Arvika R 2019

The n e w e ng l a n d j o u r na l of m e dic i n e
Case Records of the Massachusetts General Hospital
Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Alyssa Y. Castillo, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors
Case 17-2019: A 44-Year-Old Man with Joint

Pain, Weight Loss, and Chest Pain
Sheila L. Arvikar, M.D., Sara R. Schoenfeld, M.D., Andrew S. Fox, M.D.,
Varsha K. Tanguturi, M.D., and Lena D. Stuart, M.D.
Pr e sen tat ion of C a se
Dr. Sara R. Schoenfeld: A 44-year-old man was admitted to this hospital because of From the Departments of Medicine
joint pain, unintentional weight loss, and chest pain. (S.L.A., S.R.S., V.K.T.), Radiology (A.S.F.),
and Pathology (L.D.S.), Massachusetts
Ten months before admission, arthralgias developed in the shoulders. After General Hospital, and the Departments
2 months of discomfort, the patient was evaluated by a rheumatologist at another of Medicine (S.L.A., S.R.S., V.K.T.), Radi‑
hospital. Magnetic resonance imaging (MRI) of the shoulders was reportedly nor- ology (A.S.F.), and Pathology (L.D.S.),
Harvard Medical School — both in Bos‑
mal. Piroxicam was prescribed, and glucocorticoid injections to the shoulders were ton.
administered. During the next 4 months, arthralgias developed in the fingers and
N Engl J Med 2019;380:2157-67.
knees. A diagnosis of fibromyalgia was made by the rheumatologist. Naproxen DOI: 10.1056/NEJMcpc1900419
was prescribed at a dose of 250 to 500 mg two or three times daily, as needed, Copyright © 2019 Massachusetts Medical Society.
and additional glucocorticoid injections to the shoulders were administered.

Six weeks before admission, anorexia, odynophagia, and epigastric pain devel-
oped. Two weeks later, the patient began to have episodic anterior pleuritic pain,
which was characterized as sharp and was worse when he was in the supine posi-
tion; he also had intermittent dyspnea and nonproductive cough. He had fatigue
that was sometimes severe enough to prevent him from getting out of bed. One
week before admission, subjective fevers and increased dyspnea occurred.
One day before admission, the patient’s sister thought that the patient appeared
weak and ill and took him to the emergency department of a second hospital.
Laboratory test results were notable for a white-cell count of 2000 per cubic milli-
meter (normal range, 4500 to 11,000) and a hematocrit of 21% (normal range, 41 to
53). Imaging studies were obtained.
Dr. Andrew S. Fox: A posteroanterior chest radiograph showed an enlarged car-
diac silhouette, changes consistent with small bilateral pleural effusions, and mild
interstitial pulmonary edema (Fig. 1A). Computed tomography (CT) of the abdomen
and pelvis, performed after the administration of intravenous contrast material,
revealed small-volume ascites with peritoneal enhancement (Fig. 1B), a moderate-
to-large circumferential pericardial effusion, and small bilateral pleural effusions
(Fig. 1C).
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A B
C D
Figure 1. Imaging Studies.

A posteroanterior chest radiograph (Panel A) shows an enlarged cardiac silhouette (arrowhead), small bilateral pleural
effusions (arrows), and mild interstitial pulmonary edema. An axial contrast‑enhanced CT scan of the abdomen and
pelvis (Panel B) shows small‑volume ascites with peritoneal enhancement (arrow). An axial contrast‑enhanced CT
scan of the lower chest (Panel C) shows a moderate‑to‑large pericardial effusion with pericardial thickening (arrow‑
head) and small bilateral pleural effusions (arrows). A repeat axial contrast‑enhanced CT scan of the chest (Panels D
and E) shows enlargement of the pericardial effusion with pericardial enhancement (Panel D, arrowhead), enlarge‑
ment of the bilateral pleural effusions (Panel D, arrows), and enlarged axillary lymph nodes (Panel E, arrow).
Dr. Schoenfeld: The patient was transferred to an unintentional weight loss of 18 kg during
the emergency department of this hospital for the past year, polyuria, and a pruritic rash on the
further evaluation and treatment. A review of arms that had some sloughing and spared the
systems was notable for fatigue, mild bilateral hands. He had no night sweats, chills, melena,
joint pain, pleuritic pain, intermittent dyspnea, hematochezia, diarrhea, photosensitivity, dry eyes
nonproductive cough, anorexia, odynophagia, or mouth, Raynaud’s phenomenon, urinary symp-
2158 n engl j med 380;22 nejm.org May 30, 2019

