Advice
Full evidence summary
Full evidence summary
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. In the UK, the incidence of the condition is estimated to be about 3/100,000 person-years, based on general practice data (British Thoracic Society [BTS] Interstitial lung disease guideline 2008).
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. 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 and the disease can be staged according to the appearance of the lungs on a chest X‑ray:
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stage 1, hilar adenopathy alone (enlargement of the lymph nodes within the lung hilum, where the bronchus, blood vessels and nerves enter)
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stage 2, adenopathy and parenchymal (the functional tissue of the lung) disease
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stage 3, parenchymal disease alone
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stage 4, fibrosis.
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. There are significant differences in the severity of disease and organs involved depending on the ethnicity of the patient (Sarcoidosis, Oxford Textbook of Medicine).
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). African-Americans with sarcoidosis tend to have more aggressive disease and a poorer prognosis (BTS Interstitial lung disease guideline 2008).
According to the BTS guideline on interstitial lung disease (accredited by NICE), a number of factors need to be taken into account before treatment is considered for pulmonary sarcoidosis. Firstly, spontaneous remission occurs in 55–90% of people with stage 1 disease, 40–70% with stage 2 disease and 10–20% with stage 3 disease, usually within the first 6 months. Secondly, the natural history of the condition varies and it is difficult to predict the course and prognosis. Finally, the long-term effects of treatment need to be taken into account.
Because of the high rates of spontaneous remission, treatment is not recommended by BTS for:
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asymptomatic stage 1 pulmonary sarcoidosis
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asymptomatic stage 2 or 3 pulmonary sarcoidosis with mildly abnormal lung function and stable signs and symptoms.
An oral corticosteroid such as prednisolone is recommended first-line for:
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progressive lung disease determined by radiology
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significant symptoms of pulmonary or extrapulmonary disease needing treatment.
The BTS Interstitial lung disease guideline (2008) advises that other immunosuppressive or anti-inflammatory treatments have only a limited role in sarcoidosis because, when the evidence was assessed in 2008, insufficient high-quality studies were found to confirm their place in therapy. However, the guideline advises that such treatments should be considered if corticosteroids do not control the disease or if the person experiences 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.
Other treatment options that have been used for sarcoidosis include ciclosporin, hydroxychloroquine, azathioprine, chlorambucil, cyclophosphamide, leflunomide, pentoxifylline, thalidomide, infliximab and etanercept. The BTS guideline notes that these medicines have significant adverse effects and, as there is limited good-quality evidence to support their use, advises that they should be used only when disease is progressing and there are no alternatives. Lung transplantation should be considered in end stage pulmonary sarcoidosis.
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
Drug action
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).
Regulatory status
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 sarcoidosis is off‑label.
In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using infliximab outside its authorised indications. Supporting information and advice is also available from the GMC.
Cost
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.
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). However, these costs do not include any local procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy.
Evidence review
This evidence summary is based on the best available evidence for infliximab for treating pulmonary sarcoidosis. It includes 1 randomised controlled trial (RCT: Baughman et al. 2006) and 4 observational studies (a prospective 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).
A second RCT by Rossman et al. (2006) compared infliximab and placebo for treating chronic pulmonary sarcoidosis that was refractory to treatment. However, this study was excluded from the evidence summary because of severe limitations affecting its interpretation. Most importantly, it failed to recruit sufficient participants (only 19 of a planned 42) and was statistically underpowered to detect any differences between the groups, should any exist.
Randomised controlled trial
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Design: This study was a randomised, double-blind, placebo-controlled phase II study in 34 centres in the US and Europe. It evaluated the efficacy of infliximab for treating chronic, stable sarcoidosis with pulmonary involvement.
