incidence, the patient’s age, and the single inflamed joint. CPPD (sometimes referred to as pseudogout) is common in the knee of elderly patients and is high in the differential diagnosis. An infectious arthritis is probably less likely, given the sudden onset and lack of systemic symptoms, but it is a must not miss diagnosis since it would be potentially disastrous if left untreated. Both gonococcal and nongonococcal septic arthritis are possibilities. Lyme disease can affect multiple joints but most commonly causes a monoarticular arthritis of the knee. Table 27-1 lists the differential diagnosis.

Table 27-1. Diagnostic hypotheses for Mrs. K.

Mrs. K has never had a similar episode before. Her other medical problems include diabetes mellitus with diabetic nephropathy, hypertension, and hypercholesterolemia. Her medications are insulin, enalapril, atorvastatin, and hydrochlorothiazide. There is no history of alcohol or drug abuse.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: Gout

Textbook Presentation

Gout most commonly presents in older patients with severe, acute pain of the first metatarsophalangeal (MTP) joint. The pain generally begins acutely and becomes unbearable within hours of onset. Classically, patients say that they are not even able to place a bed sheet over the toe. On physical exam, the first MTP joint is warm, swollen, and red.

Disease Highlights

A.  Gout is the most common inflammatory arthritis and most common crystal-induced arthropathy.

B.  Gouty attacks occur when sodium urate crystallizes in synovial fluid inducing an inflammatory response.

C.  The primary risk factor for gout is hyperuricemia.

D.  The prevalence of gout increases with age and is more common in men than women.

E.  Location

1.  The classic location for gout is the first MTP joint (podagra).

2.  The joints of the lower extremities and the elbows are also common sites (though usually after an initial attack of podagra).

F.  Gouty attacks often occur after abrupt changes in uric acid levels. Common causes are:

1.  Large protein meals

2.  Alcohol binges

3.  Initiation of thiazide or loop diuretics

4.  Initiation of urate-lowering therapy

5.  Worsening kidney disease

G.  Gouty attacks can also be induced by trauma, illness, or surgery.

H.  The initial attack nearly always involves a single joint, while later attacks may be polyarticular (sometimes in contiguous joints).

I.  Forms of gout

1.  Acute gouty arthritis is by far the most common type of gout.

2.  Chronic arthritis can develop in patients who have untreated hyperuricemia.

3.  Tophaceous gout occurs when there is macroscopic deposition of sodium urate crystals in and around joints.

4.  The kidney can also be affected by gout. Sodium urate stones or a urate nephropathy can develop in patients.

J.  Evaluation of a patient with gout

1.  Patients with a new diagnosis of gout should be evaluated for alcoholism, chronic kidney disease, myeloproliferative disorders, and hypertension.

2.  Patients in whom gout develops before the age of thirty should be evaluated for disorders of purine metabolism.

Evidence-Based Diagnosis

A.  Acute, inflammatory, monoarticular arthritis is an absolute indication for arthrocentesis.

B.  Sampling synovial fluid will rule out potentially joint destroying septic arthritis and usually make a diagnosis.

Every acute, inflammatory joint effusion should be aspirated.

C.  Arthrocentesis

1.  Joint fluid should be sent for cell count, Gram stain, culture, and crystal analysis.

2.  Normal joint fluid is small in volume and clear with a very low cell count.

3.  Characteristics of abnormal synovial fluid are shown in Table 27-2. These numbers should be used as estimates.

Table 27-2. Characteristics of synovial fluid.

4.  Joint fluid obtained during an acute flare of a crystal arthritis will be highly inflammatory in nature.

5.  The only setting in which it is reasonable not to aspirate a monoarticular effusion is when a septic joint is extremely unlikely and there is truly no diagnostic question. This may be the case

a.  When a patient has recurrent inflammatory flares secondary to documented process (gout).

b.  When the diagnosis is clear (podagra for gout or joint trauma in a patient with a bleeding diathesis for hemarthrosis).

D.  Clinical diagnosis

1.  Despite the crucial role of arthrocentesis in the diagnosis of acute monoarticular arthritis, the diagnosis of gout can occasionally be made with some certainty without joint aspiration.

2.  The following clinical points make a diagnosis of gout probable:

a.  More than 1 attack of acute arthritis

b.  Maximal inflammation in < 1 day

c.  Monoarthritis

d.  Joint erythema

e.  First MTP involvement

f.  Unilateral MTP arthritis

g.  Unilateral tarsal acute arthritis

h.  Tophus

i.  Asymmetric joint swelling

j.  Hyperuricemia

k.  Bone cysts without erosion on radiograph

l.  Negative joint fluid culture

3.  The predictive values for these findings are

a.  6 or more of the clinical points: sensitivity, 87%; specificity, 96%; LR+, 22; LR–, 0.13

b.  5 or more of the clinical points: sensitivity, 95%; specificity, 89%, LR+, 8.6; LR–, 0.05

c.  Even in the setting of an acute inflammatory arthritis, an elevated serum uric acid (> 7 mg/dL) is only moderately helpful: sensitivity, 90%; specificity, 54%; LR+, 2.0; LR–, 0.19

4.  The presence of 6 findings highly consistent with gout rules in the diagnosis even without arthrocentesis.

5.  Fever may accompany acute attacks.

a.  Present in 44% of patients

b.  10% of patients have fevers > 39.0°C

6.  Other findings that make gout more probable are

a.  Hypertension

b.  Use of thiazide or loop diuretics

c.  Obesity

d.  Alcohol use

Treatment

A.  Therapy for gout is classified as either abortive (to treat an acute flare) or prophylactic (to prevent flares and the destructive effects on the joints and kidneys).

B.  Abortive therapy is outlined in Table 27-3.

Table 27-3. Immediate therapies for gout and their potential adverse effects.

1.  All of the therapies are effective and equally recommended in recent guidelines. The choice is usually made by the potential adverse effects.

2.  Corticosteroids are associated with fewer adverse effects when used short-term for this indication.

C.  Prophylactic therapy

1.  There are 5 basic indications for prophylactic therapy:

a.  Frequent attacks

b.  Disabling attacks

c.  Urate nephrolithiasis

d.  Urate nephropathy

e.  Tophaceous gout

2.  Although not supported by data, prophylactic therapy generally begins with nonpharmacologic interventions to decrease uric acid levels.

a.  Decrease intake of high purine foods (red meat, shellfish, yeast rich foods)

b.  Weight loss

c.  Discontinuation of medications that impair urate excretion (eg, aspirin, thiazide diuretics).

3.  Potential prophylactic treatments are listed below.

a.  Nonsteroidal anti-inflammatory drugs (NSAIDs)

b.  Colchicine

c.  Allopurinol

d.  Febuxostat

e.  Probenecid

f.  Sulfinpyrazone

g.  Uricase agents (eg, pegloticase)

4.  Xanthine oxidase inhibitors

a.  Allopurinol is usually the first antihyperuricemic drug used, although it is relatively contraindicated in patients with chronic kidney disease or liver disease.

b.  Febuxostat is at least equally effective as allopurinol but is less cost-effective.

c.  Urate-lowering therapy does not reduce the risk of gout attacks for at least 6 months and there is no definitive evidence that treated patients have fewer flares than nontreated patients.

d.  If xanthine oxidase inhibitor therapy is ineffective, uric acid excretion should be measured. Patients with low uric acid excretion (present in 80% of patients with gout) should be given a uricosuric agent.

