A Sleeping Giant

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.

History PMH      Progress 1     Lab     Progress 2     CT Scan    Biopsy   Commentary

History

A 71-year-old woman presented to her primary care doctor with abdominal pain and night sweats. Four weeks earlier, a headache, left maxillary sinus pressure, and intermittent night sweats had developed. Amoxicillin was prescribed for presumed sinusitis. Although her symptoms initially abated, after 1 week of treatment, new, diffuse abdominal pain developed, which was dull in character and persisted throughout the day. In addition, she had loose stools, with three to four bowel movements daily; associated nausea and anorexia; and worsening of her night sweats. During the 2 weeks before she saw her physician, she lost 4.5 kg (10 lb) in body weight and her headache recurred, but without chills, melena, hematochezia, or abdominal distention.

 

This elderly woman initially reported new maxillary facial pressure and headache. A critical first step in the evaluation of new headache or head pain is to rule out the possibility that the patient's headache is associated with another condition, a circumstance that would require prompt evaluation. Signs and symptoms of secondary headache, including an onset after 50 years of age, focal neurologic deficits, unusual severity, exacerbation of pain with a change in position, constitutional symptoms, and fever, require specific and possibly urgent diagnosis and management. Although the patient is older than 50 years of age, none of her initial symptoms point to a secondary cause of her headache; however, she subsequently returned with abdominal pain, nausea, and loose stools in addition to marked constitutional symptoms, including anorexia, weight loss, and worsening night sweats. The temporal association between the onset of abdominal symptoms, especially diarrhea, and the antibiotic therapy raises immediate concern about the possibility of colitis associated with Clostridium difficile. A medical history should be obtained to determine whether the patient has had cancer or immunosuppression, which would suggest the possibility of tumor recurrence or opportunistic infection, respectively.

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The patient's medical history was notable for hypertension, Raynaud's phenomenon, psoriatic arthritis, and anemia of chronic disease. One year before the diagnosis of psoriatic arthritis was made, polymyalgia rheumatica was suspected, since her symptoms included morning stiffness and pain in the shoulders and knees. Prednisone, at a dose of 10 mg per day, was prescribed, but when there was no improvement in her condition, the diagnosis of psoriatic arthritis was made. At that time, a patchy skin eruption and increased articular symptoms were noted. She reported having undergone a cholecystectomy and a hysterectomy many years before presentation. Her medications and dietary supplements included lisinopril, alendronate, calcium, vitamin D, a multivitamin, and aspirin. Etanercept, prescribed 9 months earlier for her arthritis, was discontinued at the onset of her sinus symptoms. Before beginning treatment with etanercept, the patient had a negative result of a tuberculin test with purified protein derivative. She had no known drug allergies and no history of tobacco use, alcohol abuse, or illicit-drug use. Her family history included a mother with rheumatoid arthritis, a father with psoriasis, and a sister with scleroderma. There was no record of recent travel.

 

Although a low dose of glucocorticoids is often effective in the treatment of polymyalgia rheumatica, the lack of response to a 10-mg dose of prednisone does not rule out this diagnosis. Treatment with a tumor necrosis factor α (TNF-α) antagonist (i.e., etanercept) has been associated with a slightly increased risk of infection by both common and unusual organisms. In particular, there is a higher risk of bacterial infection (e.g., with listeria, nocardia, or various mycobacteria) that are associated with granulomatous host responses. The subacute nature of the patient's gastrointestinal symptoms would be atypical for listeriosis, and the absence of pulmonary or neurologic symptoms makes nocardiosis unlikely. Moreover, the risk of these infections is higher with infliximab than with etanercept. The patient had been screened for latent tuberculous infection with a purified protein derivative, which is the standard of care before initiation of treatment with a TNF-α antagonist. Her prominent constitutional symptoms and the personal and family history of autoimmune and connective-tissue disease also call for consideration of a broad spectrum of possible noninfectious inflammatory causes of her symptoms.

