European respiratory society practice guidelines in treatment of sarcoidosis: clinical approach and suggestions

Sarcoidosis can affect any organ and thus lead to a significant impairment of quality of life, even to an increase in mortality. Neurosarcoidosis, cardiac sarcoidosis, and pulmonary fibrosis in sarcoidosis are the forms of sarcoidosis with the highest mortality rate, and with the lowest response rate to the current therapy. A group of experts in the field of sarcoidosis, supported by the European Respiratory Society, created practice guidelines in the treatment of the most common forms of sarcoidosis, and provided suggestions for further research so as to create new therapeutic protocols. The evidence was obtained by reviewing literature. The aim of this paper is to bring these guidelines closer to doctors in daily clinical practice, in order to improve patients’ quality of life and reduce mortality from sarcoidosis.

INTRODUCTION

Despite the previous research, the cause of sarcoidosis remains unknown, and its course is unpredictable [1]. Although the most common type of sarcoidosis is acute pulmonary sarcoidosis, where spontaneous regression may occur, chronic pulmonary sarcoidosis and extrapulmonary sarcoidosis (especially neurosarcoidosis and cardiac sarcoidosis) significantly impair quality of life and lead to an increase in mortality [2]. Corticosteroids remain first-line therapy for treating symptomatic disease, but there are two problems about their use: 1) certain types of the disease are not corticosteroid-responsive, (2) long-term use of corticosteroids leads to the development of significant side effects [3]. Taking all these factors into consideration, European Respiratory Society (ERS), a global association of healthcare professionals which aims to educate and improve knowledge in the field of respiratory medicine, has adopted new guidelines in the treatment of sarcoidosis [4]. The aim of this paper is to review new ERS guidelines and bring them closer to as many doctors as possible.

METHODOLOGY

Guidelines were created by a group of experts led by R. Baughman and D. Valeyre. Its members are specialists and researchers with extensive experience in the treatment of sarcoidosis, as well as patients suffering from sarcoidosis. Methodology is based on the GRADE approach which involves ranging the current guidelines, evaluating them, developing new guidelines, and evaluating them in practice [5]. The group of experts developed eight PICO (patients, interventions, comparison, outcomes) questions out of which they made 12 recommendations for seven PICO questions (Table 1). The PICO questions were developed by experts, and they pertain to the obstacles to the treatment of sarcoidosis, whereas the answers were obtained by reviewing relevant medical literature and are thus based on evidence-based medicine. In addition to the recommendations, the group of experts provided information on using alternative treatments in cases where there was not enough evidence for making recommendations. The areas of focus were pulmonary sarcoidosis, cutaneous sarcoidosis, cardiac sarcoidosis, neurosarcoidosis, sarcoidosis-associated fatigue, and sarcoidosis-associated small-fiber neuropathy. Protocols based on recommendations were created for each area. It is important to mention that the previous guidelines were created in 1999 by ERS, the American Thoracic Society (ATS), and the World Asociation of Sarcoidosis and other Granulomatous Disorders (WASOG) and that over time the emphasis has been put on two key factors: the rik of permanent organ damage or death and quality of life impairment [6],[7]. These two factors were considered first when selecting the therapy, especially anti-inflammatory therapy which is supposed to prevent these adverse events. When creating the guidelines, the group of experts relied on providing recommendations for anti-inflammatory therapy (Table 2), given that the therapy treats the complications of sarcoidosis itself (lung transplantation, hydrocephalus, insertion of a pacemaker due to rhythm disorders) with no special restrictions when compared to the same complications of a different etiology [8],[9].

Table 1. PICO questions

Table 2. Immunomodulatory drugs in sarcoidosis

TYPES OF SARCOIDOSIS

Pulmonary sarcoidosis

Pulmonary sarcoidosis is the most common type of sarcoidosis. Since it has been proven that the development of pulmonary fibrosis or pulmonary hypertension are the strongest predictors for mortality in this type of the disease, the treatment is based on maintaining a balance between controlling the disease on one hand and side effects of the therapy on the other [10],[11]. Apart from an increase in mortality, quite a few patients have significantly impaired quality of life due to the presence of problems related to respiratory symptoms, which should also be taken into consideration when choosing the type and length of therapy. In disease assessment, pulmonary function tests (spirometry, diffusing capacity of the lungs for carbon monoxide), radiography (X-ray) and computed tomography (CT) of the chest are used. Echocardiography is applied if the development of pulmonary hypertension is suspected due to damage to the lung parenchyma [12].

