Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in January 2017. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Because no randomised controlled trials were identified, this evidence summary includes 10 observational studies that assessed the effects of infliximab for treating active, unstable extrapulmonary sarcoidosis in people who had found corticosteroids and other immunosuppressants to be ineffective, or who could not tolerate these treatments (refractory sarcoidosis).

The studies included 155 cases of refractory extrapulmonary sarcoidosis, primarily in the nervous system (34%) or skin (25%), who were treated with infliximab. Of these cases, extrapulmonary sarcoidosis resolved in a third and improved in around half. However, observational studies are subject to bias and confounding and have many limitations affecting their application to clinical practice.

Adverse events seen in the studies reflected those listed in the summary of product characteristics.

According to specialists involved in this evidence summary, infliximab may be an option for some patients with severe, refractory extrapulmonary sarcoidosis (particularly cutaneous or neurological sarcoidosis); for example, those affected by disabling or disfiguring disease, or whose life expectancy is likely to be reduced.

Regulatory status: Use of infliximab for treating any manifestation of sarcoidosis is off‑label.

At the time of publication, 4 infliximab products are available: the original brand Remicade and 3 biosimilar medicines, Flixabi, Inflectra and Remsima.

Effectiveness

  • Of 155 cases of refractory extrapulmonary sarcoidosis treated with infliximab in 1 prospective open-label study (Vorselaars et al. 2015) and 9 retrospective case reviews (Aguiar et al. 2011, Chapelon-Abric et al. 2015, Doty et al. 2005, Hostettler et al. 2011, Ørum et al. 2012, Panselinas et al. 2009, Russell et al. 2013, Sweiss et al. 2005 and Van Rijswijk et al. 2013):

    • the disease resolved in 51 (33%), improved in 71 (46%), resolved or improved in 10 (with individual data for each outcome not reported, 6%), remained stable in 22 (14%) and deteriorated in 1 (1%).

    • neurological sarcoidosis (n=52) resolved in 21 (40%) improved in 24 (46%) and remained stable in 7 (13%).

    • cutaneous sarcoidosis (n=38) resolved in 14 (37%), improved in 19 (50%), resolved or improved in 4 (with individual data for each outcome not reported, 11%) and remained stable in 1 (3%).

  • The studies did not have control arms; therefore, it is unclear what proportions of patients would have seen an improvement, stabilisation or deterioration in sarcoidosis without infliximab treatment.

Safety

  • The most serious adverse effects that have been reported with infliximab include hepatitis B virus reactivation, congestive heart failure, serious infections (including sepsis, opportunistic infections and tuberculosis) and serious infusion reactions. Sarcoidosis and sarcoid-like reactions have been reported rarely. See the Remicade summary of product characteristics for a complete list.

  • Adverse events seen in the studies reflected those listed in the summary of product characteristics (for example respiratory tract infections including pneumonia, headache, joint pain, oedema and rashes).

Patient factors

  • Across the studies, about 15% of patients discontinued treatment due to adverse events.

  • Patients should be tested for hepatitis B virus and active and latent tuberculosis before starting treatment (Remicade summary of product characteristics).

  • Patients must be monitored closely for infections including tuberculosis before, during and 6 months after treatment with infliximab (Remicade summary of product characteristics).

  • The studies were undertaken in people with active, unstable sarcoidosis that was refractory to standard treatments. Results suggest that infliximab may be an option for some of these patients, but they cannot be generalised to people with stable disease or those who have not tried standard treatments.

Resource implications

  • A vial of infliximab 100 mg powder for concentrate for solution for infusion costs £419.62 for Remicade, £377.66 for Inflectra or Remsima and £377.00 for Flixabi without discounts (MIMS, November 2016).

  • A 12-month course of infliximab costs about £11,000 to £17,000 for an 80 kg person depending on the product and dosage used.

  • These costs are for the medicine only and do not include VAT, any local procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy.

  • At the time of publication, 4 infliximab products are available: the original brand Remicade, and 3 biosimilar medicines, Flixabi, Inflectra and Remsima. For more information, see the NICE key therapeutic topic on biosimilar medicines.

Introduction and current guidance

The cause of sarcoidosis is unknown, although it may be due to an inflammatory response to an environmental agent or infection. It is characterised by the presence of non-caseating granulomas (non-necrotising nodules of inflammation and scarring) in the organs. The lungs are affected in more than 90% of people with sarcoidosis. The skin is the second most commonly affected organ. Other organs such as the eyes, brain, nervous system, liver and heart may also be affected (Sarcoidosis, Oxford Textbook of Medicine).

