Hypercalcemia with methotrexate pneumonitis: A rare, important and intriguing adverse eventR Samant, S Yadav, A Khune, R Shah
Department of Rheumatology, P.D. Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai, Maharashtra, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpgm.jpgm_1180_21
Source of Support: None, Conflict of Interest: None
Keywords: Granulomatous pneumonitis, hypercalcemia, hypersensitive pneumonitis, methotrexate-induced pneumonitis
Methotrexate is one of the most commonly used immunosuppressive drugs in chronic inflammatory and malignant disorders. Common adverse effects of methotrexate included alopecia, oral ulcers, nausea, vomiting, liver dysfunction, and cytopenia. Methotrexate-induced hypercalcemia is an unusual adverse event with few cases reported in the literature., We report three patients who developed symptomatic hypercalcemia on methotrexate, probably due to granulomatous pneumonitis. No infectious organism was isolated in sputum cultures in all the three patients. Both hypercalcemia and pneumonitis resolved quickly after treatment with corticosteroids and withdrawal of methotrexate.
She was a 70-year-old woman with rheumatoid arthritis, since 1990, who had no extra-articular features or comorbidities. She was started on methotrexate, in 2007, and was well controlled on a stable dose of methotrexate 20 mg/week along with hydroxychloroquine 300 mg/day. After 8 years, in December 2015, she was admitted with a 6-week history of loss of appetite, 8 kg weight loss, intermittent fever, and dry cough. HRCT chest showed patchy peribronchial opacities in both the lower lobes and apical-posterior left upper lobe, suggesting the possibility of bronchiolitis obliterans with organizing pneumonia (BOOP) with associated small airway disease as shown in [Figure 1]. A chest physician's opinion was sought. Blood count showed WBC 7900/mm3 with P67 L26 E6 M1, Hb 12.3 gm%, and platelets 3.75 lakhs/mm3. Blood cultures were negative, and sputum gram stain, ZN stain, culture, and gene X-pert for tuberculosis yielded no organisms.
Liver function tests were normal. Her serum calcium levels done as part of metabolic profile was found to be unusually high at 13.22 mg/dL. Subsequent evaluation showed markedly raised 1,25OH D3 levels at 120 pg/mL (19.3–53.8 pg/mL) with low PTH value of <3 pg/mL (10–65) and normal 25-hydroxyvitamin D3 at 66 ng/mL (30–100). Serum creatinine was mildly raised at 1 mg% (<0.9 mg%). With the infection workup being negative and HRCT chest findings as described, she was suspected of having methotrexate-induced pneumonitis. Methotrexate was stopped, and she was started on oral prednisone 20 mg/day. Hypercalcemia was additionally managed with intravenous hydration with normal saline, and prednisone was tapered and stopped over a week. She became afebrile, her appetite improved, and was discharged in 7 days with serum calcium decreased to 8.6 mg/dL. Chest x-ray showed mild basilar reticular shadows at 3 months follow-up. Her creatinine and calcium have been normal during follow-up of 7 years after the event, and she has been continued on low-dose prednisolone 2.5 mg/day along with sulfasalazine 2.5 gm/day and hydroxychloroquine 300 mg/day for her arthritis. She did not have any significant respiratory complaints during this period.
A 69-year-old female with a 3-year history of inflammatory arthritis presented to us, in 2013, with increasing joint pain and swelling without extra-articular or systemic features. She tested positive for rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Since she was allergic to sulfasalazine, she was started on 10 mg of leflunomide per day. Though the response was satisfactory, leflunomide had to be stopped after a year because of persistent loose motions and decreased appetite. Methotrexate was introduced, in July 2017, at a low dose of 7.5 mg/week, gradually increasing to 15 mg/week. Over the next 1 year, she had significant improvement in joint pains and was doing well. After being on methotrexate for 2 years, she presented in the emergency department with 15 days history of generalized weakness, reduced appetite, dry cough, and increasing dyspnea leading to desaturation and altered sensorium. She required noninvasive respiratory support and intensive care unit (ICU) admission evaluation showed Hb 10.8 gm%, WBC 12700/mm3; DLC N86/L14/E0; platelet 5.07 lakh/mm3; Na124 mEq/L, K 3.09 mEq/L, creatinine 1.8 mg/dl, serum albumin 2.47 gm/dl and normal liver enzymes. HRCT chest showed extensive ground-glass opacities in both lung fields, tubular bronchiectasis with thickening of subpleural interstitial space suggestive of hypersensitivity pneumonitis/interstitial lung disease. [Figure 2]. 2D echo was normal. Her serum calcium level after correction for low albumin was 14.6 mg%. She had raised 1,25OH D3 levels >200 pg/mL (19.3–53.8 pg/mL) with low PTH value of 6.6 pg/mL (10–65) and normal 25-hydroxyvitamin D 53.2 ng/mL (30–100). Sputum examination did not reveal any infection. She was suspected of having methotrexate-induced pneumonitis. Methotrexate was stopped. She was started on intravenous hydration, zoledronic acid, and intravenous methylprednisolone 40 mg 8 hourly and IV antibiotics for a week. She responded with improvement in weakness, cough, and dyspnea and was discharged within a week. There was a significant improvement in chest x-ray at 2 months follow up. Repeat laboratory investigations showed normalization of creatinine, calcium 8.1 mg/dL, PO4 3.3, albumin 3.9, PTH 22.4 pg/mL, and 25 (OH) vit D3 64.09 ng/mL. She is presently doing well on cyclosporine 50 mg/day. In the last 3 years of follow-up, she has had no cough/dyspnea or recurrence of hypercalcemia.