5.  Colchicine should be used during the initiation of urate-lowering therapy to prevent recurrent gouty flares.

a.  NSAIDs may be added if necessary.

b.  Colchicine is usually continued for at least the first 6 months (longer in the case of patients with tophi) of urate-lowering therapy.

MAKING A DIAGNOSIS

The evaluation of this patient clearly requires joint aspiration. Septic arthritis is in the differential of any acutely inflamed joint. Mrs. K has 4 of the findings common for gout (maximal inflammation in < 1 day, monoarthritis, joint erythema, and asymmetric joint swelling), so although gout remains likely, especially given the presence of hypertension and her use of a thiazide, the diagnosis is not certain.

Radiographs of the knee demonstrate evidence of mild OA but no evidence of fracture. Joint fluid is aspirated from the patient’s knee.

Have you crossed a diagnostic threshold for the leading hypothesis, gout? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Calcium Pyrophosphate Deposition Disease (CPPD)

Textbook Presentation

CPPD generally presents in older patients. It may present with an acute flare (pseudogout) or, more commonly, as a degenerative arthritis with suspicious radiographic findings that distinguish it from OA. Patients often have other diseases associated with CPPD, such as hyperparathyroidism.

Disease Highlights

A.  CPPD is a crystal-induced arthropathy that can present in the following ways:

1.  Often asymptomatic: diagnosed as an incidental radiographic finding of chondocalcinosis, the linear calcifications of articular cartilage

2.  Pseudogout

a.  An acute, inflammatory, usually monoarticular arthritis

b.  Can be clinically indistinguishable from gout

3.  CPPD arthropathy

a.  A chronic arthritis that is clinically similar to OA (sometimes referred to pseudo OA)

b.  May affect joints less commonly affected by OA like the wrists, MCPs, and shoulders

4.  A chronic, inflammatory polyarthritis resembling RA

a.  Sometimes referred to as pseudo RA

b.  Seen in small percentage of patients with CPPD (~5%)

5.  Pseudoneuropathic arthropathy (rarely)

a.  Resembles a Charcot joint

b.  Destructive monoarthropathy is seen in this presentation.

B.  There are many other similarities between pseudogout and gout.

1.  Both are caused by the inflammatory response to crystals in the synovial space.

2.  Both cause acute painful monoarticular attacks.

3.  Both can cause polyarticular flares.

4.  Flares can be induced by trauma or illness.

5.  Both can potentially cause destructive arthropathy.

6.  Incidence increases with age.

C.  There are some aspects of the disease quite distinct from gout.

1.  Episodic “gout-like” flares only occur in a small percentage of patients.

2.  As above, CPPD commonly manifests as a degenerative arthritis (in about 50% of patients).

3.  It has highly specific radiologic features.

4.  It most commonly affects the knee.

Although CPPD is commonly thought of as pseudogout, it more commonly presents as a chronic degenerative arthritis.

D.  Pseudogout has been associated with a number of diseases, the most common of which are:

1.  Hyperparathyroidism

2.  Hemochromatosis

3.  Hypomagnesemia

4.  Hypophosphatasia

Evidence-Based Diagnosis

A.  Definite diagnosis of CPPD arthritis requires demonstration of the calcium pyrophosphate crystals in synovial fluid.

B.  Certain radiographic findings are quite suggestive. The classic findings are punctate and linear calcific densities, most commonly seen in the cartilage of the knees, hip, pelvis, and wrist.

C.  The following characteristics should make a clinician consider the diagnosis of CPPD:

1.  Acute arthritis of a large joint, especially the knee, in the absence of hyperuricemia.

2.  Chronic arthritis with acute flares.

3.  Chronic arthritis involving joints that would be atypical for OA such as the wrists, metacarpophalangeal (MCP) joints, and shoulders.

D.  Evaluation of a patient with pseudogout should include testing for related diseases. The evaluation generally includes measuring the levels of the following:

1.  Calcium

2.  Magnesium

3.  Phosphorus

4.  Iron, ferritin, and total iron-binding capacity (TIBC)

5.  In the right setting, markers of other rheumatologic diseases (uric acid, rheumatoid factor [RF], anti-cyclic citrullinated peptide [anti-CCP])

Treatment

A.  Treat any associated underlying disease that is present.

B.  Acute attacks can be managed with:

1.  NSAIDs

2.  Joint aspiration with corticosteroid injection

3.  Colchicine

C.  Chronic degenerative arthritis is difficult to treat. NSAIDs are usually used.

Alternative Diagnosis: Septic Arthritis

Textbook Presentation

Septic arthritis usually presents as subacute joint pain associated with low-grade fever and progressive pain and disability. Because the infection is usually caused by hematogenous spread, a risk factor for bacteremia (such as injection drug use) is sometimes present. Disseminated gonorrhea is discussed separately below.

Disease Highlights

A.  Septic arthritis usually occurs via hematogenous spread of bacteria.

B.  Joint distribution

1.  The knee is the most commonly affected joint.

2.  Monoarticular arthritis is the rule, with multiple joints involved in < 15% of patients.

3.  Infection is most common in previously abnormal joints, such as those affected by OA or RA.

C.  Staphylococcus aureus is the most common organism followed by species of streptococcus.

Evidence-Based Diagnosis

A.  Clinical findings

1.  Fever is present in most patients.

a.  One meta-analysis found that 57% of patients with septic arthritis had fever.

b.  Recognize that this means that over 40% of patients with septic arthritis are afebrile.

c.  Fever > 39.0°C is rare.

2.  Findings predictive of a septic arthritis causing joint pain are recent joint surgery (LR+ 6.9) and the presence of a prosthetic knee or hip in the presence of a skin infection (LR+ 15.0).

Fever cannot distinguish septic arthritis from other forms of monoarticular arthritis. Patients with gout may be febrile while those with septic joints may not be.

B.  Laboratory findings

1.  WBC > 10,000/mcL is seen in only 50% of patients.

2.  Definitive diagnosis is made by Gram stain and culture.

a.  The Gram stain of synovial fluid is positive in about 75% of patients with septic arthritis.

b.  The Gram stain is most likely to be positive when the infecting organism is S aureus; it is less likely to be positive when another organism is the infecting agent.

3.  Elevated synovial fluid WBC count is predictive.

a.  Synovial fluid WBC count > 100,000/mcL: LR+ 28; LR− 0.71.

b.  Lower WBC cut offs are nondiagnostic.

4.  Joint fluid culture is positive in about 90% of cases.

5.  Blood (and sputum, when appropriate) should also be cultured

a.  May help identify an organism if one is not isolated from the synovium

b.  About 50% of patients will have positive blood cultures.

Because of the potential for septic arthritis to cause joint destruction, a single, acutely inflamed joint should be assumed infected until proved otherwise.

Treatment

A.  Antibiotic therapy is directed by Gram stain findings.

B.  Empiric therapy should cover S aureus.

C.  The affected joint should also be drained, either with a needle, arthroscope, or arthrotomy (opening the joint in the operating room).

1.  Small joints can usually be drained and lavaged with serial arthrocentesis.

2.  Large joints usually require surgical drainage.

3.  The knee is an exception, a large joint that, in many cases can be treated with serial arthrocentesis.

D.  Patients who receive treatment within 5 days of symptom onset have the best prognosis.

Alternative Diagnosis: Disseminated Gonorrhea

Textbook Presentation

Disseminated gonorrhea is classically seen in young, sexually active women who have fever and joint pain. The most common presentation is severe pain of the wrists, hands, and knees with warmth and erythema diffusely over the backs of the hands. A rash may sometimes be present.

