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 CASE REPORT Fulminating Hydralazine-Induced Lupus Pneumonitis BELINDA BIRNBAUM,1 GURDIP S. SIDHU,2 ROBERT L. SMITH,2 MICHAEL H. PILLINGER,1 CLEMENT E. TAGOE3 Introduction 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 award. 1 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: email@example.com. Submitted for publication August 4, 2005; accepted October 20, 2005. AND 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 501 502 Birnbaum et al Table 1. Initial laboratory results unless otherwise indicated* Test Results Arterial blood gas WBC, ⫻ 103/mm3 Hemoglobin, gm/dl Hematocrit, % Platelets, ⫻ 103/mm3 Urinalysis 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 ANA Anti-dsDNA (Crithidia luciliae) Anti-ssDNA, units/ml Antihistone antibody, units/ml pANCA Myeloperoxidase Proteinase 3 CRP, mg/dl Anti-RNP, units/ml Anti-Smith Anti-Ro Anti-La Anti-GBM Anti–Scl-70 Anticardiolipin antibody Angiotensin-converting enzyme HIV All bacterial/fungal and viral cultures 7.45/31/49/21/86% 7.5 10.8 32.5 160 Trace protein, no blood, no RBCs, 1–3 WBCs 28†/15‡ 1.7†/0.9‡ 135 50 7.8 2.7 805 395 ⬍20 46.1 17.7 98 Negative Negative†/1:160 speckled§ Negative 82 92 Positive 40 Negative 15.7 5,632 Negative Negative Negative Negative Negative Negative Negative Negative Negative Normal range 4–11 12–16 38–47 150–450 6–22 0.7–1.4 10–42 10–40 6.4–8.2 3.8–5.1 91–180 26–140 0–39 75–181 16–47 0–20 Negative Negative†/negative§ Negative 0–19 0–10 Negative ⬍6 Negative 0–8 0–19 Negative Negative Negative Negative Negative Negative Negative Negative Negative * 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 503 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. Discussion 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 504 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 (4). 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- 505 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. 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