Methotrexate-induced Pneumonitis Research Articles

Flashy lungs and sarcoidosis: not always a sign of disease activity.

This is the case of a 68-year-old man with known cardiac sarcoidosis undergoing treatment with methotrexate who presented with new onset of dyspnea and lipothymia. FDG-PET/CT revealed pathological uptake within lung parenchyma which resolved following discontinuation of methotrexate, compatible with methotrexate-induced pneumonitis. This is the first case of methotrexate-induced pneumonitis documented by FDG-PET/CT.

Methotrexate-induced hypersensitivity pneumonitis in a patient with bullous pemphigoid.

Methotrexate-induced hypersensitivity pneumonitis in a patient with bullous pemphigoid.

High-dose methotrexate-related pneumonitis in a child with acute lymphoblastic leukemia.

Methotrexate is administered through different routes to treat childhood acute lymphoblastic leukemia. Toxicities of low, intermediate, or high doses of methotrexate have been described in the literature. Methotrexate-induced or related pneumonitis is a rare complication that leads, in most cases, to discontinuing this drug. We report a case of a 17-year-old female patient with newly diagnosed B-acute lymphoblastic leukemia who received a high-dose methotrexate on an induction course. Eight days after methotrexate infusion, she developed fever, dyspnea, hypoxemia, and dry cough. Chest computed tomography showed mosaic attenuation of lung parenchyma and bilateral interstitial infiltrate in favor of hypersensitivity pneumonitis with no evidence of bacterial or fungal infections. Methotrexate-related pneumonitis was diagnosed and corticosteroids were prescribed. Improvement of the symptomatology was noted within four days. Given the importance of methotrexate in the treatment of acute lymphoblastic leukemia, intrathecal methotrexate was administered without incident and high-dose methotrexate was re-introduced successfully two and a half months after the pneumonitis episode while using corticosteroids. According to Naranjo's algorithm, the reaction to the drug was found to be probable with a score of 6. Methotrexate is the backbone of acute lymphoblastic leukemia treatment, but numerous adverse reactions have been published of which methotrexate pneumonitis can be fatal in some cases. In this case, we concluded that this drug can be successfully reintroduced after methotrexate-related pneumonitis.

Hypercalcemia with methotrexate pneumonitis: A rare, important and intriguing adverse event.

Methotrexate leading to hypercalcaemia is a rarely reported adverse event. We present three elderly patients with inflammatory arthritis who developed hypercalcemia probably due to methotrexate-induced granulomatous pneumonitis. All patients presented with worsening non-productive cough with dyspnea, nausea, loss of appetite, and confusion. Their clinical and radiologic features were consistent with methotrexate-induced pneumonitis. On evaluation, all patients concurrently had hypercalcemia with normal 25OH D3, and low PTH with markedly elevated levels of 1,25OH D3 seen in two patients. In all three patients, hypercalcemia and pneumonia responded to hydration, corticosteroids, and methotrexate withdrawal. There was no relapse of symptoms on long term follow-up. In these three patients with inflammatory arthritis, methotrexate-induced pneumonitis led to symptomatic hypercalcemia. Unless hypercalcemia is looked for and treated in this setting, the morbidity can be high.

