Alternatives to Prednisone and Methotrexate for Sarcoidosis Treatment Reviewed

A recent review discussed other options besides prednisone and methotrexate in treating sarcoidosis, including antimetabolites similar in action to methotrexate, antimalarial agents, adrenocorticotropic hormone (ACTH) gel, biological agents, and antimycobacterial therapy, which is normally used to treat tuberculosis.

The review, “Sarcoidosis: treatments beyond prednisone and methotrexate,” was published in the journal Expert Review of Respiratory Medicine.

Sarcoidosis is a disease involving abnormal collections of white blood cells that form lumps known as granulomas. The disease usually affects the lungs (pulmonary sarcoidosis), skin, or lymph nodes. Less commonly, it can affect the eyes, liver, heart, and brain. The signs and symptoms of the disease depend on the organ involved.

The most common treatment, prednisone, is a glucocorticosteroid, a kind of hormone. It has undesirable side effects, and some cases of sarcoidosis do not improve with treatment. Methotrexate is also commonly prescribed to help lower the prednisone dose needed, but 20% to 40% of sarcoidosis cases do not respond to it. Also, fear of its toxicity, the need to monitor for toxic effects, and the roughly six months it takes to have an effect limits its use.

Azathioprine, leflunomide, and mycophenolate mofetil (MMF) all act through the same mechanism as methotrexate, and may be viable alternatives; however, trials testing these drugs are limited. Azathioprine is seen as a viable option, especially among patients who cannot tolerate methotrexate. Leflunomide is used in unresponsive cases, and MMF has been less studied for its effects.

The antimalarials (mainly the less toxic but less potent hydroxychloroquine) are mostly used in patients with skin and joint involvement, as well as hypercalcemia (high levels of calcium in the blood). But the risk of irreversible eye damage requires close ophthalmologic monitoring.

Adrenocorticotropic hormone (ACTH) gel has been tested for the treatment of pulmonary sarcoidosis. A study with ACTHAR gel showed improvements in 11 out of 29 patients (38%) and allowed a prednisone dose reduction of more than 50% in 16 patients (55%). However, nearly 40% of treated patients were unable to continue the medication, mostly due to side effects.

Biological agents (agents derived from naturally occurring substances) that target TNF-alpha (a factor linked to inflammation) are now being introduced in the treatment of sarcoidosis.

One is infliximab, which was shown to be an effective sarcoidosis therapy when the lungs, skin, or brain are affected, but also other organs. Adalimumab was shown to be effective when the skin is affected. Other anti-TNF agents, such as etanercept and golimumab, do not seem to have the same beneficial effect in sarcoidosis.

Rituximab is a drug that targets B-cells — white blood cells of the immune system — but additional studies are needed to evaluate its effectiveness.

CLEAR (concomitant levofloxacin, ethambutol, azithromycin, and rifampin) therapy, a combination of antibiotics, is an antimycobacterial therapy that is currently being tested in a Phase 2 trial (NCT02024555) in patients with pulmonary sarcoidosis.

“Given the undesirable side effects of glucocorticoids, and the existence of refractory cases, there is widespread recognition that other therapeutic options should be developed or adapted in sarcoidosis,” researchers wrote.

“Prednisone and methotrexate are well-established medications in the management of sarcoidosis, based on expert opinion and a handful of controlled trials,” they added. “Other antimetabolites (azathioprine, leflunomide, and MMF) and antimalarial agents (hydroxy- chloroquine, chloroquine) are also available for second-line therapy, but further studies are needed to better assess their benefits and risks.

“Lately, anti-TNFα and antimycobacterial therapy have shown promising results in randomized controlled trials, opening new routes for clinical management and research,” the team concluded.