Cytotoxic Agents in Sarcoidosis: Which One Should We Choose?

Adriane D.M. Vorselaars; Johanna P. Cremers; Jan C. Grutters; Marjolein Drent

Disclosures

Curr Opin Pulm Med. 2014;20(5):479-487. 

In This Article

Abstract and Introduction

Abstract

Purpose of review Sarcoidosis is a granulomatous disease which affects multiple organs. Its therapeutic management is very challenging due to the heterogeneity in disease manifestation and clinical course, as well as the potential side effects of the immunosuppressive therapy. An overview of presently available second-line and third-line systemic agents is provided.

Recent findings Because curative treatment is currently not available for sarcoidosis, nonspecific immunosuppression with prednisone remains the first-choice therapy. However, as chronic use of corticosteroids is accompanied with severe adverse events, timely implementation of appropriate steroid-sparing cytotoxic agents is important. Commonly prescribed second-line agents in sarcoidosis are methotrexate, azathioprine, leflunomide and hydroxychloroquine. Nevertheless, the evidence supporting their use is limited. Third-line treatment options, including tumor necrosis factor-alpha inhibitors infliximab and adalimumab and the experimental therapeutic rituximab, are currently reserved for patients refractory to standard therapy.

Summary A better insight into the advantages and disadvantages of second-line and third-line treatment is important. The long-term effects of immunosuppressive agents, the optimal starting and maintenance dosages, and the best interval and discontinuation regimens should be elucidated. Identified associations of polymorphisms with treatment response suggest a step towards personalized medicine. Future research should focus on the role for pharmacogenetic and phenotypic predictors of treatment response and toxicity.

Introduction

Sarcoidosis is a systemic disease with a wide variety of symptoms and a diverse clinical course, which is characterized by the formation of noncaseating granulomas.[1] Sarcoidosis management is very challenging due to the heterogeneity in disease manifestation, as well as the potential side effects of treatment.

Sarcoidosis can be self-limiting with spontaneous remission within 2–3 years in a majority of patients. However, a subgroup of patients may have chronic disease,[2] which can be very severe or even fatal. This wide variety in clinical phenotypes yields various treatment strategies (Fig. 1). The decision to treat depends on the natural history of the disease with expected response to treatment on one hand, and the potential toxicity of available pharmacological agents on the other.[3] Self-limiting disease does not necessitate treatment. However, danger of organ failure or unacceptable loss of quality of life (QOL) constitute the main indications for therapeutic intervention. Furthermore, absolute treatment indications are cardiac sarcoidosis, severe pulmonary sarcoidosis, hypercalcemia, sight-threatening ocular sarcoidosis and neurosarcoidosis.[4,5]

Figure 1.

Pharmacotherapeutic management of patients with sarcoidosis. AZA, azathioprine; GC, glucocorticosteroid; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate.

Corticosteroids remain the mainstay of first-line treatment in sarcoidosis[6,7] ( Table 1 ). Six randomized placebo-controlled trials have been performed, showing that corticosteroids significantly improve symptoms, lung function and chest radiographs compared to placebo, which were systemically reviewed by Paramothayan et al.[8]. Although the positive effects of corticosteroids in sarcoidosis are proven in the short run, it remains uncertain whether corticosteroids provide a beneficial long-term effect, for example, prevention of fibrosis.[9,10] Furthermore, downsides of treatment with corticosteroids are the common side effects when administered chronically, such as osteoporosis, diabetes mellitus or obesity.[11] In case of intolerable side effects or inefficacy, cytotoxic agents should be considered. The most commonly used second-line and third-line systemic therapeutics and their indications are discussed in this review ( Table 1 ).

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