17th January 2024

Management

The decision to commence pharmacological treatment in sarcoidosis should be considered based on the expected morbidity and mortality for the individual patient, as well as potential impacts on their quality of life. Some patients have minimal symptoms from their sarcoidosis, and introducing immunosuppressant therapy with associated side effects is not without risk. Attention should also be paid to managing patient symptoms such as fatigue with supportive lifestyle measures, such as structured exercise routines and counselling on sleep hygiene.

Steroids

In pulmonary sarcoidosis, when steroids are indicated, a commonly used regime would be 20-40mg prednisolone once daily for 4-6 weeks, followed by a tapering period to a maintenance dose of 5-10mg per day. In life-threatening disease or extrapulmonary cases such as neurosarcoidosis or cardiac sarcoid, high-dose intravenous methylprednisolone can be used as initiation therapy.

Second line immunosuppression

Indications for second-line immunosuppressive therapy:

• Progression of pulmonary disease on steroid treatment
• Unacceptable symptom burden
• Unacceptable steroid side effects or strong patient aversion to steroid treatment
• Inability to taper steroids dose to below 10-15mg prednisolone per day without rebound symptoms
• Significant contraindications to long-term steroid therapy, such as obesity, diabetes mellitus or osteoporosis

There are multiple agents of choice for steroid-sparing agents.

• Methotrexate – an anti-folate medication, introduced as a once weekly regimen of 5-10mg, it can be uptitrated to 20mg as tolerated. Once weekly folic acid 5mg should be given concurrently to reduce risk of myelosuppression. Potential side effects include pneumonitis, hepatic fibrosis and teratogenicity (both male and female patients should be counselled on this risk).
• Azathioprine – an inhibitor of purine synthesis, it causes immunosuppression by interrupting DNA and RNA formation. This affects lymphocyte proliferation in sarcoidosis. Started at 50mg once daily, it can be uptitrated to a therapeutic dose of 2mg/kg/day. Side effects include pancytopenia, increased risk of malignancy, nausea, vomiting, diarrhoea, rash, malaise and fever. Patients should have thiopurine methyltransferase (TPMT) levels tested prior to commencing treatment; those with a pre-existing enzyme deficiency are more at risk of pancytopenia, and an alternative agent should be used.
• Mycophenolate mofetil – an inhibitor of lymphocyte proliferation, this can be started at a dose of 1-1.5g twice a day. Side effects include gastrointestinal disturbances, teratogenicity as well as a small risk of neutropenia.
• Leflunomide – works as an anti-metabolite, similar to methotrexate. Can be used in preference to methotrexate due to a lower gastrointestinal toxicity profile, although it can still cause this. Other side effects include hepatotoxicity, hypertension and peripheral neuropathy.
• Cyclophosphamide – this is an alkylating agent that results in increased cell apoptosis, reducing circulating lymphocyte numbers. Use in sarcoidosis is rare due to the high side effect profile, which includes pancytopenia, haemorrhagic cystitis, nausea, vomiting, diarrhoea and alopecia.
• Hydroxychloroquine – works by increasing lysosomal pH in antigen-presenting cells. It is rarely used as monotherapy in pulmonary fibrosis, but is commonly used in cutaneous and joint disease and to treat fatigue. It can also be used as an adjunctive therapy to help with steroid weaning, at a dose of 200mg twice a day. Side effects include cardiac and retinal toxicity, in addition to gastrointestinal symptoms and headache. Prior to commencing treatment, all patients must have a baseline ECG to ensure there is no pre-existing long QTc interval, as well as a baseline ophthalmic examination.

All second-line immunosuppressive agents require frequent blood test monitoring of FBC, U&Es and LFTs. The following regime is recommended:

• 2-weekly for the first 2-months
• If stable, can reduce frequency to monthly for the next 6-months
• If stable, can reduce frequency to 3-monthly, which should be ongoing whilst the patient is on treatment

Biological agents and antifibrotics

• Infliximab is an anti-tumour necrosis factor (anti-TNF) agent. TNF is one of the cytokines that has a significant pro-inflammatory effect in sarcoidosis, promoting granuloma formation; inhibiting it, therefore, has an important therapeutic effect. Infliximab can be used as a third-line agent in combination therapy with methotrexate or azathioprine, given initially as 2-weekly infusions and then 6-8 weekly for maintenance. Side effect profile includes immunosuppression, with increased susceptibility to mycobacterium and invasive fungal infections, infusion reactions, alopecia, visual field defects and increased risk of pulmonary embolism. Prior to starting treatment, patients should be screened for latent TB infection using Interferon Gamma Release Assay (IGRA) testing. If latest TB is detected, patients should complete anti-TB treatment prior to starting infliximab.
• Antifibrotic medications such as pirfenidone and nintedanib are only licensed in the UK for idiopathic pulmonary fibrosis, but recent studies have shown a positive therapeutic effect in fibrosis secondary to sarcoidosis (4).

Lung transplantation

Bilateral lung transplantation is an option for patients with advanced fibrosis or pulmonary hypertension who have a significant, acute drop in pulmonary function (e.g., a 10% drop in FVC over a 6-month period) (4).