CASE BASED REVIEW

Methotrexate-induced pulmonary toxicity in psoriaticarthritis (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 ofpsoriatic arthritis developed cough, fever, and progressiveshortness of breath 2 weeks following initiation of metho-trexate therapy. High resolution CT of chest revealed bilateralbasal interstitial involvement and diffuse ground glassopacities. Patient, though, died despite immediate discontin-uation of methotrexate and initiation of treatment with IVmethylprednisolone and cyclophosphamide. Post-mortemexamination showed diffuse interstitial pulmonary fibrosis.Methotrexate-induced pulmonary toxicity is a serious event,unpredictable, and unusual, especially in patients withpsoriatic arthritis, and although reversible, it may be fatal.

Keywords Lung injury .Methotrexate . Psoriatic arthritis .

Pulmonary fibrosis

Introduction

Methotrexate (MTX) is an analog of folic acid with ananti-inflammatory, anti-proliferative, and immunosup-pressive activities. MTX was first used in the treatmentof malignant diseases, and has since become the goldstandard of therapy of rheumatoid arthritis (RA) and alsopsoriasis and psoriatic arthritis (PsA) [1]. It is generallywell tolerated, although adverse events can occur. Themost frequent adverse events associated with MTX are inthe gastrointestinal and central nervous systems followedwith less frequency by hepatic and hematologic abnor-malities [2–4]. Pulmonary toxicity, which is usually anacute interstitial pneumonitis can also occur, is character-ized by the presence of dyspnea, dry cough, and fever [5].Most cases of MTX-induced lung injury are reversiblefollowing discontinuation of therapy. Herein, we describeda patient with PsA who presented a fatal acute pulmonarytoxicity secondary to MTX. Potential risk factors andpathogenic mechanisms are discussed.

Material and methods

Case report

A 45-year-old female with a 4-week history of polyarticularPsA was begun on oral MTX 10 mg weekly and 1 mg ofdaily folic acid in May 2009. Past medical historyrevealed a past medical history of social smoking, andshe had been treated with prednisolone 10 mg daily andcalcium carbonate 600 mg/day. Two weeks following theinitiation of MTX therapy (June 2009), she presented tothe emergency room with a history of progressiveshortness of breath, cough, and generalized malaise of

F. Rondon :N. Spinel : C. Ochoa :C. Saavedra : E. Penaranda :A. Iglesias-GamarraRheumatology Unit, Faculty of Medicine,National University of Colombia,Bogota, Colombia

O. MendezDepartment 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, Colombiae-mail: federicorondonh@hotmail.com

L. R. Espinosae-mail: luisrolan@msn.com

Clin Rheumatol (2011) 30:1379–1384DOI 10.1007/s10067-011-1765-7

11 days in duration. On admission, her blood pressurewas 90/60 mmHg, heart rate of 126/min, respiratoryfrequency of 26/min, and temperature of 38.5°C. Physicalexamination revealed the presence of 3 mm painful ulcer-ations on the mucosa of upper lip and lateral aspect of tongue,synovitis of PIPs and DIPs of hands and feet, and psoriaticplaques on hands, extensor surfaces of elbows, and inneraspects of thighs.

Laboratory data revealed a leukocyte count of 4,700/mm3

(neutrophils 61% and lymphocytes 23%), hemoglobin of13 g/dl, platelets of 328,000/mm3, ESR of 21 mm/h,C-reactive protein of 0.6 mg/dl, rheumatoid factor andANA were negative, and PaO2/FiO2 of 200. Chest X-rayrevealed nodular reticular interstitial infiltrate in the bases(Fig. 1), and a high resolution CT of chest showed bilateralbasal non-specific interstitial infiltrate with multiple bronchi-ectasis and areas of diffuse ground glass opacities (Fig. 2).MTX was discontinued immediately, and patient was placedon piperacillin, tazobactam, and trimetropim/sulphametoxa-zol. Despite this therapy, patient’s clinical condition continuedto deteriorate with worsening of hemodynamic and oxygen-ation parameters, requiring vasopressors and mechanicalventilation support in the ICU. Bronchoscopy could not beperformed due to poor overall clinical condition. Treatmentwith IV methylprednisolone 500 mg/daily for 3 days and500 mg IV cyclophosphamide were given without a clinicalresponse. Cultures of blood, urine, oral, and trachealsecretions were negative. Patient died on the fifth hospitalday following admission.

