Treatment with Methotrexate in Patients with Sarcoidosis

3.1. Treatment for pulmonary sarcoidosis

Patients with sarcoidosis present with various types of pulmonary lesions, some of which spontaneously regress and some of which show fibrotic deterioration [16,17]. Fibrotic lesions situated along the bronchovascular bundle of the lung are likely to result in chronic airflow limitations [18] and bronchial distortions of a type often associated with infections such as nontuberculous mycobacterium, pseudomonas aeruginosa, and aspergillus fumigatus [16,19]. Some patients with pulmonary fibrosis also develop pulmonary hypertension [20]. Lung transplantation is considered when the disease progresses to a severe stage in patients under 60 years old [21,22].

Therapy itself might cause opportunistic infection under these circumstances. No medicines available at present are definitively effective at attenuating the fibrotic progression along the bronchovascular bundles. It usually takes 5-10 years before the fibrotic progression leads to chronic respiratory failure [3]. Longitudinal management and treatment must continue for long durations without adverse effects, as chronic respiratory failure persists for several years after it first manifests [3]. From this standpoint, methotrexate may be an available option for pulmonary sarcoidosis. Unlike methotrexate therapy for rheumatoid arthritis, methotrexate for sarcoidosis has seldom led to drug-related pneumonia in our clinical experience.

Presentation of two cases

Case 1: 59-year-old male, never-smoker, no occupational exposure

Patient 1 visited our institution, Central Clinic, with complaints of a severe cough and exertional dyspnea. His chest radiograph showed diffuse pulmonary lesions with fibrosis mainly distributed on the upper and middle lung fields (Figure 2 ). Transbronchial lung biopsy revealed epithelioid cell granuloma. Having found no obvious infection at the initial examination, we started the patient on prednisolone (10 mg /day) and methotrexate (6 mg/week). After therapy his symptoms gradually attenuated. The opacities decreased during treatment in radiological images, but not drastically on CT findings (Figure 3). Pulmonary function results showed improved diffusion capacity and the patient reported an abatement of his cough and exertional dyspnea. The airflow limitation, however, gradually worsened (Table 1).

Table 1.

Change in the functional or blood markers over time: 59 M Ns

FVC: forced vital capacity, FEV1: forced expiratory vital capacity one second,

DLCO: diffusion lung capacity carbon monoxide

EF: ejection fraction, Reg. : regurgitation, sPAP : systolic pulmonary artery pressure

ACE: angiotensin converting enzyme, 1,25-(OH)2 VD: 1,25-OH)2 vitamine D

No pulmonary hypertension appeared in a cardiac echogram. No blood markers suggestive of disease activity (serum ACE, 1,25-(OH)2 vitamin D) appeared in association with the treatment course (Table 1). The patient’s symptoms almost wholly abated and his prednisolone and methotrexate were tapered to 3 mg/day and 2 mg/week, respectively. No adverse effects were found during treatment.

Case 2. 60-year-old male, ex-smoker, no occupational exposure

Ocular lesions and BHL were detected by a health survey 27 years earlier, in 1982. A transbronchial lung biopsy at the time revealed epithelioid cell granuloma, and few parenchymal lesions of the lung were evident on HRCT. After an initial examination at Kyoto University, the patient moved away from Kyoto for his work. In the intervening 27 years we had no opportunity to follow his condition. In 2008, the patient visited our clinic because of exertional dyspnea and a severe cough with sputum production. Bilateral fibrotic lung lesions had developed on his upper lungs (Figure 4). Having detected no obvious infection, we started the patient on prednisolone (5 mg/day) and methotrexate (6 mg/week). His symptoms improved considerably by the end of the third month after treatment and he remained stable thereafter. Pulmonary function results also demonstrated a mild increase in %DLCO 18 months after the treatment commenced (Table 2).

Table 2.

Change in his symptoms and functions over time: 60, M, Ex, Eye, BHL, Lung 31 yrs,

FVC: forced vital capacity, FEV1: forced expiratory vital capacity one second,

DLCO: diffusion lung capacity carbon monoxide

DOE: dyspnea on exertion

Grade : Hugh Johns grade of exertional dyspnea

While the therapeutic effects in these cases were by no means stellar, they did bring about symptomatic relief, relatively good functional stabilization, and improved radiographic findings. It remains unsolved whether antifibrotic drugs such as pirfenidone are effective for fibrotic lesions in patients with sarcoidosis.

3.2. Treatment for cardiac sarcoidosis

Cardiac lesions can be patchily distributed in the four chambers of the heart. The dysfunctions they cause range from arrhythmia to right bundle block, left bundle block, and complete atrioventricular block leading to cardiac failure or cardiac arrest [23].

