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Fulminating hydralazine-induced lupus pneumonitis.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 55, No. 3, June 15, 2006, pp 501–506
DOI 10.1002/art.21987
© 2006, American College of Rheumatology
Fulminating Hydralazine-Induced
Lupus Pneumonitis
Lupus-like syndromes have been recognized following
various infections and exposure to a variety of agents,
including drugs such as procainamide, hydralazine, isoniazid, sulfasalazine, minocycline, propylthiouracil, and biologic tumor necrosis factor ␣ inhibitors (1). Drug-induced
lupus (DIL) differs from idiopathic systemic lupus erythematosus (SLE) in that DIL generally has a better prognosis, with a tendency to spare critical organ systems such
as the kidneys, central nervous system, and hematopoietic
system. Resolution of symptoms upon discontinuation of
the offending agent is the most certain way to diagnose
DIL. However, suspicion of DIL should be entertained in a
patient with a lupus-like syndrome while taking a medication known to be associated with DIL, especially in the
presence of characteristic serologies. The combination of
antihistone antibodies, anti–single-stranded DNA (antissDNA) antibodies, and normal serum complement levels
during active disease favors the diagnosis of DIL. In contrast, anti– double-stranded DNA (anti-dsDNA) antibodies
and low serum complement levels are unusual and are a
feature of active idiopathic SLE (1). Because there are no
pathognomonic features of either syndrome, differentiating DIL from idiopathic SLE can be problematic (2). Furthermore, in individuals with an appropriate diathesis,
drugs such as hydralazine can precipitate a syndrome
Dr. Pillinger is supported by a Clinician Scholar Educator
award from the American College of Rheumatology (ACR).
Dr. Birnbaum is supported by an ACR Fellowship Training
Belinda Birnbaum, MD, Michael H. Pillinger, MD: Hospital for Joint Diseases, New York University School of
Medicine, New York; 2Gurdip S. Sidhu, MD, Robert L.
Smith, MD: New York Veterans Administration Medical
Center, New York; 3Clement E. Tagoe, MD, PhD: Albert
Einstein College of Medicine/Montefiore Medical Center,
Bronx, New York.
Address correspondence to Clement E. Tagoe, MD, PhD,
Albert Einstein College of Medicine/Montefiore Medical
Center, Department of Medicine, Division of Rheumatology,
3332 Rochambeau Avenue, Centennial Building Room 423,
Bronx, NY 10467. E-mail:
Submitted for publication August 4, 2005; accepted October 20, 2005.
indistinguishable from SLE (3). Mechanisms that have
been suggested to explain the DIL phenomenon include
hapten-mediated autoimmunity and, more recently, inhibition of DNA methylase with resulting DNA hypomethylation in T cells, which can cause autoreactivity (2).
In this report, we present a rare case of severe hydralazine-induced lupus pneumonitis. Our data should alert
the clinician to the possibility that drug-induced lupus
can, on occasion, present with significant end-organ damage.
Case Report
A 36-year-old African American woman presented to the
emergency room reporting 6 weeks of fatigue, dyspnea on
exertion, weakness, dizziness, and arthralgias. She had an
8-year history of severe hypertension, without identifiable
etiology on extensive evaluation at another facility, and an
uncomplicated pregnancy 4 years prior to admission. She
was maintained on atenolol, clonidine, nifedipine, and
fosinopril, and began taking levofloxacin 3 days prior to
admission for presumed upper respiratory tract infection.
In addition, she had been taking hydralazine (100 mg/day)
for ⬎1 year for her hypertension. A routine screening chest
radiograph 5 months prior to admission had shown a bony
abnormality; a followup computed tomography (CT) scan
of the chest did not confirm the abnormality but revealed
small areas of ground glass opacities in the lower lobes
bilaterally, and borderline cardiomegaly with a small pericardial effusion. She had a 17 pack/year history of cigarette smoking and had quit 1 month prior to admission due
to worsening shortness of breath. She had no relevant
occupational exposures. A human immunodeficiency virus (HIV) test result 1 year earlier was negative.
On examination in the emergency room, she was found
to be hypotensive (blood pressure 88/28 mm Hg) and dyspneic. Hydralazine and other antihypertensives were discontinued. In the intensive care unit, her blood pressure
improved to 110/57 mm Hg, her heart rate was 106 beats
per minute, and her respiratory rate was 26 per minute.