Histopathology

Microscopic examination revealed severe and diffuseinterstitial pulmonary fibrosis, with partial collagenization,some areas of organized pneumonia, and hyperplasticchanges of bronchoalveolar epithelial atypia. No granulo-matous changes were seen (Figs. 3 and 4).

Fig. 1 Chest X-ray. Interstitial infiltrates—bibasal reticulonodular

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

1380 Clin Rheumatol (2011) 30:1379–1384

Discussion

MTX-induced pulmonary toxicity was first described in 1969following high use of MTX in a patient with acutelymphocytic leukemia [6]. In 1983, two cases of low doseand intermittent MTX-induced lung injury in RA patientswere published [7, 8]. These initial reports were followedover the past three decades by over a hundred cases of MTX-induced pulmonary toxicity, mainly acute interstitial pneu-monitis, and mostly in patients with RA and psoriasis. Ourcase is the sixth reported case of PsA associated with MTX-induced lung injury, since Black et al. first demonstrated in1964 the efficacy of MTX in psoriasis and PsA [9].

MTX-induced pulmonary toxicity is an infrequent andunpredictable adverse event, but one of the most seriouscomplications associated with MTX therapy (Table 1). Thereported prevalence of the event is between 2% and 7% inRA patients treated with low-dose MTX and associated witha mortality rate between 1% and 17% [10, 11]. Based on thedegree of MTX exposure, low cumulative dose of 300 mg vshigh MTX exposure (>300 mg), Chikura et al. suggest thatMTX-induced pneumonitis (MTX-P) can be divided intotwo groups: type 1 MTX-P that occurs early, predominatedby high neutrophils in bronchoalveolar lavage (BAL), lungfibrosis, and high mortality; and type 2 MTX-P that occurslate, predominated by high lymphocytes and less neutrophilsin BAL, less fibrosis and lower mortality [12].

The pathogenesis of MTX-induced pulmonary toxicity isnot well defined. Recent findings suggest that inflammationin MTX-induced lung injury occurs via the p38 MAPKpathway [13]. Kim et al. have shown that MTX activatesIL-1β expression and also induces phosphorylation ofvarious proteins in the p38 MAPK cascade, including

HSP27. Lastly, HSP27 activation may increase IL-8 secretion,resulting in a pulmonary inflammatory response such aspneumonitis [13]. Predisposing risk factors for MTX-inducedpulmonary injury have not been investigated in PsA, but forRA in both American and Japanese populations are thefollowing: older age, diabetes, pleuropulmonary involve-ment, prior use of DMARDs, hypoalbuminemia, malegender, increased J-HAQ score, decreased pain visual analogscore, and elevated ESR [14, 15].

MTX-induced pulmonary toxicity in PsA patients hasbeen rarely reported, and in contrast to RA, no evidence ofpulmonary fibrosis was demonstrated in a cohort of 27 PsApatients, with and without recognized risk factors aspreviously described, receiving low-dose MTX and usingsensitive imaging techniques and pulmonary function tests[16, 17]. To date, only five cases have been reported in theliterature. In 1995, Israel et al. described the first case in a71-year-old woman with PsA [18]. The patient developedsevere interstitial pneumonitis at low-dose MTX therapy.There was a good clinical response following discontinuationof MTX and treatment with systemic corticosteroids andcomplete recovery at 1 month. Transbronchial biopsy showed

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

Fig. 3 Lung histopathology. Diffuse interstitial fibrosis, as demon-strated by Masson trichrome special staining (arrows) (×20)

