*From WellStar Marietta Pulmonary Medicine (Dr. Peno-Green); Marietta Rheumatology Associates, PC (Dr. Lluberas); WellStar Pathology Department (Dr. Kingsley); and Quantum Radiology Northwest (Dr. Brantley), Marietta, GA.
Correspondence to: Laura Peno-Green, MD, FCCP, Marietta Pulmonary Medicine, 55 Whitcher St, Suite 420, Marietta, GA 30060; e-mail: firstname.lastname@example.org
Etanercept is the first anticytokine drug approved to treat rheumatoid arthritis. Side effects are infrequent, the most common being local skin reactions, headaches, and upper respiratory tract symptoms. We report the first case of lung injury that occurred while receiving this agent. Biopsy specimens of lung and skin lesions demonstrated noncaseating granulomas associated with a microscopic particulate. Withdrawal of etanercept achieved clinical stabilization, and the addition of prednisone resulted in rapid improvement.
Etanercept is a recombinant DNA-engineered fusion protein consisting of extracellular ligand protein domain for tumor necrosis factor-α and the constant portion of the human IgG molecule. It is the first anticytokine compound approved for the treatment of rheumatoid arthritis following failure of at least one disease-modifying antirheumatic drug.1 The drug is marketed under the trade name Enbrel (Immunex; Seattle, WA), packaged in dose trays containing 25 mg of the lyophilized drug, and sterile water containing 0.9% benzyl alcohol as the preservative.
The most common adverse effects associated with etanercept have been injection site reactions, headaches, and mild upper respiratory tract symptoms.2–4 Some authors have proposed an immune-mediated injury extending from this drug, but these cases have been rare.5–7 A recent letter submitted to Lancet reported four patients receiving etanercept who acquired drug-induced systemic lupus erythematosus.8 There have been no descriptions of lung injury extending from the use of this drug. We report a case of inflammatory lung injury occurring in a patient receiving etanercept.
The patient, a 50-year-old woman with a 5-year history of seropositive rheumatoid arthritis experienced suboptimal control of articular manifestations using a series of nonsteroidal anti-inflammatory agents, hydroxychloroquine, and methotrexate combined with prednisone. Her regimen was switched to etanercept alone administered twice weekly by subcutaneous injection. The articular symptoms improved considerably within several weeks. Two months later, the patient noticed progressive fatigue and malaise with no recurrence in arthralgias. Cough and exertional dyspnea developed with gradual worsening over the ensuing months. The physical examination demonstrated fine rales in the lower one-third lung fields. Scattered nonpruritic skin lesions erupted on the plantar surfaces of both feet and at the site of superficial scars located on the extremities. The chest radiograph showed a diffuse reticulonodular infiltrate (Fig 1
). High-resolution CT (HRCT) demonstrated ground-glass attenuation, with mild septal thickening, evenly distributed in the central and peripheral regions of the lung parenchyma, most dominant within the mid and lower lung regions. The total lung capacity was minimally reduced at 3.74 L (76% predicted), with the vital capacity measuring 2.45 L (84% predicted). Diffusion capacity was 8.4 mL/min/mm Hg (40% predicted) with a normal hemoglobin and no smoke exposure. Oxyhemoglobin desaturation was present by pulse oximetry with a 93% resting and 87% exercise saturation. There were no signs of right-heart failure on physical examination, and echocardiography showed normal left ventricular function. Significant laboratory data included a transient elevation in the serum creatinine level (2.0 mg/dL) associated with microscopic hematuria and an angiotensin-converting enzyme level that was within normal limits.
Transbronchial lung biopsy specimens obtained by flexible bronchoscopy revealed loosely cohesive noncaseating granulomas in both the peribronchial and alveolar tissue (Fig 2
). Located within the inflammation process were birefringent particles that polarized. Tissue stains were negative for acid-fast bacilli, fungal elements, and parasitic organisms. Mycobacterium avium-intracellulare complex (MAI) was isolated in the BAL specimen after 4 weeks of incubation. A biopsy of an acute skin lesion also showed noncaseating granulomas containing birefringent particulate.
After etanercept was discontinued, symptoms stabilized without evidence of further deterioration. A dramatic clinical improvement was observed after prednisone initiation. The reticulonodular opacities on the chest radiograph improved significantly after 4 weeks of prednisone therapy. Exercise-induced hypoxia improved, with resolution of cough and dyspnea. Constitutional symptoms and skin lesions also cleared. Serial chest radiographs showed progressive improvement over a period of 3 months, with minimal reticular opacities remaining. The pulmonary function test showed no significant change, except for an improvement in the diffusion capacity, 12.5 mL/min/mm Hg. HRCT verified that the ground-glass attenuation had cleared, but septal thickening persisted. Prednisone was discontinued after 3 months, with serial HRCT showing stable septal thickening at the sixth month follow-up, with complete resolution of lung pathology by month 12.