She was febrile to 104°F, with a room air oxygen saturation
of 88%. She had mild diffuse lymphadenopathy but no
rash, joint swelling, or effusions. Her heart and lung examinations were significant for a loud second heart sound
Birnbaum et al
Table 1. Initial laboratory results unless otherwise indicated*
Arterial blood gas
WBC, ⫻ 103/mm3
Hemoglobin, gm/dl
Hematocrit, %
Platelets, ⫻ 103/mm3
Blood urea nitrogen, mg/dl
Creatinine, mg/dl
Aspartate aminotransferase, IU/liter
Alanine aminotransferase, IU/liter
Total protein, gm/dl
Albumin, gm/dl
Lactic dehydrogenase, units/liter
Creatine phosphokinase, IU/liter
Rheumatoid factor, IU/ml
C3, mg/dl
C4, mg/dl
ESR, mm/hour
Hepatitis B and C
Anti-dsDNA (Crithidia luciliae)
Anti-ssDNA, units/ml
Antihistone antibody, units/ml
Proteinase 3
CRP, mg/dl
Anti-RNP, units/ml
Anticardiolipin antibody
Angiotensin-converting enzyme
All bacterial/fungal and viral cultures
Trace protein, no blood, no RBCs, 1–3 WBCs
Negative†/1:160 speckled§
Normal range
* WBC ⫽ white blood cell; RBC ⫽ red blood cell; ESR ⫽ erythrocyte sedimentation rate; ANA ⫽ antinuclear antibodies; anti-dsDNA ⫽ anti– doublestranded DNA; anti-ssDNA ⫽ anti–single-stranded DNA; pANCA ⫽ perinuclear antineutrophil cytoplasmic antibody; CRP ⫽ C-reactive protein;
anti-GBM ⫽ anti– glomerular basement membrane; HIV ⫽ human immunodeficiency virus.
† First hospital day.
‡ Second hospital day.
§ Repeat test at Hospital for Joint Diseases.
and bibasilar crackles. Initial laboratory values are shown
in Table 1, and were remarkable for elevated erythrocyte
sedimentation rate and C-reactive protein levels, elevated
serum lactate dehydrogenase and creatine kinase levels
(troponin-I negative), and increased serum aminotransferases. Urinalysis showed no active sediment. An arterial
blood gas confirmed marked hypoxia and respiratory alkalosis. A chest radiograph revealed an enlarged cardiac
silhouette; an echocardiogram showed no tamponade, but
revealed a moderate-sized pleural effusion (Figures 1A, B,
and C). Spiral high-resolution chest CT showed a prominent pulmonary artery, but no evidence of a pulmonary
embolus. In addition, bilateral alveolar infiltrates were
seen, as well as small bilateral pleural effusions. A small
pericardial effusion was also found (Figure 1D).
These findings were believed to be consistent with connective tissue disease, infection, and possibly lymphoma.
Autoimmune serologies; hepatitis and HIV screening; and
blood, urine, and sputum cultures were ordered. Despite
treatment with broad-spectrum antibiotics and close intensive care unit monitoring, the patient developed progressive hypoxia and fevers to 105°F on the third hospital day.
Delirium and worsening hypoxia necessitated intubation
and mechanical ventilation. Results of an open lung biopsy and bronchoalveolar lavage showed no evidence of
vasculitis or pulmonary hemorrhage. Intravenous solumedrol (1 gm/day for a planned 3-day course) was initiated for presumed lupus pneumonitis. The patient underwent plasmapheresis once, on the third hospital day.
However, she became hypotensive, and despite cardiovas-
Acute Lupus Pneumonitis
Figure 1. Radiographic studies of the patient’s lungs during the course of the illness.
A, Admission radiograph (posteroanterior view) showing bibasilar infiltrates and
mild cardiomegaly. Chest radiographs (anteroposterior views) at days B, 3 and C, 4
after admission showing progressive diffuse infiltrates and suggesting increased cardiomegaly. D, Chest computed tomography scan, obtained on day 3, demonstrating
interstitial infiltrates and pericardial effusion.
cular support with vasopressor therapy she died on the
fourth hospital day. Results of further laboratory testing
were available the following day (Table 1) and confirmed
the presence of antinuclear, antihistone, and anti-ssDNA
antibodies, as well as antimyeloperoxidase antibodies (anti-MPO) and perinuclear antineutrophil cytoplasmic antibody (pANCA).