Although a certain number of patients with pulmonary sarcoidosis are asymptomatic, previous studies have shown that the introduction of oral corticosteroids improves/stabilizes pulmonary functions and enhances them [13]. Parenteral administration of corticosteroids has not shown significant beneficial effects in comparison with oral administration [14]. Besides, inhaled corticosteroids have not shown significant beneficial effects [15]. Studies have proven the most potent effect of corticosteroid therapy in the early stages of the disease, with the length of therapy between 3 and 6 months. Therapies lasting for less than three months are associated with disease recurrence, whereas therapies exceeding six months lead to an increased risk of side effects of corticosteroids [13]. Initially, the administration of 20mg of prednisone is recommended, with dose correction depending on symptoms, biomarkers, X-ray, pulmonary function tests, and side effects of corticosteroid therapy.

If disease control has not been achieved or if significant side effects of corticosteroid therapy have occurred, it is recommended that methotrexate should be introduced to maintain pulmonary function and quality of life. It should be noted that methotrexate monotherapy has not provided a significant improvement in pulmonary function, but combined with corticosteroid therapy it allows for a reduction in the dose of corticosteroids and thus reduces the risk of treatment-related complications [16],[17]. When it comes to other immunomodulators, only infliximab has been useful in treating chronic pulmonary sarcoidosis unresponsive to corticosteroids and/or methotrexate [18]. Other immunomodulators (azathioprine, leflunomide, mycophenolate mofetil, hydroxychloroquine) have also shown beneficial effects, but large-scale studies with clearer comparisons are needed so that they could take a more significant position in treating pulmonary sarcoidosis [19]. Orally administered antifibrotic drugs nintedanib and pirfenidone, as well as tumor necrosis factor (TNF) inhibitors and their biosimilars may be potentially useful, but their application remains theoretical [20]. If effectiveness of orally administered antifibrotics were proven, they would first be applied in stage IV pulmonary sarcoidosis, i.e., pulmonary fibrosis in sarcoidosis, considering that this type has all characteristics of progressive pulmonary fibrosis: deterioration of clinical presentation and pulmonary function per unit of time, distinctive changes observed in high-resolution CT, and a significant increase in mortality [21]. Orally administered antifibrotic nintedanib has already been applied in treating pulmonary fibrosis within connective tissue diseases, so it is possible to expect it to show beneficial effects in treating stage IV pulmonary sarcoidosis as well [22].

Cutaneous sarcoidosis

Cutaneous involvement is present in approximately 30% of patients with sarcoidosis and it is usually the first sign of the disease [23]. The degree of involvement and the types of changes vary significantly leading to impaired quality of life. Due to uneven distribution, the treatment is primarily focused on aesthetically significant lesions, so local, i.e., topical, application of therapy is also possible [24]. The tendency of spontaneous remission is low, so if remission is not achieved with local therapy, systemic administration of immunomodulators is needed. Reviewing the available literature, we have concluded that corticosteroid monotherapy often does not lead to satisfactory disease control, so it is necessary to combine it with other immunomodulators. Therapy with topical corticosteroids is advised in treating localized, individual lesions of the plaque or papule type, but recurrence is still very common. In case of extensive lesions or chronic lesions of the lupus pernio type, it is necessary to combine oral corticosteroids with another immunomodulator, chloroquine, hydroxychloroquine and methotrexate being prefered over others [25]. If disease control has not been achieved by applying corticosteroids, either as monotherapy or in combination with other immunomodulators, the administration of infliximab is advised. It should be noted that when using infliximab patients are more prone to infections, as well as that there are serious allergic reactions when using the medication [26],[27]. The accessibility of cutaneous changes significantly facilitates the development of new therapeutic agents, so new modalities can be expected.