Disease Highlights

A.  Disseminated gonorrhea is a disease with rheumatologic manifestations that is seen in young, sexually active persons.

B.  Women are 3 times more likely to have the disease than men.

Disseminated gonorrhea usually occurs in patients without a history of a recent sexually transmitted infection.

C.  Disseminated gonorrhea presents in 1 of 2 ways (with a good deal of overlap): a classic septic arthritis or a triad of tenosynovitis, dermatitis, and arthralgia.

1.  The triad presentation reflects a high-grade bacteremia with reactive features.

2.  The tenosynovitis presents predominantly as a polyarthralgia of the hands and wrists.

3.  The rash is a scattered, papular, or vesicular rash.

4.  The more classic, monoarticular septic joint presentation occurs in about 40% of patients.

5.  Table 27-4 gives the frequency of various findings in these 2 types of presentation.

Table 27-4. Physical signs and culture results in patients with disseminated gonorrhea.

Evidence-Based Diagnosis

A.  Diagnosis is based on isolating the organism.

B.  Besides synovial fluid cultures, blood cultures, pharyngeal cultures, and PCR testing of urine or genital swabs should be sent.

C.  If all cultures are negative, the disease can still be diagnosed if there is a high clinical suspicion and a rapid response to appropriate antibiotics.

Negative cultures do not necessarily exclude the diagnosis of disseminated gonorrhea.

Treatment

A.  Ceftriaxone 1 g IV or IM every 24 hours or cefotaxime 1 g IV every 8 hours.

B.  IV therapy is generally recommended for 24–48 hours after improvement.

Alternative Diagnosis: Lyme Disease

Textbook Presentation

Lyme disease presents in different ways at different stages of the disease. A classic presentation of the joint symptoms is a patient with acute, inflammatory knee pain who has been in an area where the disease is endemic. There may be a history of a previous tick bite, rash, or nonspecific febrile illness.

Disease Highlights

A.  Lyme disease is caused by the spirochete Borrelia burgdorferi, transmitted by a number of species of Ixodes ticks.

B.  The tick most commonly transmits the disease during its nymphal stage.

C.  In the United States, the range of the Ixodes tick has spread to include the entire east coast, the south to as far west as central Texas, much of the Midwest (Michigan, Northern Illinois, Wisconsin, Minnesota), and the west coast.

D.  The clinical picture varies somewhat between the United States and Europe and Asia. The presentation in the United States is discussed below.

E.  Peak incidence is in June and July, with disease occurring from March through October.

F.  Transmission from a tick that has been discovered and removed is very low.

1.  Transmission from infected nymphal ticks generally occurs only after 36–48 hours of attachment (longer for adult ticks).

2.  In 1 study, no erythema migrans developed from any tick bite in which the tick was removed in < 72 hours.

G.  Lyme disease is generally divided into 3 stages:

1.  Early localized disease

a.  Skin findings are most common, usually a large area of localized erythema.

(1)  80% of patients have an acute rash.

(2)  50% of the rashes occur below the waist.

(3)  The mean diameter of the rash is 10 cm.

(4)  About 60% of the rashes are an area of homogeneous erythema.

(5)  About 30% of rashes are the more classic target lesion.

(6)  About 10% of the patients have multiple lesions.

Only about 30% of patients with Lyme disease have the classic target rash on presentation.

b.  Other symptoms include

(1)  Myalgias and arthralgias (59%)

(2)  Fever (31%)

(3)  Headache (28%)

2.  Early disseminated disease (weeks to a couple of months after the bite) usually involves the central nervous system (CNS) and the heart.

a.  CNS disease is more common than cardiac and includes headache, facial nerve palsy, lymphocytic meningitis, and radiculopathy.

b.  Cardiac disease generally involves conduction abnormalities (heart block).

3.  Joint symptoms predominate late in the disease.

a.  Occur in about 60% of untreated patients beginning about 6 months after infection.

b.  Monoarticular knee arthritis is the most common finding.

c.  Intermittent attacks or an oligoarticular arthritis may also occur.

d.  A very small proportion of patients go on to have a chronic syndrome dominated by subjective complaints.

Evidence-Based Diagnosis

A.  Definitive diagnosis of Lyme disease is based on clinical characteristics, exposure history, and antibody titers.

B.  Antibodies are insensitive early in the disease and are thus not helpful in the setting of acute infection.

C.  Antibodies are nearly 100% sensitive in the setting of arthritis.

Treatment

A.  There are multiple antibiotic regimens effective in the treatment of localized and disseminated Lyme disease.

B.  Prophylactic treatment with a single dose of doxycycline given after a tick bite is effective at preventing Lyme disease but is generally not recommended given the low likelihood of being infected with Lyme disease after a recognized tick bite, even in endemic areas.

C.  Treatment of arthritis caused by Lyme disease consists of 4 weeks of oral antibiotics.

D.  Chronic symptoms that develop after appropriate treatment of Lyme disease do not respond to intensive antibiotic therapy.

CASE RESOLUTION

Mrs. K’s synovial fluid aspiration yielded 25 mL of translucent, yellow fluid. The WBC was about 55,000/mcL with 56% PMNs. The Gram stain was negative, and crystal exam with polarized light microscopy demonstrates negatively birefringent crystals consistent with monosodium urate crystals, thus making the diagnosis of gout.

The inflammatory joint fluid is consistent with the exam. Acute gout is commonly associated with very inflamed joints, often with very high WBC counts. The positive crystal exam makes the diagnosis of gout.

The patient was treated with NSAIDs and colchicine with a good response. Because this was Mrs. K’s first attack, prophylactic therapy was not instituted.

CHIEF COMPLAINT

PATIENT

Mrs. C is a 50-year-old woman who comes to your office complaining of joint pain. She reports the pain has been present for about 2 years. The pain affects her hands and her wrists. She describes the pain as “a dull aching” and “a stiffness.” It is worst in the morning and improves over 2–3 hours. She says that on particularly bad days she uses NSAIDs with moderate relief.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Although morning stiffness is common with many types of arthritis, Mrs. C’s prolonged symptoms are suggestive of an inflammatory arthritis. She does not seem to have other systemic symptoms, and she has no history of a recent infection. At this point, pivotal features are the polyarticular and inflammatory nature of the joint pain and the chronicity of the symptoms.

Considering these points, as well as the fact that the patient is a middle-aged woman, RA has to lead the differential. The chronicity, age at onset, and joint distribution all support this diagnosis. Psoriatic arthritis can be indistinguishable from RA, especially early in its course, and needs to be considered. SLE can also present as a chronic, inflammatory arthritis. The patient is older than the average age of onset for SLE, and we have not heard about other organ system involvement.

Degenerative arthropathies, such as OA and CPPD, should be considered, but the joint distribution and inflammatory nature of the arthritis makes these less likely. Table 27-5 lists the differential diagnosis.

Table 27-5. Diagnostic hypotheses for Mrs. C.

Mrs. C is otherwise well, except for a history of mild hypertension managed with an angiotensin-receptor blocker. She reports no other joint pains. She does not have a history of psoriasis.

Her vital signs are temperature, 37.1°C; BP, 128/84 mm Hg; pulse, 84 bpm; RR, 14 breaths per minute. Her general physical exam is essentially normal. There is a 2/6 systolic ejection murmur. Joint exam reveals limited range of motion of the MCPs and wrists bilaterally. There is swelling of the third and fourth MCP on the right and the third on the left. There is pain at the extremes of motion and a boggy quality to the joints. A detailed skin exam is normal. The patient is wearing nail polish on the day of the visit.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: RA

Textbook Presentation

RA is most commonly seen in middle-aged patients with a symmetric polyarthritis manifesting itself with painful, stiff, and swollen hands. Morning stiffness is often a predominant symptom. Swollen and tender wrists, MCP, and proximal interphalangeal (PIP) joints are usually seen on exam. Laboratory evaluation may reveal an anemia of inflammation and positive RF and anti-citrullinated protein antibody (ACPA, sometimes called anti-CCP).