Case Records of the Massachuset ts Gener al Hospital
toms, penile lesion or discharge, orthopnea, or sium, bilirubin, amylase, lipase, and thyrotropin
edema. were normal; additional laboratory test results
The patient’s medical history was notable for are shown in Table 1. Urinalysis was notable for
malaria and depression. Medications included yellow, slightly cloudy urine, with 1+ urobilino-
bupropion and naproxen as needed. Diphenhydra gen (normal value, negative), 2+ protein (normal
mine had caused oral and facial swelling and value, negative), 0 to 2 erythrocytes per high-
pruritus. The patient was born and raised in power field (normal range, 0 to 2), and 3 to 5 leu-
sub-Saharan Africa and had immigrated to New kocytes per high-power field (normal range, <10).
England 18 years earlier; he had not traveled An electrocardiogram showed sinus rhythm at a
outside the United States in 15 years. He was rate of 96 beats per minute, subtle PR-segment
currently unemployed. He was divorced and had depression, and borderline low limb-lead voltage.
been sexually active with women, most recently A chest radiograph showed an enlarged cardiac
7 months before the current presentation. He silhouette and small bilateral pleural effusions.
lived with his sister and his two young children; Echocardiography was performed.
one son had had symptoms of an upper respira- Dr. Varsha K. Tanguturi: Echocardiography re-
tory infection 2 weeks earlier. The patient revealed normal left ventricular size and function.
ported that he had had a 7-year period of heavy There was a moderate-sized pericardial effusion
beer drinking but had been abstinent for almost with diffuse fibrin deposition. There was brief
20 years; he had smoked 1 pack of cigarettes right ventricular diastolic inversion without sub-
daily for 12 years but had quit 15 years earlier. stantial respirophasic variation (i.e., variation from
There was no history of illicit drug use. There expiration to inspiration) in the intracardiac
was no family history of heart disease, human Doppler-flow velocities. The inferior vena cava
immunodeficiency virus (HIV) infection, tuber- was not dilated.
culosis, autoimmune disease, or cancer. Dr. Schoenfeld: Intravenous normal saline and
On examination, the temperature was 37.7°C, esomeprazole were administered, and the pa-
the heart rate 100 beats per minute, the blood pres- tient was admitted to the cardiology unit of this
sure 93/57 mm Hg (pulsus paradoxus, 12 mm Hg), hospital.
the respiratory rate 18 breaths per minute, and the On the second day, the patient’s temperature
oxygen saturation 96% while the patient was reached 39.1°C. Blood specimens were obtained
breathing ambient air. The height was 173 cm, for culture, and an induced-sputum specimen
the weight 54.3 kg, and the body-mass index was obtained for microbiologic studies, including
(the weight in kilograms divided by the square mycobacterial smear and culture. Testing of a
of the height in meters) 18.1. The patient had nasopharyngeal sample was negative for influ-
signs of chronic illness, including cachexia and enza A and B. Screening tests for HIV types 1 and
bitemporal wasting. The jugular venous pressure 2 and HIV p24 antigen, antibodies to Lyme dis-
was 14 cm of water. He had a yellow coating on ease, and heterophile antibodies were negative.
the tongue but no lesions in the mouth. He had Serologic testing for IgG antibodies to cytomega-
scaling and dry skin on the arms and chest but lovirus was positive. A purified protein derivative
no overt rash. Diffuse subcentimeter lymph nodes was planted to assess for a response to Mycobacte-
in the cervical chain were palpable, as were larger rium tuberculosis antigens. The systolic blood pres-
bilateral axillary lymph nodes. The heart rhythm sure remained within a range of 90 to 100 mm Hg,
was tachycardic and distant, and the lungs were with the heart rate ranging from 100 to 110 beats
clear. There was mild epigastric tenderness, with- per minute; runs of nonsustained ventricular
out rebound or guarding. Shoulder abduction tachycardia occurred, the longest of which was
was limited to 90 degrees bilaterally, and there 28 beats. Intravenous magnesium and amioda-
was pain on external rotation. The knees were rone were administered.
warm, with moderate effusions, and there was On the third day, the patient’s temperature
pain on knee flexion. The patient had synovitis reached 39.7°C. The systolic blood pressure re-
and tenderness of the wrists and proximal inter- mained within a range of 90 to 100 mm Hg, and
phalangeal joints. The rest of the examination runs of nonsustained ventricular tachycardia per-
was normal. sisted. The prothrombin time was 14.5 seconds
Results of blood tests for phosphorus, magne- (normal range, 11.0 to 14.0), the partial-thrombo-

