(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/125402 Al 27 July 2017 (27.07.2017) P O P C T

(51) International Patent Classification: NJ 08543-4000 (US). CONNOLLY, Sean, Eugene; Bris C12Q 1/68 (2006.01) tol Myers Squibb, 3401 Princeton Pike, Lawrence NJ 08648 (US). (21) International Application Number: PCT/EP20 17/050928 (74) Agent: COLLIN, Matthieu; Inserm Transfert 7 rue Watt, 75013 Paris (FR). (22) International Filing Date: 18 January 2017 (18.01 .2017) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, English (25) Filing Language: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 16305047.9 19 January 2016 (19.01.2016) EP KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (71) Applicants: INSERM (INSTITUT NATIONAL DE LA MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, SANTE ET DE LA RECHERCHE MEDICALE) NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, [FR/FR]; 101, rue de Tolbiac, 75013 Paris (FR). UNI- RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, VERSITE DE ROUEN [FR/FR]; 76 130 Mont-Saint- TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Aignan (FR). CENTRE HOSPITALIER UNI- VERSITAIRE DE ROUEN [FR/FR]; 76000 Rouen (FR). (84) Designated States (unless otherwise indicated, for every BRISTOL-MYERS SQUIBB COMPANY [US/US]; kind of regional protection available): ARIPO (BW, GH, Route 206 and Province Line Road, Princeton, New Jersey GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 08543 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: LEQUERRE, Thierry; UFR DE MEDECINE DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, ET DE PHARMACIE - INSERM U905 22 boulevard LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Gambetta, 76183 Rouen (FR). VITTECOQ, Olivier; IN SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, SERM 905, Faculte de Medecine-Pharmacie, 22 Boulevard GW, KM, ML, MR, NE, SN, TD, TG). Gambetta, 761 83 Rouen Cedex (FR). DERAMBURE, Celine; INSERM 905, Faculte de Medecine-Pharmacie, 22 Published: Boulevard Gambetta, 76183 Rouen Cedex (FR). GOZ- — with international search report (Art. 21(3)) ARIU LE BARS, Manuela; BMS Rueil Malmaison, 3 rue Joseph Monier, 92500 Rueil-Malmaison Cedex (FR). — with sequence listing part of description (Rule 5.2(a)) TOWNSEND, Robert, Martin; PO Box 4000, Princeton,

o (54) Title: METHODS OF PREDICTING DRUG RESPONSIVENESS OF PATIENTS SUFFERING FROM AUTOIMMUNE IN FLAMMATORY DISEASES

(57) Abstract: The present invention relates to methods of predicting drug responsiveness of patients suffering from autoimmune in flammatory diseases. In particular, the present invention relates to a method of predicting whether a patient suffering from an autoimmune inflammatory disease will achieve a response with an agent that interrupts the T-cell co-stimulatory signal mediated o through the CD28-CD80/CD86 pathway comprising i) determining the expression level of at least one gene selected from the group consisting of RNASE3, BLOC1S1, COX6A1 and PTRH2 ii) comparing the expression level determined at step i) with a predeter mined reference value and iii) concluding that there is probability that the patient will achieve a response when the level determined o at step i) is lower than the predetermined reference value or concluding that there is probability that the patient will not achieve a re - sponse when the level determined at step i) is higher than the predetermined reference value. METHODS OF PREDICTING DRUG RESPONSIVENESS OF PATIENTS SUFFERING FROM AUTOIMMUNE INFLAMMATORY DISEASES

FIELD OF THE INVENTION: The present invention relates to methods of predicting drug responsiveness of patients suffering from autoimmune inflammatory diseases.