A 72-year-old male presented to us with a 2-month history of severe inflammatory arthritis involving hands, shoulders, elbow, knees, and ankles. There was no history of inflammatory back pain, skin rash, or eye complaints. There was a preceding history of diarrhoea a month prior to the present symptoms requiring 4–5 days of treatment. Family history was negative for any arthritis or skin-related issues. On evaluation, rheumatoid factor, anti cyclic citrullinated peptide (anti-CCP), and HLA B27 were negative. His HB was 9.9gm/dl, white blood counts, and platelets were raised at 19,820/mm3 and 4.09 lakhs/mm3, respectively. Renal, hepatic, and thyroid function tests were normal. ESR was raised at 91 mm at 1 h. Whole-body PET CT did not show any focus of infection or malignancy but revealed increased metabolic activity in affected joints and no abnormality in the lungs. Chest x-ray was normal. With a working diagnosis of reactive arthritis, he was initiated on 20 mg methotrexate weekly in Aug 2017. Due to the severity of arthritis, he was also given prednisone 0.5 mg/kg, tapered rapidly and stopped over a month. He responded well to the treatment with complete resolution of symptoms. However, 40 days after starting methotrexate, in October 2017, he was admitted in his home town with dry cough, acute dyspnoea, decreased oral intake, and altered sensorium. He was drowsy with no focal neurological deficit and was tachypnoeic with bibasilar crepitations. He required ICU admission with nasal oxygen support. His Hb was 10.2 gm/dl, WBC 8720/mm3, and platelets 3.47 lakhs/mm3. Serum creatinine was raised at 1.6 mg% (<1 mg%). Chest x-ray showed alveolar opacities in bilateral lung fields. HRCT chest revealed widespread ground-glass attenuation with patchy consolidation in bilateral lung fields indicative of hypersensitivity pneumonitis. CT brain showed diffuse brain atrophy with ischemic changes in periventricular white matter. He was initially managed as having lower respiratory tract infection with acute renal injury and started on antibiotics. His sputum and blood cultures were negative for any infection. Concurrently, he was also found to have hypercalcemia with a corrected serum calcium of 14.38 mg/dL. His 25 hydroxyvitamin D level was 56.2 ng/mL and intact PTH level was 8.43 pg/mL (15–68). He was suspected of having methotrexate-induced hypersensitivity pneumonitis at this stage. Subsequently, methotrexate was stopped, and he was managed on a short tapering course of oral prednisone (maximum 20 mg/day), on which he improved. The patient was discharged after improvement on the eighteenth day after admission with normal creatinine and calcium of 8.4 mg/dl. He came to us for review 6 days post-discharge. Repeat chest x-ray showed almost complete resolution, as shown in [Figure 3]. After 5 years post-discharge, he is well controlled on leflunomide 10 mg alternate days without recurrence of symptoms or hypercalcemia. Clinical features, laboratory and imaging features of the three patients is shown in [Table 1].
Interstitial lung disorders such as nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP) and bronchiolitis obliterans organizing pneumonia (BOOP) are common manifestations of lung parenchymal involvement in inflammatory arthritis, particularly rheumatoid arthritis. Infection and, on rare occasions, methotrexate used to treat arthritis can cause pneumonitis in these patients. The frequency of methotrexate-related pneumonitis has been reported to range between 0.3% to 11.6%, depending on the methodology used and the criteria applied for diagnosis., It usually occurs within a year of starting methotrexate but has been reported as late as after 30 years of use. Several risk factors like age >60 years, male gender, diabetes mellitus, hypoalbuminemia, previous use of disease-modifying antirheumatic drugs (DMARDs), renal dysfunction, and pre-existing lung disease have been identified, but the extent of their contribution remains uncertain., In patients receiving methotrexate, criteria to diagnose hypersensitivity pneumonia are shown in [Table 2]., It generally has an acute or subacute onset of dry cough, fever, and dyspnoea. Treatment requires immediate cessation of methotrexate and commencement of glucocorticoids. In our patients, pneumonitis occurred 8 years, 2 years, and 40 days after initiation of methotrexate. There was a subacute onset of fever, cough, and dyspnoea in all the three patients. All the three cases fulfilled two major criteria and three minor criteria required to diagnose methotrexate-associated pneumonitis.