Cardiac sarcoidosis

Clinically manifest cardiac involvement is found in a small number of patients with sarcoidosis, but it is supposed to be present in up to 30% of cases [28]. It is most often clinically manifested as various rhythm disorders, from ectopic foci to atrioventricular blocks [29]. Previous studies have shown a reduction in mortality if patients are prescribed corticosteroids in the manifest illness stage, especially in case of atrioventricular blocks due to sarcoidosis. Currently, there is no clear evidence of beneficial effects of corticosteroid therapy combined with immunomodulators (methotrexate, azathioprine, mycophenolate mofetil, leflunomide and cyclophosphamide) compared to corticosteroid monotherapy [30]. Besides, high doses of corticosteroids (>0.5mg/kg) have not shown greater beneficial effects than the doses < 0.5mg/kg, but they have been associated with a greater number of side effects of corticosteroid therapy. In cardiac sarcoidosis, myocardial inflammation results in granulomas compressing myocytes on one hand, and toxic effect of released inflammatory mediators on the other. The direct consequence is the enlargement of the heart chambers, especially the left ventricle, which leads to an increase in mortality, and suppression of inflammation by corticosteroids directly reduces these adverse events [31],[32],[33]. In case of refractory disease, it is possible to use anti-TNF antibodies [34].

Neurosarcoidosis

Clinical presentation of sarcoidosis varies significantly as granulomas may occur in any part of the nervous system [35]. Neurosarcoidosis is practically always symptomatic, so it is necessary to start the treatment as soon as possible [36]. The recommended first-line therapy includes the administration of corticosteroids, followed by a combination with methotrexate in the first place, whereas infliximab is recommended if disease control has not been achieved. These recommendations are based on several variables: clinical improvement, disease progression, quality of life, and adverse reactions to therapy. A review of literature has shown that the frequency of recurrence is significantly lower in patients on corticosteroid therapy than in those with no therapy. Recurrence rate is lower in patients where the use of corticosteroids is combined with another therapy (methotrexate, azathioprine, mycophenolate mofetil) in comparison with patients on corticosteroid monotherapy. Studies have also shown that corticosteroid therapy has a better effect than monotherapy with other immunomodulators, so it can be concluded that corticosteroids are primary therapeutic agents for disease control [37]. In retrospective studies, infliximab has proved to be effective in improving radiographic findings on MRI of the endocranium and in reducing symptoms, but prospective studies are needed to confirm this. Also, combined use of infliximab and high doses of corticosteroids is potentially significant, as this combination could reduce adverse effects of high doses of corticosteroids [35],[36]. A major obstacle to testing the therapy for neurosarcoidosis is the fact that it is relatively rare, so multicenter studies will be needed.

Small fiber neuropathy

Small fiber neuropathy is an entity in itself. SFN rarely occurs as an individual entity and its pathophysiological basis involves the loss of thin myelinated and unmyelinated nerve fibers, which results in sensory disturbances, pain syndromes, and autonomic nervous system disorders. Considering different clinical presentation, which can be a consequence of other diseases as well, and the absence of a gold standard in diagnostics, it is believed that a large number of patients with SFN remain undiagnosed [38]. Due to these difficulties in detecting SFN, the group of recommendations cannot provide clear treatment guidelines. Anti-TNF monoclonal antibodies are relatively successfully used in treating SFN of other etiologies, and their use in sarcoidosis requires further studies. First of all, it is necessary to define diagnostic criteria for SFN in sarcoidosis, as well as draw physicians’ attention to this entity [39].

Sarcoidosis-associated fatigue

Sarcoidosis-associated fatigue is fatigue which is not a result of any organ being affected with disease. It is one of the most common symptoms and it is responsible for a significant reduction in quality of life, and it can even be present in complete regression [41],[42]. The mechanism of sarcoidosis-associated fatigue is not clear yet, so it is necessary to exclude other potential causes. Also, considering that fatigue is purely subjective symptom, there is a need to develop special questionnaires with the idea of quantifying it and thus facilitating interpretation and treatment decisions. Unlike the previously presented guidelines, the group of experts here emphasize pulmonary rehabilitation with the use of methylphenidate or armodafinil if rehabilitation does not improve symptoms. Pharmacotherapy has significant limitations in the form of side effects (insomnia, development of addiction, anxiety), so study data on its effectiveness are also rather limited [42],[43]. The main limitation in giving stronger recommendations is a lack of knowledge about the long-term effectiveness of both pharmacotherapy and physiotherapy, so long-term prospective studies are needed.

CONCLUSION

Variability in clinical presentation of sarcoidosis remains a challenge in clinical practice. Chronic pulmonary sarcoidosis, pulmonary fibrosis or extrapulmonary types of sarcoidosis (neurosarcoidosis and cardiac sarcoidosis in the first place) significantly impair quality of life and increase mortality. A group of ERS experts investigated the most common problems in treating sarcoidosis in clinical practice and, relying on previous research, they defined therapeutic protocols for treating the most common types of sarcoidosis and proposed potential research directions concerning new therapeutic modalities.