BACKGROUND OF THE INVENTION: Inflammatory autoimmune diseases represent a public health major concern. For instance, (RA) is the most common form of inflammatory rheumatism involving small joints which are the seat for swelling and pain with structural damage, responsible for functional disabilities if no treatment is proposed. To avoid joint destruction and disabilities, treatment should aim at reaching a target, such as remission or low disease activity in all patients, suppressing systemic and joint inflammation as soon as possible (1-3). According to the American, European and French recommendations for management of RA, (MTX) should be started first, as soon as a diagnosis of RA is made (1-3). But, despite its potent anti-inflammatory action, with or without corticosteroids, MTX leads to low disease activity states in 25-50% of patients with early RA and to remission states in only 10- 20% of RA patients at 6-12 months (4). Advancement over the last few decades of our understanding of RA pathophysiology has led to the development of new treatments designed to act against a precise therapeutic target. These new molecules called 'biologies' include -alpha (TNFa) blocking agents such as , certolizumab, , and ; an interleukin-1 -receptor antagonist (ILl-Ra, ); an inhibitor of the co-stimulation pathways implicated in T-lymphocyte activation [CTLA4-Ig or (ABA)]; a monoclonal (mAb) binding to CD20 expressed on B cells (); a binding IL-6R () (5). All these agents have proven efficacy in reducing joint inflammation and, thus pain, and limiting or stopping joint destruction in association with the anchor drug MTX (5). After failure of this latter to reach remission, the rheumatologist may add to MTX a biologic such as anti-TNFa, ABA, anakinra or tocilizumab. No one molecule has proven its clinical superiority over the others in terms of efficiency (6-10). Moreover, two head to head studies comparing adalimumab and tocilizumab in monotherapy, and ABA and adalimumab both with MTX, do not reveal any difference in their clinical efficiency and their safety profiles ( 11-13). In addition, no response to these treatments is obtained in approximately -30% of RA patients, and the response to all these is highly variable from one patient to another. This is probably because RA is a syndrome grouping several entities with different pathophysiological mechanisms, with a spectrum ranging from the most 'inflammatory' forms, susceptible of responding to directed against proinflammatory cytokines (anti-TNFa, anti-IL6, etc), to the most 'autoimmune' forms, able to respond better to anti-cellular therapies (rituximab and ABA). Nevertheless, prescription of conventional treatments, and that of biologies agents, remains highly empirical (1-3). Presently, we are still unable to predict the clinical efficacy of these treatments in a given patient because of RA heterogeneity and the existence of subgroups of patients susceptible to respond better to one molecule than another. Given the increasing number of available molecules, such identification of predictive markers represents a major stake in rheumatology in order to optimize their prescription only to those patients susceptible of responding and avoiding side effects. In a context of personalized medicine, large scale analysis of gene expression to predict drug responsiveness is a relevant and original approach which has shown its utility in cancer or kidney transplant (14, 15). Gene expression profiling is clearly a powerful method for biomarker discovery and development of personalized medicine in the field of rheumatology (16-18). This approach has allowed us to identify and validate two gene combinations both associated with MTX, which are able to predict infliximab or anakinra responsiveness but on -small cohorts- of RA patients (19, 20). Even if our results were obtained with small cohorts, the proof of concept of gene expression profile as a predictor of drug responsiveness in RA was further confirmed by an independent team (21). This concept has been consolidated by other teams with other molecules such as tocilizumab, rituximab, adalimumab with cohorts not exceeding 68 RA patients (22-24). The involvement of genes belonging to these signatures is sometimes broken up. Indeed, candidate genes are involved in the signaling pathway and are linked with RA immune processes for tocilizumab or rituximab (22-24). To date, no gene expression profile as biomarker of ABA responsiveness has been published.

SUMMARY OF THE INVENTION: The present invention relates to methods of predicting drug responsiveness of patients suffering from autoimmune inflammatory diseases. In particular, the present invention is defined by the claims. DETAILED DESCRIPTION OF THE INVENTION: One of the major challenges in the management of inflammatory autoimmune diseases such as rheumatoid arthritis (RA) is to identify biomarkers to predict drug responsiveness in a context of personalized medicine. In the present invention, the inventors aimed to identify a gene expression profile predictive of abatacept response in rheumatoid arthritis. From a first subset of 36 RA patients, a combination including 87 transcripts found by microarray study was able to separate almost perfectly responders and non-responders to abatacept. Next, an independent subset of 32 RA patients allowed the inventors to validate a minimal signature with only 4 genes by qRT-PCR. This latter signature classified 81% of RA patients with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders compared to non-responders. Dysregulation of these genes was independent of inflammation and was specific to abatacept response. Pre-silencing of ETC genes is associated with future response to MTX/ABA and might be a crucial key of susceptibility for abatatecp responsiveness. Since abatacept is CTLA4 molecule that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway, the gene signature identified by the inventor could thus be suitable for predicting whether patients suffering from and autoimmune inflammatory disease could achieve a response with those type of drugs. Accordingly, a first object of the present invention relates to a method for predicting whether a patient suffering from an autoimmune inflammatory disease will achieve a response with an agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway comprising i) determining the expression level of at least one gene selected from the group consisting of RNASE3, BLOC1S1, COX6A1 and PTRH2 ii) comparing the expression level determined at step i) with a predetermined reference value and iii) concluding that there is probability that the patient will achieve a response when the level determined at step i) is lower than the predetermined reference value or concluding that there is probability that the patient will not achieve a response when the level determined at step i) is higher than the predetermined reference value. In some embodiments, the patient suffers from an autoimmune inflammatory disease selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic dermatitis, x-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma, systemic scleroderma, sclerosis, systemic sclerosis, multiple sclerosis (MS), spino-optical MS, primary progressive MS (PPMS), relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, and ataxic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, transmural colitis, autoimmune inflammatory bowel disease, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome, adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis, Rasmussen's encephalitis, limbic and/or brainstem encephalitis, uveitis, anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, autoimmune uveitis, glomerulonephritis (GN), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), rapidly progressive GN, allergic conditions, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematodes such as cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), lupus erythematosus