At postmortem examination, the lungs showed diffuse
alveolar damage with extensive organization, and interstitial plasma cell infiltrate. There was no evidence of vasculitis (Figures 2A and B). Electron microscopy of lung tissue
demonstrated tubuloreticular structures (TRS) in the cytoplasm of endothelial cells, and cylindrical confronting
cisternae (CCC) in the cytoplasm of bronchial ciliated and
intermediate epithelial cells (Figures 2C and D, respectively). A mild chronic inflammatory infiltrate was present
in the epicaridum, consistent with pericarditis. The kidneys showed no evidence of vasculitis or the presence of
other abnormalities.
The prevalence of lupus pneumonitis is difficult to determine rigorously, as there are no specific diagnostic tests.
Statistics from retrospective data and small case studies
estimate a prevalence of acute lupus pneumonitis of up to
12% in patients with active SLE (4). Matthay et al (5)
published the largest case series (12 patients) of acute
lupus pneumonitis in 1975, including 6 patients in whom
pneumonitis was the presenting manifestation of lupus.
Pulmonary symptoms were present from 1 to 30 days prior
to hospitalization. All patients were hypoxic, had no evidence of infection, and were treated for pneumonitis with
steroids; 7 of the 12 received azathioprine as well. There
was a 50% mortality rate. Survivors had persistent pulmonary function abnormalities, including severe restrictive
ventilatory defects.
On radiologic examination, acute lupus pneumonitis
presents with bilateral pulmonary infiltrates, including
diffuse acinar infiltrates with predilection for the lung
bases (5). Although established disease is commonly appreciated on chest radiographs, early disease may require
high-resolution CT and pulmonary function tests (PFTs)
for diagnosis (4). Multiple radiologic studies have corroborated that patients with asymptomatic SLE have abnormalities both on high-resolution CT and PFTs, even when
chest radiographs are normal (6,7). However, there are
Birnbaum et al
Figure 2. Light and electron microscopic studies of the patient’s open lung biopsy. Hematoxylin and eosin stains
showing diffuse alveolar damage, including A, perivascular and interstitial lymphocytic infiltration and B,
thickening of hyaline membranes (arrow). Electron microscopy showing C, an endothelial cell with cytoplasmic
tubuloreticular structures (TRS; arrows) and D, a bronchiolar ciliated epithelial cell with cytoplasmic cylindrical
confronting cisternae (CCC; arrows). Both TRS and CCC are induced by acid-labile interferon-␣, which is present
in very high concentrations in patients with systemic lupus erythematosus. CCC are typically induced by higher
interferon-␣ levels, and the patients harboring them are commonly sicker.
probably insufficient data at this time to recommend treatment based solely on high-resolution CT findings of interstitial lung disease in a patient with asymptomatic lupus.
The pathologic picture of acute lupus pneumonitis is variable. Alveolitis, interstitial edema, and hyaline membranes may all be observed on histologic examination,
including autopsy studies. Lymphocytic and plasma cell
infiltrates may also occur. Immunoglobulin deposits also
occur variably. Persistent inflammation can lead to fibrosis
Hydralazine was first reported to produce a lupus-like
syndrome in 1953 (8). The incidence of hydralazine DIL
has been estimated at 5.4% in patients receiving 100 mg/
day and at 10.4% in those receiving 200 mg/day. Women,
and individuals with slow acetylation of hydralazine by
hepatic N-acetyltransferase, are more likely to be affected
(1). In contrast, it has been reported that African Americans develop hydralazine DIL less frequently than other
populations (9). Pulmonary involvement, including pleuritis, pulmonary vascular disease, or parenchymal lung
disease such as pneumonitis, is rarely seen in the DIL
syndromes, unlike idiopathic lupus in which pulmonary
involvement is seen in 38 – 89% of cases (1). This has been
particularly true for hydralazine, with only 3 prior reports
in the literature. Bass (10) described a 48-year-old hypertensive woman who developed hemoptysis, pulmonary
infiltrates, positive antinuclear antibody (ANA), and anti-
DNA antibodies; her symptoms subsided 2 weeks after
cessation of hydralazine. Schattner et al (11) described a
58-year-old woman who developed interstitial lung disease while receiving hydralazine at a dosage of 100 mg/day
for hypertension. Acetylation was slow in that patient.
