Interstitial pneumonia in a patient undergoing treatment with leflunomide: drug-induced toxicity?

Abstracts

Leflunomide is an anti-rheumatic drug with immunomodulating effects. Granulomatous interstitial pneumonia has never been described in association with the use of this drug. We report the case of a 33-year-old female patient who presented with chest pain, weight loss and pulmonary infectious syndrome during the fifth month of monotherapy with leflunomide for rheumatoid arthritis, which advanced to respiratory insufficiency in the sixth month. Radiologic findings revealed pulmonary intersticial infiltrates, as well as bilateral alveolar infiltrates (mainly in the upper and medium lobes) and scattered micronodules. However, no mediastinal abnormalities were detected. Leflunomide was suspended. After resolution of the infection, interstitial reticulonodular lesions persisted, predominantly in the upper 2/3 of the right lung and in the center of the left lung, interspersed with a ground-glass pattern in the superior lobes. Surprisingly, pulmonary biopsy revealed tuberculoid granulomas without caseous necrosis. A thorough etiological investigation was carried out, but no etiologic agent was identified. After four months, the condition spontaneously and completely disappeared. This profile suggests that the pulmonary complications seen in this case were the result of leflunomide use.

Lung diseases, interstitial; Lung

O leflunomide é uma droga anti-reumática com ação imunomoduladora. Pneumonia intersticial granulomatosa nunca foi descrita com o uso de leflunomide. Relata-se o caso de uma mulher de 33 anos que apresentou dor torácica, emagrecimento e síndrome infecciosa respiratória no quinto mês de monoterapia com leflunomide para artrite reumatóide, progredindo para insuficiência respiratória no sexto mês. A radiografia de tórax revelou infiltrado pulmonar intersticial e alveolar bilateral predominando em lobos superior e médio, micronódulos esparsos e ausência de alterações mediastinais. Suspendeu-se o leflunomide. Após a resolução da infecção persistiram lesões intersticiais retículo-nodulares predominantemente na periferia dos terços superiores do pulmão direito e terço médio do pulmão esquerdo, entremeadas por padrão de vidro fosco em lobos superiores. Biópsia pulmonar a céu aberto revelou granulomas tuberculóides sem necrose central. Foi realizada extensa investigação etiológica, que resultou negativa. Ocorreu resolução espontânea do quadro após quatro meses. O quadro sugere que as manifestações pulmonares neste caso foram causadas pelo leflunomide.

Doenças pulmonares intersticiais; Pulmão

CASE REPORT

Interstitial pneumonia in a patient undergoing treatment with leflunomide: drug-induced toxicity?

Jonatas Reichert^I; Adriane Reichert^II; Luci Iolanda Bendhack^I; Lucia de Noronha^III, Dante Escuissato^IV; Acir Rachid Filho^V

^IPulmonologist and TE-SBPT (Specialist, as designated by the Brazilian Society of Pulmonology and Phthisiology)

^IIDoctoral student

^IIIAdjunct Professor in the Department of Pathology

^IVHead Professor in the Department of Pathology

^VAdjunct Professor in the Department of Rheumatology and President of the Rheumatology Society of Paraná

^{Correspondence}

ABSTRACT

Leflunomide is an anti-rheumatic drug with immunomodulating effects. Use of this drug has never before been associated with granulomatous interstitial pneumonia.

We report the case of a 33-year-old female patient who presented with chest pain, weight loss and pulmonary infectious syndrome during the fifth month of monotherapy with leflunomide for rheumatoid arthritis, which advanced to respiratory insufficiency in the sixth month. Radiologic findings revealed pulmonary infiltrates in the interstice, as well as bilateral alveolar infiltrates (mainly in the upper and middle lobes) and scattered micronodules. However, no mediastinal abnormalities were detected. Leflunomide was suspended. After resolution of the infection, interstitial reticulonodular lesions persisted, predominantly in the upper 2/3 of the right lung and in the medial portion of the left lung, interspersed with a ground-glass pattern in the superior lobes. Surprisingly, pulmonary biopsy revealed no caseous necrosis in the tuberculous granulomas. A thorough etiological investigation was carried out, but no etiologic agent was identified. After four months, the condition spontaneously and completely resolved, suggesting that the pulmonary complications seen in this case resulted from the use of leflunomide.

Key words: Lung diseases, interstitial/chemically induced. Lung/drug effects.

