Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in December 2016 . See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
A randomised controlled trial (RCT) found that, in 138 people with stable pulmonary sarcoidosis, infliximab improved mean percent of predicted forced vital capacity (FVC) at week 24 by 2.5% compared with placebo; this was statistically significant. However, although some individual patients with stable disease, especially those with more severe symptoms, may see greater benefits, it is unclear whether this small, average improvement in this disease-oriented outcome is clinically important on a population basis. There were no statistically significant differences between infliximab and placebo in health-related quality of life, dyspnoea and 6‑minute walking distance at week 24.
Three uncontrolled, non-comparative observational studies in a total of 60 people with refractory pulmonary sarcoidosis found that infliximab improved mean percent of predicted FVC or vital capacity (VC, not forced) from baseline by about 7%. Across these studies, improvements were also seen in other lung function outcomes, markers of disease activity and quality of life. The results suggest that infliximab may be effective in a small subset of people with active, unstable pulmonary sarcoidosis for whom corticosteroids and other treatments have proven ineffective or who cannot tolerate these treatments (refractory pulmonary sarcoidosis), in whom life expectancy may be reduced. However, observational studies have many limitations and better quality evidence is needed to confirm this.
Adverse events seen in the studies reflected those listed in the summary of product characteristics.
The evidence supports British Thoracic Society (BTS) guidance that immunosuppressants such as infliximab have only a limited role in pulmonary sarcoidosis because there are insufficient high-quality studies to confirm their place in therapy and they have significant adverse effects. The guidance advises that immunosuppressants should be used only when disease is refractory to standard treatments and when there are no pharmacological alternatives.
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.
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Effectiveness
These results are statistically significant.
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Safety
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Patient factors
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Resource implications
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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 (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 recommended first-line. The BTS advises that other immunosuppressive or anti-inflammatory treatments have only a limited role in sarcoidosis. However, such treatments should be considered if corticosteroids do not control the disease or have intolerable adverse effects. There is some evidence to support the use of methotrexate as a steroid-sparing agent and this is recommended as the immunosuppressant of choice for pulmonary sarcoidosis. Lung transplantation should be considered in end stage pulmonary sarcoidosis (BTS Interstitial lung disease guideline 2008).
This evidence summary considers the best available evidence for infliximab for treating pulmonary sarcoidosis. A related evidence summary has considered infliximab for extrapulmonary sarcoidosis.
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.
Evidence review
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This evidence summary includes 1 randomised controlled trial (RCT) and 4 observational studies.
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The RCT by Baughman et al. (2006) compared infliximab 3 mg/kg and infliximab 5 mg/kg with placebo in 138 people with chronic, stable pulmonary sarcoidosis who were taking regular doses of corticosteroids and/or immunosuppressants.
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The RCT found that infliximab (3 mg/kg and 5 mg/kg combined, n=93) improved percent of predicted forced vital capacity (FVC) at week 24 by 2.5% compared with placebo (n=45, p=0.038); this was statistically significant. There were no statistically significant differences between infliximab and placebo in health-related quality-of-life scores or dyspnoea scores at weeks 24 or 52. There were also no differences between the groups in 6‑minute walking distance at week 24.
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A prospective non-comparative study by Vorselaars et al. (2015) and 3 case series by Ørum et al. (2012), Russell et al. (2013) and Van Rijswijk et al. (2013) considered infliximab (usually 3–5 mg/kg) for treating people with chronic sarcoidosis in their lungs or other organs who either had a suboptimal response to the usual treatments, or who could not tolerate those treatments (refractory sarcoidosis). In subsets of people with pulmonary sarcoidosis, infliximab statistically significantly improved:
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Mean percent predicted FVC by 6.6% at 26 weeks in Vorselaars et al. (2015) (n=28, p=0.0007, 8 treatments). An increase of more than 10% was seen in 13/28 people (p value not reported).
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Mean percent predicted FVC by 7.1% at 25 months in Ørum et al. (2012) (n=9, p value not reported, mean 15 treatments).
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Mean percent predicted vital capacity (VC, not forced) by 7.6% at 18 weeks in Van Rijswijk et al. (2013) (n=23, p<0.0001, 6 treatments). An increase of more than 10% was seen in 12/23 people (p value not reported).
In these studies, improvements were also seen in other lung function outcomes and in markers of disease activity and inflammation.
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No statistically significant differences in lung function outcomes were seen in the study by Russell et al. (2013). However, when objective clinical outcomes (such as imaging) were used, pulmonary sarcoidosis resolved or improved in 8/15 people (p value not reported, mean duration 46 months, about 36 treatments). This study mainly included African-American people; sarcoidosis is more severe and difficult to treat in this population.
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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.
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In the RCT by Baughman et al. (2006), 2/44 people taking placebo and 5/91 people taking infliximab discontinued treatment due to adverse events. In Vorselaars et al. (2015), 8/56 patients discontinued infliximab (2 of whom died) and in Russell et al. (2013) 3/26 discontinued infliximab. No treatment discontinuations were reported in the other studies.
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The studies have many limitations affecting their application to clinical practice. Although Baughman et al. (2006) found that infliximab statistically significantly improved the disease-oriented primary outcome (mean percent predicted FVC) at 24 weeks compared with placebo, it is unclear whether the small, average improvement was clinically important. Also, there were no statistically significant differences in any of the major patient-oriented outcomes at 24 weeks. All patients in the study by Baughman et al. (2006) were taking stable background corticosteroid and/or immunosuppressant therapy. Also, sarcoidosis did not need to be active or refractory to treatment. From this RCT, it is not known whether infliximab would be more effective in the small subset of people with active, refractory pulmonary sarcoidosis, in whom life expectancy may be reduced.
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The uncontrolled observational studies in this evidence summary were undertaken in people with refractory sarcoidosis, and the improvement in percent of predicted FVC seen in the observational studies was generally higher than in the RCT by Baughman et al. (2006) (around 7%, compared with 2.5%). However, observational studies are more subject to bias and confounding than RCTs. Also, as is usual for a rare disease, all the studies had small sample sizes.
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Disease-oriented outcomes were primarily used in the observational studies. Van Rijswijk et al. (2013) and Vorselaars et al. (2015) did find some statistically significant improvements in health-related quality of life in people with sarcoidosis in their lungs or other organs. However, these improvements did not always reach the level considered to be clinically important. Although improvements in FVC or VC and other lung function outcomes were seen in most of the studies, the minimal clinically important changes for sarcoidosis are unclear. Nevertheless, some patients seem to have seen substantial benefits and, in people with severe and active refractory disease, even stabilisation of lung function may be preferable to further deterioration.
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The evidence supports BTS guidance that immunosuppressants such as infliximab have only a limited role in pulmonary sarcoidosis because there are insufficient high-quality studies to confirm their place in therapy and they have significant adverse effects. The guidance advises that immunosuppressants should be used only when disease is refractory to standard treatments and when there are no pharmacological alternatives.
Context and estimated impact for the NHS
According to MIMS (October 2016), 1 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 course of infliximab treatment based on the doses of infliximab and treatment regimens used in the study by Baughman et al. (2006) (3 mg/kg or 5 mg/kg at weeks 0, 2, 6, 12, 18 and 24) ranges from about £7,000 to £10,000 for an 80 kg person (see table 3 in full text of context and estimated impact for the NHS for more information). 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.
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.
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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. |