REMICADE® (infliximab) and Sarcoidosis

Effectiveness of Infliximab in Refractory FDG PET-Positive Sarcoidosis
Vorselaars AD, Crommelin HA, Deneer VH, et al
Eur Respir J. 2015;46:175-185

Symptom Relief in Severe Sarcoidosis
Sarcoidosis is a systemic disorder of unknown etiology. Although it may be self-limited and mild enough in some patients not to require therapy, many patients will experience severe symptoms owing to the damaging effects of sarcoidosis on multiple organ systems, particularly the lungs, heart, eyes, nervous system, and joints.

If an analgesic does not provide symptom relief, the standard first-line therapy is an oral corticosteroid. If symptoms persist or fail to respond, another anti-inflammatory agent (such as methotrexate or azathioprine) may be used, but in a significant proportion of patients, the disease will still not be controlled. These patients have an unmet need.

A few trials have explored the effect of an anti-tumor necrosis factor (TNF)-alpha drug, of which infliximab (Remicade™) is one.[1,2] The results, although positive, were not sufficiently impressive for the sponsor to continue with its development. The present prospective open-label trial provides further evidence of the effect of infliximab in 56 patients with disease severity that was not adequately controlled by conventional therapy.

Patients with severe sarcoidosis that was unresponsive to first- and second-line therapy or who had severe adverse effects to corticosteroids received infusions of infliximab (5 mg/kg of body weight) monthly for 6 months. The outcomes of interest included lung function tests, inflammatory markers (such as interleukin (IL)-2 receptor), angiotensin-converting enzyme (ACE) levels, PET scans of the organs of interest, and quality-of-life questionnaires. Each patient served as his or her own control.

Statistically significant results of the trial were as follows:

Lung function (in patients who had significant lung disease at baseline) increased by a mean of 5%;

All four patients with skin lesions experienced “marked improvements”; and

ACE levels and IL-2R markers improved significantly.

Whole-body PET showed substantial clearance of lung disease. Overall, the investigators claimed that there were excellent responses in 40% of patients, good responses in 39%, partial responses in a further 17%, and no response in only 4%.

Adverse events included three hospitalizations for pneumonia, one death from respiratory failure, peritonitis in one patient who was receiving peritoneal dialysis, and one discontinuation of therapy owing to gastrointestinal symptoms. Allergic reactions and antibody formation occurred in two patients. Most patients experienced no adverse events.

One limitation of the study is that it was not randomized or placebo-controlled. The investigators justified this by pointing out that at least one previous randomized, placebo-controlled study had shown improvements with infliximab therapy,[1] and consequently it would have been unethical to include a placebo group. (The pharmaceutical company that sponsored that trial has declined to commit further funds to follow-up with the infliximab program for sarcoidosis).

The present study showed improvements that were statistically and clinically significant in a large proportion of patients. Perhaps the reason why results in this trial were better is that the patients enrolled in it were sicker than the population enrolled in the previous study.

It is notable that the patients in this trial had severe sarcoidosis and were in a late stage of the disease, and essentially all conventional treatments had failed. Furthermore, the dose of infliximab used in this trial was higher than that used in previous studies, both for sarcoidosis and for other systemic inflammatory disorders.

An additional consideration is that sarcoidosis is an indolent chronic disease, and patients with severe disease typically require treatment for many years. Those patients are vulnerable to many of the side effects of corticosteroid therapy. An alternative treatment is needed for them.

In the United States, infliximab is approved for Crohn disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, but not for sarcoidosis. As for other anti-TNF–alpha inhibitors, infections, including tuberculosis, are possible adverse events.