Management Challenges in Sarcoidosis
Case Continued
The patient was started on methotrexate after discussion about the potential adverse effects of bone marrow suppression, hepatotoxicity, and pneumonitis. He was screened for latent tuberculosis and viral hepatitis prior to starting methotrexate. The dosage was 7.5 mg per week along with folic acid once a week. We gradually increase the dose in increments of 2.5 mg every 2 weeks with a view to reach 15 mg every week as maintenance therapy. In severely obese patients, a dose of up to 20 mg weekly is occasionally considered if 15 mg is suboptimal after careful clinical assessment.
The patient failed to make significant progress after being on methotrexate for a period of 6 months and lung function tests continued to demonstrate a persistent decline with symptomatic worsening of dyspnea and cough.
What are treatment options in refractory sarcoidosis?
Options to consider in the setting of refractory sarcoidosis are leflunomide, hydroxychloroquine, or combination therapy of methotrexate and leflunomide. Leflunomide has been shown to be of similar efficacy to methotrexate as demonstrated by a retrospective analysis of 32 patients treated with the drug in a tertiary care center [22]. Complete or partial response was noted in 12 of 17 patients treated solely with leflunomide and 13 of 15 treated in conjunction with methotrexate. Hence, combination therapy has been suggested as a viable option for these patients who fail to respond to initial glucocorticoid agents and alternative immunosuppressive drugs, as combination therapy may enhance efficacy with reduced toxicity if considered in a rational manner after careful selection of patients [23].
How should the symptom of fatigue be addressed?
The patient had ongoing fatigue during the treatment period with corticosteroids and alternative immunosuppressants. Fatigue, noted in a majority of patients with sarcoidosis [24], is one of the commonest symptoms of sarcoidosis and one of the most difficult to treat. We recommend excluding alternative etiologies of fatigue when confronted with this symptom and evaluating for associated comorbidities such as thyroid dysfunction, vitamin D deficiency, and hypoadrenalism. Extra-pulmonary sarcoidosis seems to be associated with fatigue in comparison to sarcoidosis restricted to the pulmonary system [25]. Furthermore, there is a paucity of good quality data on the benefit of pharmacological intervention for treatment of fatigue. A small double-blind randomized study of 10 patients demonstrated a positive impact of treatment with dexmethylphenidate hydrochloride (d-MPH) for a period of 8 weeks [26]. However, the small sample and lack of long-term outcomes data make it difficult to draw firm conclusions based on the findings of this study and larger randomized trials are warranted to investigate this important aspect of sarcoidosis before recommending a pharmacological agent routinely for this disabling symptom.
What are the pharmacological agents for cutaneous sarcoidosis?
Corticosteroids (local and or systemic) are the mainstay of treatment in cutaneous sarcoidosis. However, patients who fail to respond to these agents or develop significant adverse effects should be offered second-line agents in the form of hydroxychloroquine/chloroquine, methotrexate, or leflunomide. It is important to acknowledge that the evidence of benefit for these agents is derived from uncontrolled studies [27–29]. Anti-malarial agents are usually well tolerated; patients do require a baseline ophthalmological assessment and subsequent periodic examinations to monitor for any ocular toxicity associated with their use. Leflunomide is also a second-line option in cutaneous disease and is associated with lesser toxicity than methotrexate [22]. More recently, topical tacrolimus has shown promising results in isolated case reports [30–33]. Hence, it may be considered a treatment option in refractory cutaneous sarcoidosis.
Is there a role for anti-TNF therapy in the management of sarcoidosis? Should it be considered for the case patient?
Tumour necrosis factor-α (TNF-α) is implicated in the pathogenesis of sarcoidosis and is believed to have a significant role in the inflammatory processes in sarcoidosis. It is released from alveolar macrophages of patients with active disease and is involved in formation and maintenance of granulomas in the lung tissue. There has been significant progress in therapeutic options alternative to traditional immunosuppressants such as corticosteroids and TNF-α inhibition has been on the horizon as a treatment strategy for few years. It may be considered as a steroid-sparing agent or a third-line treatment option in refractory cases.
The initial evidence of benefit of anti-TNF therapy comes from case reports and small case series [34,35]. However, there have been 2 RCTs published so far invest-igating infliximab in sarcoidosis [36,37]. Baughman and colleagues [36] evaluated 138 patients with chronic pulmonary sarcoidosis in a double-blind study. There was a statistically significant improvement in FVC after 24 weeks of therapy with infliximab as compared to placebo (2.5% increase in mean FVC % predicted from baseline, P = 0.038). However, there was no improvement in any of the secondary outcome variables including SGRQ (St George’s Respiratory Questionnaire), 6-minute walk distance, and dyspnea scores. The benefit seemed to be more pronounced in the severe disease category on post-hoc analysis. The clinical significance of these findings are however unclear and it is difficult to draw firm conclusions based on the findings of this study alone.
The other RCT exploring the role of infliximab in sarcoidosis was conducted by Rossman et al [37]. This multi-center phase II study was conducted to evaluate the safety and tolerability of the drug in active pulmonary sarcoidosis (stage II to IV). The trial had a small number of participants with only 19 patients and failed to show a significant improvement in lung function after 6 weeks of treatment. Furthermore, 4 patients developed serious adverse events after treatment. Doty and colleagues [34] retrospectively analysed 10 patients treated with infliximab for refractory sarcoidosis and found subjective and objective evidence of improvement in all patients. This therapy resulted in reduction of corticosteroid dosage in 83% of cases (5 out of 6). However, adverse reactions were noted in 3 cases, including development of angioimmunoblastic lymphoma in one case. A retrospective study of 16 consecutive unselected cases of refractory sarcoidosis by Chapelon-Abric and colleagues [38] demonstrated a positive response in a majority of cases. However 38% of patients experienced a relapse. Furthermore, 44% of patients (7 out of 16) had infectious complications associated with anti-TNF therapy. Finally, infliximab may be used successfully in treating severe small fibre neuropathy [39] and should be considered in refractory cases where neuropathy is associated with autonomic dysfunction.