Table 1. Laboratory Data.*

plastin time 36.4 seconds (normal range, 22.0 to
35.0), and the prothrombin-time international
Reference Range, On Evaluation, normalized ratio 1.1 (normal range, 0.9 to 1.1).
Variable Adults† This Hospital
Additional imaging studies were obtained.
Hemoglobin (g/dl) 13.5–17.5 6.1 Dr. Fox: CT of the chest, performed after the
Hematocrit (%) 41.0–53.0 20.3 administration of intravenous contrast material,
Mean corpuscular volume (fl) 80.0–100.0 72.2 revealed enlargement of the bilateral pleural ef-
Mean corpuscular hemoglobin (pg) 26.0–34.0 21.7 fusions to a moderate size, with loculation of
Mean corpuscular hemoglobin level (g/dl) 31.0–37.0 30.0
pleural effusions on the right side, as well as
enlargement of the pericardial effusion (Fig. 1D).
White-cell count (per mm3) 4500–11,000 2800
There were enlarged bilateral axillary lymph
Differential count (%) nodes (Fig. 1E).
Neutrophils 40–70 80.7 Dr. Schoenfeld: On the fourth day, the patient’s
Lymphocytes 22–44 13.3 temperature was 38.8°C. The heart rate increased
Monocytes 4–11 3.9 to 120 beats per minute, and the systolic blood
Eosinophils 0–8 0.7 pressure was 80 to 90 mm Hg.
Dr. Tanguturi: Repeat echocardiography revealed
Basophils 0–3 0.0
preserved left ventricular function. There was a
Platelet count (per mm3) 150,000–400,000 313,000
large circumferential pericardial effusion (mea-
Sodium (mmol/liter) 135–145 136 suring 3 cm); the pericardial effusion was larger
Potassium (mmol/liter) 3.4–5.0 4.0 than it had been on the echocardiogram ob-
Chloride (mmol/liter) 100–108 101 tained 3 days earlier and was causing diastolic
Carbon dioxide (mmol/liter) 23–32 23 inversion of the right ventricular free wall and
Urea nitrogen (mg/dl) 8–25 23
right atrium (Fig. 2). The presence of right ven-
tricular diastolic inversion suggests increased
Creatinine (mg/dl) 0.60–1.50 0.95
intrapericardial pressure and a 20% decrease in
Glucose (mg/dl) 70–110 73
cardiac output, and the presence of right atrial
Calcium (mg/dl) 8.5–10.5 7.9 compression during more than one third of the
Total protein (g/dl) 6.0–8.3 5.7 cardiac cycle is nearly 100% sensitive and spe-
Albumin (g/dl) 3.3–5.0 2.5 cific for tamponade.1 There was diffuse fibrin
Alanine aminotransferase (U/liter) 10–55 58 deposition along the visceral pericardium, a find-
ing suggestive of chronicity. There was respiro-
Aspartate aminotransferase (U/liter) 10–40 70
phasic variation of 40% in the Doppler-flow
Alkaline phosphatase (U/liter) 45–115 252
velocities across the mitral valve. Respirophasic
Troponin T (ng/ml) <0.03 <0.01 variation of at least 30% in the Doppler-flow
Erythrocyte sedimentation rate (mm/hr) 0–13 105 velocities across the mitral valve is considered to
C-reactive protein (mg/liter) <8.0 86.0 be suggestive of cardiac tamponade caused by
Lactate dehydrogenase (U/liter) 110–210 273 increased filling of the right ventricle during
Iron (μg/dl) 30–160 9
inspiration, with compression of the right ven-
tricular free wall and subsequent decreased fill-
Iron-binding capacity (μg/dl) 230–404 103
ing of the left ventricle.1 There was new dilata-
Ferritin (μg/liter) 10–200 1921
tion of the inferior vena cava without compression
* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. during inspiration, a finding suggestive of ele-
To convert the values for creatinine to micromoles per liter, multiply by 88.4. vated pressures on the right side of the heart.
To convert the values for glucose to millimoles per liter, multiply by 0.05551. To Catheterization of the right side of the heart
convert the values for calcium to millimoles per liter, multiply by 0.250. To con‑
vert the values for iron and iron-binding capacity to micromoles per liter, mul‑ revealed elevation and equalization of diastol-
tiply by 0.1791. ic pressures, with a right atrial pressure of
† Reference values are affected by many variables, including the patient popu
lation and the laboratory methods used. The ranges used at Massachusetts
20 mm Hg, a right ventricular end-diastolic pres-
General Hospital are for adults who are not pregnant and do not have medi‑ sure of 24 mm Hg, and a pulmonary capillary
cal conditions that could affect the results. They may therefore not be appro‑ wedge pressure of 20 mm Hg; these findings are
priate for all patients.
consistent with cardiac tamponade. Pericardio-

