Clin Rheumatol (2011) 30:13791384 DOI 10.

1007/s10067-011-1765-7

CASE BASED REVIEW

Methotrexate-induced pulmonary toxicity in psoriatic arthritis (PsA): case presentation and literature review
Federico Rondon & Odilio Mendez & Nestor Spinel & Carlos Ochoa & Cristian Saavedra & Edgar Penaranda & Ignacio Garcia-Valladares & Luis R. Espinoza & Antonio Iglesias-Gamarra

Received: 2 April 2011 / Accepted: 21 April 2011 / Published online: 26 May 2011 # Clinical Rheumatology 2011

Abstract A 45-year-old female with a 4-week history of psoriatic arthritis developed cough, fever, and progressive shortness of breath 2 weeks following initiation of methotrexate therapy. High resolution CT of chest revealed bilateral basal interstitial involvement and diffuse ground glass opacities. Patient, though, died despite immediate discontinuation of methotrexate and initiation of treatment with IV methylprednisolone and cyclophosphamide. Post-mortem examination showed diffuse interstitial pulmonary fibrosis. Methotrexate-induced pulmonary toxicity is a serious event, unpredictable, and unusual, especially in patients with psoriatic arthritis, and although reversible, it may be fatal. Keywords Lung injury . Methotrexate . Psoriatic arthritis . Pulmonary fibrosis
F. Rondon : N. Spinel : C. Ochoa : C. Saavedra : E. Penaranda : A. Iglesias-Gamarra Rheumatology Unit, Faculty of Medicine, National University of Colombia, Bogota, Colombia O. Mendez Department of Pathology, Hospital San Carlos Foundation, Bogota, Colombia I. Garcia-Valladares : L. R. Espinoza (*) Rheumatology Sections, LSU Health Sciences Center, New Orleans, LA, USA F. Rondon (*) Rheumatology Unit, Faculty of Medicine, National University of Colombia, Cra. 30 No. 45-03, Building 471, 5th Floor, Office 510, Bogota, Colombia e-mail: federicorondonh@hotmail.com L. R. Espinosa e-mail: luisrolan@msn.com

Introduction Methotrexate (MTX) is an analog of folic acid with an anti-inflammatory, anti-proliferative, and immunosuppressive activities. MTX was first used in the treatment of malignant diseases, and has since become the gold standard of therapy of rheumatoid arthritis (RA) and also psoriasis and psoriatic arthritis (PsA) [1]. It is generally well tolerated, although adverse events can occur. The most frequent adverse events associated with MTX are in the gastrointestinal and central nervous systems followed with less frequency by hepatic and hematologic abnormalities [24]. Pulmonary toxicity, which is usually an acute interstitial pneumonitis can also occur, is characterized by the presence of dyspnea, dry cough, and fever [5]. Most cases of MTX-induced lung injury are reversible following discontinuation of therapy. Herein, we described a patient with PsA who presented a fatal acute pulmonary toxicity secondary to MTX. Potential risk factors and pathogenic mechanisms are discussed.

Material and methods Case report A 45-year-old female with a 4-week history of polyarticular PsA was begun on oral MTX 10 mg weekly and 1 mg of daily folic acid in May 2009. Past medical history revealed a past medical history of social smoking, and she had been treated with prednisolone 10 mg daily and calcium carbonate 600 mg/day. Two weeks following the initiation of MTX therapy (June 2009), she presented to the emergency room with a history of progressive shortness of breath, cough, and generalized malaise of

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Fig. 1 Chest X-ray. Interstitial infiltratesbibasal reticulonodular