The Japanese Society of Sarcoidosis and Other Granulomatous Disorders published revised guidelines for the diagnosis of cardiac sarcoidosis [24]. These guidelines proposed criteria for definite diagnosis and clinical diagnosis: 1) Definite group, histological diagnosis by cardiac biopsy; 2) Clinical diagnosis group, negative biopsy with proven extracardiac sarcoidosis and satisfaction of 1 of 4 major criteria and 2 or more minor criteria. The major criteria were advanced AV block, basal thinning of the ventricular septum, positive cardiac gallium uptake, and left ventricular ejection fraction of less than 50 %. The minor criteria were abnormal ECG findings (ventricular tachycardia, multifocal frequent premature ventricular contractions, complete right bundle branch block pathologic Q waves, or abnormal axis deviation, UCG abnormality (regional wall motion abnormalities, ventricular aneurysm, or unexplained increase in wall thickness), perfusion defects detected by myocardial scintigraphy, delayed gadolinium enhancement of the myocardium on cardiac MRI scanning, and interstitial fibrosis or monocyte infiltration greater than moderate grade by endomyocardial biopsy. As the positive biopsy rate seems to be lower, the aforesaid guidelines are useful in a patients with proven noncardiac sarcoidosis and suspected cardiac involvement [23].

Regarding treatment, published data on several uncontrolled series of patients with cardiac sarcoidosis have suggested that steroids may be a valuable therapy for this condition. Yet no randomized control data are available to support this. In a retrospective series of 48 cases of cardiac sarcoidosis from Japan, high-dose steroid therapy seemed to be ineffective for patients with a pretreatment left ventricular ejection fraction of less than 30%, whereas improvement in ejection fraction and a decrease in left ventricular end-diastolic volume was seen in patients with a pretreatment ejection fraction of between 30% and 55% [4]. In a retrospective study from France, corticosteroid therapy improved abnormal echocardiographic parameters in 78% of cases and symptoms completely resolved in 9 of 17 patients presenting with congestive heart failure [25]. In a retrospective study of cardiac sarcoidosis in 30 Japanese patients who received 40 mg or more of prednisone daily and 45 patients who received less than 30 mg/d, there was no apparent survival benefit of high-dose prednisone over the lower dose [13].

No data are available to support the efficacy of additional immunosuppressive therapy for cardiac sarcoidosis with cyclophosphamide, methotrexate, or cyclosporine. Infliximab and etanercept, agents used against rheumatoid arthritis via their actions against tumor necrosis factor-α, have recently been proposed as treatments for some forms of chronic, refractory sarcoidosis [26].

3.3. Methotrexate for the treatment of cardiac sarcoidosis

This chapter presents the findings of a small open label comparative study by our group.

Long-term functional changes of ejection fraction on echocardiography were compared between patients who received combination therapy (low-dose prednisolone and methotrexate) and patients who received corticosteroids only.

As shown in table 3, there were no significant differences in sex distribution, duration of sarcoidosis, the number of lesions, or the frequency of pace maker implantation, though the age at the time of drug introduction tended to be higher in the patients treated with corticosteroids. There were no significant differences in the number of lesion sites, except for the number renal stones (higher in patients on corticosteroids). There were no significant differences in abnormal findings on electrocardiogram between the two groups (Table 4). Guided by these findings, we followed the ejection fraction (%) at one-year intervals after the introduction of the therapy. As shown in Table 5, ejection fraction stabilized in the combination therapy group 3 to 5 years after the first treatment.

In the corticosteroid group, cardiac enlargement was found on plain chest radiographs at 3 to 5 years after the commencement of therapy in association with a decrease in ejection fraction (see, for example, Figs. 6 and 7). Meanwhile, combination therapy restored or stabilized the ejection fraction and cardiac enlargement on chest radiograph (see, for example, Figs. 8 and 9).

Eight patients received methotrexate in our clinic after treatment with corticosteroid therapy in another hospital. Some presented with decreased ejection fraction suggestive of congestive heart failure when they came to our clinic. Yet even for those patients, the add-on methotrexate improved the ejection fraction over a period years.

During long-term treatment with methotrexate and low-dose of prednisolone, there were no serious adverse effects such as bone marrow suppression, opportunistic infection, or drug-related pneumonia in our series.

At present we propose the following therapeutic strategy: in patients with cardiac sarcoidosis (especially those with pace makers because of complete AV block), a combination therapy of low-dose prednisolone and methotrexate as the initial treatment following long-term maintenance therapy will stabilize cardiac function with few adverse effects. A large-scale controlled prospective study to assess this approach will of course be warranted.