Typical side effects are hepatotoxicity and leukopenia, necessitating regular liver test and blood count monitoring . In case of MTX-induced gastrointestinal side effects, splitting of the oral dose or parenteral administration can be considered [15▪▪]. A recent meta-analysis in rheumatoid arthritis (RA) showed that MTX was associated with a small increased risk of respiratory infections [relative risk (RR) 1.11, 95% confidence interval (CI) 1.02–1.21], without an increased risk of noninfectious respiratory events or pulmonary death compared to other agents, suggesting a lower risk than previously assumed [23▪].
Azathioprine is a purine antagonist which derives its anti-inflammatory effect mainly through reducing B- and T-cell proliferation. Sarcoidosis specialists consider AZA to be the second-choice steroid-sparing agent for sarcoidosis . No RCTs have been performed on AZA in sarcoidosis treatment. Reported efficacy is mainly anecdotal with three case series describing a positive outcome [24–26]. Although AZA has a similar efficacy and toxicity profile as MTX, a higher number of infections were described [17▪]. AZA is often used in cases when MTX is contraindicated or failed to induce response. One study found that half of the patients who failed to respond to MTX had a positive response when they switched to AZA .
Most common side effects are infections, gastrointestinal complaints, hepatic function decline and bone marrow depression [17▪]. AZA is metabolized by thiopurine S-methyltransferase (TPMT), and patients with low TPMT levels can develop severe neutropenia. TPMT genotyping is advised before starting treatment with AZA to reveal patients susceptible to toxicity [28,29].
Leflunomide (LEF) represses lymphocyte responses only for actively stimulated lymphocyte clones . In 2003, Majithia et al.  reported an improvement in 78% of 32 sarcoidosis patients who were treated with LEF. However, until now, no RCTs are available. A retrospective study evaluating 32 sarcoidosis patients with pulmonary and ocular sarcoidosis showed an improvement in 80% of patients on LEF monotherapy or combination therapy with MTX . The most recent available study, investigating 76 sarcoidosis patients retrospectively, demonstrated a significant steroid-sparing effect of LEF, an improvement in forced vital capacity (FVC) and at least a partial response in 83% of the involved extrapulmonary organs . MTX/LEF combination therapy tended to achieve a better response .
Reported side effects include gastrointestinal symptoms, liver test abnormalities and peripheral neuropathy [32,33]. A recently reported safety issue with LEF is silent liver fibrosis . In sarcoidosis, LEF is especially used as an alternative or if needed in addition to MTX and is suggested to have comparable efficacy with less toxicity [35▪]. However, since studies directly comparing the effectiveness and side effects of LEF and MTX are lacking, future prospective trials are necessary to ground this recommendation. In RA, the occurrence of hepatotoxicity and neutropenia when using either MTX or LEF seems to be comparable .
Mycophenolate mofetil (MMF), a reversible inosine monophosphate dehydrogenase inhibitor, can be considered another promising immunomodulatory agent [42,43]. Several case series of patients with sarcoidosis-associated uveitis, central nervous system and mucocutaneous involvement have shown positive results [43–46]. A recent study found significant reductions of glucocorticosteroid dosages in patients with chronic pulmonary sarcoidosis . In general, MMF is well tolerated with dose-dependent and usually self-limiting mild gastrointestinal side effects, but leukocytopenia and infections can also be present [42,43,45,46].
Cyclophosphamide, a cytostatic agent, leads to inhibition of lymphocyte number and function with suppression of both cellular and humoral immunity. Case series have shown its use in neurosarcoidosis and cardiac sarcoidosis [47–51]. Adverse events consist of gastrointestinal complaints, infections, bone marrow suppression and hemorrhagic cystitis [51,52,53▪].
Thalidomide reduces tumor necrosis factor-alpha (TNF-α) release from alveolar macrophages, hereby reducing granuloma formation . Its use has been described in cutaneous sarcoidosis [55–57]. Whether thalidomide is effective in pulmonary sarcoidosis remains debatable, with conflicting results being published [58,59]. The most serious adverse effect is peripheral neuropathy, often resolving after dose reduction or discontinuation . The well known severe teratogenic effects of thalidomide warrant precautionary measures.
Pentoxifylline, a nonselective phosphodiesterase inhibitor, reduces inflammation by inhibition of TNF-α synthesis and activity and is effective in pulmonary sarcoidosis [60,61]. However, the frequently observed gastrointestinal side effects limit its routine use [60,61].
Apremilast, a new phosphodiesterase type 4 inhibitor that blocks the synthesis of proinflammatory cytokines, was recently found to be effective in cutaneous sarcoidosis .