A B
C D
Figure 2. Echocardiographic Studies.

A transthoracic echocardiogram obtained in a subcostal view (Panel A) shows a circumferential pericardial effusion
with diastolic compression of the right atrium (arrow). A parasternal long‑axis view of the heart (Panel B) shows an
anterior effusion with compression of the right ventricular free wall (arrow). An additional subcostal view (Panel C)
shows a dilated inferior vena cava with no compression with respiration. On analysis of respirophasic variation in
the transmitral Doppler‑flow velocities (Panel D), the Doppler‑flow velocities across the mitral valve show up to
40% variation (normal range, <20%) from expiration to inspiration (arrows).
centesis was notable for retrieval of 570 ml of antibodies, antibodies to hepatitis B virus, and
bloody fluid, which reduced the intrapericardial IgM antibodies to parvovirus.
pressure from 18 mm Hg to 3 mm Hg. Diagnostic test results were received, and ad-
Dr. Schoenfeld: Gram’s staining of the pericar- ditional diagnostic tests were performed.
dial fluid revealed abundant neutrophils and very
few mononuclear cells but no organisms. The Differ en t i a l Di agnosis
glucose level was 77 mg per deciliter (4.3 mmol
per liter), the lactate dehydrogenase level 1487 U Dr. Sheila L. Arvikar: Many features of this patient’s
per liter, and the total protein level 4.0 g per presentation are nonspecific, but the disease
deciliter. The red-cell count was 18,000 per cubic process that involved the pericardium and caused
millimeter, and the nucleated-cell count 9439 tamponade deserves foremost consideration and
per cubic millimeter, 93% of which were neutro- will probably provide key clues that point us to-
phils. Microbiologic culture of the pericardial ward the diagnosis. The differential diagnosis of
fluid was also performed. Cytologic examination pericarditis and pericardial effusion varies on the
of the pericardial fluid for malignant cells was basis of geography. In the United States, approxi-
negative, as were additional blood tests, includ- mately 80% of cases of pericarditis are idio-
ing an interferon-γ release assay for tuberculosis pathic, 5 to 10% are due to cancer, 2 to 7% are due
and tests for rheumatoid factor, antitreponemal to autoimmune or pericardial-injury syndromes,