Laboratory data revealed a leukocyte count of 4,700/mm3 (neutrophils 61% and lymphocytes 23%), hemoglobin of 13 g/dl, platelets of 328,000/mm3, ESR of 21 mm/h, C-reactive protein of 0.6 mg/dl, rheumatoid factor and ANA were negative, and PaO2/FiO2 of 200. Chest X-ray revealed nodular reticular interstitial infiltrate in the bases (Fig. 1), and a high resolution CT of chest showed bilateral basal non-specific interstitial infiltrate with multiple bronchiectasis and areas of diffuse ground glass opacities (Fig. 2). MTX was discontinued immediately, and patient was placed on piperacillin, tazobactam, and trimetropim/sulphametoxazol. Despite this therapy, patients clinical condition continued to deteriorate with worsening of hemodynamic and oxygenation parameters, requiring vasopressors and mechanical ventilation support in the ICU. Bronchoscopy could not be performed due to poor overall clinical condition. Treatment with IV methylprednisolone 500 mg/daily for 3 days and 500 mg IV cyclophosphamide were given without a clinical response. Cultures of blood, urine, oral, and tracheal secretions were negative. Patient died on the fifth hospital day following admission. Histopathology Microscopic examination revealed severe and diffuse interstitial pulmonary fibrosis, with partial collagenization, some areas of organized pneumonia, and hyperplastic changes of bronchoalveolar epithelial atypia. No granulomatous changes were seen (Figs. 3 and 4).

11 days in duration. On admission, her blood pressure was 90/60 mmHg, heart rate of 126/min, respiratory frequency of 26/min, and temperature of 38.5C. Physical examination revealed the presence of 3 mm painful ulcerations on the mucosa of upper lip and lateral aspect of tongue, synovitis of PIPs and DIPs of hands and feet, and psoriatic plaques on hands, extensor surfaces of elbows, and inner aspects of thighs.

Fig. 2 HRCT of chest. Bilateral interstitial infiltrate, bronchiectasis, and diffuse ground glass opacities (arrows)

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Discussion MTX-induced pulmonary toxicity was first described in 1969 following high use of MTX in a patient with acute lymphocytic leukemia [6]. In 1983, two cases of low dose and intermittent MTX-induced lung injury in RA patients were published [7, 8]. These initial reports were followed over the past three decades by over a hundred cases of MTXinduced pulmonary toxicity, mainly acute interstitial pneumonitis, and mostly in patients with RA and psoriasis. Our case is the sixth reported case of PsA associated with MTXinduced lung injury, since Black et al. first demonstrated in 1964 the efficacy of MTX in psoriasis and PsA [9]. MTX-induced pulmonary toxicity is an infrequent and unpredictable adverse event, but one of the most serious complications associated with MTX therapy (Table 1). The reported prevalence of the event is between 2% and 7% in RA patients treated with low-dose MTX and associated with a mortality rate between 1% and 17% [10, 11]. Based on the degree of MTX exposure, low cumulative dose of 300 mg vs high MTX exposure (>300 mg), Chikura et al. suggest that MTX-induced pneumonitis (MTX-P) can be divided into two groups: type 1 MTX-P that occurs early, predominated by high neutrophils in bronchoalveolar lavage (BAL), lung fibrosis, and high mortality; and type 2 MTX-P that occurs late, predominated by high lymphocytes and less neutrophils in BAL, less fibrosis and lower mortality [12]. The pathogenesis of MTX-induced pulmonary toxicity is not well defined. Recent findings suggest that inflammation in MTX-induced lung injury occurs via the p38 MAPK pathway [13]. Kim et al. have shown that MTX activates IL-1 expression and also induces phosphorylation of various proteins in the p38 MAPK cascade, including

Fig. 4 Lung histopathology. Atypical hyperplasia bronchiolar epithelium (arrow)

HSP27. Lastly, HSP27 activation may increase IL-8 secretion, resulting in a pulmonary inflammatory response such as pneumonitis [13]. Predisposing risk factors for MTX-induced pulmonary injury have not been investigated in PsA, but for RA in both American and Japanese populations are the following: older age, diabetes, pleuropulmonary involvement, prior use of DMARDs, hypoalbuminemia, male gender, increased J-HAQ score, decreased pain visual analog score, and elevated ESR [14, 15]. MTX-induced pulmonary toxicity in PsA patients has been rarely reported, and in contrast to RA, no evidence of pulmonary fibrosis was demonstrated in a cohort of 27 PsA patients, with and without recognized risk factors as previously described, receiving low-dose MTX and using sensitive imaging techniques and pulmonary function tests [16, 17]. To date, only five cases have been reported in the literature. In 1995, Israel et al. described the first case in a 71-year-old woman with PsA [18]. The patient developed severe interstitial pneumonitis at low-dose MTX therapy. There was a good clinical response following discontinuation of MTX and treatment with systemic corticosteroids and complete recovery at 1 month. Transbronchial biopsy showed