Similarly, Ripe and Nilsson (12) described pulmonary infiltrations during dihydralazine treatment in a patient with
slow isoniazid inactivation.
Our case had several noteworthy features. The patient
met only 2 of the 4 required American College of Rheumatology classification criteria for SLE, namely serositis
(pleuritis and pericarditis) and positive serologies (ANA)
(13). However, she did have arthralgias, which, although
not constituting a research criterion for lupus, are more
commonly seen in DIL than in frank arthritis. A definite
diagnosis of DIL could not be formally made because she
died before the effects of hydralazine withdrawal could be
known. However, although the patient’s race (9) and severity of disease might speak in favor of a diagnosis of
idiopathic SLE, the absence of anti-dsDNA and anti-Sm
antibodies and the presence of antihistone antibodies as
well as anti-ssDNA are much more characteristic of DIL
(1,2). Her low serum C3 level and presence of anti-RNP
antibodies were not incompatible with DIL, since both
abnormalities have been reported (14,15). The sparing of
her kidneys also favors the diagnosis of DIL.
The patient also had positive pANCA and anti-MPO
Acute Lupus Pneumonitis
titers, raising the possibility of a primary vasculitis. Indeed, hydralazine has been implicated in ANCA-positive
vasculitis (16). In one retrospective study of 250 patients
with anti-MPO titers, 10 of the 30 patients with the highest
titers were noted to be taking hydralazine; all 10 had
ANCA-positive vasculitis (17). Five (50%) of those patients receiving hydralazine had lung involvement, and 9
(90%) had renal involvement. However, autopsy findings
did not support a diagnosis of vasculitis in our patient.
Rather, it would appear that the use of hydralazine may
predispose to autoimmune diatheses with both DIL-like
and ANCA-like serologic features. In the aforementioned
study, 9 patients taking hydralazine had ANAs and 9 had
antibodies to elastase. In another study, it was noted that
anti-MPO antibodies were consistently found in hydralazine-induced lupus, but in only 21% of patients with
idiopathic SLE (18). Thus, the presence of anti-MPO antibodies further favors the diagnosis of hydralazine DIL as
opposed to idiopathic SLE in our patient.
Also noteworthy in this case was the long duration of
hydralazine use prior to decompensation. It is likely, however, that the patient’s DIL preceded her acute illness by
many months, as evidenced by her arthralgias, and the
finding of ground glass infiltrates and pericardial effusion
on CT findings 6 months earlier. Whether early discontinuation of hydralazine would have prevented the progression of her illness cannot, unfortunately, be ascertained.
Her acute decompensation may have related to this persistent antigen (hydralazine) challenge, or to the addition of
an extra trigger in the form of her presumed viral upper
respiratory tract infection. In this regard, we note the report by Schattner et al, in which the combination of hydralazine and cytomegalovirus infection appeared to precipitate acute lupus pneumonitis (11).
Finally, we note the use, in this case, of TRS and CCC to
assist in the diagnosis of a lupus-family illness. TRS are
induced by high levels of acid-labile interferon-␣, which is
present in very high concentrations in both SLE and acquired immunodeficiency syndrome (19). Because our patient was negative for HIV, the presence of TRS and CCC
supported a lupus diagnosis. Although TRS are features of
idiopathic lupus, they have occasionally been reported in
DIL as well; therefore, their identification does not assist in
the differentiation of idiopathic SLE from DIL (20).
Treatment of DIL involves cessation of the suspect drug
and in some cases a need for systemic steroids and cytotoxic therapy. The clinical response to these measures is
often relatively rapid, with a slower return of serologies,
particularly the return of ANAs to normal. Anti-ssDNA
antibodies and ANCAs may persist for longer periods (18).
Our patient received high-dose systemic steroids, but not
cyclophosphamide. Given the unusually fulminant course
of her illness, it is unlikely that she would have had time
to respond to either cyclophosphamide or the discontinuation of hydralazine.