disseminatus, lupus (including nephritis, cerebritis, pediatric, non-renal, extra renal, discoid, alopecia), juvenile onset (Type I) diabetes mellitus, including pediatric insulin- dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis, lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large vessel vasculitis, polymyalgia rheumatica, giant cell (Takayasu's) arteritis, medium vessel vasculitis, Kawasaki's disease, polyarteritis nodosa, microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen- antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti- phospholipid antibody syndrome, allergic neuritis, Bechet's or Behcet's disease, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens- Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus, optionally pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus- membrane pemphigoid, pemphigus erythematosus, autoimmune polyendocrinopathies, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathies, chronic neuropathy, IgM polyneuropathies, IgM- mediated neuropathy, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis); subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, allergic encephalomyelitis, experimental allergic encephalomyelitis (EAE), myasthenia gravis, thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis, bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac disease, Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AGED), autoimmune hearing loss, opsoclonus myoclonus syndrome (OMS), polychondritis such as refractory or relapsed polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis, optionally benign monoclonal gammopathy or monoclonal gammopathy of undetermined significance, MGUS, peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressler's syndrome, alopecia greata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, leishmaniasis, trypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post- streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant cell polymyalgia, endocrine ophthamopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired splenic atrophy, infertility due to antispermatozoan antobodies, non-malignant thymoma, vitiligo, SCID and Epstein-Barr virus-associated diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Lesihmania, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Lofiler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, ischemic re-perfusion disorder, reduction in blood pressure response, vascular dysfunction, antgiectasis, tissue injury, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, reperfusion injury of myocardial or other tissues, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, acute serious inflammation, chronic intractable inflammation, pyelitis, pneumonocirrhosis, diabetic retinopathy, diabetic large-artery disorder, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis. As used herein, the term "response" or "responsiveness" refers to an improvement in at least one relevant clinical parameter as compared to an untreated patient diagnosed with the same pathology (e.g., the same type, stage, degree and/or classification of the pathology), or as compared to the clinical parameters of the same patient prior to interferon treatment. In particular, the term "non responder" refers to a patient not experiencing an improvement in at least one of the clinical parameter and is diagnosed with the same condition as an untreated patient diagnosed with the same pathology (e.g., the same type, stage, degree and/or classification of the pathology), or experiencing the clinical parameters of the same patient prior to the treatment. Typically the response is associated with a decrease in the disease activity which can be determined by any conventional method well known in the art. For instance, in rheumatoid arthritis, the disease activity can be measured according to the standards recognized in the art. The "Disease Activity Score" (DAS) is a measure of the activity of rheumatoid arthritis. In Europe the DAS is the recognized standard in research and clinical practice. The following parameters are included in the calculation (Van Gestel AM, Prevoo MLL, van't Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Arthritis Rheum 1996; 39:34- 40): Number of joints tender to the touch (TEN), Number of swollen joints (SW), Erythrocyte sedimentation rate (ESR), Patient assessment of disease activity (VAS; mm). Thus a "responder patient" refers to a patient who shows or will show a clinically significant relief in the disease when treated with the treatment. When the disease is rheumatoid arthritis, typically the response is defined as follows according to the EULAR response criteria: Table A : The EULAR response criteria are defined as follows:

The term "predicting whether a patient will achieve a response", as used herein refers to the determination of the likelihood that the patient will respond either favorably or unfavorably to the treatment. Especially, the term "prediction", as used herein, relates to an individual assessment of any parameter that can be useful in determining the evolution of a patient. As will be understood by those skilled in the art, the prediction of the clinical response to the treatment, although preferred to be, need not be correct for 100% of the patients to be diagnosed or evaluated. The term, however, requires that a statistically significant portion of patients can be identified as having an increased probability of having a positive response. Whether a patient is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John

Wiley & Sons, New York 1983. Preferred confidence intervals are at least 50%, at least 60%>, at least 70%>, at least 80%>, at least 90%> at least 95%. The p-values are, preferably, 0.2, 0.1 or 0.05. The term "blood sample" means any blood sample derived from the patient that contains nucleic. Peripheral blood is preferred, and mononuclear cells (PBMCs) are the preferred cells. The term "PBMC" or "peripheral blood mononuclear cells" or "unfractionated PBMC", as used herein, refers to whole PBMC, i.e. to a population of white blood cells having a round nucleus, which has not been enriched for a given sub-population. Typically, these cells can be extracted from whole blood using Ficoll, a hydrophilic polysaccharide that separates layers of blood, with the PBMC forming a cell ring under a layer of plasma. Additionally, PBMC can be extracted from whole blood using a hypotonic lysis which will preferentially lyse red blood cells. Such procedures are known to the expert in the art. The template nucleic acid need not be purified. Nucleic acids may be extracted from a sample by routine techniques such as those described in Diagnostic Molecular Microbiology: Principles and Applications (Persing et al. (eds), 1993, American Society for Microbiology, Washington D.C.). According to the invention the blood sample is obtained from the patient prior to the treatment. All the genes related to the present invention are known per se, and listed in the below Table A. In the present specification, the name of each of the genes of interest refers to the internationally recognised name of the corresponding gene, as found in internationally recognised gene sequences and protein sequences databases, including in the database from the HUGO Gene Nomenclature Committee, that is available notably at the following Internet address : http://www.gene.ucl.ac.uk/nomenclature/index.html . In the present specification, the name of each of the various biological markers of interest may also refer to the internationally recognised name of the corresponding gene, as found in the internationally recognised gene sequences and protein sequences database Genbank. Through these internationally recognised sequence databases, the nucleic acid and the amino acid sequences corresponding to each of the biological marker of interest described herein may be retrieved by the one skilled in the art. Table B : genes of the present invention.

