Efficacy of Remission-induction Regimen With Infliximab for Severe Extrathoracic Sarcoidosis (EFIRTES)
Efficacy of Remission-induction Regimen With Infliximab for Severe Extrathoracic Sarcoidosis (EFIRTES)
The present study was designed to assess the efficacy of infliximab in a 2-period study :

 -  An initial period with comparison of infliximab versus placebo and allowing the
 determination of the primary criteria

 -  Then an extension period in which the 2 arms will receive infliximab (in the placebo
 group : 5 perfusions and in the experimental group 3 supplemental perfusions). Finally,
 the 2 groups will receive 5 injections of infliximab There is little evidence in the
 literature of when and how infliximab should be administered in sarcoidosis. We
 hypothesized, from our personal experience in 30 cases (18 of which were reported in a
 retrospective trial (14), that infliximab would have a very quick activity. So it
 appeared reasonable to evaluate the primary criterion at 6 weeks after initiation of the
 treatment.
Sarcoidosis is a multisystemic granulomatous disease of unknown cause . Sarcoidosis is
 chronic and progressive in 25 % of the patients. Although mediastinal lymph nodes and lung
 are the most frequently sites affected, extrathoracic localizations may occur. In particular,
 cardiac or neurological localizations are frequently associated with a chronic disease, with
 subsequent morbidity and mortality. Such patients require long term therapy to avoid organ
 dysfunction which may occur with fibrosis.

 If cyclophosphamide remains the "historical" treatment to treat resistant sarcoidosis, it can
 present serious adverse effects such as infections and gonadic toxicity which may be a
 problem in young people. As infliximab has demonstrated a real efficacy in resistant
 sarcoidosis, we challenged that it could be a valuable option for resistant extra-thoracic
 sarcoidosis.

 The population studied will be the patients with clinical and radiological presentation
 concordant with sarcoidosis

 This study is a phase 3, randomized, controlled, parallel group trial, designed to assess the
 efficacy of infliximab in a 2-period study :

 In the first part, patients will be randomly assigned in a 1:1 ratio to receive either
 infliximab or placebo. Both patients and investigators will be blind regarding study
 treatment. Concomitantly, patients will be treated with usual care (i.e. steroids at the dose
 of 0.5 mg/kg/d with a program of tapering dose).

 In the second open-labelled part, all the patients will receive infliximab treatment,
 steroids tapering regimen and low-dose methotrexate left to the investigator choice or, in
 case of contra-indication, azathioprine.

 Finally, the 2 groups will receive 5 injections of infliximab

 Infliximab will be used at a dose of 5 mg/kg at D1,D15 then every 4 weeks because in our
 experience, extrathoracic severe localization require such dosage and may be resistant to the
 low dosage (3 mg/kg). This dosage is also the dose usually recommended for extra-thoracic
 localizations.

 Disease activity and ePOST score will be evaluated at the inclusion, W6 and after 5
 injections (2 weeks after W20 for placebo group or W14 for experimental group). Severity
 assessment score (ePOST score) will be assessed by the physician in charge of the patient.
 This score reflects the sarcoidosis activity in 17 organs and has been validated in previous
 studies.

 Remission at week 6 will be defined as: Percentage of patients who have a severity assessment
 score (ePOST score) inferior to 1 in all organs and absence of hypercalcemia at W6, whatever
 the corticosteroid dosage received.
Inclusion Criteria:

 -  Clinical and radiological presentation confirming sarcoidosis

 -  Presence of non caseating granuloma in at least one organ

 -  Presence of at least one extrathoracic localization, including hypercalcemia

 -  Exclusion of other causes of granuloma

 -  Presence of serious organ involvement or relapse/apparition of a new localization
 despite a first-line immunosuppressive drug

 -  Age superior or equal to 18 years

 Exclusion Criteria:

 -  Pregnancy or breast feeding or women in age of pregnancy without efficient
 contraception

 -  Patients with multiple sclerosis

 -  Patients with prior history of any cancer in the 5 years before inclusion (except for
 cutaneous basocellular cancers),

 -  Patients with a history of hypersensitivity to infliximab to other murine proteins, or
 to any of the excipients

 -  Patients with untreated tuberculosis or current other severe infections such as
 sepsis, abscesses, and opportunistic infections• Patients with moderate or severe
 heart failure (NYHA class III/IV)

 -  Concurrent vaccination with live vaccines during therapy

 -  Inability to understand information about the protocol

 -  Adult subject under legal protection or unable to consent.

 -  No informed consent

 -  Absence of affiliation to National French social security system

 -  Patients with severe renal failure, severe hepatic impairment, hepatocellular
 insufficiency, chronic respiratory insufficiency, risk of angle closure glaucoma, risk
 of urinary retention related to urethroprostatic disorders, certain evolving viral
 diseases (including hepatitis, herpes, varicella, zoster), psychotic states still not
 controlled by treatment