Disease Highlights

A.  RA is the paradigm for idiopathic inflammatory arthritides.

B.  The sine qua non of RA is the presence of an inflammatory synovitis, most commonly involving the hands. This synovitis eventually forms a destructive pannus that injures articular and periarticular tissue.

C.  RA is common and debilitating.

1.  The prevalence of RA is about 1%.

2.  As many of 28% of patients stop working within a year of diagnosis.

RA should be considered in any adult with a chronic, symmetric polyarthritis.

D.  Common findings in RA are:

1.  Symmetric arthritis of the hands

2.  Presence of serum RF and ACPA

3.  Presence of radiographic changes typical of RA on hand and wrist radiographs.

2.  Prolonged morning stiffness (> 30–60 minutes) is a classic finding in those with inflammatory arthritis.

Prolonged morning stiffness is a clue to an inflammatory arthritis.

E.  The joints most commonly involved are

1.  Hand

a.  Wrists, MCP, and PIP joints are most commonly affected.

b.  Distal interphalangeal (DIP) joints are often spared.

c.  Ulnar deviation of the MCPs as well as swan neck and boutonnière deformities are classic findings.

d.  Figure 27-2 shows a hand with some of the classic findings of RA.

Figure 27-2. Rheumatoid arthritis of the hand.

2.  Elbow

3.  Knee

4.  Ankle

5.  Cervical spine

a.  Usually presents as neck pain and stiffness.

b.  C1–C2 instability can occur secondary to associated tenosynovitis.

(1)  This can produce cervical myelopathy.

(2)  Advisable to radiographically image the cervical spines of patients with RA prior to elective endotracheal intubation.

F.  Once RA is established, joint destruction begins to occur and can be seen on radiographs. The chronic synovitis causes erosions of bone and cartilage.

G.  Long-standing RA can cause severe joint deformity through destruction of the joint and injury to the periarticular structures.

H.  Nonarticular findings in RA

1.  Rheumatoid nodules, when present, are usually over extensor surfaces.

2.  Dry eyes are common.

3.  Pulmonary nodules or interstitial lung disease

4.  Pericardial disease

a.  Asymptomatic pericardial effusion is most common.

b.  Restrictive pericarditis can occur.

5.  Anemia of inflammation (see Chapter 6) is a typical finding in RA.

Evidence-Based Diagnosis

A.  The diagnosis of RA can be difficult because it may resemble other causes of inflammatory arthritis around the time of onset.

B.  Morning stiffness is a not a useful diagnostic test for RA. Test characteristics for morning stiffness > 30 minutes:

1.  Sensitivity, 74–77%; specificity, 48–52%

2.  LR+, 1.4–1.6; LR–, 0.54–0.44.

C.  Serologies

1.  RF is a nonspecific test.

a.  It is occasionally positive in healthy people and in a number of inflammatory states such as infections, sarcoidosis, and periodontal disease.

b.  The test characteristics of RF vary in different studies but a meta-analysis found the following: sensitivity, 69%; specificity, 85%; LR+, 4.86; LR−, 0.38.

2.  ACPA is a newer test that is more predictive of RA than RF. The same meta-analysis found the following: sensitivity, 62%; specificity, 95%; LR+, 12.46; LR−, 0.36.

A positive ACPA is very predictive of a diagnosis of RA.

3.  In practice, RF and ACPA are used together. Patients are at high risk for RA when these tests are positive.

D.  The American College of Rheumatology (ACR) has developed diagnostic criteria for RA (Table 27-6).

Table 27-6. 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA.

1.  These criteria are meant to be used in patients who have clinical synovitis of at least 1 joint not explained by another disease.

2.  A score of ≥ 6/10 fulfills the criteria.

3.  Although meant to standardize research and not to be used as diagnostic criteria, they are helpful in highlighting the clinical characteristics of RA.

4.  The test characteristics of the ACR criteria vary depending on when in the course of the illness they are evaluated and the end point used for the diagnosis of RA. Representative sensitivities and specificities: 62–84% and 60–78%, respectively.

E.  Other very specific findings are the presence of rheumatoid nodules (LR+ > 30) and consistent radiographic changes (LR+ 11).

Treatment

A.  The treatment for RA is really the purview of the rheumatologist.

B.  Early, aggressive therapy is thought to markedly improve long-term outcomes.

C.  The treatments are often divided into those that treat the symptoms of the disease and those that modify the course of the disease.

D.  The drugs used to treat the symptoms of the disease are:

1.  NSAIDs

a.  Generally used early in the course of the disease for symptom relief while a diagnosis is being made.

b.  Rarely, patients with very mild disease can remain on these medications alone.

2.  Corticosteroids

a.  Generally provide excellent symptom control but due to significant long-term side effects are used in the lowest dose and for the least time possible.

b.  Their effect on slowing joint destruction from RA is controversial.

E.  Disease-modifying antirheumatic drugs (DMARDs)

1.  Traditional DMARDs include

a.  Hydroxychloroquine

b.  Methotrexate

c.  Leflunomide

d.  Sulfasalazine

2.  Biologic DMARDs include

a.  Etanercept

b.  Infliximab

c.  Abatacept

d.  Rituximab

3.  The newest DMARD tofacitinib is a drug that inhibits cytokine and growth factor signaling through interference with Janus kinases.

4.  A common course of therapy would begin with low-dose prednisone and methotrexate. In patients not adequately controlled, the next step is would be the addition of hydroxychloroquine or biologic, such as etanercept.

MAKING A DIAGNOSIS

The presentation of Mrs. C’s symptoms is typical for RA. She already fulfills 4 of the ACR criteria for RA. Further evaluation should be directed toward gathering other information that might suggest RA and make other diagnoses less likely.

A CBC with iron studies, RF, ACPA, and antinuclear antibodies (ANA) are done. Radiographs are ordered with fine details of the hands.

Have you crossed a diagnostic threshold for the leading hypothesis, RA? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Psoriatic Arthritis

Textbook Presentation

Psoriatic arthritis most commonly presents as joint pain in middle-aged patients with a history of psoriasis. There are signs and symptoms of an inflammatory arthritis often involving the wrists, MCP, PIP, and DIP joints. Exam of the skin reveals psoriasis and psoriatic nail changes.

Disease Highlights

A.  Psoriasis is a very common skin disease that can be complicated by arthritis.

B.  Psoriatic arthritis is one of the seronegative spondyloarthropathies.

1.  The seronegative spondyloarthropathies are diseases characterized by inflammatory axial spine involvement, asymmetric peripheral arthritis, enthesopathy, and inflammatory eye diseases.

2.  Patients with these diseases classically have a negative ANA and RF, giving the group the “seronegative” moniker.

3.  Other seronegative spondyloarthropathies are ankylosing spondylitis, reactive arthritis, and the arthritis associated with inflammatory bowel disease.

C.  The distribution of the arthritis in psoriatic arthritis is variable but follows 3 general presentations:

1.  Oligoarthritis often involving large joints and the hands. Dactylitis, a swelling of the entire finger causing a “sausage digit” secondary to both arthritis and tenosynovitis, is a classic finding.