In some embodiments, the expression of at least 1, 2, 3, 4, or more genes are determined in the blood sample obtained from the patient. In some embodiments, the method of the present invention comprises determining the expression levels of RNASE3, BLOC IS1, COX6A1 and PTRH2 are determined in the blood sample obtained from the patient. Methods for determining the expression level of a gene are well known in the art. The nucleic acid sample used for detecting the target sequence may be a DNA sample or an R A sample. The latter may be preliminarily converted into cDNA before proceeding with said detection. Conventional methods typically involve polymerase chain reaction (PCR). For instance, U.S. Pat. Nos. 4,683,202, 4,683,195, 4,800,159, and 4,965,188 disclose conventional PCR techniques. PCR typically employs two oligonucleotide primers that bind to a selected target nucleic acid sequence. Primers useful in the present invention include oligonucleotides capable of acting as a point of initiation of nucleic acid synthesis within the target nucleic acid sequence. A primer can be purified from a restriction digest by conventional methods, or it can be produced synthetically. If the template nucleic acid is double-stranded (e.g. DNA), it is necessary to separate the two strands before it can be used as a template in PCR. Strand separation can be accomplished by any suitable denaturing method including physical, chemical or enzymatic means. One method of separating the nucleic acid strands involves heating the nucleic acid until it is predominately denatured (e.g., greater than 50%, 60%, 70%>,

80% , 90%o or 95% denatured). The heating conditions necessary for denaturing template nucleic acid will depend, e.g., on the buffer salt concentration and the length and nucleotide composition of the nucleic acids being denatured, but typically range from about 90°C to about 105°C for a time depending on features of the reaction such as temperature and the nucleic acid length. Denaturation is typically performed for about 30 sec to 4 min (e.g., 1 min to 2 min 30 sec, or 1.5 min). If the double-stranded template nucleic acid is denatured by heat, the reaction mixture is allowed to cool to a temperature that promotes annealing of each primer to its target sequence on the target nucleic acid sequence. The temperature for annealing is usually from about 35°C to about 65°C (e.g., about 40°C to about 60°C; about 45°C to about 50°C). Annealing times can be from about 10 sec to about 1 min (e.g., about 20 sec to about 50 sec; about 30 sec to about 40 sec). The reaction mixture is then adjusted to a temperature at which the activity of the polymerase is promoted or optimized, i.e., a temperature sufficient for extension to occur from the annealed primer to generate products complementary to the template nucleic acid. The temperature should be sufficient to synthesize an extension product from each primer that is annealed to a nucleic acid template, but should not be so high as to denature an extension product from its complementary template (e.g., the temperature for extension generally ranges from about 40°C to about 80°C (e.g., about 50°C to about 70°C; about 60°C). Extension times can be from about 10 sec to about 5 min (e.g., about 30 sec to about 4 min; about 1 min to about 3 min; about 1 min 30 sec to about 2 min). Examples of primers that could be suitable for determining the expression level of the genes related to the invention are described in the EXAMPLE. PCR involves use of a thermostable polymerase. The term "thermostable polymerase" refers to a polymerase enzyme that is heat stable, i.e., the enzyme catalyzes the formation of primer extension products complementary to a template and does not irreversibly denature when subjected to the elevated temperatures for the time necessary to effect denaturation of double-stranded template nucleic acids. Generally, the synthesis is initiated at the 3' end of each primer and proceeds in the ' to 3 direction along the template strand. Thermostable polymerases have been isolated from Thermus fiavus, T. ruber, T. thermophilus, T. aquaticus, T. lacteus, T. rubens, Bacillus stearothermophilus, and Methanothermus fervidus. Nonetheless, polymerases that are not thermostable also can be employed in PCR assays provided the enzyme is replenished. Typically, the polymerase is a Taq polymerase (i.e. Thermus aquaticus polymerase). The primers are combined with PCR reagents under reaction conditions that induce primer extension. Typically, chain extension reactions generally include 50 mM KC1, 10 mM

Tris-HCl (pH 8.3), 15 mM MgC12, 0.001% (w/v) gelatin, 0.5-1.0 µg denatured template DNA, 50 pmoles of each oligonucleotide primer, 2.5 U of Taq polymerase, and 10% DMSO. The reactions usually contain 150 to 320 µΜ each of dATP, dCTP, dTTP, dGTP, or one or more analogs thereof. Quantitative PCR is typically carried out in a thermal cycler with the capacity to illuminate each sample with a beam of light of a specified wavelength and detect the fluorescence emitted by the excited fluorophore. The thermal cycler is also able to rapidly heat and chill samples, thereby taking advantage of the physicochemical properties of the nucleic acids and thermal polymerase. In order to detect and measure the amount of amplicon (i.e. amplified target nucleic acid sequence) in the sample, a measurable signal has to be generated, which is proportional