METHOTREXATE-INDUCED PNEUMONITIS

TOPIC: Lung Pathology TYPE: Fellow Case Reports INTRODUCTION: Methotrexate is an analogue of folic acid that inhibits cellular proliferation by inducing an intracellular deficiency of folate coenzymes. Lung toxicity, while rare, often occurs after weeks to months of low dose oral methotrexate therapy. CASE PRESENTATION: A 46 year old male with a history of T cell lymphoma status post chemotherapy on POMP maintenance therapy and pleurX catheter for malignant pleural effusion presented to the ED with fever for 4 days. Associated symptoms were dry cough, chills, and fatigue. He denied drug allergies.BP 153/84, HR 135, SpO2 98% on room air, and temperature 101.5F. WBC was 3.2 and COVID PCR was negative. Broad spectrum antibiotics were initiated. CT thorax showed upper lobe predominant ground-glass opacities suggestive of a multifocal pneumonia or drug reaction. He became hypoxic requiring 3L of oxygen and underwent bronchoscopy. Transbronchial biopsy revealed lung parenchyma with isolated giant cells and loosely formed granulomas consistent with hypersensitivity pneumonia. Left upper lobe broncho-alveolar lavage had lymphocytic predominance and elevated CD4:CD8 ratio (4.7), all supporting the diagnosis of methotrexate pneumonitis. Empiric treatment for PJP and Prednisone were started. Viral, bacterial, fungal studies and PJP stain were negative. Antibiotics were stopped and steroids were continued for 2 weeks. His symptoms improved and fevers subsided. As an outpatient, repeat CT thorax and PFTs were ordered and he continues to improve clinically. DISCUSSION: There is a set of criteria to establish the diagnosis. Major criteria includes: 1. hypersensitivity pneumonitis by histopathology without pathogenic organisms 2. imaging with diffuse ground-glass or consolidative opacities 3. negative blood cultures (if febrile) and initial sputum cultures (if produced). Minor criteria includes: 1. dyspnea for <8 weeks 2. nonproductive cough 3. SpO2< 90% on room air at initial evaluation 4. DLCO < 70% of predicted for age and 5. WBC < 15k. Methotrexate pneumonitis is definite if major criteria 1 or 2 and major criterion 3 are present with three of the five minor criteria and probable if major criteria 2 and 3 plus two of the five minor criteria are present (1). Our patient met all major criteria and four minor criteria. CONCLUSIONS: Although rare with a prevalence of 0.3-11.6% (1,3), methotrexate pneumonitis has a mortality rate of 13-17.6% (2,4). Patients should be advised about the possibility of lung toxicity. Some data suggests patients should be screened for lung disease prior to medication initiation (5) and clinicians should be cautious using the drug in patients with underlying lung disease (6). REFERENCE #1: Salehi, Mashal et al. "Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30 years of use: a case report." Journal of medical case reports vol. 11,1 174. 28 Jun. 2017, doi:10.1186/s13256-017-1333-0 DISCLOSURES: No relevant relationships by Bianca Dominguez, source=Web Response No relevant relationships by Gurjot Garcha, source=Web Response No relevant relationships by Wael Nasser, source=Web Response No relevant relationships by Olatunji Otegbeye, source=Web Response

Pneumopathie interstitielle aiguë chez une patiente traitée par méthotrexate : atteinte tardive avec neutrophilie et éosinophilie dans le lavage bronchoalvéolaire

Methotrexate-induced pneumonitis is a rare but potentially fatal side effect. It is a diagnosis of exclusion. There are early and late forms and different cell patterns in the bronchoalveolar lavage (BAL). We present a case of acute interstitial lung disease in a 54-year-old patient who had been taking methotrexate for a year and a half for rheumatoid arthritis. After excluding other causes and based on the diagnostic criteria of Searles and McKendry, we could reasonably identify methotrexate as the cause of the lung disease. It was of late onset and the BAL showed neutrophilia and eosinophilia. Methotrexate-induced pneumonitis is a diagnosis of exclusion. A late onset combined with the predominance of neutrophils and eosinophils in BAL is rare in the literature, demonstrating the wide heterogeneity of methotrexate-related interstitial lung disease.

Low-dose methotrexate-induced acute pneumonitis in patient with bullous pemphigoid

Low-dose methotrexate-induced acute pneumonitis in patient with bullous pemphigoid

Methotrexate-induced Hypersensitivity Pneumonitis appearing after 30\xa0years of use: a case report

BackgroundMethotrexate has been implicated in a variety of lung complications, one of which is hypersensitivity pneumonitis. Hypersensitivity pneumonitis most often occurs within the first year of starting low-dose orally administered methotrexate. We present a case of methotrexate-induced hypersensitivity pneumonitis after 30 years of methotrexate use, which is the first case to be reported so far.Case presentationA 77-year-old African American woman with a history of rheumatoid arthritis presented with progressively worsening shortness of breath and nonproductive cough. She was on a daily dose of 2.5 mg of methotrexate that had been orally administered for the last 30 years. A physical examination was significant for fever of 38.2 °C (100.8 °F), tachycardia, bilateral basal crackles, and oxygen saturation of 88% on room air. A laboratory work up was significant for normal white blood cell count, increased eosinophil count of 18.3%, and erythrocyte sedimentation rate of 111 mm/hour. Sputum cultures were negative for any bacterial pathogens including acid-fast bacilli. Influenza and respiratory syncytial viral infection were ruled out. A (1-3)-B-D-glucan assay (Fungitell®) was within normal limits. Pulmonary embolism was ruled out and echocardiography was normal. A chest X-ray showed hazy opacity with prominent reticulation within the upper lung fields bilaterally, right greater than the left with no pleural effusion. Lung computed tomography revealed nonspecific bilateral upper lung opacification. A pulmonary function test was significant for no obstruction, normal maximum voluntary ventilation, and no restriction, with mildly decreased diffusion. Methotrexate was stopped, and our patient was started on prednisone 60 mg orally administered daily with dramatic clinical and radiologic improvement.ConclusionsMethotrexate-induced hypersensitivity pneumonitis usually occurs in the initial few weeks to months of starting treatment with methotrexate; however, it can occur late during therapy too, and prompt diagnosis is crucial as it is a reversible condition when diagnosed early.