Table 1 MTX-induced pulmonary toxicity: clinical presentation forms 1. Acute interstitial pneumonitis 2. Interstitial fibrosis 3.Bronchiolitis obliterans organizing pneumonia 4. Pleuresy/pleural effusion 5. Pulmonary nodules 6. Non-cardiogenic pulmonary edema 7. Bronchitis/hyperreactivity of airways

Fig. 3 Lung histopathology. Diffuse interstitial fibrosis, as demonstrated by Masson trichrome special staining (arrows) (20)

1382 D dyspnea, C cough, F fever (>38.3C), M malaise, W weakness, HRCT high resolution computer tomography, N normal, NA not available, A present case, PDN prednisone, MP methylprednisolone, CYC cyclophosphamide, MTX methotrexate, WBC white blood cells PDN 50 mg/day3 days Betamethasone 8 mg/day PDN 2 mg/kg/day PDN 10 mg/day, azathioprine 100 mg/day None

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Table 2 Clinical characteristics and laboratory findings of patients with psoriatic arthritis treated with methotrexate

mononuclear inflammatory infiltrate and minimal interstitial fibrosis. In 1997, Salaffi et al. reported the second PsA patient who developed MTX-induced acute interstitial pneumonitis [19]. There was a favorable clinical response following discontinuation of MTX and initiation of IV betamethasone. The authors, however, did not report bronchial washing nor biopsy findings. In 2004, Mazokopakis et al. reported the third PsA patient with MTX-induced lung toxicity [20]. They described a 54-year-old male patient who developed fatal interstitial pneumonitis 1 month after initiation of lowdose MTX therapy, despite treatment with high-dose systemic corticosteroids and discontinuation of MTX. Bronchoalveolar lavage demonstrated alveolitis with predominant mononuclear cells (lymphocytes and macrophages), and lung biopsy showed non-specific interstitial fibrosis with hyperplasia of pneumocytes type 2 and squamous metaplasia. Balbir-Gurman et al. reported a patient with PsA with negative RF and CCP antibodies who developed massive sterile pleural empyema and multiple cavitary pulmonary nodules during MTX therapy [21]. Manuel et al. also reported a 64-year-old male with PsA who presented with a 6-week history of dry cough without other respiratory symptoms and had been placed on MTX 9 years previously. A chest CT showed multiple pulmonary nodules, and percutaneous needle biopsy showed some viable lung parenchyma and mild chronic inflammation. Pulmonary nodules disappeared upon discontinuation of MTX [22]. These characteristics are common to patients (RA, psoriasis, PsA, Crohns) developing MTX-related pulmonary toxicity, which were also present in our PsA patient. The clinical and demographic characteristics of the six PsA patients (including ours) exhibiting MTX-induced pulmonary toxicity are shown in Table 2. Of the total, three were females and three males with an age range of 45 and 71 years, respectively. Most presented with dyspnea, cough, and fever >38.3C. Fatigue and generalized malaise were present in five patients including ours. Clinical presentation was acute in most patients with duration of symptoms of less than a month. At hospitalization, the majority of patients had an elevated ESR, hypoxemia, and interstitial involvement on chest radiograph. High resolution CT of chest performed in four

MTX total doses (mg)

Treatment

300 240 120

840

6,750 108 N 13 42 days

MTX duration (weeks)

60 16 8

52

PaO2 (mmHg)

52 59.6 52

NA

WBC (mm)

N 6.6 6.2

NA Diffuse uptake patterna Diffuse ground glass opacities

Multiple pulmonary nodules, cavitation, massive effusion Mutiple nodules 14 days D, C, F

HRCT of chest

Interstitial infiltrate/alveolar Diffuse interstitial infiltrate Interstitial infiltrate medial and apical/alveolar Multiple infiltrates, massive left-sided effusion Multiple pulmonary nodules 28 days Abrupt 10 days D, C, F D, C, F, M D, C, F,W

Symptoms duration

Chest X-ray

Signs and symptoms

D,C,F,M

11 days

Intersticial infiltrates, basal reticulonodular

Diffuse ground glass opacities, bronchiectasies

4.7

45

20

MP 500 mg/day, CYC

67-Gallium lung scan

Table 3 MTX-induced pulmonary toxicity: proposed diagnostic criteria [29] Clinical picture compatible with hypersensitivity reaction Interstitial infiltrates on chest radiograph Exclusion of lung infection or other disease Pathologic findings consistent with drug-induced damage Probable disease, three criteria; possible disease, two criteria