Abbreviations used in this paper:

AFB – Acid-fast bacilli

BOOP – Bronchiolitis obliterans organizing pneumonia

DNA – Deoxyribonucleic acid

BAL – Bronchoalveolar lavage

PAS – Periodic acid-Schiff

PaCO₂ – Partial pressure of carbon dioxide

PaO₂ – Partial pressure of oxygen

CX – Chest radiograph

CAT – Computerized axial tomography

BSR – Blood sedimentation rate

Introduction

In the lungs, various endogenous and exogenous chemical substances are captured, stored and metabolized. Adverse drug reactions also frequently implicate the lungs.^(1-3) The effects of these events on matrix repair, oxidant and anti-oxidant, proteolytic, and immune systems have been investigated, although the exact mechanisms of most of those reactions are unknown. Various clinical syndromes have been associated with adverse drug reactions. Among these are pulmonary hypertension and hemorrhage, edema, chronic interstitial diseases, acute pulmonary infiltrate, adult respiratory distress syndrome, bronchiolitis obliterans, pleural effusion, and bronchospasm.⁽⁴⁾

Granulomatous interstitial pneumonia has been most commonly associated with administration of carbamazapine, methotrexate or sulfasalazine.⁽⁴⁾ However, leflunomide, a recently developed anti-rheumatic immunomodulator, has never been implicated in granulomatous interstitial pneumonia.

Case report

A 33-year-old female patient, with chest pain and weight loss over a 1-month period, developed respiratory insufficiency and infectious syndrome. The patient suffered from rheumatoid arthritis and a 6-month regimen of specific monotherapy with leflunomide was prescribed. Despite the use of symptomatic medications and broad-spectrum antibiotics, the patient showed no improvement and presented to the emergency department of our hospital. Upon admission, she presented with severe asthenia, fever, pale skin, tachypnea and an absence of swollen cervical lymph nodes, as well as bubbling sounds at the lung bases and crackling sounds in other areas. No abdominal alterations were found and there was no edema or cyanosis in the extremities.

An initial chest radiograph revealed pulmonary infiltrates in the interstice and in the bilateral alveoli, mainly in the upper and middle lobes. Infiltrates in the bilateral interstice and scattered micronodules, but no mediastinal abnormalities, were identified in a CAT scan of the chest (figure 1A and 1B). Initial laboratory tests were performed. The complete blood count included: leucocytes (5500); rods (14%); eosinophils (3%); blood sedimentation rate (BSR, 55); creatinine (0.9 mg/dL); transaminase; partial pressure of oxygen (PaO₂, 73 mmHg); and partial pressure of carbon dioxide (PaCO₂, 30.7 mmHg). Blood cultures (3 samples) were negative.

Two bronchoscopies (including bronchoalveolar lavage) were performed and were negative for neoplastic cells, viral cytopathic alterations, Pneumocystis carinii, acid-fast bacilli (AFB) and fungi. A differential count of 300 cells showed 69% macrophages, 8% neutrophils, 20% leucocytes, and 3% epithelial cells. All cultures were negative for anaerobic bacteria and one culture was positive for coagulase-negative staphylococci. No pathological abnormalities were detected in the transbronchial biopsy.

Leflunomide was suspended and broad-spectrum antibiotic therapy was used as an experimental treatment during the 15-day admission. From day 10 forward, fever declined, as did dyspnea, and there was general improvement, evidenced in part by progressive reabsorption of alveolar lesions. Clinical and radiological findings later confirmed complete reabsorption of the alveolar lesions. However, interstitial reticulonodular lesions persisted, mainly in the periphery of the upper 2/3 of the right lung and of the middle 1/3 of the left lung, interspersed with ground-glass opacity in the superior lobes (Figures 2A and 2B). Further clinical investigation ruled out pneumocystosis, tuberculosis, sarcoidosis and collagenosis. Pulmonary function tests were considered normal throughout.

Anatomopathological examination performed through biopsy of the left superior cervical ganglion (Maloney non-palpable lymph node) and of the lung (thoracotomy) revealed chronic granulomatous inflammation with tuberculous granulomas formed of epithelial histiocytes in a compact arrangement, without caseous necrosis or well-defined lymphocytic coronas. Langhans-type giant multinucleate cells were also observed. In the walls of the alveoli and of the bronchioles, granulomas were observed, together with the resulting partial destruction of a bronchial wall (Figures 3 and 4). Tissue samples cut from various layers were stained using periodic acid-Schiff (PAS) and the Grocott method for fungi and the Fite-Faraco method for AFB. No positive stainings were observed.

Discussion

The lesions seen in the initial radiographs and CAT scan of the chest could be attributable to the infectious process (tuberculosis, atypical pneumonia), to non-infectious pulmonary diseases, such as bronchiolitis obliterans organizing pneumonia (BOOP) and non-cardiogenic pulmonary edema, or to adverse drug reaction. The tuberculous granulomas found in the anatomopathological examination might suggest tuberculosis, paracoccidioidomycosis, sarcoidosis, granulomatous interstitial pneumonia or adverse drug reaction.^(5,6)

Classical tuberculosis was ruled out because the clinical and pathological findings indicated an interstitial pattern, the granulomas presented no caseous necrosis and staining for AFB was negative. Although the interstitial pattern of the lesions is consistent with miliary tuberculosis, that disease can also be ruled out because (in addition to the reasons mentioned above) the outcome was incompatible with that diagnosis.⁽⁵⁾