4% are due to tuberculosis, and less than 1% are of cancer. Lymphoma, metastatic disease, and
due to a purulent bacterial infection.2 However, mesothelioma are possible causes of malignant
in developing countries, the epidemiology of peri- pericardial effusion. However, the patient’s im-
cardial disease is quite different, such that 70% aging studies did not suggest a primary source
of cases are attributed to tuberculosis. Does the of cancer, and cytologic examination of the peri-
nature of this patient’s pericardial effusion pro- cardial fluid was negative. Although he had for-
vide us with any clues? The pericardial effusion merly smoked tobacco, he had no known expo-
was fibrinous, exudative, and neutrophilic, but sure to asbestos; the absence of asbestos exposure
these features are not helpful in distinguishing decreases the likelihood of mesothelioma. The
the cause. Tamponade, however, may be more enlarged bilateral axillary lymph nodes on CT
often associated with infection and cancer than may be revealing and will need to be investi-
with other causes. The presence of a bloody ef- gated further.
fusion may also suggest tuberculosis and cancer.
This patient did not have drug exposures, abnor- Rheumatic Disease
mal renal function, recent trauma, or invasive Could the patient have a rheumatic disease? The
procedures that would explain the development joint symptoms at the onset of illness, anemia,
of pericarditis. Thus, we are left with infection, lymphopenia, and elevated levels of ferritin and
cancer, and inflammatory diseases as the major inflammatory mediators are suggestive of an
diagnostic considerations in this case. autoimmune process. The rheumatic diseases that
are most commonly associated with pericardial
Infection involvement include systemic lupus erythemato-
The patient was originally from sub-Saharan sus, rheumatoid arthritis, adult-onset Still’s dis-
Africa, and therefore, particular consideration ease, and systemic sclerosis. Systemic sclerosis
needs to be given to infections common in that is unlikely in this case, given the absence of
region of the world. He had clinically significant Raynaud’s phenomenon and sclerodactyly. The
constitutional symptoms, including fevers and absence of hilar lymphadenopathy and pulmo-
weight loss, which suggest the possibility of nary infiltrates makes sarcoidosis unlikely. The
tuberculosis. However, he had no family history patient had no muscle weakness suggestive of
or other findings suggestive of tuberculosis. His inflammatory myopathy or sicca symptoms sug-
interferon-γ release assay was negative, but the gestive of Sjögren’s syndrome. He had no history
sensitivity of this test in patients with active tuber- of oral and genital ulcers typical of Behçet’s dis-
culosis can vary, depending on the site of infec- ease or bowel symptoms suggestive of inflam-
tion and the patient’s immune status. The dura- matory bowel disease. The absence of vasculitic
tion of his illness would be rather long for a viral rash, neuropathy, and hematuria makes vasculi-
infection. The presence of odynophagia could be tis an unlikely diagnosis.
suggestive of esophageal candidiasis, which can Rheumatoid arthritis, adult-onset Still’s dis-
occur in patients with HIV infection, but HIV ease, and systemic lupus erythematosus could
testing was negative; odynophagia could also be all explain the joint symptoms, pericarditis, fe-
attributed to esophageal compression by the large vers, anemia, and lymphadenopathy. Leukopenia
pericardial effusion. Furthermore, although the is more typical of systemic lupus erythematosus
patient had leukopenia at presentation, he was than of the other conditions, but it can occur in
not known to be immunocompromised. He had certain forms of rheumatoid arthritis and adult-
not recently been in any areas in which fungal onset Still’s disease.
or parasitic infections are endemic. The negative
Gram’s stain of the pericardial fluid is reassur- Rheumatoid Arthritis
ing and is not consistent with a typical bacterial This patient had some features that are not
infection. typical of rheumatoid arthritis, including a joint
distribution with predominant involvement of
Cancer large joints. Patients with rheumatoid arthritis
Fevers, weight loss, and lymphadenopathy, along usually present with symmetric polyarthritis that
with hematologic abnormalities, are suggestive affects small joints in the hands and feet. Pericar-