2.  A polyarthritis similar to RA

3.  A spinal arthritis

D.  Psoriatic arthritis can be indistinguishable from RA, especially early in the course of both diseases.

1.  Radiographs of the hands can show erosions.

2.  About 10% of patients with psoriatic arthritis have a positive RF.

E.  Distinguishing features include:

1.  Common involvement of DIP joints

2.  Spine involvement that is uncommon in RA

3.  Arthritis mutilans, a syndrome in which there is marked boney destruction around joints causing “telescoping digits.”

Evidence-Based Diagnosis

A.  The most diagnostic feature of psoriatic arthritis is the presence of psoriasis.

1.  Psoriasis precedes the development of arthritis in about 70% of cases.

2.  Arthritis and psoriasis begin contemporaneously in about 15% of patients.

3.  15% of patients do not have psoriasis (at the time of their arthritis diagnosis) although there may be a family history of the skin disease.

B.  A very careful skin exam should be done in all patients in whom the diagnosis is suspected.

C.  Nail findings

1.  Psoriasis can cause recognizable changes in the nails (pitted, “oil stained” nails).

2.  Nail changes occur in only about 20% of people with psoriasis but in about 80% of people with psoriasis and arthritis.

3.  Nail changes are especially common in people with DIP arthritis.

A detailed skin and nail exam is important when considering the diagnosis of psoriatic arthritis. Nail polish should be removed for the visit.

Treatment

The treatment of psoriatic arthritis is similar to the treatment of RA.

Alternative Diagnosis: SLE

Textbook Presentation

SLE classically presents in a young woman with fatigue and arthritis, commonly of the hands. There are often suspicious findings in the history such as an episode of pleuritis or undiagnosed anemia.

Disease Highlights

A.  SLE is a systemic autoimmune disease primarily affecting women of childbearing age.

B.  Various groups are more prone to disease.

1.  Female:male ratio is about 9:1.

2.  About 5% of patients report a first-degree relative with the disease.

3.  Women of color are most commonly affected.

C.  Almost every organ can be involved, although the joints, skin, serosa, and kidneys are most commonly affected.

D.  The pathogenesis of the disease is related to the formation of autoantibodies to a number of nuclear antigens. The ANA is the most common.

E.  The most common features of SLE, both at presentation and later in follow-up, are listed in Table 27-7.

Table 27-7. Clinical manifestations of SLE at onset and during disease.

Evidence-Based Diagnosis

A.  The diagnosis of SLE, especially in people with mild disease, can be difficult.

B.  The ACR has developed criteria to standardize the diagnosis for research purposes.

1.  The criteria are:

a.  Malar rash

b.  Discoid rash

c.  Photosensitivity

d.  Oral ulcers

e.  Arthritis (nonerosive arthritis)

f.  Serositis (pleuritis or pericarditis)

g.  Kidney disorder (proteinuria or cellular casts)

h.  Neurologic disorder (headache, seizures, or psychosis without other cause)

i.  Hematologic disorder (hemolytic anemia or any cytopenia)

j.  Immunologic disorder (anti-ds-DNA, anti-SM, or antiphospholipid antibodies)

k.  Positive ANA

2.  The diagnosis of SLE requires the presence of 4 or more of these criteria.

3.  Although the same reservations about using diagnostic criteria clinically that were discussed above in the section on RA apply here, the SLE criteria are frequently used.

C.  Newer diagnostic criteria have also been developed by the Systemic Lupus International Collaborating Clinics (SLICC) group.

1.  These criteria, referenced at the end of the chapter, give somewhat greater primacy to serologic and pathologic evidence of SLE.

2.  A patient may fulfill the criteria with biopsy-proven SLE nephritis and the presence of ANA or anti-ds-DNA antibodies.

D.  The test characteristics for the diagnostic criteria are given in Table 27-8. Also included in this table are the test characteristics for the various individual criteria.

Table 27-8. Test characteristics for the ACR and SLICC criteria and individual criteria in the diagnosis of SLE.

E.  Satisfaction of the ACR criteria or the presence of the anti-Sm antibody is highly supportive of the diagnosis of SLE. Failure to fulfill the SLICC criteria or the absence of ANA argue strongly against SLE.

F.  Autoantibodies

1.  Measuring autoantibodies in SLE provides important diagnostic information.

2.  ANA and anti-ds-DNA

a.  ANA is the most sensitive test for SLE. It is nonspecific.

b.  Anti-ds-DNA and anti-Sm are highly specific. They are also associated with the presence of lupus nephritis.

c.  ANA does not vary with disease activity while anti-ds-DNA does.

A negative ANA essentially rules out SLE. A positive anti-ds-DNA or anti-Sm essentially rules in SLE.

d.  Staining patterns are often reported with the ANA.

(1)  These patterns correlate, to some extent, with the other specific antibodies discussed below and their use has, to a great extent, been supplanted by these tests.

(2)  In general, the meanings of the staining patterns are as follows:

(a)  Homogeneous: Seen in SLE, RA, and drug-induced lupus

(b)  Peripheral: Most specific pattern for SLE

(c)  Speckled: Least specific pattern. Commonly seen with low titer ANAs in people without rheumatic disease

(d)  Nucleolar: Common in patients with scleroderma and Raynaud phenomenon.

3.  Other serologies are helpful because they tend to be associated with various subsets of disease.

a.  Anti-RNP: Associated with Raynaud phenomenon and myositis and highly sensitive for mixed connective tissue disease.

b.  Anti-SSA/Ro and anti-SSB/La: Associated with Sjögren syndrome and photosensitivity

c.  Anti-ribosomal P: Highly specific for SLE

4.  Table 27-9 outlines a variety of serologies that may be obtained in persons in whom rheumatologic disease is suspected.

Table 27-9. Common serologies in rheumatologic diseases.

G.  Complement

1.  Complement levels are helpful in tracking the activity of SLE but are nonspecific.

2.  C3, C4, and CH50 levels tend to decline during episodes of lupus activity.

Treatment

A.  Similar to RA, the treatment of SLE is complicated and the purview of the rheumatologist.

B.  In general, NSAIDs, corticosteroids, and immunosuppressants are the mainstays of therapy.

C.  NSAIDs are generally used for symptomatic relief of inflammatory symptoms with careful monitoring because of their potential nephrotoxic effects.

D.  Corticosteroids and hydroxychloroquine are commonly used in long-term therapy and high-dose corticosteroids are used for disease exacerbations.

E.  Cyclophosphamide, mycophenolate mofetil, and azathioprine are the most commonly used immunosuppressants in SLE. They are used most widely for the treatment of lupus nephritis.

CASE RESOLUTION

Mrs. C’s laboratory and radiology test results are as follows: Hb, 10.5 g/dL; HCT, 31.0%; serum ferritin, 95 ng/mL (nl > 45 ng/mL); serum iron, 36 mcg/dL (nl 40–160 mcg/dL); TIBC, 200 mcg/dL (nl 230–430 mcg/dL); RF, 253 international units/mL (nl < 10 international units/mL); anti-CCP 1000 units/mL (nl < 100 units/mL) ANA, 2560 titer (nl < 80); anti-ds-DNA, < 10 titer (nl < 10); radiographs of hand, periarticular erosions of the 3 clinically involved MCP joints.

