An interesting new test for SFN is corneal confocal microscopy. Photographs are taken of the cornea and a quantitative assessment of nerve fibers is made. A correlation has been established between the severity of neuropathy and progressive corneal nerve degeneration [49,50]. Unfortunately, this technique is not widely available, and has not yet been validated against other measures of SFN. The changes demonstrated during treatment for SFN did not correlate with other markers of SFN .
Initial therapy consists of glucocorticoids, usually oral prednisone. For a patient with severe disease or disease progressing despite oral therapy, high-dose intravenous methylprednisolone may be useful. High-dose oral prednisone has been shown to be as effective as high-dose intravenous steroids . Most of the prednisone recommendations are based on retrospective studies, and the dosage of prednisone varies. Failure of steroid monotherapy is common, because of severity of the disease or because of the toxicity of the high-dose prednisone used in neurosarcoidosis. In one study, over 80% of patients went on to second and third-line therapy .
The next step involves a steroid-sparing or second-line agent. MTX has been the most widely used steroid-sparing agent for sarcoidosis . In one of the few case series examining the use of MTX specifically for neurosarcoidosis, the response rate was 63% . More recently, neurosarcoidosis patients treated with MTX were successfully weaned down to prednisone in half of cases and maintained on that regimen for years . Mycophenolate, another steroid-sparing second-line agent, has a different toxicity profile than methotrexate and may be more rapidly effective in treating neurosarcoidosis . However, in one study, mycophenolate treatment was associated with a significantly higher relapse rate when prednisone was withdrawn .
The use of two other cytotoxic agents, azathioprine and leflunomide, is based on studies of nonneurosarcoidosis patients. In one large study, azathioprine was as effective as methotrexate but associated with some more toxicity . Leflunomide has been reported to be an effective alternative to methotrexate with a different toxicity profile [60,61]. However, leflunomide can cause a peripheral neuropathy, which limits its use in neurosarcoidosis .
The next step is the use of TNF-α inhibitors. Although not all TNF-α inhibitors have been successful in sarcoidosis, the monoclonal anti-TNFα antibody infliximab was found to be superior to placebo in treating advanced pulmonary sarcoidosis [63,64]. A Delphi study amongst the world's leading sarcoidologists resulted in practical recommendations for the use of TNF-α inhibitors in sarcoidosis, to support clinicians in the management of patients with refractory sarcoidosis . Based on expert experience and recent studies, infliximab is now considered the main third-line treatment option in sarcoidosis. Two recent studies reported on relatively large studies of infliximab for neurosarcoidosis in the United States and France [66▪,67]. In both of these series, response to treatment was seen even when other therapies had failed. Unfortunately, infections and other toxicities were encountered in a significant number of cases [66▪], although these were similar to those for second-line treatment options . Treatment withdrawal was associated with a high rate of relapse of the disease [66▪,67]. Treatment with infliximab is expensive, creating a barrier limiting universal access to this effective therapeutic agent. Recently, biosimilars of infliximab have become available. In view of the working mechanism of the original biological and that of the biosimilars, it is highly likely that the therapeutic effect of both agents is comparable. Hence, inclusion of biosimilars in the treatment regime could lower the costs of TNF-α inhibitors in sarcoidosis . The infliximab biosimilar inflectra proved to be effective in the treatment of refractory sarcoidosis, with a safety profile comparable to that of the reference product infliximab [69,70▪].
Currently, there is no cure for SFN, and only symptomatic relief of complaints is achieved [46▪]. Unfortunately, symptomatic treatment for neuropathic pain often provides only partial relief from pain, without effects on autonomic dysfunction, and is often associated with (sometimes severe) side-effects. Some data suggest some effectiveness of immunoglobulins and TNF-α inhibitors [38,77,78▪]. Whether these expensive treatments should be initiated as a causative treatment for SFN is unclear and is currently being investigated. Cibinetide (ARA290) seems a promising new drug to relieve pain and increase corneal and skin nerve fiber density in sarcoidosis-associated SFN [48,79,80]. However, a recent placebo-controlled trial demonstrated changes in corneal nerve fibers, but not in symptoms . Further studies, including a wider dose range, are needed to clarify the role of this drug.
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