Cytotoxic Agents in Sarcoidosis: Which One to Choose?
In this overview, we presented knowledge about the systemic treatment of sarcoidosis. Now we will discuss the gap of knowledge regarding sarcoidosis treatment and some future directions with emphasis on personalized medicine.
Unfortunately, little data are available to provide evidence-based guidance regarding the treatment of sarcoidosis in clinical practice. Recommendations are especially derived from extrapolations from evidence in other chronic inflammatory diseases or based on experience and eminence-based medicine.
The clinical presentation and course of sarcoidosis show a wide variety. Often the course of various organ manifestations is unpredictable. Moreover, exactly defined response criteria and clinical endpoints are lacking; therefore, pharmacological studies with well defined disease phenotypes are difficult and the definition of treatment response is challenging. The number of participants in studies investigating the efficacy of drug treatment is usually low and studies directly comparing the various treatment options are lacking. Furthermore, in general, pharmaceutical companies are less interested to conduct clinical trials in rare diseases like severe sarcoidosis. The gap of knowledge in the field of second-line and third-line therapeutics underlines the need for multicenter cooperation in research.
The review summarizes the short-term results of the immunosuppressive therapy. Information concerning the long-term effectiveness is virtually not available. This remains an important subject necessitating research attention. The question is whether systemic sarcoidosis therapy can prevent organ damage and improve QOL. Furthermore, another difficult issue is the discontinuation of treatment in stable disease. The optimal period before successful withdrawal of treatment is achievable has not been established yet. Future research is necessary to determine in which sarcoidosis patients and after what treatment duration treatment discontinuation can be considered. Moreover, attention should be paid to starting and maintenance dosages, interval and discontinuation regimens.
'Personalized medicine' is a term which is used to indicate the selection of the most appropriate pharmacological therapy for an individual patient implying maximal effectiveness with minimal side effects. As sarcoidosis can have various disease manifestations and a variable clinical course, response to pharmacological treatment is diverse. Little is known on whether specific patient and disease characteristics can possibly predict response to currently available therapy in sarcoidosis. Apart from the exploration of the existence and value of these phenotypic predictors of response, the principles of pharmacogenetics also become increasingly important in personalized medicine. The genetic characteristics of a patient might interact with a drug, affecting its pharmacological action and leading to different treatment efficacy and toxicity. Drug selection based on a patient's genotype has the potential to avoid unnecessary exposures to potentially toxic drugs and to aim for effective, cheaper and faster disease control. Given the small number of participants in pharmacological studies in sarcoidosis, research into the influence of genetic variants on treatment outcome is difficult. Nevertheless, some steps towards personalized medicine in sarcoidosis have been taken. An example is TPMT genotyping, as already mentioned, which can be used in patients starting AZA therapy. The lower the TPMT activity, the higher the risk of developing toxicity, especially myelosuppression. Furthermore, genetic analysis has previously revealed a number of polymorphisms in genes coding for TNF-α, with a role in the clinical and prognostic diversity of sarcoidosis. The variant A allele of the TNF-α G-308A gene was shown to be more frequently present in patients with Löfgren's syndrome, whereas absence of the variant A allele (GG genotype) was associated with progression to a more severe or persistent pulmonary disease course. Recently, absence of the variant A allele in sarcoidosis patients refractory to conventional treatment was shown to be associated with better response to TNF-α inhibitors, suggesting a possible role for TNF-α G-308A polymorphism genotyping when optimizing therapy. In other diseases, the value of genotyping for this polymorphism and other genetic patterns has been studied more extensively. In RA, for example, multiple analyses have been made to evaluate the value of genetics when predicting treatment response to MTX and other drugs. In sarcoidosis, the value of pharmacogenetics when tailoring pharmacotherapy needs to be further explored. Large (international) cohort studies are necessary to gain more insight.
Discussion
In this overview, we presented knowledge about the systemic treatment of sarcoidosis. Now we will discuss the gap of knowledge regarding sarcoidosis treatment and some future directions with emphasis on personalized medicine.
Limitations of Current Evidence
Unfortunately, little data are available to provide evidence-based guidance regarding the treatment of sarcoidosis in clinical practice. Recommendations are especially derived from extrapolations from evidence in other chronic inflammatory diseases or based on experience and eminence-based medicine.
The clinical presentation and course of sarcoidosis show a wide variety. Often the course of various organ manifestations is unpredictable. Moreover, exactly defined response criteria and clinical endpoints are lacking; therefore, pharmacological studies with well defined disease phenotypes are difficult and the definition of treatment response is challenging. The number of participants in studies investigating the efficacy of drug treatment is usually low and studies directly comparing the various treatment options are lacking. Furthermore, in general, pharmaceutical companies are less interested to conduct clinical trials in rare diseases like severe sarcoidosis. The gap of knowledge in the field of second-line and third-line therapeutics underlines the need for multicenter cooperation in research.
The review summarizes the short-term results of the immunosuppressive therapy. Information concerning the long-term effectiveness is virtually not available. This remains an important subject necessitating research attention. The question is whether systemic sarcoidosis therapy can prevent organ damage and improve QOL. Furthermore, another difficult issue is the discontinuation of treatment in stable disease. The optimal period before successful withdrawal of treatment is achievable has not been established yet. Future research is necessary to determine in which sarcoidosis patients and after what treatment duration treatment discontinuation can be considered. Moreover, attention should be paid to starting and maintenance dosages, interval and discontinuation regimens.
Future Directions: Personalized Medicine
'Personalized medicine' is a term which is used to indicate the selection of the most appropriate pharmacological therapy for an individual patient implying maximal effectiveness with minimal side effects. As sarcoidosis can have various disease manifestations and a variable clinical course, response to pharmacological treatment is diverse. Little is known on whether specific patient and disease characteristics can possibly predict response to currently available therapy in sarcoidosis. Apart from the exploration of the existence and value of these phenotypic predictors of response, the principles of pharmacogenetics also become increasingly important in personalized medicine. The genetic characteristics of a patient might interact with a drug, affecting its pharmacological action and leading to different treatment efficacy and toxicity. Drug selection based on a patient's genotype has the potential to avoid unnecessary exposures to potentially toxic drugs and to aim for effective, cheaper and faster disease control. Given the small number of participants in pharmacological studies in sarcoidosis, research into the influence of genetic variants on treatment outcome is difficult. Nevertheless, some steps towards personalized medicine in sarcoidosis have been taken. An example is TPMT genotyping, as already mentioned, which can be used in patients starting AZA therapy. The lower the TPMT activity, the higher the risk of developing toxicity, especially myelosuppression. Furthermore, genetic analysis has previously revealed a number of polymorphisms in genes coding for TNF-α, with a role in the clinical and prognostic diversity of sarcoidosis. The variant A allele of the TNF-α G-308A gene was shown to be more frequently present in patients with Löfgren's syndrome, whereas absence of the variant A allele (GG genotype) was associated with progression to a more severe or persistent pulmonary disease course. Recently, absence of the variant A allele in sarcoidosis patients refractory to conventional treatment was shown to be associated with better response to TNF-α inhibitors, suggesting a possible role for TNF-α G-308A polymorphism genotyping when optimizing therapy. In other diseases, the value of genotyping for this polymorphism and other genetic patterns has been studied more extensively. In RA, for example, multiple analyses have been made to evaluate the value of genetics when predicting treatment response to MTX and other drugs. In sarcoidosis, the value of pharmacogenetics when tailoring pharmacotherapy needs to be further explored. Large (international) cohort studies are necessary to gain more insight.
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