Table 1 MTX-induced pulmonary toxicity: clinical presentationforms

1. Acute interstitial pneumonitis 5. Pulmonary nodules

2. Interstitial fibrosis 6. Non-cardiogenicpulmonary edema

3.Bronchiolitis obliteransorganizing pneumonia

7. Bronchitis/hyperreactivityof airways

4. Pleuresy/pleural effusion

Clin Rheumatol (2011) 30:1379–1384 1381

mononuclear inflammatory infiltrate and minimal interstitialfibrosis. In 1997, Salaffi et al. reported the second PsA patientwho developed MTX-induced acute interstitial pneumonitis[19]. There was a favorable clinical response followingdiscontinuation of MTX and initiation of IV betamethasone.The authors, however, did not report bronchial washing norbiopsy findings. In 2004, Mazokopakis et al. reported thethird PsA patient with MTX-induced lung toxicity [20].They described a 54-year-old male patient who developedfatal interstitial pneumonitis 1 month after initiation of low-dose MTX therapy, despite treatment with high-dosesystemic corticosteroids and discontinuation of MTX.Bronchoalveolar lavage demonstrated alveolitis with pre-dominant mononuclear cells (lymphocytes and macro-phages), and lung biopsy showed non-specific interstitialfibrosis with hyperplasia of pneumocytes type 2 andsquamous metaplasia. Balbir-Gurman et al. reported a patientwith PsA with negative RF and CCP antibodies whodeveloped massive sterile pleural empyema and multiplecavitary pulmonary nodules during MTX therapy [21].Manuel et al. also reported a 64-year-old male with PsAwho presented with a 6-week history of dry cough withoutother respiratory symptoms and had been placed on MTX9 years previously. A chest CT showed multiple pulmonarynodules, and percutaneous needle biopsy showed someviable lung parenchyma and mild chronic inflammation.Pulmonary nodules disappeared upon discontinuation ofMTX [22]. These characteristics are common to patients(RA, psoriasis, PsA, Crohn’s) developing MTX-relatedpulmonary toxicity, which were also present in our PsApatient.

The clinical and demographic characteristics of the sixPsA patients (including ours) exhibiting MTX-inducedpulmonary toxicity are shown in Table 2. Of the total,three were females and three males with an age range of45 and 71 years, respectively. Most presented withdyspnea, cough, and fever >38.3°C. Fatigue and general-ized malaise were present in five patients including ours.Clinical presentation was acute in most patients withduration of symptoms of less than a month. At hospital-ization, the majority of patients had an elevated ESR,hypoxemia, and interstitial involvement on chest radio-graph. High resolution CT of chest performed in four

Tab

le2

Clin

ical

characteristicsandlabo

ratory

find

ings

ofpatientswith

psoriatic

arthritis

treatedwith

metho

trexate

References

Age/sex

Signs

and

symptom

sSym

ptom

sdu

ratio

nChestX-ray

HRCTof

chest

WBC

(mm³)

PaO

2

(mmHg)

MTX

duratio

n(w

eeks)

MTX

total

doses(m

g)Treatment

[18]

71/F

D,C,F

28days

Interstitialinfiltrate/alveolar

NA

N52

6030

0PDN

50mg/day×3days

[19]

62/M

D,C,F,

MAbrupt

Diffuse

interstitialinfiltrate

Diffuse

uptake

pattern

a6.6

59.6

1624

0Betam

ethasone

8mg/day

[20]

58/M

D,C,F,W

10days

Interstitialinfiltratemedial

andapical/alveolar

Diffuse

grou

ndglassop

acities

6.2

528

120

PDN

2mg/kg

/day

[21]

48/F

D,C,F

14days

Multip

leinfiltrates,massive

left-sided

effusion

Multip

lepu

lmon

aryno

dules,

cavitatio

n,massive

effusion

NNA

5284

0PDN

10mg/day,

azathiop

rine

100mg/day

[22]

64/M

C42

days

Multip

lepu

lmon

aryno

dules

Mutiple

nodu

les

13N

108

6,75

0Non

e

A45

/FD,C,F,M

11days

Intersticialinfiltrates,basal

reticulon

odular

Diffuse

grou

ndglass

opacities,bron

chiectasies

4.7

452

20MP50

0mg/day,

CYC

Ddy

spnea,

Ccoug

h,F

fever(>38

.3°C

),M

malaise,W

weakn

ess,

HRCT

high

resolutio

ncompu

tertomog

raph

y,N

norm

al,NA

notavailable,

Apresentcase,PDN

prednisone,MP

methy

lpredn

isolon

e,CYCcyclop

hosphamide,

MTXmetho

trexate,

WBCwhite

bloo

dcells

a67

-Galliu

mlung

scan

Table 3 MTX-induced pulmonary toxicity: proposed diagnosticcriteria [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