Atypical mycobacteriosis can present an interstitial pattern in immunosuppressed patients, with similar clinical and radiological findings (including the absence of necrosis). Nevertheless, in such cases, AFB staining is usually positive and the condition tends to persist, not improving without intervention.^(4,5)

The diagnosis of fungal lesions, such as paracoccidioidomycosis, can be easily ruled out since such granulomas usually contain centralized areas of liquefying necrosis with neutrophilic inflammation and the PAS and Grocott stainings for fungi would have been positive. The most common radiological findings for histoplasmosis are bilateral adenomegaly and bilateral reticulonodular infiltrate in the hilum. In cryptococcosis, the most common finding is a solitary nodule which is usually peripheral, subpleural and non-capsulated. Since clinical findings were not compatible with either condition and PAS and Grocott stainings for fungi were negative, these diagnoses were also discarded.^(4,5)

Granulomatous reactions may be caused not only by infection but also by pulmonary interstitial emphysema, a disease in which granulomas form around large air-filled cysts. This differs from hypersensitivity pneumonitis, in which granulomas are found in the interstice.⁽⁶⁾

If radiological scans indicated sarcoidosis, the patient would present advanced pulmonary parenchymal disease and potentially serious fibrogenic reactions, a condition in which the lesions would not resolve spontaneously without pharmacological intervention. Granulomas resulting from sarcoidosis do not present lymphocytic coronas or centralized caseous necrosis and are located in the pulmonary interstice, enveloping the perivascular space like a mitten.^(5,6) Although the granulomas found showed neither well-formed lymphocytic coronas nor centralized necrosis, they were mainly located in the pulmonary interstice and around the bronchioles. In addition, during clinical and radiological follow-up, there was no evidence of pulmonary fibrogenic reaction in the evolution of the disease. Furthermore, the lesions regressed progressively and spontaneously without corticoid medication. Therefore, sarcoidosis was also ruled out.

When not related to the administration of idiopathic or autoimmune drugs, granulomatous interstitial pneumonitis tends to persist, not resolving without intervention. Other histological aspects such as intra-alveolar histiocytes, septal fibrosis, and BOOP foci reveal its anatomopathological characteristics.⁽⁴⁾

There are 3 criteria that can be used to determine whether there is a relationship between the administration of a certain drug and adverse clinical findings.⁽⁴⁾ First, a temporal relationship must exist between drug administration and the adverse event. Second, drug suspension should be followed by improvement of the condition or, in the case of readministration, subsequent administration of the same drug should be followed by recurrence of the event. Finally, alternate explanations for the adverse event must be ruled out. In this study, drug suspension was followed by improvement of the condition. In addition, clinical symptoms of the disease emerged within a reasonable time frame following drug administration. Moreover, all other diagnostic hypotheses were discarded.

Drug-induced granulomatous interstitial disease has been associated with the use of carbamazapine, methotrexate, sulfasalazine, nitrofurantoin, and procarbazine.⁽⁴⁾ However, it has never been associated with the use of leflunomide.

Leflunomide is a recently developed anti-rheumatic drug used in the treatment of rheumatoid arthritis and possesses immunomodulating (anti-inflammatory and anti-proliferative) effects. The active metabolite in leflunomide inhibits dihydroorotate dehydrogenase, which is a rate-limiting enzyme involved in the de novo synthesis of pyrimidine. Since T-cells strongly depend on newly synthesized pyrimidine for the production of DNA prior to cell division, the inhibition of pyrimidine synthesis greatly limits T-cell expansion, which is considered central to the induction and maintenance of chronic inflammation in rheumatoid arthritis.^(7-9) Some possible adverse respiratory reactions to leflunomide are cough, upper and lower respiratory tract infections, asthma, dyspnea, epistaxis, and "other pulmonary alterations".⁽¹⁰⁾ The toxicity spectrum of leflunomide is described as similar to that of methotrexate, although to date there have been no studies correlating leflunomide with interstitial pneumonitis.^(10,11)

In light of the fact that there was an apparent temporal correlation between previous and recent use of leflunomide and the identification of post-infection interstitial reticulonodular lesions, adverse drug reaction was suspected. In addition, progressive, spontaneous regression of those lesions was observed after the drug was discontinued (follow up for more than 2 years) (Figure 5). Therefore, since exhaustive clinical, radiological, and anatomopathological investigation also ruled out any alternative diagnosis, we hypothesize that leflunomide administration was involved in the development of the interstitial inflammatory symptoms seen in this patient.

References

Submitted: 28/4/03. Accepted, after revision: 30/7/03.

* Study received the "Best Case Report" award at the XXXI Brazilian Congress of Pulmonology and Phthisiology – October 2002, São Paulo.

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Publication Dates

• Publication in this collection
  12 May 2004
• Date of issue
  Dec 2003

History

• Accepted
  30 July 2003
• Received
  28 Apr 2003