Age/sex

71/F 62/M 58/M

48/F

64/M [22]

References

[18] [19] [20]

[21]

45/F

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patients demonstrated ground glass opacities, interstitial involvement of basal and peripheral lungs, nodules (one cavitary), and pleural effusion in one. Pulmonary function tests revealed restrictive pattern, with diminished CO diffusion capacity. Low-dose MTX between 520 mg/ week was used in all patients, and mean exposure to MTX prior to initiation of symptoms was 41.3 weeks with a range between 2 and 108 weeks. Accumulated MTX dose was between 20 and 6,750 mg. Most patients received systemic corticoids at variable doses, and cyclophosphamide and azathioprine were used in two patients. Similarly to toxicity in other organ systems including hematopoietic, MTX-induced pulmonary toxicity does not bear relationship to the dose nor duration of therapy, being considered an idiosyncratic reaction [23]. Dyspnea, dry cough, fever, and generalized malaise are the most common presenting symptoms. Cyanosis, hypoxemia, and restrictive changes in pulmonary function tests are also frequently present. Most patients exhibit radiological changes characterized by interstitial infiltrates in lung bases on plain radiographs, and high resolution CT being the most reliable technique to determine the extent of pulmonary involvement [24]. Acute presentation is the most frequent form of clinical presentation occurring in days or weeks and often times follow a fatal course (acute respiratory insufficiency). The subacute form is the most common, has an insidious course, occurring over weeks and associated with peripheral and cutaneous eosinophilia. Chronic presentation evolves over several months and manifests with pulmonary fibrosis, pleural effusion, and pulmonary nodules [11]. During the diagnostic work-up, it is mandatory to rule out an infectious process, mainly Pneumocystis jiroveci [25]. Bronchopulmonary lavage is very useful to rule out infection processes. Histopathologically, MTX-induced pneumonitis is characterized by interstitial pneumonitis, bronchiolitis, and giant cell formation. BAL shows in most patients lymphocytic alveolitis (CD4+), and in a much lesser extent polymorphonuclear infiltrate with CD8+ cells, suggestive of immune-mediated tissue damage [26]. The presence of atypical epithelial cells (hyperplasia of type 2 pneumocytes) signals the establishment of fibrosis pulmonary secondary to MTX [11]. Diffuse alveolar damage and granuloma formation have also been described. Lung biopsy is not always indicated but is helpful in ruling out other causes of lung pathology [11]. To date, there are no clinical characteristics or specific laboratory tests diagnostic of MTX-induced pulmonary toxicity. History of exposure to MTX, the presence of interstitial infiltrates in chest radiographs or high resolution CT, and exclusion of other pulmonary pathologies constitute the most important clues in the diagnosis. Histology consistent with the described MTX-induced lung findings assists in the

diagnosis [26]. There are no validated diagnostic criteria, although some have been proposed that lack sensitivity and specificity [2729]. Carson et al. proposed a diagnostic criteria with emphasis in characteristic histopathologic findings, radiologic interstitial pulmonary involvement, and exclusion of infectious processes are the most commonly used [29] (Table 3). Treatment of MTX-induced pulmonary toxicity requires immediate discontinuation of MTX, use of systemic corticosteroids, and supportive care. There is no control, prospective studies about the use of corticosteroids in MTX-induced pulmonary toxicity, but clinical experience suggests that they accelerate the recovery of pneumonitis in affected patients. High doses (methylprednisolone 1 mg/kg/day) with slow tapering according to patients clinical response should be used [29]. Clinical improvement occurs before radiological improvement, and although fatal at times, most patients recovered without sequel. Patients with a prior history of MTX-induced pulmonary toxicity should not be rechallenged [11]. Methotrexate is highly effective in inflammatory disorders including PsA and generally has a very good safety profile. Pulmonary toxicity is an infrequent and unpredictable adverse event with diverse forms of presentation. A history of exposure, radiologic pulmonary involvement, exclusion of infection, and biopsy findings are important for its diagnosis. Treatment consists of immediate discontinuation and the use of systemic corticosteroids. Most patients experience full recovery, but it may be fatal.

Disclosures None

References
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