The diagnosis of RA is now fairly certain. The clinical picture, as well as the laboratory tests showing an anemia of chronic inflammation, elevated RF and anti-CCP, and positive ANA, all support the diagnosis. (About 40% of patients with RA have positive ANAs.) While the first step in management is to control Mrs. C’s symptoms (NSAIDs and prednisone are likely to accomplish this), she should be referred immediately to a rheumatologist so DMARD therapy can be initiated. There are already signs of joint destruction on the radiographs.

CHIEF COMPLAINT

PATIENT

Ms. T is a 21-year-old woman who comes to see you complaining of rash and joint pain for the past 2 days. She reports being well until 2 days ago when she awoke with pain in both knees and mild pain in both wrists. No other joints were involved. She also noted a nonpruritic rash on her distal arms and legs. She describes the rash as “splotchy.” The joint pain has worsened over the last 2 days, and she reports that both her knees are swollen.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Ms. T has acute onset polyarticular joint symptoms. From her history of knee swelling, it is likely that she has arthritis rather than arthralgia. The pivotal points are acute onset and polyarticular involvement. Considering these points, and limiting the differential diagnosis based on the patient’s demographics and associated symptoms, we are able to come up with a fairly short list of probable etiologies.

Given the acuity of the illness, infectious arthritides need to be strongly considered. Many viral illnesses can cause arthritis. Parvovirus is probably the most common. Bacterial illnesses can cause polyarthritis in myriad ways. Septic arthritides, discussed above, can be polyarticular as can disseminated gonorrhea. Bacterial endocarditis can cause aseptic polyarthritis and can cause arthralgias. Acute rheumatic fever classically causes a migratory polyarthritis and rash. Lyme disease, discussed above, is most commonly monoarticular but can present in a polyarticular fashion. Reactive arthritis, occurring after enteric or urogenital infections, is also a possibility.

Although less likely, given the acute onset, primary rheumatologic diseases must also be considered. In a young woman with arthritis and a rash, SLE needs to be included on the differential diagnosis. As discussed above, rash, arthralgias, and arthritis are among the most common presenting symptoms in patients with SLE. In addition to the acuity of the onset, the lack of other organ system involvement would be a little unusual for patients with SLE. RA would be less likely given the patient’s age; however, Still disease, a variant of RA, may present acutely in young patients.

Given that the viral arthritides are more common than bacterial ones and, as far as we know, the patient has been previously well, viral arthritis is probably more likely than bacterial disease. Table 27-10 lists the differential diagnosis.

Table 27-10. Diagnostic hypotheses for Ms. T.

On further history, Ms. T reports that, for the last 2–3 days she has experienced fatigue, myalgias, and fever to 39.4°C. There were no other symptoms.

She reports no travel outside Chicago, where she is a college junior, for the last year. She reports no known exposure to ticks and admits that she is seldom outside of the city. She does not use recreational drugs. She is not sexually active.

On physical exam, she appears healthy. Her vital signs are temperature, 36.9°C; BP, 106/68 mm Hg; pulse, 84 bpm; RR, 14 breaths per minute. On extremity exam, her wrists have normal range of motion but there is pain with extremes of flexion and extension in the wrists and MCPs. There is mildly decreased range of motion and warmth in the knees as well as small effusions.

Skin exam reveals a diffuse erythematous rash with macules on the hands, feet, and distal extremities. Palms and soles are spared. The remainder of the exam is normal. There is no heart murmur.

The patient’s history supports our initial hypothesis. The history of a recent febrile illness makes a viral or other postinfectious arthritis most likely. Lyme disease and bacterial endocarditis are very unlikely given her lack of suspicious exposure and the fact that she is otherwise presently well. SLE remains on the differential but is less likely.

In a patient with acute polyarthritis, a detailed history of recent illnesses must be taken.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: Parvovirus

Textbook Presentation

Parvovirus is commonly seen in young people who are in contact with children (mothers, teachers, daycare workers, and pediatricians). Symptomatic parvovirus may present with a flu-like illness, macular rash, arthralgias/arthritis, or any combination of these symptoms. Joint symptoms generally improve over the course of weeks.

Disease Highlights

A.  There are 5 major manifestations of parvovirus infection in humans.

1.  Erythema infectiosum (fifth disease) in children

2.  Acute arthropathy in adults

3.  Transient aplastic crises in patients with chronic hemolytic diseases

4.  Chronic anemia in immunocompromised persons

5.  Fetal death complicating maternal infection prior to 20 weeks gestation.

B.  In adults, infection usually includes some combination of viral symptoms, arthritis, and rash.

1.  Nonspecific viral symptoms are seen in about half of infected patients and include fever, malaise, headache, myalgia, diarrhea, and pruritus.

2.  Arthropathy accompanies about 30% of adult infections.

a.  The arthritis is a symmetric polyarthritis.

b.  Commonly involved joints are elbows, wrists, knees, ankles, feet.

3.  The rash is seen in about 35% of people and lasts 2–3 days.

a.  It is usually a peripheral macular rash that occasionally spreads to the trunk.

b.  Many different rashes have been described.

C.  The incidence of parvovirus infection peaks between January and June.

D.  Attack rates are 50–60%.

E.  Contact with children is common among patients.

F.  Other viruses cause arthritis less commonly (Table 27-11).

Table 27-11. Other viral causes of arthritis.1

Evidence-Based Diagnosis

A.  The diagnosis of parvovirus is made by identifying parvovirus specific IgM in the serum of patients with a suspicious symptom complex.

B.  The differential diagnosis of parvovirus includes SLE and the differentiation of these diseases can be challenging.

1.  Both may present with arthritis, arthralgias, and rash.

2.  Both are more common in women than men.

3.  ANA can be transiently elevated in patients with parvovirus.

Treatment

A.  The treatment of parvovirus is symptomatic.

B.  NSAIDs generally provide good relief of symptoms.

C.  Symptoms usually resolve within a couple of weeks, but as many as 10% of patients have symptoms that last longer.

MAKING A DIAGNOSIS

Ms. T was treated with NSAIDs and given a return appointment in 1 week. Laboratory tests were performed and revealed the following: basic metabolic panel, normal; liver biochemical tests, normal; WBC, 6800/mcL; Hb, 12.9 g/dL; HCT, 37.9%; platelet, 182,000/mcL; ESR, 68 mm/h; rapid strep test, negative. HIV test, ANA, streptococcal antibody titers, blood cultures, and parvovirus titer were pending when she left her first appointment.

Have you crossed a diagnostic threshold for the leading hypothesis, parvovirus? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Parvovirus, or another viral arthritis, is highest on the differential diagnosis. Laboratory testing to rule in the most likely disease and rule out other possible diseases is essential. The normal liver biochemical tests rule out hepatitis B as the cause of the patient’s symptoms. Negative blood cultures will make endocarditis even less likely than it is based on the history alone. Lyme disease was thought so unlikely that serologies were not sent. Stool cultures were sent to evaluate the possibility of a reactive arthritis.

Alternative Diagnosis: Reactive Arthritis

Textbook Presentation

Reactive arthritis classically presents as a subacute, oligoarticular arthritis, often involving the knees, ankles, and back. Physical exam reveals arthritis. There may be a history of an antecedent infection and symptoms of urethritis and conjunctivitis.

Disease Highlights

A.  Reactive arthritis is an acute arthritis complicating enteric and urogenital infections.

B.  Manifestations of the disease begin 1–4 weeks after the inciting infection, but more often than not, the inciting infection is asymptomatic.

Reactive arthritis often presents without an apparent antecedent infection.

C.  Reactive arthritis is one of the seronegative spondyloarthropathies and thus shares features with other diseases in this class.