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Patients: Patients were included if they had histologically proven sarcoidosis for at least 1 year (mean 7 years), evidence of parenchymal disease on chest X‑ray, a forced vital capacity (FVC) of 50% to 85% of the predicted value (mean 69%), a Medical Research Council dyspnoea score of at least grade 1, and stable treatment with at least 10 mg daily of prednisone or equivalent (mean about 13 mg) or at least 1 immunosuppressant for at least 3 months. The medication regimens and doses were to remain stable during the study (51% received corticosteroids only, 7% received immunosuppressants only and 42% received both). Exclusion criteria included serious infection with 2 months of screening and opportunistic infection within 6 months of screening, and history of latent treated or untreated tuberculosis. Baseline characteristics were generally similar between the groups.
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Intervention and comparison: 138 patients (mean age 47 years, 67% white) were randomised 1:1:1 to receive intravenous infusions of placebo (n=45), infliximab 3 mg/kg (n=46) or infliximab 5 mg/kg (n=47) at weeks 0, 2, 6, 12, 18 and 24 and were followed up for 52 weeks. It is unclear if allocation was concealed.
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Outcomes: the primary end point was the change from baseline in the percent of predicted FVC at week 24. Major secondary end points included the St. George's Respiratory Questionnaire (SGRQ) total score (range 0 to 100, with higher scores indicating lower health-related quality of life: a change of 4 units is generally considered clinically important), Borg's CR10 dyspnoea score (range 0 to 10, with higher scores indicating worse dyspnoea) and 6-minute walk test (6‑MWT) distance (with longer distances indicating better function). Other secondary outcomes included adverse events and assessment of sarcoidosis in extrapulmonary organs.
Table 1 Summary of results for Baughman et al. 2006
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Placebo |
Infliximab 3 mg/kg |
Infliximab 5 mg/kg |
All infliximab |
Analysis |
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Randomised |
n=45 |
n=46 |
n=47 |
n=93 |
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Efficacy |
n=45 |
n=46 |
n=47 |
n=93 |
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Primary outcome: change from baseline in % predicted FVC at week 24 (LS mean) |
0.0% |
2.8% |
2.2% |
2.5% |
Versus placebo: 3 mg/kg: difference 2.8%, p=0.041 5 mg/kg: difference 2.2%, p=0.116, NS All infliximab: difference 2.5%, p=0.038 |
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Selected secondary outcomes: |
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Change from baseline in SGRQ total score at week 52 (LS mean ± SE) |
−2.4±2.1 |
−2.9±2.2 |
−3.4±2.1 |
−3.1±1.6 |
Versus placebo 3 mg/kg: difference −0.5, NS 5 mg/kg: difference −1.0, NS All infliximab: difference −0.7, NS |
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Change from baseline in CR10 score at week 52 (LS mean ± SE) |
0.7±2.4 |
0.5±2.2 |
0.1±2.1 |
0.3±2.1 |
Versus placebo 3 mg/kg: difference 0.2, NS 5 mg/kg: difference 0.6, NS All infliximab: difference 0.4, NS |
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Change from baseline in 6‑MWT distance (metres) at week 52 (LS mean ± SE)a |
−19.9±9.4 |
17.1±9.4 |
−1.8±9.5 |
7.6±6.6 |
Versus placebo 3 mg/kg: difference 37.0, p=0.007 5 mg/kg: difference 18.1, NS All infliximab: difference 27.5, p=0.019 |
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Safety b |
n=44 |
n=45 |
n=46 |
n=91 |
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Patients reporting serious adverse events at week 52 |
18.2% (8/44) |
24.4% (11/45) |
21.7% (10/46) |
23.1% (21/91) |
Statistical analysis not reported |
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Patients reporting adverse events at week 52 |
93.2% (41/44) |
88.9% (40/45) |
87.0% (40/46) |
87.9% (80/91) |
Statistical analysis not reported |
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Patients reporting infections that needed antimicrobial treatment at week 52 |
61.4% (27/44) |
57.8% (26/45) |
50.0% (23/46) |
53.8% (49/91) |
Statistical analysis not reported |