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The patient was referred to the emergency room for further evaluation. She appeared to be in mild distress. Her temperature was 39.0°C (102.2°F), her heart rate 103 beats per minute, her blood pressure 138/60 mm Hg, her respiratory rate 18 breaths per minute, and her oxygen saturation 98% while she was breathing ambient air. There was no tenderness over the maxillary or frontal sinuses or the temporal arteries, nor was there any cervical, supraclavicular, axillary, or inguinal lymphadenopathy. Cardiac examination revealed a regular rate and rhythm, with a 2/6 holosystolic murmur at the left sternal border, without radiation. Pulses were equal throughout, and there were no bruits. Bowel sounds were normal. The abdomen was diffusely tender on palpation, and there was no distention, rebound, or guarding; the liver span was normal, and the spleen was not palpable. There was no stool in the rectal vault, and the residue was guaiac-negative. There was no rash. Examination of the joints revealed no evidence of synovitis. The remainder of the physical examination was normal.

 

The patient is febrile and tachycardic, but her blood pressure is normal, making a diagnosis of acute sepsis unlikely. There is no evidence of active sinusitis, and there is no lymphadenopathy. It would be important to know whether her murmur was present during previous physical examinations. The presence of a new or preexisting murmur might increase suspicion for endocarditis if there is no other apparent source of her fever. Her abdomen is tender, but there are no peritoneal signs. The findings on examination of the skin and joints reduce the likelihood of a synovial inflammatory process or septic arthritis.

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The initial laboratory evaluation revealed a serum sodium level of 138 mmol per liter, potassium 5.3 mmol per liter, chloride 103 mmol per liter, bicarbonate 26 mmol per liter, blood urea nitrogen 16 mg per deciliter (5.7 mmol per liter), creatinine 0.8 mg per deciliter (71 μmol per liter), alanine aminotransferase 107 U per liter, aspartate aminotransferase 82 U per liter, alkaline phosphatase 567 U per liter, and total bilirubin 0.3 mg per deciliter (5.1 μmol per liter). Levels of amylase and lipase were normal. A complete blood count revealed a white-cell count of 10,800 per cubic millimeter, a hematocrit of 27.6%, a hemoglobin level of 8.8 mg per deciliter, and a platelet count of 892,000 per cubic millimeter. The mean corpuscular volume was 85 μm3, and the red-cell distribution width 13.5%. A manual differential count revealed 70% neutrophils, 0% band forms, 21% lymphocytes, 5% monocytes, and 4% eosinophils. Urinalysis showed 0 to 2 leukocytes, 3 to 5 erythrocytes, and rare bacteria per high-power field. A chest radiograph was normal.

 

The laboratory results are consistent with a systemic inflammatory response, possibly of rheumatologic origin. The absence of a clinically significant leukocytosis or a left shift (an increase in levels of immature neutrophil forms circulating in the peripheral blood) reduces the likelihood that the patient's symptoms have an infectious cause, although this possibility cannot be ruled out. The complete blood count reveals anemia and a marked thrombocytosis. Although she has mild hyperkalemia, the normal anion gap reduces the likelihood of acute mesenteric infarction. The increase in the level of alkaline phosphatase is out of proportion to the mild elevation in aminotransferases, and the bilirubin level is normal; this pattern may be seen in cases of early biliary obstruction or may be a nonspecific marker of inflammation. At this point, I would order further tests to differentiate a possible flare of her rheumatologic disease from an infectious process. Elevations in the erythrocyte sedimentation rate and the level of C-reactive protein can occur in the presence of both processes; a positive result of antinuclear antibody testing is nonspecific, but high levels suggest rheumatologic disease. I would also order iron studies, blood cultures, stool tests forC. difficile, and serologic tests for hepatitis.

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The patient remained ill, with fever and abdominal pain. The erythrocyte sedimentation rate was more than 140 mm per hour, and the level of C-reactive protein was 200 mg per liter (normal range, 0 to 7.9). A test for antinuclear antibodies was positive, with a titer of 1:160, and tests for antibodies against double-stranded DNA, Smith antigen, and Ro, La, and ribonuclear protein were negative. Tests for antibodies against smooth muscle and filamentous actin were also negative. The iron level was 17 μg per deciliter (3.0 μmol per liter), ferritin 618 μg per liter, and haptoglobin 566 mg per deciliter (normal range, 30 to 200). The reticulocyte count was 1.7%. Blood cultures, stool cultures, and the results of an enzyme-linked immunosorbent assay (ELISA) for C. difficile toxin were negative, as were serologic tests for viral hepatitis and a rapid plasma reagin test.