Tumor necrosis factor-α, which is thought to be excessively produced by macrophages in sarcoidosis patients, has an important role in the cascade of granuloma formation [63,64]. Infliximab, a chimeric monoclonal antibody against TNF-α, has been studied in several manifestations of sarcoidosis. Two RCTs investigating infliximab have been performed in patients with chronic pulmonary sarcoidosis [65,66]. The largest demonstrated a significant increase in FVC of 2.5% in a study of 138 patients, with a greater improvement in more severe disease . Additional subgroup analysis revealed positive effects on extrapulmonary symptoms and it may be particularly effective for lupus pernio and neurosarcoidosis . A retrospective cohort study in 48 patients showed that apart from a significant improvement of 7.6% in FVC, there is also a reduction of disease activity measured by 18F-fluorodeoxyglucose PET (18F-FDG-PET) and improvement in QOL [68▪]. Furthermore, infliximab therapy has a positive effect on cognition and fatigue in sarcoidosis . A recent study in 111 sarcoidosis patients treated with infliximab or adalimumab showed that patients without the TNF-α-308A variant allele (GG genotype) had a three-fold higher response rate [70▪▪].
Recently, the first long-term results of treatment with infliximab have been described. Infliximab was found to be beneficial in 14/16 (88%) patients treated for at least 12 months . Another study in 26 pulmonary and extrapulmonary sarcoidosis patients described an improvement in 58.5% of the organs studied after a treatment duration up to 85 months, without major toxicity .
Side effects of infliximab are infection risk and cardiac failure in prone patients. Prior to initiation of infliximab, all patients should be screened for current or previous tuberculosis infection, because an increased risk of tuberculosis reactivation exists . Furthermore, allergic reactions to infliximab may occur, which appear to be less frequent with concurrent use of MTX or other cytotoxic drugs to reduce the risk of antibodies directed against infliximab . Annual influenza vaccination and periodic pneumococcal vaccination for all patients receiving biological agents is recommended according to rheumatology guidelines [76,77].
Adalimumab is a fully human TNF-α monoclonal antibody, which was shown beneficial in cases of refractory pulmonary, eye and cutaneous sarcoidosis. It also has a positive effect on cognition and fatigue in sarcoidosis [18,69,78,79]. A recent cohort study of 26 sarcoidosis patients with uveitis showed improvement of intraocular inflammatory signs in 85% and stabilization in 15% of patients treated with adalimumab . Furthermore, a case series of 10 sarcoidosis patients demonstrated a significant decrease in 18F-FDG-PET activity, without improvement in pulmonary function or inflammatory parameters . In a recent RCT involving 16 patients, adalimumab was found to be effective and save in treatment of cutaneous sarcoidosis [82▪▪]. Most recently, adalimumab was shown to be effective in 75% of patients (n = 35), who were suffering from different sarcoidosis localizations [70▪▪]. The success rate of treatment is likely to be dependent on the adalimumab dosing regimen and the administration interval used .
Toxicities are usually similar to infliximab, but the risk of allergic reactions is less likely given the human nature of adalimumab [35▪]. To prevent antidrug antibody formation, concomitant MTX or other cytotoxic drug use is advised. A recent study showed a significant higher median adalimumab level and a better clinical response in RA patients using both adalimumab and MTX .
Rituximab is a monoclonal antibody targeting the B-cell-specific protein CD20. With recent findings of B cells as emerging key players in sarcoidosis [85▪▪], a rationale behind systematic B cell ablative therapy in sarcoidosis exists. Rituximab was successfully administered in ocular sarcoidosis, with a significant steroid reduction in all four patients treated . More recently, the first prospective phase I/II clinical trial on rituximab in patients with pulmonary sarcoidosis (n = 10), refractory to steroids or second-line agents, demonstrated an inconsistent clinical response without the occurrence of severe side effects [87▪].
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 [88▪].
‘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 [89▪]. 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 [89▪]. 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 [90,91], 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 [70▪▪]. 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 [89▪,93,94]. In sarcoidosis, the value of pharmacogenetics when tailoring pharmacotherapy needs to be further explored. Large (international) cohort studies are necessary to gain more insight.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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78. Kamphuis LS, Lam-Tse WK, Dik WA, et al. Efficacy of adalimumab in chronically active and symptomatic patients with sarcoidosis
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79. Judson MA. Successful treatment of lupus pernio with adalimumab. Arch Dermatol 2011; 147:1332–1333.
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Randomized controlled trial investigating the effect of adalimumab in cutaneous sarcoidosis.
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86. Lower EE, Baughman RP, Kaufman AH. Rituximab for refractory granulomatous eye disease. Clin Ophthalmol 2012; 6:1613–1618.
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The first trial investigating rituximab in sarcoidosis.
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