57-Year-Old Man With Hip Pain and Lytic Bone Lesions

57-year-old man presented to his primary care physician with a 2-year history of progressive right hip pain. His medical history was notable for hyperlipidemia. He was up-to-date on sex- and agespecific cancer screening. The patient had no history of chest pain, palpitations, shortness of breath, cough, or other cardiac, respiratory, neurologic, or visual symptoms. He had no recent travel history or occupational or social contact with persons who were ill. Physical examination revealed an obese man (body mass index [calculated as weight in kilograms divided by height in meters squared], 40.34 kg/m 2 ) with normal vital signs and unremarkable findings on cardiac, respiratory, abdominal, neurologic, and lymphatic examination. No pain or tenderness was elicited on examination. He was treated initially with nonopioid pain medications. Sacroiliac corticosteroid injections were minimally beneficial. Results of a complete blood cell count (CBC) and electrolyte panel were normal with the exception of an elevated serum calcium level of 11.7 mg/dL (reference range, 8.9-10.1 mg/dL). Ultimately, magnetic resonance imaging (MRI) of his lumbar spine revealed numerous punched-out lytic lesions in the lumbar vertebra and pelvis. He underwent computed tomography (CT) of his chest, abdomen, and pelvis that identified further lytic lesions as well as multiple splenic lesions concerning for metastases. Two separate CT-guided bone biopsy samples of the lytic lesions in the lumbar vertebra did not elicit an etiology of the lesions.

Methotrexate-Induced Pneumonitis: Heterogeneity of Bronchoalveolar Lavage and Differences between Cancer and Rheumatoid Arthritis

Our knowledge on bronchoalveolar lavage (BAL) of methotrexate-induced pneumonitis (MTX-P) is fragmentary and based on data that are sometimes apparently conflicting. Aim of this review was to provide a comprehensive overview on the BAL features of MTX-P arising from cases published to date, and to determine the cytological patterns and any differences between cancer and rheumatoid arthritis patients, the two patient subsets among which this complication more often occurs. English-language articles published up to November 2013 were systematically searched through PUBMED, EMBASE, and other databases. Adult patients with a proven diagnosis of MTX-P and careful mention of each BAL parameter were examined. Seventeen articles for a total of 47 patients were included. Four BAL patterns with a variably combined lymphocytosis and two with prominent neutrophilia were identified. A more intense lymphocytosis (P=0.004) and a more depressed CD4/CD8 ratio (P=0.01) were found in cancer patients compared with rheumatoid arthritis patients. In MTX-P, cytological analysis of BAL may disclose up to six different patterns. In MTX-P affecting cancer patients, BAL tends to show the typical features of hypersensitivity pneumonitis, while, in rheumatoid arthritis patients, it is more heterogeneous, with a less intense lymphocytosis, a more pronounced neutrophilia, and a higher CD4/CD8 ratio. These differences could be related to a disparity in baseline pulmonary conditions between the two background diseases, i.e., to the presence of previously healthy lungs in cancer patients, and lungs already involved by the immune-mediated inflammatory processes, often not manifestly, in rheumatoid arthritis patients.

Alveolar Foamy Macrophages and Mast Cells in Bronchoalveolar Lavage of Methotrexate-induced Pneumonitis

Methotrexate-induced pneumonitis (MTX-P) is an unusual adverse drug reaction that typically manifests as an interstitial lung disease (ILD). Early diagnosis of this complication is desirable because discontinuation of MTX with or without steroid administration often results in a fast recovery. Conversely, a delay or a misdiagnosis may lead to death. Diagnostic workup is often problematic because underlying diseases leading to methotrexate administration, notably rheumatoid arthritis (RA), and opportunistic infections because of drug-induced immune impairment can also produce an ILD. In this clinical setting, bronchoalveolar lavage (BAL) plays a key role either in excluding infectious agents, especially in febrile presentations, or in looking for malignant cells. Unfortunately, BAL does not have specific features to allow clinicians to differentiate MTX-P from RA-associated ILD. Here, we present 2 definite cases of MTX-P in RA patients. BAL differential cell counts and alveolar CD4/CD8 values were found to be in agreement with those reported in the literature, but an increase in mast cells and the presence of foamy macrophages have never been reported among previously published cases. The presence of both mast cells and foamy macrophages could be helpful in differentiating MTX-P from many drug-unrelated ILDs, but does not assist in distinguishing MTX-P from Pneumocystis jiroveci pneumonia and RA-associated bronchiolitis obliterans organizing pneumonia.