 

The elevations in the erythrocyte sedimentation rate and levels of C-reactive protein, ferritin, and haptoglobin are markers of an acute-phase reaction that confirm the presence of an intense inflammatory response; however, serologic tests that would indicate a flare of a specific autoimmune process were negative. An extreme elevation of the erythrocyte sedimentation rate (≥100 mm per hour) is found in several conditions, including cancers, infections, and collagen vascular diseases. The results of the iron studies in this patient are consistent with the known diagnosis of anemia of chronic disease. Given her persistent symptoms and nonspecific examination results, a computed tomographic (CT) scan of the abdomen is warranted.

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CT of the abdomen revealed abnormal intimal thickening of the thoracic and abdominal aorta (Figure 1AFIGURE 1Abdominal CT and MRI Scans Obtained before Treatment.) that extended into the superior mesenteric artery and the proximal left common iliac artery. The liver and spleen appeared normal, and there was no small-bowel dilatation, ascites, free air, or bowel-wall thickening. There was no evidence of appendiceal-wall thickening, enhancement, or fat stranding, which would suggest appendicitis. A T1-weighted magnetic resonance imaging (MRI) scan of the chest and upper abdomen, obtained after the administration of gadolinium, confirmed diffuse intimal thickening and enhancement in the wall of the thoracic and abdominal aorta (Figure 1B). There was moderate-to-severe narrowing at the origin of the left subclavian artery and mild narrowing at the origins of the celiac and superior mesenteric arteries.

 

The thickening of the arterial wall seen on both the CT and MRI scans could be the result of atherosclerosis or inflammation; however, the area of enhancement in the vessel wall probably indicates edema, suggesting an inflammatory process. In addition to the vessel inflammation and edema seen on the CT scan, the MRI scan shows stenoses at various points along the aortic branches; together, these findings suggest aortitis rather than atherosclerosis. Takayasu's arteritis can affect the aorta and its branches, but this disease typically occurs before a person reaches 40 years of age. Infectious causes of aortitis include syphilis and salmonellosis, but the results of a rapid plasma reagin test and blood cultures were negative. Whereas a form of periaortitis can occur with severe atherosclerotic disease, the imaging studies did not show this degree of atherosclerosis. Certain connective-tissue diseases are associated with aortitis, including Behçet's syndrome, relapsing polychondritis, and giant-cell arteritis. All these conditions can be manifested as arthralgia. However, the absence of aphthous or genital ulcers reduces the likelihood of Behçet's syndrome, and there are none of the deformities that can occur as a result of weakened cartilage in polychondritis. Given the patient's age, giant-cell arteritis is the most likely unifying diagnosis. Biopsy of the temporal artery should be performed.

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Temporal-artery biopsy revealed dense inflammatory infiltrates, including polymorphonuclear leukocytes, lymphocytes, macrophages, and eosinophils, extending into the media, with fragmentation of the internal elastic lamina. These findings are consistent with a diagnosis of giant-cell arteritis (Figure 2FIGURE 2Biopsy Specimens of the Temporal Artery.).

 

The inflammation and stenoses seen on abdominal imaging studies reflect the widespread involvement of giant-cell arteritis. In rare instances, patients with giant-cell arteritis that involves the abdominal aorta have mesenteric ischemia or infarction, which leads to presentations similar to that of this patient. Glucocorticoid therapy should be initiated.

 

High-dose glucocorticoid therapy was started immediately, and the patient's abdominal pain and constitutional symptoms rapidly resolved. Follow-up abdominal imaging performed 4 months later showed resolution of the thickening and enhancement in the aorta (Figure 3FIGURE 3Abdominal MRI Scans Obtained before and after Glucocorticoid Treatment.).