In conclusion, we have reported a case of acute lupus
pneumonitis induced by the use of hydralazine. The patient’s disease course was particularly fulminant for DIL,
which may have related to the long duration of hydralazine use, even in the face of arthralgias and early, incidental identification of lung inflammation and a pericar-
dial effusion. The severity of her DIL might also have
related to a predisposing diathesis, although her acetylation activity was never ascertained. We conclude that the
outcome of hydralazine-induced lupus is not always benign, and that significant morbidity and even death may
follow severe organ compromise. Moreover, African American persons are not always spared, an observation that
may be particularly relevant as hydralazine becomes more
available for the management of heart disease in the African American population (21). Therefore, there should be
heightened awareness of the syndrome and monitoring of
therapy with prompt discontinuation of suspect drugs
when adverse events occur.
We are very grateful to Miss Ping Louie for her technical
1. Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis
Clin North Am 1994;20:61– 86.
2. Antonov D, Kazandjieva J, Etugov D, Gospodinov D, Tsankov
N. Drug-induced lupus erythematosus. Clin Dermatol 2004;
22:157– 66.
3. Ihle BU, Whitworth JA, Dowling JP, Kincaid-Smith P. Hydralazine and lupus nephritis. Clin Nephrol 1984;22:230 – 8.
4. Pines A, Kaplinsky N, Olchovsky D, Rozenman J, Frankl O.
Pleuro-pulmonary manifestations of systemic lupus erythematosus: clinical features of its subgroups: prognostic and
therapeutic implications. Chest 1985;88:129 –35.
5. Matthay RA, Schwarz MI, Petty TL, Stanford RE, Gupta RC,
Sahn SA, et al. Pulmonary manifestations of systemic lupus
erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore) 1975;54:397– 409.
6. Cheema GS, Quismorio FP Jr. Interstitial lung disease in systemic lupus erythematosus. Curr Opin Pulm Med 2000;6:
424 –9.
7. Kim JS, Lee KS, Koh EM, Kim SY, Chung MP, Han J. Thoracic
involvement of systemic lupus erythematosus: clinical,
pathologic, and radiologic findings. J Comput Assist Tomogr
2000;24:9 –18.
8. Morrow JD, Schroeder HA, Perry HM Jr. Studies on the control of hypertension by hyphex. II. Toxic reactions and side
effects. Circulation 1953;8:829 –39.
9. Irias JJ. Hydralazine-induced lupus erythematosus-like syndrome. Am J Dis Child 1975;129:862– 4.
10. Bass BH. Hydralazine lung. Thorax 1981;36:695– 6.
11. Schattner A, Sthoeger Z, Geltner D. Effect of acute cytomegalovirus infection on drug-induced SLE. Postgrad Med J 1994;
70:738 – 40.
12. Ripe E, Nilsson BS. Pulmonary infiltrations during dihydralazine treatment in a slow isoniazid-inactivator. Scand J Respir
Dis 1972;53:56 – 63.
13. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus
erythematosus [letter]. Arthritis Rheum 1997;40:1725.
14. Ghose MK. Pericardial tamponade: a presenting manifestation
of procainamide-induced lupus erythematosus. Am J Med
15. Munves EF, Schur PH. Antibodies to Sm and RNP: prognosticators of disease involvement. Arthritis Rheum 1983;26:
848 –53.
16. Short AK, Lockwood CM. Antigen specificity in hydralazine
associated ANCA positive systemic vasculitis. QJM 1995;88:
775– 83.
17. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated
antineutrophil cytoplasmic antibody–positive vasculitis:
prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum 2000;43:405–13.
18. Nassberger L, Sjoholm AG, Jonsson H, Sturfelt G, Akesson A.
Autoantibodies against neutrophil cytoplasm components in
systemic lupus erythematosus and in hydralazine-induced
lupus. Clin Exp Immunol 1990;81:380 –3.
Birnbaum et al
19. Luu JY, Bockus D, Remington F, Bean MA, Hammar SP.
Tubuloreticular structures and cylindrical confronting cisternae: a review. Hum Pathol 1989;20:617–27.
20. Pavlidakey GP, Hashimoto K, Heller GL, Daneshvar S. Chlorpromazine-induced lupuslike disease: case report and review
of the literature. J Am Acad Dermatol 1985;13:109 –15.
21. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr,
Ferdinand K, et al. Combination of isosorbide dinitrate and
hydralazine in blacks with heart failure [published erratum
appears in N Engl J Med 2005;352:1276]. N Engl J Med 2004;
351:2049 –57.
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lupus, fulminating, hydralazine, pneumonitis, induced
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