Inflammatory diseases may display atypical features making such patients impossible to classify. Management of these cases in daily practice cannot rely on the results of clinical trials nor on guidelines. DNA and RNA mapping have become major tools to understand and sometimes direct the treatment strategy in oncology. This study aims to test whether a precise analysis of molecular pathways in inflammatory, non classified diseases, can constitute a predictive tool of therapeutic efficiency

This is a phase IIb study. The main objective of this study is to evaluate the efficacy of targeted treatments in patients displaying a non-classified, severe and resistant inflammatory disease. Targeted treatments for each patient will have been selected through an algorithm based on molecular analysis of specific altered inflammatory signaling pathway.

Treatments consist in targeted therapies approved in other indications (Kineret®, Humira®, Stelara®, Cosentyx®, Roactemra® and Rituximab®) that will be given once selected using molecular analysis and decision making procedure by the Scientific committee.

For each patient, one targeted treatment will be administered according to the SmPC procedure for a treatment period of 6 months.

Primary efficacy endpoint:

Response will be assessed at month 6 with a composite endpoint defined as improvement of at least 2 of the 3 following parameters:

• 50% improvement of the systemic activity assessed by the clinician following a visual analog scale (0-10 mm),
• and/or 50% improvement of cutaneous activity assessed by the involved skin surface area,
• and/or 50% decrease or normalisation of biological markers of inflammation (either CRP, ESR or fibrin).

An independent adjudication committee blinded to the treatment received, will review primary endpoint for all patients based on clinical files and standardized photographs, to validate the response.

Other secondary criteria will be assessed. Overall, this study will require a molecular analysis done on patient's tissue, the final aim being to evaluate efficiency and tolerance of targeted treatments chosen in a personalized analysis when classification is impossible.

Inclusion Criteria:

• Patients (men or women) aged 18 years old and over
• Patients presenting inflammatory non classified disease targeting at least 2 organs involvement: skin, lymph nodes, hemopoietic system, joints, digestive tract, eye, nerves and brain tissues, respiratory tract, cardio-vascular disorders, genito-urinary tract including kidney, musculo-skeletal tissues. Skin involvement is mandatory in order to be able to compare involved and non-involved tissue
• Signed informed consent

The disease should be considered as non-classified despite classical and adapted investigations and evaluation through expert committee meeting.

The disease alters significantly quality of life. The impairment of quality of life will be assessed based on the investigator's assessment.

The disease has been resistant to at least two prior lines of treatment [for example : Hydroxychloroquine, Chloroquine, Colchicine, Methotrexate, Ciclosporine, Azathioprine, Mycophenolate mofetil, Disulone, Corticosteroids (prednisone, prednisolone, dexamethasone, methylprednisolone…)].

Exclusion Criteria:

• Patients presenting disease which is not featured by lesional and healthy skin areas, easy to biopsy

• Patients refusing biopsies

• Pregnancy

• Women of child-bearing potential unable to receive highly efficient contraception such as combined oral contraceptives, intra-uterine disposals, hormonal implants or the use of male condoms recommended in case of unstable or irregular partner or as a replacement method for transient unacessebility to hormonal method

• Breastfeeding

• Patients presenting disease needing urgent therapeutic measures

• Patients without health insurance or social security

• Participation in another interventional trial

• Patients under legal protection

• Patients unable to respect the wash out delay of previously taken medications before biopsy and before treatment initiation :

  • Hydroxychloroquine (wash out period = 30 days)
  • Chloroquine (wash out period = 7 days)
  • Colchicine (wash out period = 7 days)
  • Methotrexate (wash out period = 7 days)
  • Ciclosporine (wash out period = 14 days)
  • Azathioprine (wash out period = 14 days)
  • Mycophenolate mofetil (wash out period = 14 days)
  • Disulone (wash out period = 7 days)
  • Corticosteroids (=prednisone, prednisolone, dexamethasone, methylprednisolone) (wash out period = 7 days for doses greater than 5mg)

• Patients with contra-indications to treatments : Severe or active infections including tuberculosis