This case demonstrates the development of a systemic inflammatory process, with the lung being the major target organ. To our knowledge, this is the first reported case of lung injury occurring while receiving etanercept. A cause-and-effect relationship must be established before implicating a drug as the inducing agent.9 Constitutional symptoms did not occur until the drug was instituted. Symptoms clearly escalated while receiving the drug. Once the drug was discontinued, a plateau was observed in symptom severity. These temporal features strongly suggest that etanercept plays a role in the induction of this systemic inflammatory process.
The differential diagnosis for this case includes rheumatoid lung injury, methotrexate toxicity, and MAI infection. In rheumatoid lung disease, the development and progression of nonarticular symptoms usually parallel arthritic complaints. With methotrexate lung injury, the symptoms usually occur during drug administration. Signs of the systemic inflammatory process in this patient began at least 2 months after the arthritis was controlled and methotrexate stopped. MAI was only cultured from the BAL specimen. Acid-fast bacilli stains were negative, and the pathologic process resolved without relapse with steroids alone. These observations support colonization of MAI rather than infection.
Sarcoidosis requires consideration since it is steroid responsive and characterized by nonnecrotizing granulomas. There are rare reports of sarcoidosis occurring in association with rheumatoid disease.10The absence of bulky lymphadenopathy and a normal angiotensin-converting enzyme level argue against sarcoidosis. Thickening of the peribronchovascular interstitium is usually a dominant feature in sarcoidosis11and was not identified. Granulomas that are loosely cohesive, as described for this case, are more characteristic for a hypersensitivity injury, rather than sarcoidosis.12 Each of these observations is not a sensitive finding for sarcoidosis and can be influenced by random sampling. Even though sarcoidosis cannot be excluded, the temporal relationship between drug and the pathologic process cannot be ignored. We, therefore, propose that etanercept was the precipitating agent for this patient’s lung injury. This injury was either a direct effect of the drug through a hypersensitivity pathway or an indirect effect by inducing a sarcoid-like condition.
An unexpected finding was the crystalline particulate centered within the noncaseating granulomatous. We initially suspected microscopic embolization as the origin for these inclusions. Careful scrutiny of patient technique excluded contamination of the injectant or improper drug delivery. Manufacturer contamination was also unlikely since lot numbers varied throughout her treatment course. Drug embolization was believed to be improbable, since Immunex Corporation verified that a case of drug embolization was never identified with both premarketing and postmarketing data. Birefringent crystalline inclusions have been described with noncaseating granulomas,12unrelated to IV drug usage or inhalation exposure, but are usually not numerous. Researchers have demonstrated that these inclusions are primarily calcium oxylate crystals.13–14 Some investigators have proposed that these crystals play a role in the inflammatory pathway.15 For our patient, the role and composition of these inclusions remain to be determined, but their existence seems more than coincidental.
The cornerstone of treatment for drug-induced lung injury is drug removal. The indications for prednisone are less clear. For this case, a distinct and rapid improvement was observed after adding prednisone, suggesting a possible role for early prednisone initiation when etanercept-induced lung injury is suspected. This observation also begs the question whether the true incidence of drug-induced injury has been underestimated by the frequent practice of combining etanercept with other immune-modulating agents, such as prednisone or methotrexate.
We propose that etanercept-induced lung injury be considered in any patient who acquires respiratory symptoms with interstitial infiltrates while receiving this agent. The diagnosis is one of exclusion. Since this injury appears to be a systemic process, other organs should be evaluated, particularly the skin. Treatment should consist of drug removal, and prednisone should be administered early in clinically compromised individuals.
Follow-up chest radiographs and clinical examinations over the following 12 months after manuscript submission showed complete resolution of alveolar and interstitial abnormalities. The Immunex Corporation was contacted early in this patient’s course with continued correspondence, the most recent being in January 2002. As a result of this case, they performed an extensive review of their premarketing and postmarketing data. With this detailed review, they could find no cases of granulomatous inflammation, foreign-body embolization, or lung injury.
Abbreviations: HRCT = high-resolution CT; MAI = Mycobacteium avium-intracelluare complex
The authors thank Robert Santoianni of Emory University, Department of Pathology, for preparation of the photomicrographs, and Dr. William Fulkerson of Duke University Medical Center, Department of Pulmonary Medicine, for comments and review of the article.
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