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Patients who discontinued treatment due to adverse events |
4.5% (2/44) |
Not reported |
Not reported |
5.5% (5/91) |
Statistical analysis not reported |
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Abbreviations: 6‑MWT, 6-minute walk test distance (with longer distances indicating better function); CR10, Borg's CR10 dyspnoea score (range 0 to 10, with higher scores indicating worse dyspnoea); FVC, forced vital capacity; LS, mean; NS, not significant; p, p value; SE, standard error; SGRQ, St. George's Respiratory Questionnaire (range 0 to 100, with higher scores indicating lower health-related quality of life: a change of 4 units is generally considered clinically important); URTI, upper respiratory tract infection. a Uses last observation carried forward methodology. b One patient in each group withdrew consent. |
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Observational studies
Table 2 Summary of non-comparative observational studies
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Study design |
Patients |
Interventions |
Selected outcomes |
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Prospective, uncontrolled open-label study in the Netherlands Investigated infliximab for refractory sarcoidosis |
56 patients (mean age 48 years, 87.5% white) with severea sarcoidosis (mean duration 6.8 years, 80% stage 2–4) unresponsive to first- and second-line treatmentb or who had had severe adverse effects from treatmentsc,d. In the total study population, stable or deteriorating pulmonary function was seen in the 6 months before infliximab was initiated. 34 patients (61%) primarily had pulmonary sarcoidosis. 28 of these were treated for a pulmonary indication. At baseline, mean FVC was 73.6% predicted and mean SUVmax in lung parenchyma was 9.0 (indicating high disease activity). |
Infliximab 5 mg/kg at weeks 0 and 2 then every 4 weeks for 6 months (8 infusions). Prednisolone dose could be tapered. |
At 26 weeks in the 28 patients with a pulmonary treatment indication:
At 26 weeks in the total population, measures of health-related quality of life statistically significantly improved (mean PGA −14.6 from baseline of 61.0, p<0.0001: mean SF‑36 +8.2 from baseline of 40.6, p=0.009). At 26 weeks in 19 patients taking prednisolone, the mean daily dose decreased by 8.8 mg (p=0.001). No patients increased their concomitant immunosuppressant dose. 8 patients had severe adverse effects: 7 of these discontinued treatment and 2 later died. 1 person discontinued treatment for an undisclosed reason. 13 patients had mild adverse effects. |
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Retrospective case review in Denmark Investigated infliximab for refractory sarcoidosis |
12 patients (mean age 34 years at diagnosis, 92% white) with sarcoidosis (mean duration 5.8 years, 75% stage 2–4) refractory to standard immunotherapy (n=2) or with intolerable adverse effects on standard therapy (n=2) or both (n=8). Treatments at baseline included prednisolone (n=12), methotrexate (n=11) and azathioprine (n=6). 9 patients had pulmonary sarcoidosis. |
The initial infliximab dose was 5 mg/kg in 1 patient and 3 mg/kg in 11 patients (increased to 5 mg/kg in 2 patients) at weeks 0, 2 and 6. For most patients treatment was then administered 8‑weekly (mean duration 25 months, mean number of treatments 15). Patients also received other immunosuppressants. |
In patients with pulmonary sarcoidosis, measures of pulmonary function (including FEV1, FVC and TLC) improved following infliximab. For example, compared with baseline, mean % predicted FVC increased by:
No changes in pulmonary staging on X‑ray were seen in these patients. Markers of disease activity were raised at baseline in 6/9 patients and became normal with treatment. 2 patients discontinued treatment due to adverse effects. |
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Retrospective case review in the US Investigated infliximab for refractory sarcoidosis |
26 patients (mean age 51 years, 81% African-American) with sarcoidosis (average duration 14.9 years, staging not reported) refractory to corticosteroids or DMARDs or both, or who could not tolerate these treatments. Previous treatments included corticosteroids (n=24), methotrexate (n=20) and hydroxychloroquine (n=23). 15 patients had pulmonary sarcoidosis. |