 

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COMMENTARY

Giant-cell arteritis, the most common form of systemic vasculitis in patients older than 50 years of age, typically involves large and medium-size arteries.The classic manifestations are headache, jaw claudication, polymyalgia rheumatica, and visual symptoms. 1 However, 40% of patients present with less typical manifestations, such as masses in the breast or ovary, peripheral neuropathy, the syndrome of inappropriate antidiuretic hormone secretion, or mesenteric ischemia.2 Dermatologic manifestations, such as edema, urticaria, purpura, and scalp ulceration and necrosis, occur infrequently. In a large case series of patients with giant-cell arteritis, the erythrocyte sedimentation rate was higher than 50 mm per hour in more than 95% of patients and higher than 100 mm per hour in more than 40%.3 Patients with an erythrocyte sedimentation rate below 40 mm per hour tend to have fewer constitutional symptoms.4 Elevated levels of C-reactive protein and hepatic enzymes (particularly alkaline phosphatase), a normocytic anemia, hypoalbuminemia, reactive thrombocytosis, and increased immunoglobulin levels are also commonly associated with giant-cell arteritis.3 These laboratory abnormalities typically resolve with glucocorticoid therapy.

In retrospect, many of the patient's presenting symptoms were consistent with a diagnosis of giant-cell arteritis. A headache occurs in two thirds of patients with this disorder. Although usually temporal, the pain may be frontal, occipital, or generalized. In addition, the headache can wax and wane; this may explain the apparent improvement with antibiotics in this patient. Approximately 40 to 60% of patients with giant-cell arteritis have symptoms of polymyalgia rheumatica1; thus, the patient's earlier presentation with joint pain may represent the clinical overlap of these conditions, since both can include distal articular involvement. Although most patients with giant-cell arteritis present with symptoms referable to vasculitis of the cranial arteries, the characteristic inflammation can involve any large or medium-size artery, including the aorta and its branches. Vessel-wall inflammation with luminal narrowing may cause ischemia that is manifested as jaw claudication (owing to the occlusion of arteries that feed the pterygoid muscles), vision loss or diplopia (owing to the involvement of the ophthalmic artery), arm claudication (owing to the involvement of the subclavian artery), or abdominal pain (owing to mesenteric ischemia). The physical examination should include assessment of the temporal artery for tenderness and attention to diminished pulses or bruits indicative of more widespread vasculitis. Mesenteric ischemia is an uncommon manifestation, largely because of the rich vascular supply to the mesentery and the patchy segmental pattern of inflammation that is characteristic of giant-cell arteritis.5 Catastrophic complications such as bowel infarction, aortic dissection, or frank aortic rupture can occur, although they are rare.

In addition to CT and MRI, the use of 18F-fluorodeoxyglucose–positron-emission tomography (18F-FDG–PET) and ultrasonography can help to visualize inflammation in the aorta and visceral vessels.6,7 Although 18F-FDG–PET can be particularly helpful in diagnosing large-vessel vasculitis, its usefulness for clinical monitoring remains uncertain, since 18F-FDG can persist in tissues for up to 6 months, despite the clinical resolution of symptoms.7 Because patients with giant-cell arteritis have an increased risk of aortic aneurysm as a late complication,2 a high index of suspicion for aneurysm is warranted in the presence of abdominal symptoms. Ultrasonography can be used not only in the initial diagnosis of aortitis but also in screening for the development of abdominal aneurysm.

Ultimately, this patient was successfully treated with glucocorticoids. Acute cases of uncomplicated giant-cell arteritis can generally be controlled with the administration of 40 to 60 mg of prednisone daily; this dose is typically tapered slowly over a period of 9 to 12 months. For patients with visual loss, aortitis, or other widespread involvement, a higher dose is recommended (e.g., 1000 mg of methylprednisolone administered intravenously each day for 3 days, followed by oral therapy at a dose of 1 mg per kilogram of body weight per day).8,9, Methotrexate, infliximab, and etanercept have been evaluated for use as glucocorticoid-sparing agents in randomized, placebo-controlled trials, but the data from these studies are conflicting; further investigation is needed. 10-12 A phase 2 randomized trial designed to compare long-term outcomes and remission and relapse rates after treatment with glucocorticoids, with or without methotrexate, is ongoing (ClinicalTrials.gov number, NCT00004686).

This patient's presentation and clinical course underscore the need to consider a diagnosis of giant-cell arteritis when manifestations of the involvement of large arteries are present — even in the absence of classic cranial manifestations. Although the clinical symptoms of aortitis are present in a minority of patients with giant-cell arteritis, failure to detect this underrecognized complication can have devastating consequences. Given the high prevalence of giant-cell arteritis, particularly among elderly patients, clinicians must be alert to the less typical manifestations of this common disease

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