Sarcoidosis can present in a wide variety of ways, ranging from mild, acute self-limiting disease to chronic disease involving several organs and causing severe symptoms and functional impairment. The prognosis is generally good and sarcoidosis resolves in most people within 2 to 5 years. However, about 25% of people will develop residual fibrosis in the lungs or elsewhere. Disease-related mortality is reported to be about 5%, with the most common causes of death being from lung, cardiac and neurological disease that is refractory to therapy (Sarcoidosis, Oxford Textbook of Medicine).

Because of the high rates of spontaneous remission, treatment is not recommended for people with no or mild symptoms. If treatment is needed, corticosteroids are usually recommended first-line. Other treatments that may be added if the disease does not respond, or if a steroid-sparing agent is needed, include methotrexate, hydroxychloroquine, leflunomide and infliximab (Sarcoidosis, Oxford Textbook of Medicine).

This evidence summary considers the best available evidence for infliximab for treating common manifestations of chronic, refractory extrapulmonary sarcoidosis. A related evidence summary has considered infliximab for pulmonary sarcoidosis.

Full text of introduction and current guidance.

Product overview

Infliximab is a biological human monoclonal antibody, which inhibits tumour necrosis factor (TNF) alpha (a cell signalling protein or cytokine involved in systemic inflammation) reducing disease activity (Remicade summary of product characteristics).

At the time of publication, 4 infliximab products are available: the original brand Remicade, and 3 biosimilar medicines, Flixabi, Inflectra and Remsima. For more information see the NICE key therapeutic topic on biosimilar medicines, which provides links to other resources including answers to commonly asked questions about biosimilar versions of infliximab.

Infliximab is licensed for treating rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis (Remicade summary of product characteristics). Use of infliximab for treating any manifestation of sarcoidosis is off‑label.

Full text of product overview.

Evidence review

  • This evidence summary is based on the best available evidence for infliximab for treating chronic, refractory extrapulmonary sarcoidosis in any organ. Because no randomised controlled trials were identified, it includes 10 observational studies that were undertaken in people with active, unstable sarcoidosis (pulmonary or extrapulmonary) for whom corticosteroids and other immunosuppressants had proven ineffective, or who could not tolerate these treatments (refractory sarcoidosis). Studies which looked at individual manifestations of sarcoidosis were not included, nor were studies in stable sarcoidosis.

  • The 10 included studies are a prospective study by Vorselaars et al. (2015) (n=56, main indication extrapulmonary sarcoidosis in 22 patients) and 9 retrospective case reviews by Aguiar et al. (2011) (n=10, main indication extrapulmonary sarcoidosis in 9 patients), Chapelon-Abric et al. (2015) (n=16, including 21 extrapulmonary sarcoidosis indications), Doty et al. (2005) (n=10, main indication extrapulmonary sarcoidosis in all 10 patients), Hostettler et al. (2011) (n=16, main indication extrapulmonary sarcoidosis in 11 patients), Ørum et al. (2012) (n=12, including 9 extrapulmonary sarcoidosis indications), Panselinas et al. (2009) (n=14, main indication extrapulmonary sarcoidosis in 13 patients), Russell et al. (2013) (n=26, including 38 extrapulmonary sarcoidosis indications), Sweiss et al. (2005) (n=9, main indication extrapulmonary sarcoidosis in all 9 patients) and Van Rijswijk et al. (2013) (n=45, main indication extrapulmonary sarcoidosis in 22 patients).

  • Eight of the studies (1 prospective study and 7 retrospective case reviews) reported 52 cases of refractory neurological sarcoidosis treated with infliximab, including 23 with sarcoidosis in the brain and central nervous system. Of these 21 (40%) experienced complete remission, 24 (46%) experienced partial remission and 7 (13%) experienced no change in the disease.

  • Outcomes for 38 cases of refractory cutaneous sarcoidosis treated with infliximab, including 13 reported to be lupus pernio (lesions on the face), were included in 9 of the studies (1 prospective study and 8 retrospective case reviews). Lesions resolved in 14 (37%), improved in 19 (50%), resolved or improved in 4 (with individual data for each outcome not reported, 11%) and remained stable in 1 (3%).

  • Thirteen patients with various manifestations of refractory ocular sarcoidosis were reported in 7 retrospective case reviews. Ocular sarcoidosis resolved with infliximab treatment in 3 patients (23%) and improved in 8 patients (62%): no change was seen in 2 patients (15%).