The average maximum infliximab dose was 511 mg (range 300–1000 mg) given on average every 5.5 weeks (range 4–6 weeks). The average duration of treatment was 46.2 months. |
After 46.2 months, in 15 patients, using objective clinical outcomes (such as imaging), pulmonary sarcoidosis:
(p values not reported) No statistically significant differences were seen from baseline in FEV1, FVC or TLC (2%, 4% and 11% improvement respectively). Adverse effects were seen in 15/26 patients, 3 of whom discontinued infliximab. |
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Retrospective case review in the Netherlands Investigated infliximab for refractory sarcoidosis |
45 patients (mean age 49 years, ethnicity not reported) with sarcoidosis (mean duration 7.6 years, 73% stage 2–4) refractory to regular medication or who had severe adverse effects with these medicines. Baseline treatments included prednisone (n=12) methotrexate (n=1) or both (n=30). 23 patients had pulmonary sarcoidosise. |
Infliximab 5 mg/kg at weeks 0, 2, 6, 10, 14 and 18. Methotrexate was also started in 8 patients. |
In the total study population, after 18 weeks, statistically significant improvements were seen in markers of disease activity on F‑FDG PET, lung function and health-related quality of life. In 23 patients with pulmonary sarcoidosis, the mean changes in % predicted VC and FEV1 were 7.6% (p<0.0001) and 7.9% (p<0.0001) respectively. Improvements in VC and FEV1 remained significant when the 8 patients newly taking methotrexate were excluded. VC improved by 10–20% in 8 patients and over 20% in 4 patients. FEV1 improved by 10–20% in 5 patients and by over 20% in 7 patients. Infliximab was well-tolerated. 1 patient was hospitalised. |
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Abbreviations: 6-MWT, 6-minute walk test distance; DMARD, disease modifying anti-rheumatic drug; F‑FDG PET, 18F‑fluorodeoxygucose by positron emission tomography; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; PGA, patient global assessment, a measure of health-related quality of life (range 0–100 with higher scores indicating worse health); SD, standard deviation; SF‑36, 36-item Short Form health survey (range 0 to 100 with lower scores indicating a worse level of functioning); SUVmax, maximised standardised uptake value on F-FDG PET, a marker of disease activity and inflammation; TLC, total lung capacity; TNF tumour necrosis factor; VC, vital capacity (not forced). a Based on loss of function (for example, lung function or cardiac function), impaired quality of life and disease activity on F‑FDG PET at baseline. b 93% of patients had used at least 2 immunosuppressant treatments (mainly corticosteroids, methotrexate and azathioprine); 13 patients had previously received TNF‑alpha inhibitors. c For example, worsening diabetes, psychological deterioration or liver function disorders. d Exclusion criteria included vaccination within the previous 3 months, active or untreated latent tuberculosis and serious infections in the last 2 months. e Severe dyspnoea on exertion or a decline in pulmonary function tests despite treatment with immunosuppressant medicines. |
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Clinical effectiveness
Randomised controlled trial
Baughman et al. (2006) found that, in people with stable pulmonary sarcoidosis who were taking regular doses of corticosteroids and/or immunosuppressants, infliximab (3 mg/kg and 5 mg/kg combined, n=93) improved mean percent of predicted FVC at week 24 by 2.5% compared with placebo (n=45, p=0.038); this was statistically significant. However, it is unclear whether this small, average improvement in this disease-oriented outcome is clinically important.
There were no statistically significant differences between infliximab and placebo in mean SGRQ total scores or Borg's CR10 dyspnoea scores at weeks 24 or 52. There were also no differences between the groups in mean 6‑minute walking distance at week 24. However, at week 52, 6‑minute walking distance improved in the infliximab 3 mg/kg and the combined infliximab group (but not the 5 mg/kg group) compared with placebo (p=0.007 and p=0.019 respectively: see table 1 for more information); this was statistically significant.