to the amount of amplified product. All current detection systems use fluorescent technologies. Some of them are non-specific techniques, and consequently only allow the detection of one target at a time. Alternatively, specific detection chemistries can distinguish between non- specific amplification and target amplification. These specific techniques can be used to multiplex the assay, i.e. detecting several different targets in the same assay. For example, SYBR® Green I probes, High Resolution Melting probes, TaqMan® probes, LNA® probes and Molecular Beacon probes can be suitable. TaqMan® probes are the most widely used type of probes. They were developed by Roche (Basel, Switzerland) and ABI (Foster City, USA) from an assay that originally used a radio-labelled probe (Holland et al. 1991), which consisted of a single- stranded probe sequence that was complementary to one of the strands of the amplicon. A fluorophore is attached to the 5' end of the probe and a quencher to the 3' end. The fluorophore is excited by the machine and passes its energy, via FRET (Fluorescence Resonance Energy Transfer) to the quencher. Traditionally, the FRET pair has been conjugated to FAM as the fluorophore and TAMRA as the quencher. In a well-designed probe, FAM does not fluoresce as it passes its energy onto TAMRA. As TAMRA fluorescence is detected at a different wavelength to FAM, the background level of FAM is low. The probe binds to the amplicon during each annealing step of the PCR. When the Taq polymerase extends from the primer which is bound to the amplicon, it displaces the 5' end of the probe, which is then degraded by the 5'-3' exonuclease activity of the Taq polymerase. Cleavage continues until the remaining probe melts off the amplicon. This process releases the fluorophore and quencher into solution, spatially separating them (compared to when they were held together by the probe). This leads to an irreversible increase in fluorescence from the FAM and a decrease in the TAMRA. In some embodiments, the predetermined reference value is a threshold value or a cut off value. Typically, a "threshold value" or "cut-off value" can be determined experimentally, empirically, or theoretically. A threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. For example, retrospective measurement of expression level of the gene in properly banked historical patient samples may be used in establishing the predetermined reference value. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative). Typically, the optimal sensitivity and specificity (and so the threshold value) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data. For example, after determining the level of the marker in a group of reference, one can use algorithmic analysis for the statistic treatment of the measured levels of the marker in samples to be tested, and thus obtain a classification standard having significance for sample classification. The full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests. ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate ( 1-specificity). It reveals the relationship between sensitivity and specificity with the image composition method. A series of different cut-off values (thresholds or critical values, boundary values between normal and abnormal results of diagnostic test) are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis. On the ROC curve, the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values. The AUC value of the ROC curve is between 1.0 and 0.5. When AUO0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate. When AUC is higher than 0.9, the accuracy is quite high. This algorithmic method is preferably done with a computer. Existing software or systems in the art may be used for the drawing of the ROC curve, such as: MedCalc 9.2.0.1 medical statistical software, SPSS 9.0, ROCPO WER. SAS, DESIGNROC.FOR, MULTIREADER POWER.SAS, CREATE-

ROC.SAS, GB STAT VIO.O (Dynamic Microsystems, Inc. Silver Spring, Md., USA), etc. In some embodiments, when the expression level of more than one gene is determined in the blood sample obtained from the patient, a score which is composite of said expression levels may be calculated and compared with a predetermined reference value, wherein when the score is higher than the predetermined reference value it is concluded that the patient will achieve a response. As used herein the term "agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway" refers to any molecule that e.g. binds with CD80, CD86, or CD28 providing inhibition of CD28 co-stimulation in the T cells of the patient. CD28 is a molecule expressed on T cells that provides co-stimulatory signals needed for activation. CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2). The agent of the present invention aims at inhibiting naive T-cell activation, thus having the potential to selectively inhibit T-cell response to specific antigens instead of broad . Effector-memory T-cell responses are less dependent on CD28 co-stimulation and, presumably, are less inhibited by co-stimulation blockade. (Lo DJ, Weaver TA, Stempora L, et al. Am J Transplant 201 1 ; 11: 22—33.) Studies in both animals and human beings have shown that interruption of the co- stimulatory second signal beneficially affects autoimmunity. Typically, the agent of the present invention is a small organic molecule, a recombinant polypeptide or an antibody (e.g. an