ditis can occur in rheumatoid arthritis, but peri- and prevalence of lupus are highest among per-
tonitis is rare. Although a test for rheumatoid sons of African descent.7 Lupus is more severe in
factor was negative in this case, we are not pro- persons of African descent than in persons of
vided with results of a test for anti–citrullinated European descent,8,9 and serositis is more com-
protein antibodies. Patients with severe extra mon.10 In addition, the disease is more severe
articular involvement are often seropositive for and hematologic abnormalities and serositis are
rheumatoid autoantibodies, particularly rheuma- more common in men than in women.11
toid factor.3 Finally, the patient had leukopenia, Lupus may affect any organ and is a clinically
which can develop in the context of Felty’s syn- heterogeneous disease. Constitutional symptoms,
drome4 — a rare disorder, characterized by the rashes, arthritis, and serositis are common mani-
triad of rheumatoid arthritis, splenomegaly, and festations. Another hallmark feature is immuno-
neutropenia, that usually occurs in patients with logic abnormalities, such as an elevated level of
long-standing rheumatoid arthritis who are pos- antinuclear antibodies (ANAs). Pericarditis is the
itive for rheumatoid factor. However, this patient most common cardiac manifestation of lupus.
had lymphopenia rather than neutropenia, and he Symptomatic pericarditis may develop in 25% of
did not have splenomegaly on clinical examination patients and is often accompanied by pleuritis;
or abdominal imaging. subclinical pericarditis is even more common.12
Tamponade, however, is rare, occurring in 1 to
Adult-Onset Still’s Disease 2.5% of patients with lupus.13,14 In patients with
The constellation of arthritis, serositis, and fevers, systemic lupus erythematosus, tamponade has
along with the elevated serum ferritin level and been associated with hemolytic anemia, renal dis-
abnormal results on liver-function tests, may fit ease, hypocomplementemia, and female sex.14,15
better with the diagnosis of adult-onset Still’s The pericardial fluid is typically a neutrophilic,
disease. The patient did not have the typical eva- inflammatory exudate.14
nescent rash that usually occurs with fever. The diagnosis of systemic lupus erythemato-
Leukopenia is not a typical feature of adult-onset sus is based on clinical and laboratory features.
Still’s disease; in fact, leukocytosis is one of the There are no formal diagnostic criteria. However,
major criteria for diagnosis.5 However, leukopenia classification criteria, including the American
can occur in the presence of the macrophage College of Rheumatology (ACR) criteria16 and
activation syndrome, a form of hemophagocytic the Systemic Lupus International Collaborating
lymphohistiocytosis that can develop in the con- Clinics (SLICC) criteria,17 are helpful in consider-
text of rheumatic disorders, most frequently ing the diagnosis. This patient meets at least
systemic juvenile idiopathic arthritis and adult- three clinical criteria (Table 2); he may meet
onset Still’s disease. Patients with this syndrome more criteria, depending on the results of addi-
generally have a low-to-normal erythrocyte sedi- tional immunologic studies, such as ANA and
mentation rate, whereas the rate was markedly anti–double-stranded DNA (dsDNA) antibody
elevated (105 mm per hour) in this patient. In testing. It is unclear whether he had any compo-
addition, in patients with hemophagocytic lym- nent of hemolysis in addition to anemia of
phohistiocytosis, cytopenias usually involve all chronic disease. He had mild coagulation abnor-
three cell lineages, and neutropenia, rather than malities, but his status with regard to antiphos-
lymphopenia, is a diagnostic feature.6 pholipid antibodies is unknown. Proteinuria was
noted on urinalysis, but further details are not
Systemic Lupus Erythematosus described. Finally, his reported rash with scaling
One might not initially suspect a diagnosis of could suggest discoid lupus erythematosus but
systemic lupus erythematosus in this case, given could also be an incidental condition, such as
that 90% of affected patients are female. How- eczema or tinea.
ever, this diagnosis could explain all the features In summary, I think this patient’s clinical
of this patient’s presentation, including the ar- presentation is most consistent with a diagnosis
thritis, pericarditis and other types of serositis, of systemic lupus erythematosus. To establish
fevers, lymphadenopathy, lymphopenia, anemia, this diagnosis, additional testing is needed, in-
and possible renal involvement. The incidence cluding tests for ANAs, anti-dsDNA antibodies,