Observational studies
The prospective study by Vorselaars et al. (2015) found that infliximab 5 mg/kg statistically significantly improved mean percent of predicted FVC by 6.6% in 28 people with refractory pulmonary sarcoidosis (p=0.0007) at 26 weeks. An increase of more than 10% was seen in 13 people (p value not reported). Statistically significant improvements were also seen in other measures of pulmonary function (for example, mean percent of predicted FEV1 5.8%, p<0.0001) and in markers of disease activity and inflammation (for example, mean SUVmax of the lung parenchyma −5.3, p value not reported). Measures of health-related quality of life statistically significantly improved in the total study population with refractory sarcoidosis in their lungs or other organs (n=56). See table 2 for more information.
In this study, the authors reported that baseline pulmonary function tests did not predict treatment outcome. In people with refractory pulmonary sarcoidosis, baseline SUVmax of the lung parenchyma was associated with percent predicted FVC, with a high SUVmax associated with a better response to treatment.
The retrospective case review by Ørum et al. (2012) found that pulmonary function improved with infliximab (3 or 5 mg/kg) in 9 people with refractory pulmonary sarcoidosis. Compared with baseline, mean percent of predicted FVC increased by 5.1% after 7 treatments (n=5, p value not reported) and 7.1% after the last dosage (n=9, p value not reported, mean treatment duration 25 months). No changes were seen in pulmonary staging on X‑ray. In 6 patients with raised markers of disease activity at baseline, mean values became normal with treatment.
In their retrospective case review of people (81% African-American) with refractory sarcoidosis treated with infliximab (average dose 511 mg), Russell et al. (2013) found mixed results for pulmonary sarcoidosis. When objective clinical outcomes (such as imaging) were used, the disease resolved or improved in 8 out of 15 people after a mean treatment duration of 46 months (p value not reported). In 2 people, pulmonary sarcoidosis worsened. No statistically significant differences from baseline were seen in FEV1, FVC or TLC (2%, 4% and 11% improvement respectively).
In 23 patients with refractory pulmonary sarcoidosis treated with infliximab 5 mg/kg in the retrospective case review by Van Rijswijk et al. (2013), mean percent predicted vital capacity (VC, not forced) and FEV1 improved by 7.6% (p<0.0001) and 7.9% (p<0.0001) respectively at 18 weeks. VC improved by 10–20% in 8 patients and over 20% in 4 patients. FEV1 improved by 10–20% in 5 patients and by over 20% in 7 patients. In the total study population with refractory sarcoidosis in their lungs or other organs (n=45), statistically significant improvements were seen in markers of disease activity and inflammation, lung function and health-related quality of life.
Safety and tolerability
Summary of product characteristics (Remicade)
In clinical trials of infliximab for the licensed indications, upper respiratory tract infection was the most common adverse drug reaction, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. Other very common adverse effects (occurring in 1 in 10 people 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 associated with the use of TNF‑alpha inhibitors that have also 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.
Infliximab is contraindicated in people with tuberculosis or other severe infections, and people with moderate or severe heart failure (New York Heart Association; NYHA class III/IV). In 2014, the Drug Safety Update from the Medicines and Healthcare products Regulatory Agency (MHRA) advised that all patients should be assessed for active and latent tuberculosis before starting treatment with a TNF‑alpha inhibitor.
Patients must be monitored closely for infections including tuberculosis before, during and 6 months after treatment with infliximab. Caution should be used when considering the use of infliximab in patients with chronic infection or in those with a history of recurrent infections, including concomitant immunosuppressive therapy. Caution is also advised in people with hepatitis B virus infection and mild heart failure.
Randomised controlled trial
In the study by Baughman et al. 2006, the proportions of patients who had adverse events were similar across the treatment groups. The most commonly reported adverse events (in more than 15% of patients in any group) were upper respiratory tract infection, coughing, dyspnoea and pain (sarcoidosis, bronchitis, headache and back pain). Infusion reactions were generally mild and occurred in similar proportions of infliximab- and placebo-treated patients. No cases of fungal infection, tuberculosis or opportunistic infections were reported.