antibody having specificity for CD28, C80 or CD86). In some embodiments, the agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway is a CTLA-4 molecule. As used herein the term "CTLA4" has its general meaning in the art and refers to the cytotoxic T-lymphocyte-associated antigen 4. CTLA4 which is also known as CD 152, is a protein involved in the regulation of the immune system. Naturally occurring CTLA4 is described in U.S. Pat. Nos. 5,434,131 , 5,844,095, and 5,851 ,795. An exemplary human amino acid sequence is represented by SEQ ID NO:l. Natural CTLA4 proteins are encoded by the CTLA4 gene. CTLA4 is a cell surface protein, having an N-terminal extracellular domain, a transmembrane domain, and a C-terminal cytoplasmic domain. The extracellular domain binds to and/or interferes with target antigens, such as CD80 and CD86, serves as nature natural break of T cell stimulation. The extracellular domain of the CTLA4 molecule begins with methionine at position + 1 and ends at aspartic acid at position +124. SEQ ID NO:l: CTLA-4_homo sapiens MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAAT MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYL GIGNGTQIYVIDPEPCPD SDFLLWILAAVSSGLFFYSFLLTAVSLSKMLKKRSPL TTGVYVKMPPTEPECEKQFQPYFIPIN As used herein the term "CTLA4 molecule" refers to a molecule comprising a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) extracellular domain. In some embodiments, the extracellular domain of CTLA4 comprises a portion of the CTLA4 protein that recognizes and binds to at least one B7 (CD80/86) antigen such as a B7 antigen expressed on B cells and on antigen presenting cells (APCs). The extracellular domain may also include fragments or derivatives of CTLA4 that bind a B7 antigen. The CTLA4 extracellular domain can also recognize and bind CD80 and/or CD86. The extracellular domain may also include fragments or derivatives of CTLA4 that bind a binds CD80 and/or CD86. In some embodiments, the CTLA4 molecule of the present invention is a recombinant , where a fusion protein is defined as one or more amino acid sequences joined together using methods well known in the art. In some embodiments, the CTLA4 molecule contains at least a portion of an immunoglobulin, such as the Fc portion of an immunoglobulin. Conventionally said type of fusion proteins are designated "immunoadhesin". In some embodiments, the immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM. In some embodiments, the immunoglobulin sequence is an immunoglobulin constant domain (Fc region). Immunoadhesins can possess many of the valuable chemical and biological properties of human . Since immunoadhesins can be constructed from a human protein sequence with a desired specificity linked to an appropriate human immunoglobulin hinge and constant domain (Fc) sequence, the binding specificity of interest can be achieved using entirely human components. Such immunoadhesins are minimally immunogenic to the patient, and are safe for chronic or repeated use. The artisan skilled in the art can easily select the most appropriate Fc domain (Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol. 2010 May;10(5):301-16. doi: 10.1038/nri2761. Review.). In some embodiments, the Fc region includes or not a mutation that inhibits complement fixation and/or Fc receptor binding (Zheng et al, Transplantation. 2006 Jan 15;81(1):109-16). In some embodiments, the Fc region is a native sequence Fc region. In some embodiments, the Fc region is a variant Fc region. In some embodiments, the Fc region is a functional Fc region. As used herein, the term "Fc region" is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. In some embodiments, the adhesion portion and the immunoglobulin sequence portion of the immunoadhesin are linked by a minimal linker. In some embodiments, the CTLA4 molecule is abatacept. Abatacept is a soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin Gl (IgG 1). Abatacept is produced by recombinant DNAtechnology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. Abatacept was developed by Bristol-Myers Squibb and is disclosed, for example, in U.S. Pat. 5,851 ,795, U.S. Pat. 7,455,835, and EP1962886. The amino acid sequence of abatacept is represented by SEQ ID NO:2. SEQ ID NO:2: Abatacept MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATY MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYL GIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK In some embodiments, the CTLA molecule is that is the result of altering two amino acids in the CD80/86 binding portion of the abatacept compound (L104E and A29Y). This slight change in chemistry resulted in a 10-fold increase in the ability to inhibit T-cell activation when compared in vitro. Belatacept (L104EA29YIg) is the first biologic agent approved for primary maintenance immunosuppression, selectively blocking the CD28 co-stimulation pathway to prevent T-cell activation (Larsen, CP. et al, Am. J. Transplant., 5:443-453 (2005)). The amino acid sequence of belatacept is represented by SEQ ID NO:3. SEQ ID NO:3: Belatacept MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATY MMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYE GIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK In some embodiments, the CTLA4 molecule is MAXY-4, which is also a protein derived from abatacept but having increased binding to CTLA4 targets, ant that is currently in preclinical development