1382 Clin Rheumatol (2011) 30:1379–1384

patients demonstrated ground glass opacities, interstitialinvolvement of basal and peripheral lungs, nodules (onecavitary), and pleural effusion in one. Pulmonary functiontests revealed restrictive pattern, with diminished COdiffusion capacity. Low-dose MTX between 5–20 mg/week was used in all patients, and mean exposure to MTXprior to initiation of symptoms was 41.3 weeks with arange between 2 and 108 weeks. Accumulated MTX dosewas between 20 and 6,750 mg. Most patients receivedsystemic corticoids at variable doses, and cyclophospha-mide and azathioprine were used in two patients.

Similarly to toxicity in other organ systems includinghematopoietic, MTX-induced pulmonary toxicity doesnot bear relationship to the dose nor duration of therapy,being considered an idiosyncratic reaction [23]. Dyspnea,dry cough, fever, and generalized malaise are the mostcommon presenting symptoms. Cyanosis, hypoxemia, andrestrictive changes in pulmonary function tests are alsofrequently present. Most patients exhibit radiologicalchanges characterized by interstitial infiltrates in lungbases on plain radiographs, and high resolution CT beingthe most reliable technique to determine the extent ofpulmonary involvement [24].

Acute presentation is the most frequent form of clinicalpresentation occurring in days or weeks and often timesfollow a fatal course (acute respiratory insufficiency). Thesubacute form is the most common, has an insidious course,occurring over weeks and associated with peripheral andcutaneous eosinophilia. Chronic presentation evolves overseveral months and manifests with pulmonary fibrosis,pleural effusion, and pulmonary nodules [11]. During thediagnostic work-up, it is mandatory to rule out an infectiousprocess, mainly Pneumocystis jiroveci [25]. Bronchopul-monary lavage is very useful to rule out infection processes.

Histopathologically, MTX-induced pneumonitis is char-acterized by interstitial pneumonitis, bronchiolitis, and giantcell formation. BAL shows in most patients lymphocyticalveolitis (CD4+), and in a much lesser extent polymor-phonuclear infiltrate with CD8+ cells, suggestive ofimmune-mediated tissue damage [26]. The presence ofatypical epithelial cells (hyperplasia of type 2 pneumocytes)signals the establishment of fibrosis pulmonary secondaryto MTX [11]. Diffuse alveolar damage and granulomaformation have also been described. Lung biopsy is notalways indicated but is helpful in ruling out other causes oflung pathology [11].

To date, there are no clinical characteristics or specificlaboratory tests diagnostic of MTX-induced pulmonarytoxicity. History of exposure to MTX, the presence ofinterstitial infiltrates in chest radiographs or high resolutionCT, and exclusion of other pulmonary pathologies constitutethe most important clues in the diagnosis. Histology consistentwith 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 andspecificity [27–29]. Carson et al. proposed a diagnosticcriteria with emphasis in characteristic histopathologicfindings, radiologic interstitial pulmonary involvement, andexclusion of infectious processes are the most commonlyused [29] (Table 3).

Treatment of MTX-induced pulmonary toxicityrequires immediate discontinuation of MTX, use ofsystemic corticosteroids, and supportive care. There isno control, prospective studies about the use of cortico-steroids in MTX-induced pulmonary toxicity, but clinicalexperience suggests that they accelerate the recovery ofpneumonitis in affected patients. High doses (methylprednis-olone 1 mg/kg/day) with slow tapering according to patient’sclinical response should be used [29]. Clinical improvementoccurs before radiological improvement, and although fatalat times, most patients recovered without sequel. Patientswith a prior history of MTX-induced pulmonary toxicityshould not be rechallenged [11].

Methotrexate is highly effective in inflammatory disordersincluding PsA and generally has a very good safety profile.Pulmonary toxicity is an infrequent and unpredictable adverseevent with diverse forms of presentation. A history ofexposure, radiologic pulmonary involvement, exclusion ofinfection, and biopsy findings are important for its diagnosis.Treatment consists of immediate discontinuation and the useof systemic corticosteroids. Most patients experience fullrecovery, but it may be fatal.

Disclosures None

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