At week 52, serious adverse events had occurred in 18.2% (8/44) of patients in the placebo group and 23.1% (21/91) of patients in the infliximab group. The most commonly reported serious adverse events (in more than 3% of patients in any group) were pneumonia, sarcoidosis and cardiac failure. Two patients taking placebo (4.5%) and 5 patients taking infliximab (5.5%) discontinued treatment due to adverse events. One person taking placebo died of respiratory failure caused by progression of sarcoidosis. One person taking infliximab 5 mg/kg died of epithelioid sarcoma after the study finished.
Observational studies
In the prospective study by Vorselaars et al. (2015), 8/56 patients (14%) discontinued infliximab: 3 with pneumonia (1 of whom died), 1 with respiratory failure due to disease progression (who subsequently died), 1 with peritonitis (who was known to be on peritoneal dialysis), 1 with gastrointestinal problems, 1 with allergies and 1 who did not wish to continue for undisclosed reasons. Over 26 weeks, 13/56 patients (23%) had mild adverse effects including respiratory tract infections, headache, dizziness, oedema and joint pain. Thirty four patients had no adverse effects.
Over 46 months, in the retrospective study by Russell et al. (2013), adverse effects were seen in 15/26 patients (58%), 3 of whom discontinued infliximab treatment for severe pneumonia, a positive tuberculosis test and recurrent sinusitis. The most common adverse effects were minor infection (n=4), rash (n=4) and pneumonia (n=3).
Van Rijswijk et al. (2013) (n=45, duration 18 weeks) reported that few adverse effects were documented and the majority were mild. One patient was hospitalised with pneumonia. In the study by Ørum et al. (2012), 2 patients discontinued infliximab due to adverse effects (n=12, mean duration 25 months).
Evidence strengths and limitations
The RCT by Baughman et al. (2006) found that infliximab improved the disease-oriented primary outcome (mean percent predicted FVC) at 24 weeks compared with placebo in people with stable pulmonary sarcoidosis. This is statistically significant; however, it is unclear whether the average improvement was clinically important. Also, there were no statistically significant differences in any of the major patient-oriented outcomes (such as health-related quality of life, dyspnoea or walking distance) at 24 weeks.
It is important to note that patients in the study had stable disease and were taking regular background corticosteroid and/or immunosuppressant therapy. Therefore, the results from this study may not reflect the effectiveness of infliximab in people with pulmonary sarcoidosis who have active, unstable disease for whom corticosteroids and other treatments have proven ineffective (or who cannot tolerate these treatments), in whom life expectancy may be reduced. It is possible that a small number of people in the study responded well to infliximab treatment, with little or no benefit seen in the majority, diluting the overall effect of infliximab observed in the study. Most people in the study had mildly impaired lung function and/or stage 2 or 3 pulmonary sarcoidosis but post hoc exploratory analyses suggested that patients with more severe sarcoidosis might benefit more from infliximab treatment than those with milder disease. However, these analyses have limitations and should be regarded as hypothesis-generating only. Further RCTs would be useful to answer this question but would be very difficult to perform because of the rarity of severe, refractory disease and issues around selecting an ethical comparator.
The uncontrolled observational studies in this evidence summary were undertaken in patients with refractory sarcoidosis. However, observational studies are more subject to bias and confounding than RCTs and interpretation of these studies is further limited by the absence of any form of comparator. The study by Vorselaars et al. (2015) was undertaken prospectively but was open-label. The other 3 studies were retrospective case series. Limitations of these include differences in the management and follow-up of individual patients, inconsistent and incomplete recorded data, loss to follow-up and, potentially, missed patients. As is usual for a rare disease, the studies had small sample sizes, particularly when considering the effects of infliximab on sarcoidosis in individual organs.
The studies are relevant to the overall UK population, although the study by Russell et al. (2013) mainly included people of African-American ethnicity. Sarcoidosis has been shown to be more severe and difficult to treat in this population, which is reflected in the lower (non-significant) improvements in lung function seen in this study, compared with the other observational studies.