by Perseid Therapeutics, LLC and Astellas Pharma, Inc. for treatment of autoimmune diseases and transplant rejection. In some embodiments, the agent of the present invention is administered in combination with another drug. For instance, the agent may be administered in combination with methotrexate. As used herein, the term "methotrexate" is synonymous with "MTX" and means a molecule that includes, in part, a 2,4-diamino substituted pterine ring moiety linked at the 6 position to the amino group of a p-aminobenzoyl moiety, the p-aminobenzoyl moiety having a methylated amino group and linked to a glutamic acid moiety through an amide bond. Methotrexate functions as an inhibitor of dihydrofolate reductase (DHFR), decreasing the production of tetrahydrofolate (THF) from dihydrofolate (DHF). As a consequence, methotrexate indirectly inhibits purine and thymidine synthesis and amino acid interconversion. Methotrexate also exhibits anti-proliferative activity through inhibition of thymidylate synthesis, which is required for production of DNA (Calvert, Semin. Oncol. 26:3- 10 (1999)). A further object of the present invention relates to a method of treating an inflammatory autoimmune disease in a patient in need thereof comprising i) predicting whether the patient will achieve a response with an agent that interrupts the T-cell co- stimulatory signal mediated through the CD28-CD80/CD86 pathway ii) and administering the agent when it is concluded that there is probability that the patient will achieve a response. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). In some embodiments, when is concluded that there is a probability that the patient will not achieve a response, the patient can then be administered with another treatment. In some embodiments, said treatment may consist in a TNFa-blocking agent. By "TNFa- blocking agent" or "TBA", it is herein meant a biological agent which is capable of neutralizing the effects of TNFa. Said agent is a preferentially a protein such as a soluble TNFa receptor, e.g. Pegsunercept, or an antibody. In some embodiments, the TBA is a monoclonal antibody. In some embodiments, the TBA is selected in the group consisting of Etanercept (Enbrel®), Infliximab (Remicade®), Adalimumab (Humira®), (Cimzia®), and golimumab (Simponi®). In some embodiments, the patient is adminitsed with another anti-inflammatory biological drug. By "anti-inflammatory biological drug", it is herein meant a biological agent (typically a recombinant protein, including recombinant antibodies) with anti-inflammatory properties. This includes drugs directed to inflammatory cytokines such as IL-lbeta, IL-6, IL-15, IL-17, IL-18, and IL-23 (in particular TBAs) or to a receptor of such inflammatory cytokines (e.g. IL-IRa such as anakinra or IL- 6R such as tocilizumab). This also notably includes the following biological agents (preferably recombinant proteins, including recombinant antibodies). In some embodiments, the patient can also be administered with an agent capable of depleting the B cells such as anti-CD20 antibodies (e.g. rituximab (Rituxan®)). Typically, the agents of the present invention are administered to the patient in the form of pharmaceutical compositions. The pharmaceutical composition as provided herewith may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of provided herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. [0054] The compounds described herein including pharmaceutically acceptable carriers can be delivered to a patient using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

FIGURES: Figure 1: Ancillary study design from the APPRAISE trial. Of 104 RA patients enrolled in the APPRAISE trial, 68 were included in our ancillary study after discarding patients with missing data or poor quality R A samples. Among them, two subsets of RA patients -one for discovery and one for validation- were designated. The first step of this ancillary study was to identify clinical parameters to predict MTX/ABA response. The second step was to identify gene combination able to predict MTX/ABA response. To perform that, a first subset of 36 RA patients was used to identify clinical parameters or genes combination to predict drug responsiveness. Next, the second subset including 32 RA patients was used to validate these clinical parameters or genes combination. Figure 2 : Incapacity of clinical and biological parameters to predict methotrexate/abatacept response. Two independent statistical methods were performed to identify parameters to predict drug responsiveness with subset 1. Next, the prediction efficiency of these parameters was checked with subset 2. A : In subset 1, 4 variables were selected by logistic regression: C-reactive protein (CRP), tender joint count, methotrexate dose and disease duration. In subset 2, these 4 variables allowed good classification of 12 out of 19 responders (R) and 6 out of 13 non-responders (NR). A total of 14 patients out of 32 were misclassified. B : In subset 1, linear discriminant analysis was performed to balance each parameter by coefficient of linear discriminant analysis calculation. In subset 2, these data allowed good classification 13 out of 19 R and 6 out of 13 NR. A total of 13 patients out of 32 were misclassified. DAS28: disease activity score 28. CRP: C reactive protein. Sen: sensibility; Spe: specificity; PPV: positive predictive value; NPV: negative predictive value.