Table 2. Classification Criteria for Systemic Lupus Erythematosus.*

body tests, both of which were positive. The ANA
test showed homogeneous nuclear staining, with
Present in This Patient intense staining of the chromosomal regions of
Criterion before Diagnostic Testing
cells in mitosis, and was positive up to the high-
Clinical est dilution (1:5120). A homogeneous ANA pat-
Arthritis Yes tern is seen in most patients with systemic lupus
Serositis Yes erythematosus but can also been seen in patients
Renal involvement Possible
with rheumatoid arthritis, systemic sclerosis,
Sjögren’s syndrome, and other autoimmune dis-
Acute cutaneous lupus erythematosus No
eases. This pattern is produced by anti-dsDNA
Chronic cutaneous lupus erythematosus Possible antibodies, histone–DNA complexes, and other
Alopecia No histones.18 The anti-dsDNA antibody assay was
Oral ulcers No positive up to a dilution of 1:80. A positive anti-
Neurologic involvement No dsDNA antibody test is specific for systemic lupus
Hemolytic anemia Possible erythematosus and distinguishes it from most
forms of drug-induced lupus, which would gen-
Leukopenia or lymphopenia Yes
erally be associated with a negative anti-dsDNA
Thrombocytopenia No
antibody test.
Immunologic Unknown Biopsy of an axillary lymph node was subse-
Antinuclear antibodies quently performed, and examination of the biopsy
Anti–double-stranded DNA antibodies specimen revealed a moderately enlarged lymph
Anti-Sm antibodies node with mostly preserved architecture and
Antiphospholipid antibodies
scattered lymphoid follicles, areas of paracortical
hyperplasia, and patent sinuses (Fig. 3A). There
Low complement levels
were foci of necrosis with apoptotic debris and
Positive direct Coombs’ test many histiocytes, including some with vacuolated
* According to the Systemic Lupus International Collaborating Clinics (SLICC) cytoplasm (Fig. 3B). No granulocytes were pres-
criteria,17 a classification of systemic lupus erythematosus requires the patient ent in the necrotic foci, and no granulomas or
to meet at least 4 of the 17 criteria, including at least 1 clinical criterion and viral inclusions were seen. There were clusters of
1 immunologic criterion, or to have evidence of lupus nephritis on biopsy.
plasmacytoid dendritic cells. On flow cytometry,
no clonal B-cell population or unusual T-cell
and complement levels. Measurement of the urine population was present. Immunostains showed
protein level and examination of urinary sediment a normal distribution of B cells and T cells; there
would help to determine whether there is renal were many CD20+ B cells in follicles and along
involvement. I would also perform further test- sinuses, as well as many interfollicular CD3+
ing for hemolysis, including a direct Coombs’ T cells, which were appropriately composed of
test, as well as testing for antiphospholipid anti- more CD4+ T cells than CD8+ T cells (Fig. 3C
bodies. Regardless of the immunologic test re- and 3D). Immunohistochemical staining for kappa
sults, it would be necessary to rule out alterna- and lambda immunoglobulin light chains showed
tive diagnoses, such as tuberculosis and cancer. many scattered polytypic plasma cells. Staining
To that end, examination of the pericardial fluid for CD123 showed clusters of plasmacytoid den-
for acid-fast bacilli and a lymph node biopsy dritic cells.
should be performed. In summary, these findings are consistent
with reactive lymphoid hyperplasia with foci of
Dr . Sheil a L . A rv ik a r’s Di agnosis necrosis and no evidence of cancer. This histo-
pathological appearance is most consistent with
Systemic lupus erythematosus. Kikuchi’s disease or lupus lymphadenitis, entities
that are essentially indistinguishable on the basis
Di agnos t ic Te s t ing of histologic features alone. The presence of
hematoxylin bodies or the Azzopardi phenome-
Dr. Lena D. Stuart: The diagnostic laboratory tests non on basement membranes of blood vessels is
in this case were the ANA and anti-dsDNA anti- associated with lupus lymphadenitis,19 and these

A B
C D
Figure 3. Lymph Node–Biopsy Specimen.

Hematoxylin and eosin staining (Panel A) shows mostly preserved architecture with focal necrosis. At higher magni‑
fication (Panel B), there are necrotic areas with apoptotic debris and histiocytes with vacuolated cytoplasm. On immu‑
nostaining (Panels C and D), CD20+ B cells are appropriately concentrated in follicles (Panel C) and CD3+ T cells are
present mostly outside the follicles (Panel D).
findings were absent in this case. However, in determine the extent and severity of the disease.
a patient with markedly elevated ANA and anti- Given the association between the presence of
dsDNA antibody levels, the histopathological anti-dsDNA antibodies and glomerulonephritis,
findings are consistent with a diagnosis of sys- it was critical to evaluate the patient for lupus
temic lupus erythematosus. nephritis.20 In the absence of a history of lupus
nephritis, the ACR guidelines recommend per-
forming a urinalysis and monitoring the urine
Discussion of M a nagemen t
protein:creatinine ratio, the anti-dsDNA antibody
Dr. Schoenfeld: This patient met both the 1997 level, and the serum creatinine, C3, and C4 lev-
ACR classification criteria and the 2012 SLICC els every 6 months.21 The presence of persistent
classification criteria for systemic lupus erythe- proteinuria (with urinary protein excretion of
matosus.16,17 Testing was negative for antiphos- >0.5 g per 24 hours), active urinary sediment
pholipid antibodies, including anticardiolipin (with >5 red cells and >5 white cells per high-
IgM and IgG antibodies, β2-glycoprotein IgM power field in the absence of infection), or red-
and IgG antibodies, and a lupus anticoagulant. cell or white-cell casts on urinalysis would be
Bacterial and mycobacterial cultures of the peri- suggestive of lupus nephritis. In this patient, the
cardial fluid were negative. initial urinalysis showed 2+ protein. However,
In this patient with a new diagnosis of sys- repeat urinalysis was negative for protein, and the
temic lupus erythematosus, it was important to total protein:creatinine ratio in a spot urine sam-