Disease-oriented outcomes were primarily used in the 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 lung and 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.
The improvement in percent of predicted FVC seen in the studies in people with refractory sarcoidosis was generally higher than in the RCT by Baughman et al. (2006) in people with stable sarcoidosis (around 7%, compared with 2.5%). This may be because people with refractory sarcoidosis experience more inflammation, which may respond to infliximab. However, more studies are needed to confirm this.
From the studies included in the evidence review, the optimal dose, administration regimen and duration of infliximab treatment is unclear. Also, it is not known whether any benefits obtained in the short term will be maintained long term.
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. 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
Cost effectiveness
No studies were identified on the cost effectiveness of infliximab for treating any manifestation of sarcoidosis.
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).
The table below shows the cost of infliximab treatment based on the doses of infliximab and treatment regimens used in the RCT by Baughman et al. (2006). 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.
Table 3 Cost of a course of infliximab treatment
|
Infliximab dosea |
Administration regimen |
Cost of Flixabib |
Cost of Inflectra or Remsimab |
Cost of Remicade |
|
3 mg/kg, 240 mg |
Weeks 0, 2, 6, 12, 18 and 24 |
£6,786.00 |
£6,797.88 |
£7,553.16 |
|
5 mg/kg, 400 mg |
£9,048.00 |
£9,063.84 |
£10,070.88 |
|
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a Based on treating an 80 kg person. b For more information on biosimilar medicines 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. |
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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.
Relevance to NICE guidance programmes
NICE has not published any guidance on managing sarcoidosis. The use of infliximab for sarcoidosis is not appropriate for referral for a NICE technology appraisal and is not currently planned into any other NICE work programme.
NICE has published guidance on many of the licensed indications for infliximab. Please see the NICE website for more information.
References
Baughman RP, Drent M, Kavuru M et al. (2006) Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. American Journal of Respiratory and Critical Care Medicine 174: 795–802
Baughman RP and Lower EE (2013) Sarcoidosis. In Warrell DA, Cox TM, and Firth JD, editors. Oxford Textbook of Medicine (5 ed.) Oxford: Oxford University Press [online; accessed 20 June 2016]
Napp Pharmaceuticals Limited (2016) Remicade summary of product characteristics [online; accessed 23 June 2016]
Ørum M, Hilberg O, Krag S et al. (2012) Beneficial effect of infliximab on refractory sarcoidosis. Danish medical journal 59: A4535
Rossman MD, Newman LS, Baughman RP et al. (2006) A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases 23: 201–8
Russell E, Luk F, Manocha S et al. (2013) Long term follow-up of infliximab efficacy in pulmonary and extra-pulmonary sarcoidosis refractory to conventional therapy. Seminars in Arthritis and Rheumatism 43: 119–24
The British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society (2008) Interstitial lung disease guideline. Thorax 63: v1–v58
Van Rijswijk HNAJ, Vorselaars ADM, Ruven HJT et al. (2013) Changes in disease activity, lung function and quality of life in patients with refractory sarcoidosis after anti-TNF treatment. Expert Opinion on Orphan Drugs 1: 437–443
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Development of this evidence summary
The integrated process statement sets out the process NICE uses to select topics for the evidence summaries for unlicensed/off-label medicines and how the summaries are developed, quality assured and approved for publication.
Expert advisers
Dr Colm Leonard, Consultant Thoracic Physician and Honorary Senior Lecturer, University Hospital of South Manchester NHS Foundation Trust
Athol U Wells, Professor of Respiratory Medicine, Royal Brompton Hospital, London
Declarations of interest
Dr Colm Leonard has been an investigator in trials of new drugs in idiopathic pulmonary fibrosis involving the following companies; Roche; Boehringer Ingelheim; InterMune; AstraZeneca and Actelion. He does not accept honoraria from these companies but his department has gained funding from clinical trial work and he has attended conferences paid for by these companies.
Professor Athol U Wells declared no relevant interests.
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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. |
ISBN: 978-1-4731-2224-6