The pathology of methotrexate pneumonitis is not well understood. It is considered by many investigators to be a hypersensitivity reaction and is not related to the cumulative or weekly dose of methotrexate. Imokawa et al. published a study that reviewed 123 patients with methotrexate pneumonitis. Lungs were examined histologically in 49 of these cases, including post mortem histological examination. Interstitial inflammation and fibrosis were the most common histological findings. Granuloma formation was reported in 17 (34.7%) of the patients, with 7 of them having non-necrotizing or noncaseating granulomas and the remaining ten having no description of the granulomas. This provides some contemporary evidence of granulomatous pathology in methotrexate pneumonitis.
In 1996, Cook et al. reported a case of hypercalcemia with methotrexate pneumonitis, possibly due to pulmonary granulomatous pneumonitis. They described a similar case of a 72-year-old female with rheumatoid arthritis who developed pneumonitis after being on methotrexate for 8 weeks. The patient also had hypercalcaemia (corrected calcium 3.18 mmol/L) with low PTH, normal 25-OH vitamin D3, and high normal 1,25 dihydroxy D3 suggestive of granulomatous pneumonitis. As in our patients, hypercalcemia and pneumonia resolved within a couple of weeks with hydration, diuretics, and prednisolone. Unlike our cases, they had done bronchoalveolar lavage, which showed epithelioid macrophages on the basis of which they suggested that macrophages in the granuloma might autonomously produce extrarenal 1,25-OH2 vitamin D3 that is unresponsive to normal feedback mechanisms. Patel et al. published an abstract with a similar complication in an elderly male treated with low-dose methotrexate for eczema who developed lung injury and hypercalcemia after 3 years of methotrexate use. Their patient, too, had normal 25OH D3 levels, low PTH levels, and high 1,25 dihydroxy D3 levels and responded well to a 2-week course of prednisone. There was a complete resolution on chest X-ray at 3 months, and spirometry was normal. They emphasized that although exceedingly rare, it is important to consider methotrexate-induced granulomatous injury as a cause of hypercalcemia. As seen in our patients, hypercalcemia can present with nausea, anorexia, vomiting, abdominal pain, and mental confusion. All of these patients had the clinical picture consistent with methotrexate-associated pneumonia and had elevated levels of 1,25 dihydroxy D3 levels with normal 25OH D3 levels suggestive of the granulomatous disorder. In the light of the clinical context and the literature review, hypercalcemia in our patients is likely due to methotrexate-induced granulomatous pneumonitis. A probable pathogenic mechanism is shown in [Figure 4].
Other possibilities for pneumonitis in methotrexate-treated arthritis patients include underlying interstitial lung disease or secondary infection. However, in cases of chronic ILD, lung abnormalities develop over time and do not completely resolve with treatment. The development of methotrexate-induced pneumonitis is subacute, and lung abnormalities improve with a short course of steroid treatment and methotrexate withdrawal. Sputum and blood cultures need to be done to rule out both conventional and atypical infections. Bronchoalveolar lavage can be helpful in doubtful cases.
Renal insufficiency in the context of hypercalcemia can arise via several mechanisms, such as prerenal involvement due to vomiting or direct alterations of intravascular tone and glomerular permeability. All our patients had a mild increase in serum creatinine which completely reversed after treatment of hypercalcemia. 1, 25 OH2 D3 levels were estimated in cases 1 and 2 and found to be high with normal 25 (OH) D3. It is important to note that all three patients were elderly, with a reduced renal reserve, and at an higher risk of development of methotrexate lung injury and toxicity.
Methotrexate-induced pneumonitis should be suspected in a patient on methotrexate, especially when the presentation of dry cough and dyspnoea is acute or subacute, and HRCT picture is suggestive of hypersensitivity pneumonitis. Potential infection should always be ruled out. Early initiation of steroids for a short duration will improve overall outcome. Hypercalcemia should be checked and, if present, should be evaluated by doing serum 1,25OH2 D3, 25OH2 D3, and PTH levels. Hypercalcemia in our patients resolved with hydration, glucocorticoids, and bisphosphonates. Calcitonin and rarely dialysis may be needed in severe cases.
These three cases highlight an extremely rare but important adverse effect, that is, methotrexate-induced hypercalcemia likely due to granulomatous pneumonitis in a series of elderly patients with inflammatory arthritis. This occurred early or even after long-term use of stable doses of methotrexate. All patients responded well to methotrexate withdrawal and a short course of corticosteroid treatment and had a monophasic course. The morbidity can be high unless hypercalcemia is looked for and treated in the context of suspected methotrexate lung toxicity.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]