ple was 0.26; the creatinine level remained 24 hours. We considered the addition of azathio-
stable throughout his hospital admission. On prine, but he was deficient in thiopurine methyl-
the basis of these findings, we did not think the transferase, the enzyme that metabolizes aza-
patient had lupus nephritis, and the decision thioprine. Given the risk of severe cytopenias,
was made to monitor these measures closely in azathioprine was avoided. Given the clinically
follow-up. significant arthritis, we recommended metho-
Patients who have mild manifestations of lu- trexate, but the patient declined this treatment
pus, such as skin and joint involvement, can be and also declined treatment with mycophenolate
treated with hydroxychloroquine and low-dose mofetil. He was discharged from the hospital
prednisone or nonsteroidal antiinflammatory while he was receiving prednisone and hydroxy-
drugs. Patients who have clinical manifestations, chloroquine.
such as skin, joint, hematologic, or non–life- The patient was followed in the rheumatology
threatening serositis, are treated with hydroxy- clinic but frequently missed appointments. He
chloroquine and moderate-dose prednisone and tapered the dose of prednisone, initially under
are often also treated with another immunosup- the guidance of rheumatology and then on his
pressive agent, such as methotrexate, azathio- own, over the course of 1.5 years, and he discon-
prine, mycophenolate mofetil, or belimumab.22,23 tinued hydroxychloroquine on his own. He did
Patients who have severe, organ-threatening dis- well for 3.5 years, without flares or evidence of
ease, such as this patient (who had tamponade), nephritis, until he presented to the emergency de-
are often treated with high-dose glucocorticoids partment with pleuritic chest pain and arthral-
and also with a glucocorticoid-sparing agent, such gias. Chest CT revealed pleural effusions, and he
as cyclophosphamide, mycophenolate mofetil, or had recurrent leukopenia and anemia. Treatment
azathioprine. In the absence of a contraindica- with prednisone improved his condition, and treat-
tion, all patients with systemic lupus erythemato- ment with hydroxychloroquine was restarted. The
sus would be treated with hydroxychloroquine, patient attended one follow-up visit after that,
given its numerous benefits, including increased but he has not returned to the rheumatology
survival, decreased disease damage, and fewer clinic since.
flares, as well as improved renal function, fewer
thrombotic complications, and potentially im- Fina l Di agnosis
proved glycemic status and lipid profiles.24-33
After the diagnosis of systemic lupus erythe- Systemic lupus erythematosus.
matosus was established in this patient, treatment This case was presented at the Medical Case Conference.
with intravenous methylprednisolone (60 mg No potential conflict of interest relevant to this article was
reported.
per day) was started. The patient had clinically Disclosure forms provided by the authors are available with
significant improvement in his condition within the full text of this article at NEJM.org.
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Campo E, Harris NL, Quintanilla-Martinez sis in systemic lupus erythematosus: re- Copyright © 2019 Massachusetts Medical Society.


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The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Case 17-2019: A 44-Year-Old Man with Joint

Pr e sen tat ion of C a se

and additional glucocorticoid injections to the shoulders were administered.

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Figure 1. Imaging Studies.

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Table 1. Laboratory Data.*

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Figure 2. Echocardiographic Studies.

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Table 2. Classification Criteria for Systemic Lupus Erythematosus.*

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Figure 3. Lymph Node–Biopsy Specimen.

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