1.  The arthritis is typically an asymmetric oligoarthritis, usually involving the large joints of the lower extremities.

a.  Knees, ankles, and joints in the feet are the most common locations.

b.  Dactylitis, heel pain, and back pain also occur in 50–60% of patients.

2.  Presence of the HLA B-27 antigen predicts more severe arthritis and more protracted disease.

D.  The presentation of reactive arthritis often includes extra-articular manifestations such as enthesitis, tendinitis, bursitis, urethritis, or conjunctivitis.

1.  Urethritis is frequently the first finding followed by eye findings and then arthritis.

2.  Other associated findings include rash, nail changes, and oral ulcers.

3.  Table 27-12 shows the prevalence of various findings from an early study.

Table 27-12. Features of reactive arthritis.

E.  The bacteria commonly implicated in reactive arthritis are

1.  Shigella

2.  Salmonella

3.  Yersinia

4.  Campylobacter

5.  Chlamydia

F.  The incidence of reactive arthritis varies by organism.

1.  Studies of outbreaks of gastrointestinal infections have provided incidences of 0–29%.

2.  Population-based studies, performed on people who had positive stool cultures for an enteric pathogen, have yielded incidence on the order of 1–3 cases/100,000.

G.  Gastrointestinal infections are equally likely to be the inciting event in men and women. Arthritis complicating chlamydial infection is rare in women.

H.  The age at diagnosis is generally in the 30s.

Evidence-Based Diagnosis

A.  The diagnosis is a clinical one.

B.  Although there are no agreed upon diagnostic criteria, proposed ones have included major criteria (asymmetric monoarticular or oligoarticular arthritis of the lower extremities and a preceding enteric or urogenital infection) and minor criteria (evidence of a triggering infection or persistent evidence of synovial inflammation).

C.  A high clinical suspicion is warranted in a young patient with an inflammatory, asymmetric oligoarthritis.

Treatment

A.  In most patients, symptoms resolve within 1 year.

B.  NSAIDs are useful in treating the acute symptoms.

C.  Culture-positive enteric or chlamydial infections should be treated.

D.  A subset of patients experience relapse, development of a chronic arthritis, or development of ankylosing spondylitis.

E.  There has been some recent suggestion that patients with a chronic arthritis, negative traditional cultures, but evidence of persistent chlamydial infection (positive synovial fluid or blood polymerase chain reaction [PCR]) be treated with antibiotics.

Alternative Diagnosis: Rheumatic Fever

Textbook Presentation

Rheumatic fever classically presents in a child in the weeks following streptococcal pharyngitis. The 5 cardinal manifestations are arthritis, carditis, rash, subcutaneous nodules, and chorea. The arthritis is typically migratory, involving the knees, ankles, and hands.

Disease Highlights

A.  Rheumatic fever is an inflammatory disease that follows streptococcal pharyngitis by 2–4 weeks.

B.  Unlike in children, clinical documentation of a previous streptococcal infection is rare in adults and the most pronounced symptoms are joint pain and stiffness.

C.  The arthritis is classically a migratory polyarthritis.

1.  Individual joints are usually affected for less than a week.

2.  The joints in the legs are usually affected first.

3.  Subjective complaints are often more prominent than objective findings.

D.  Carditis

1.  May involve any, or all, parts of the heart—pericarditis, myocarditis, endocarditis, or pancarditis.

2.  Endocarditis commonly causes valvular lesions that may progress over years to symptomatic valve disease, especially mitral stenosis.

Evidence-Based Diagnosis

A.  The diagnosis of rheumatic fever is based on the Jones Criteria.

B.  The criteria require evidence of an antecedent group A streptococcal infection (culture, antibody titer) with either 2 major criteria or 1 major and 2 minor criteria (Table 27-13).

Table 27-13. Jones criteria for the rheumatic fever.

Treatment

A.  Anti-inflammatories

1.  Aspirin is the mainstay of therapy.

2.  Corticosteroids are given to patients with severe carditis.

B.  Antibiotics

1.  Penicillin for eradication of streptococcal infection.

2.  Lifelong prophylactic therapy with penicillin is usually recommended after the initial therapy.

CASE RESOLUTION

Parvovirus clearly fits this patient’s presentation. Reactive arthritis is possible although the patient has not had a gastrointestinal or urogenital infection. Rheumatic fever seems less likely. Although she does have multiple Jones criteria (polyarthritis, arthralgia, elevated erythrocyte sedimentation rate [ESR]) and although the lack of a sore throat during the recent illness is not terribly helpful, the patient does not have a migratory arthritis or evidence of present streptococcal carriage.

Ms. T’s final test results included negative streptococcal antibody titers and blood cultures. Her ANA was positive (titer 1:80) as was her parvovirus IgM. She was treated with NSAIDs with good relief of her symptoms. Her rash resolved over 3–4 days, and joint pain was gone at a follow-up visit 2 weeks later.

CHIEF COMPLAINT

PATIENT

Mr. L is a 55-year-old man who comes to see you complaining of right hip pain. He reports suffering with the pain for about 2 years. The pain is worst in the morning and evening. In the morning, it is associated with stiffness. The stiffness lasts about 5 minutes and then improves. At the end of the day he routinely feels a dull ache that is worse if he has had a very active day. He recently noticed that he is unable to cross his legs (right over left) without discomfort.

At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?

RANKING THE DIFFERENTIAL DIAGNOSIS

Mr. L is a middle-aged man with chronic, monoarticular symptoms. The time course, single joint involvement and noninflammatory nature of the process (we have not heard about warmth, erythema, or prolonged morning stiffness) are the pivotal points in this case.

Reviewing the initial differential diagnosis, the articular process that best fits the history is OA, a chronic, noninflammatory, often monoarticular arthritis. OA is so common in older adults that it becomes the diagnosis to disprove in all patients who have pain at all consistent with OA. The disease most commonly affects the fingers, knees, hips, and spine. CPPD, as was discussed previously, is another chronic degenerative arthritis that could produce similar symptoms and should be considered.

In patients with noninflammatory monoarticular symptoms, we also have to consider the specific periarticular symptoms that can affect the particular joint.

When considering the periarticular syndromes that cause hip pain, it is important to identify where exactly the patient feels the pain. Lumbar spine disease with radicular symptoms can cause pain in the buttocks or lateral hip. Trochanteric bursitis is a common cause of lateral hip pain. Inguinal hernias may cause groin pain. Femoral stress fractures may cause groin or lateral hip pain. Although such stress fractures are rare and are most commonly seen in young women, they should not be missed. Use of bisphosphonates or corticosteroids should raise the possibility of other causes of hip abnormalities, femoral shaft fractures and osteonecrosis, respectively. Table 27-14 lists the differential diagnosis.

Table 27-14. Diagnostic hypotheses for Mr. L.

“Hip pain” is a nonspecific complaint. It is important to identify the exact location of the pain.

When asked to pinpoint the location of his pain, Mr. L reports that he primarily feels it in the groin. Rest, ibuprofen, and heat all seem to help the pain. He comes in today because he is in more constant pain, and he has begun to limp on bad days. His past history is remarkable only for mild asthma. He denies any previous injury to the hip. He has never been hospitalized or taken corticosteroids. His only medication is albuterol.

Vital signs are temperature, 37.0°C; RR, 12 breaths per minute; BP, 132/70 mm Hg; pulse, 72 bpm. On physical exam, there is no warmth, erythema, or tenderness around the hip or over the trochanteric bursa. Testicular and hernia exam are normal. Flexion and extension of the right hip are nearly normal. There is decreased range of motion in hip rotation with about 10 degrees in internal rotation and 20 degrees in external rotation.

Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?

Leading Hypothesis: OA

Textbook Presentation

OA most commonly presents in older patients as chronic joint pain and stiffness. Pain is usually worse with activity and improves with rest. Knees, hips, and hands are most commonly affected. On examination of the joints, there is bony enlargement without significant effusions. Mild tenderness may be present along the joint lines. There is limited range of motion. Radiographs are diagnostic.

Disease Highlights

A.  OA is a disease of aging, with peak prevalence in the eighth decade. However, as obesity is a risk factor, it may be seen in much younger people with severe obesity.

B.  More common in women than men

C.  Although often referred to as “wear and tear” arthritis, the pathophysiology is actually quite complicated.

D.  Joint destruction manifests as a loss of cartilage with change to the underlying bone seen as bony sclerosis and osteophyte formation.

E.  Joint distribution

1.  OA is most common in the knees, hips, hands, and spine.

2.  Nearly any joint can be affected.

3.  Non–weight-bearing joints other than the hand, such as the elbow, wrist, and shoulder, are less commonly affected by OA. The ankle is also not a common location.

F.  Classic symptoms include

1.  Pain with activity

2.  Relief with rest

3.  Periarticular tenderness

4.  Occasional mildly inflammatory flares

5.  Gelling: Joint stiffness brought on by rest and rapidly resolving with activity.

6.  Late in the disease, constant pain with joint deformation and severe disability is common.

G.  Physical exam findings

1.  In general, there is bony enlargement, crepitus, and decreased range of motion without signs of inflammation or synovial thickening.

2.  Knee

a.  Crepitus

b.  Tenderness on joint line

c.  Varus or valgus displacement of the lower leg related to asymmetric loss of the articular cartilage.

3.  Hip

a.  Marked decrease first in internal and then external rotation

b.  Groin pain with rotation of the hip

4.  Hand

a.  Tenderness and bony enlargement of the first carpometacarpal joint

b.  Joint involvement in decreasing order of prevalence is DIP, PIP, MCP.

c.  Heberden nodes (prominent osteophytes of the DIP joints)

d.  Bouchard nodes (prominent osteophytes of the PIP joints)

e.  Figure 27-3 shows a hand with some of the classic findings of OA.

Figure 27-3. Osteoarthritis of the hand.

5.  Spine

a.  Signs of spinal OA vary depending on location.

b.  Pain and limited range of motion are common.

c.  Radicular symptoms resulting from osteophyte impingement on nerve roots is seen.

d.  Spinal stenosis with associated symptoms (radiculopathy and pseudoclaudication) can result from bony hypertrophy (see Chapter 7, Back Pain).

Evidence-Based Diagnosis

A.  The diagnosis of OA is clinical, based on a compatible history, physical exam, and radiologic findings.

B.  Because of the high prevalence of OA, the diagnosis should lead the differential in any patient with suspicious symptoms.

B.  Diagnostic criteria have been established.

1.  Hand

a.  Pain, aching, or stiffness

b.  Three of the following

(1)  Hard tissue enlargement of at least 2 of the following joints:

(a)  Second and third DIP joints

(b)  Second and third PIP joints

(c)  First MCP joint

(2)  Hard tissue enlargement of 2 or more DIP joints

(3)  Fewer than 3 swollen MCP joints

(4)  Deformity of at least 1 of the joints listed in above entries a through c.

2.  Hip

a.  Hip pain

b.  Two of the following:

(1)  ESR < 20 mm/h

(2)  Osteophytes on radiograph

(3)  Joint-space narrowing on radiograph

3.  Knee: There are multiple criteria, the easiest to remember is

a.  Knee pain

b.  Osteophytes on radiograph, and

c.  One of the following

(1)  Age older than 50 years

(2)  Stiffness < 30 minutes

(3)  Crepitus

D.  The test characteristics for these criteria are shown in Table 27-15.

Table 27-15. Test characteristics for the diagnostic criteria of OA.

Treatment

A.  Nonpharmacologic

1.  Patient education and improved social support have been shown to improve pain and improve the efficacy of pharmacologic interventions.

2.  Weight loss decreases the symptoms of lower extremity OA.

3.  Physical and occupational therapy can help patients with functional impairment due to OA.

B.  Pharmacologic

1.  There is a remarkable amount of controversy regarding the most effective therapies for OA. The controversy stems from the lack of high-quality, comparative, long-term trials of therapies.

2.  Acetaminophen

a.  Frequently used as initial therapy given its low side-effect profile.

b.  Recent data has questioned its efficacy.

3.  NSAIDs are probably more effective than acetaminophen for severe OA.

4.  Oral combinations of glucosamine and chondroitan sulfate probably are modestly effective in some patients and have a very favorable side-effect profile.

5.  Intra-articular medications

a.  Intra-articular corticosteroids are very effective for pain relief in acute flares of OA.

b.  Hyaluronic acid given by intra-articular injection may provide a small benefit to some patients.

6.  Tramadol and opioid analgesics are reasonable choices for patients with severe symptoms.

C.  Surgical

1.  Arthroscopic surgery for OA is probably ineffective.

2.  Hip and knee replacement can have remarkable effects on decreasing pain and improving function in patients in whom conservative therapy has failed.

MAKING A DIAGNOSIS

Mr. L’s history and physical exam are very suggestive of OA, but CPPD remains a possibility. Most of the periarticular syndromes that were considered initially have been made unlikely by the exam. Lumbar spine disease with radicular symptoms would not cause the limited range of motion that is seen on the patient’s exam. The predominant symptom in patients with trochanteric bursitis is tenderness over the bursa. Mr. L does not have a hernia on exam. Femoral stress fractures may cause groin pain but should not really cause limited range of motion. That said, this is a diagnosis that must not be missed, so further consideration should be given.

The working diagnosis of OA was made and the patient was given 1000 mg of acetaminophen twice daily. A radiograph was ordered.

Have you crossed a diagnostic threshold for the leading hypothesis, OA? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?

Alternative Diagnosis: Femoral Stress Fractures

Textbook Presentation

Femoral stress fractures are most commonly seen in young female athletes. Symptoms begin acutely with groin pain that persists and worsens as the day progresses. On physical exam, there is often mild tenderness over the proximal one-third of the femur. Range of motion of the hip is normal. Radiographs are usually normal.

Disease Highlights

A.  Like other types of stress fractures, femoral stress fractures are most common in:

1.  Athletes who have recently increased their level of training

2.  Women

3.  Persons with decreased bone density

B.  The most common stress fractures are tibial and metatarsal.

C.  Femoral stress fractures usually present with hip or groin pain with preserved range of motion of the hip.

Evidence-Based Diagnosis

A.  Stress fractures in general and femoral stress fractures in particular are often not seen on initial radiographs.

B.  MRI and bone scans are considered the diagnostic test of choice.

Treatment

A.  Many stress fractures heal with reduced physical activity and short-term immobilization.

B.  Femoral stress fractures may resolve with decreased weight bearing (crutches) or may require casting or internal fixation.

CASE RESOLUTION

The patient’s hip radiograph showed changes consistent with OA.

The combination of a high clinical suspicion, pain, and consistent findings on a radiograph confirms the diagnosis.

REVIEW OF OTHER IMPORTANT DISEASES

Periarticular Syndromes

There are textbooks written about the numerous periarticular syndromes that commonly present to primary care physicians, orthopedists, and rheumatologists. Table 27-16 briefly outlines some of the most common.

Table 27-16. Some common periarticular pain syndromes.

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