  • Refractory lymph node sarcoidosis was reported for 14 patients who received infliximab in 4 retrospective case reviews. Of these, the disease resolved or improved in 6 (43%), was unchanged in 7 (50%) and deteriorated in 1 (7%).

  • Across 5 retrospective case reviews of infliximab for refractory sarcoidosis, 4 patients had the disease in bones (1 in the bone marrow), 3 patients had it in muscles and 2 patients had it in joints. The sarcoidosis resolved with treatment in 3 patients (33%), improved in 5 patients (56%) and remained unchanged in 1 patient (11%). One patient who initially saw improvements subsequently worsened.

  • Seven patients in 3 retrospective case series received infliximab for refractory cardiac sarcoidosis. Of these 4 (57%) experienced complete remission of the disease and 3 (43%) experienced partial remission.

  • Refractory sarcoidosis in the upper respiratory tract was treated with infliximab in 6 patients reported in 4 retrospective case reviews. It resolved in 3 patients (50%), improved in 1 patient (17%) and remained unchanged in 2 patients (33%).

  • Across 5 of the retrospective case reviews in the evidence summary, 2 patients had sarcoidosis in the spleen and 4 patients had sarcoidosis in the liver. The disease resolved with infliximab treatment in 2 patients (33%), improved in 2 patients (33%) and was unchanged in 2 patients (33%).

  • Of 2 patients, kidney sarcoidosis resolved in 1 and improved in the other. One patient with oesophageal sarcoidosis and 7 patients with severe fatigue also saw improvements in the disease.

  • Across the studies, about 15% of patients discontinued treatment due to adverse events. The adverse events seen in the studies reflect those listed in the Remicade summary of product characteristics. According to the summary of product characteristics, in clinical trials of infliximab for the licensed indications, upper respiratory tract infection was the most common adverse drug reaction (25.3% with infliximab compared with 16.5% with control). Other very common adverse effects (occurring in 1 in 10 patients or more) include viral infections (such as influenza and herpes virus infection), headache, sinusitis, abdominal pain, nausea, generalised pain and infusion-related reactions. The most serious adverse drug reactions that have been reported with infliximab include hepatitis B virus reactivation, congestive heart failure, serious infections (including sepsis, opportunistic infections and tuberculosis) and serious infusion reactions. Sarcoidosis and sarcoid-like reactions have been reported rarely. See the summary of product characteristics for a complete list.

  • Observational studies are subject to bias and confounding and have many limitations affecting their application to clinical practice. The study by Vorselaars et al. (2015) was undertaken prospectively but was open-label. The other 9 studies were retrospective case series, which were generally undertaken in single centres. Other limitations of case series include differences in the management and follow-up of individual patients, inconsistent and incomplete recorded data, loss to follow-up and, potentially, missed patients. All of the studies in the evidence summary were uncontrolled and, as is usual for rare diseases, had small sample sizes, particularly when considering the effects of infliximab on sarcoidosis in individual organs. Many of the outcomes assessed were surrogate or disease-oriented outcomes, rather than patient-oriented outcomes, and the level of response was often determined by a single specialist clinician only. Definitions of response to treatment were often not reported and may have varied across the studies. Nevertheless, some patients seem to have seen substantial benefits and, in people with severe and active refractory disease, even stabilisation of the condition may be preferable to further deterioration.

  • According to specialists involved in this evidence summary, infliximab may be an option for some patients with severe, refractory extrapulmonary sarcoidosis (particularly cutaneous or neurological sarcoidosis); for example, those affected by disabling or disfiguring disease, or whose life expectancy is likely to be reduced.

Full text of evidence review.

Context and estimated impact for the NHS

According to MIMS (November 2016), a vial of infliximab 100 mg powder for concentrate for solution for infusion costs £419.62 for Remicade, £377.66 for Inflectra or Remsima and £377.00 for Flixabi (excluding VAT). Using these products, the cost of a 12-month course of infliximab treatment is about £11,000 to £17,000 for an 80 kg person depending on the product and dosage used (generally 3 mg/kg or 5 mg/kg at weeks 0, 2 and 6, then 6-weekly). However, these costs are for the medicine only (excluding VAT) and do not include any local procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy. They also assume that vials are used for only 1 patient and are not shared between patients.

Full text of context and estimated impact for the NHS.

Information for the public

A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non-technical language and may be especially helpful for people with sarcoidosis who are thinking about trying infliximab.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.