Methotrexate-Induced Pulmonary Toxicity

Methotrexate is a widely used medication with an array of recognized side effects. The present report describes a case of methotrexate-induced pneumonitis in a patient with psoriasis, and demonstrates the hallmark clinical and investigational findings that support this infrequently encountered diagnosis. The ensuing discussion reviews the pathogenesis, management and prevention of this adverse drug reaction.

Update 2011: leflunomide in rheumatoid arthritis – strengths and weaknesses

Leflunomide is often used as a first choice disease-modifying antirheumatic drug after methotrexate. New data are available for efficacy and safety in both, monotherapy and combination with biologicals. New data on efficacy demonstrate comparable effect sizes for leflunomide and methotrexate in the treatment of signs and symptoms in combination with tumour necrosis factor-blocking agents and rituximab. Equipotency has also been demonstrated by a recent radiographic outcome study on methotrexate and leflunomide monotherapy. Pharmacogenetic studies indicate an impact of polymorphisms on the variability in serum levels of the compound with potential relevance to effectiveness and tolerability in individual patients. Genetic factors are also likely to contribute to the significantly increased risk for leflunomide-induced pulmonary disease reported in Asia. Because pre-existing interstitial lung disease as well as methotrexate-induced pneumonitis have been identified as risk factors for leflunomide-induced pulmonary disease, the use of leflunomide as an alternative to methotrexate is limited under these conditions. Effectiveness of leflunomide renders it a potent treatment option in rheumatoid arthritis. The known tolerability issues resulting in a less favourable adherence to therapy constitutes a weakness. However, documented data from large registries indicate that leflunomide is safe as far as the contraindications and recommendations for monitoring are regarded.

Methotrexate-induced pneumonitis in Crohn’s disease

&#x0D; &#x0D; &#x0D; Methotrexate (MTX) is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable fre- quency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA) is reported. In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohn's disease who presented non-productive cough, fever and dyspnea on exer- cise. Chest X-ray demonstrated bilateral interstitial infil- trates and at computed tomography (CT) ground-glass opac- ities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alter- ations was achieved through MTX withdrawal and the intro- duction of corticosteroid therapy.&#x0D; &#x0D; &#x0D;

Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA

Interstitial lung disease (ILD) is a frequently encountered and sometimes life-threatening complication among patients with rheumatoid arthritis (RA). In this study, we aim to clarify the incidence of and risk factors for ILD using a large observational cohort of RA patients. We analyzed the database from a large observational cohort of Japanese RA patients, the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. We defined as interstitial pneumonia (IP) computed tomography (CT) pattern of nonspecific interstitial pneumonia or diffuse alveolar damage. Newly developed IP was identified from patient reports over 2.5 years (April 2004 to October 2006) and was confirmed by extensive medical record, chest X-ray radiograph, and CT. The raw and age/gender-adjusted incidence of IP were reported. IP risk factors were analyzed using a nested case–control design was employed using conditional logistic regression analysis with a stepwise method. Thirty-seven patients among 5,699 RA patients were diagnosed with newly developed IP, including 18 cases with methotrexate-induced pneumonitis (MTX-IP) and 15 cases with IP associated with RA (RA-IP). The age-adjusted incidence of MTX-IP among total patients, males, and females was 3.775, 6.667, and 1.013 per 1,000 cases, respectively, and of RA-IP among total patients, males, and females was 1.056, 1.452, and 0.677 per 1,000 cases, respectively. Conditional logistic regression analysis after stepwise variable selection identified male gender, increased Japanese version of the Health Assessment Questionnaire (J-HAQ) score, decreased pain visual analog scale (VAS), and elevated erythrocyte sedimentation rate as significant risk factors for MTX-IP, while the only risk factor for RA-IP was male gender. The incidence of and risk factors for IP in RA patients were determined in a large observational cohort of RA patients in Japan.

Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA

Interstitial lung disease (ILD) is a frequently encountered and sometimes life-threatening complication among patients with rheumatoid arthritis (RA). In this study, we aim to clarify the incidence of and risk factors for ILD using a large observational cohort of RA patients. We analyzed the database from a large observational cohort of Japanese RA patients, the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. We defined as interstitial pneumonia (IP) computed tomography (CT) pattern of nonspecific interstitial pneumonia or diffuse alveolar damage. Newly developed IP was identified from patient reports over 2.5 years (April 2004 to October 2006) and was confirmed by extensive medical record, chest X-ray radiograph, and CT. The raw and age/gender-adjusted incidence of IP were reported. IP risk factors were analyzed using a nested case-control design was employed using conditional logistic regression analysis with a stepwise method. Thirty-seven patients among 5,699 RA patients were diagnosed with newly developed IP, including 18 cases with methotrexate-induced pneumonitis (MTX-IP) and 15 cases with IP associated with RA (RA-IP). The age-adjusted incidence of MTX-IP among total patients, males, and females was 3.775, 6.667, and 1.013 per 1,000 cases, respectively, and of RA-IP among total patients, males, and females was 1.056, 1.452, and 0.677 per 1,000 cases, respectively. Conditional logistic regression analysis after stepwise variable selection identified male gender, increased Japanese version of the Health Assessment Questionnaire (J-HAQ) score, decreased pain visual analog scale (VAS), and elevated erythrocyte sedimentation rate as significant risk factors for MTX-IP, while the only risk factor for RA-IP was male gender. The incidence of and risk factors for IP in RA patients were determined in a large observational cohort of RA patients in Japan.

Methotrexate-induced pneumonitis in Crohn's disease. Case report and review of the literature.

Methotrexate (MTX) is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable frequency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA) is reported.In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohn's disease who presented non-productive cough, fever and dyspnea on exercise. Chest X-ray demonstrated bilateral interstitial infiltrates and at computed tomography (CT) ground-glass opacities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alterations was achieved through MTX withdrawal and the introduction of corticosteroid therapy.

Methotrexate-induced pneumonitis in a patient with Crohn's disease

Pulmonary toxicity is a well recognised but infrequent adverse event of treatment with methotrexate. The vast majority of cases have occurred in patients with rheumatoid arthritis; here we present the case of a 44-year old woman with ileo-colonic Crohn's disease who developed methotrexate pneumonitis. The patient had a 10 year history of Crohn's disease and, in the last 18 months, she was treated with oral methotrexate because of steroid-dependency and intolerance to thiopurines. She was admitted to the hospital because of acute dyspnoea, non-productive cough and fever. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity, and pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity. Blood cultures for pathogenic bacteria or fungi were negative as well as serologic tests against major pneumotropic agents. Methotrexate-induced lung injury was considered: the drug was discontinued and the patient received a steroid course with rapid symptomatic improvement. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal. To our knowledge this is the second reported case of methotrexate-induced pneumonitis occurring in a patient with Crohn's disease. A definite diagnosis has been made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings.

Lymphocyte transformation test is not helpful for the diagnosis of methotrexate-induced pneumonitis in patients with rheumatoid arthritis

Background The pathophysiology underlying methotrexate (MTX)-induced pneumonitis has been considered as a hypersensitive reaction. The lymphocyte transformation test (LTT) is frequently used to detect hypersensitivity. Whereas previous reports have proposed that the LTT is not ideal to detect hypersensitivity to MTX, it has not been directly confirmed. Methods Forty rheumatoid arthritis (RA) patients (24 patients currently taking MTX and 16 patients with a past history of MTX administration) and 13 healthy subjects were recruited. LTT with MTX was used to assess thymidine incorporation. An MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay was also performed. The mitogenic activity was expressed as the Stimulatory Index (SI). The activity of RA was assessed by the disease activity score 28 (DAS28). Results In the presence of MTX, the SI measured by the LTT and by the MTS assay showed an inverse correlation. The presence of MTX significantly elevated the SI values measured by the LTT. However, the SI values were significantly lower in RA patients currently taking MTX than those of patients not currently taking MTX, although DAS28 was not different. Furthermore, a past history of MTX-induced pneumonitis did not affect the SI values. Conclusion LTT with MTX in RA patients is not appropriate to detect MTX-induced pneumonitis.

Methotrexate Induced Pneumonitis: A Review Article

Low dose methotrexate (MTX) is used frequently in a wide variety of conditions. This includes rheumatological conditions such as rheumatoid arthritis (RA) and non-rheumatological conditions such as inflammatory bowel disease. One of the most serious although infrequent side effects of low dose MTX is MTX induced pneumonitis (MTX-P). The latest literature on epidemiology, risk factors, pathophysiology and clinical features of MTX-P will be critically reviewed and highlighted. This review will pay special attention to diagnostic criteria, high resolution computerised tomography (HRCT) scan findings, and when to consider bronchoalveolar lavage (BAL) and lung biopsy. We propose the 2008 diagnostic criteria adapted from existing criteria. We will also discuss the new issue of interstitial lung disease (ILD) in patients receiving both methotrexate and anti-TNF therapy. Keywords: Methotrexate, interstitial lung disease, pneumonitis, chest high resolution computed tomography (HRCT), diagnostic criteria, tumour necrosis factor (TNF)