EXAMPLE: Material & Methods Patients A total of 68 RA patients from the APPRAISE trial (25) were enrolled in this ancillary study. The APPRAISE study assessed the capability of the composite power of Doppler and gray-scale ultrasound score to measure the early effect and time-course of response to treatment with abatacept in biologic-naive patients with active RA despite MTX therapy (25). APPRAISE (NCT00767325) including initially 104 RA patients was a 24-weeks, Phase Illb, open-label, multicentre, single-arm study conducted at 2 1 sites across Europe (Denmark, France, Germany, Hungary, Italy, Norway, Spain and the UK) (25). Eligible patients were >18 years of age, had American College of Rheumatology (ACR)-defined RA according to the 1987 classification criteria for at least 6 months (47), and on MTX (>15 mg/week) for at least 3 months prior to baseline, with a stable MTX dose for at least 28 days before baseline (except in cases of intolerance to MTX). Patients were required to have active disease, defined by a baseline DAS28(CRP) score of >3.2 or tender and swollen joint counts of >6 and a CRP level greater than the upper limit of normal. All patients received intravenous (IV) infusions of ABA at a weight-titered dose of 10 mg/kg at baseline (day 1), and at weeks 2, 4, 8, 12, 16, 20 and 24, in addition to stable doses of concomitant MTX (>15 mg/week). MTX dose increases were not permitted, and dose decreases were allowed only in cases of intolerance. Oral corticosteroid use (stable dose of <10 mg prednisone/day) was permitted during the study. For this study, 5 ml of whole blood were collected in PAXgene RNA tube (PreAnalytiX, Qiagen) just before the first infusion and 6 months later and stored at -80°C until use. Clinical evaluation and response to MTX ABA Several clinical characteristics were collected at baseline and 6 months later: age, gender, disease duration, MTX and corticosteroid doses. Disease activity was evaluated at all efficacy assessment visits (baseline, weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24) using DAS28(CRP) calculated from 28 tender joints, 28 swollen joints, CRP and patient global assessment (VAS; 0-10 scale). The response to MTX/ABA was evaluated at 6 months with the EULAR response criteria based on DAS28(CRP) (48). These patients were classified according to their response as R (good responders from EULAR criteria) or NR (moderate responders and no responders from EULAR criteria) (48). The study was approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC) and local ethics committees, and was conducted in accordance with the ethical principles underlying the European Union Directive 2001/20/EC and the United States Code of Federal Regulations on Good Clinical Practice, as defined by the International Conference on Harmonisation. All patients provided written informed consent. RNA preparation Total RNAs from whole blood were extracted with PAXgene blood RNA according to the manufacturer's recommendations (Qiagen PreAnalytiX GmbH, Courtaboeuf, France) and stored at -80°C until use. Total RNA from 10 healthy donors (5 women and 5 men) were pooled and were used as an internal standard reference. The quality and quantity of isolated mRNAs were assessed using the 2100 Bioanalyzer (Agilent Technologies, Santa Clara, California, USA) and the Nanodrop (Thermo Scientific, Wilmington, USA). Only RNA samples with a minimal RNA integrity number of 7 were used for subsequent experiments. Microarrays Whole human genomic DNA microarrays were used to analyze two-colored gene expression profiling (4x44K Whole Human Genome, Agilent Technologies). Each RA patient was labeled by Cyanine-5 and co-hybridized with a Cyanine-3 labeled RNA control pool according to the manufacturer's instructions (Low Input QuickAmp Labeling Kit, Agilent Technologies). Briefly, 100 ng of RNAs were labeled with cyanine-5 CTP (RA patients) or cyanine-3 CTP (control pool). Co-hybridization was performed at 65°C for 17 hours using a hybridization kit (Agilent Technologies). After wash steps, the microarrays were scanned with a 5µΜ pixel size using the DNA Microarray Scanner GB (Agilent Technologies). Image analysis and extraction of raw and normalized signal intensities (Lowess) were performed with Feature Extraction Software 10.5.1.1 (Agilent Technologies). The data were in agreement with the Minimum Information About a Microarray Experiment guidelines and were deposited in the National Center for Biotechnology Information's Gene Expression Omnibus. The data are accessible using the following accession number: GSE68215. N on uniform spots and saturated spots or spots with intensities below the background were not taken into account. Only spots, which passed these quality controls on 100% of arrays, were selected for further analysis. Hierarchical clustering was performed with Pearson coefficient metric and complete linkage to build the transcripts and sample dendrograms. Quantitative reverse transcription-PCR (qRT-PCR) cDNA was synthesized from 1µg RNA samples using random primers and M-MLV enzyme (InvitrogenTM, Carlsbad, USA). qRT-PCR was performed using a Lightcycler as instructed by the manufacturer (RocheTM, Meylan, France). qRT-PCR reactions for each sample were performed in duplicate using SYBR-Green (RocheTM, Meylan, France) and values were normalized using geometric mean of three control genes (18S, ACTB, B2M) defined by geNorm algorithm (49). Sequences of primers (EurogentecTM, Fremont, USA) used for qRT-PCR were: BLOC1S1 forward, 5'-AAGC AGACAGGCCAGTGGAT-3 ' ; BLOC1S1 reverse, 5'-CAGTGCAGTGGC AATGGTG-3 '; RNASE3 forward, 5'- CAGGAGCC ACAGCTCAGAGA-3 '; RNASE3 reverse, 5'- GAGCCCTCCACACCCATAAG-3'; COX6A1 forward, 5'- CCACTTCCAACTGGCTACGA-3'; COX6A1 reverse, 5'- AAGCAAAGGGATGGGAGACC-3 '; PTRH2 forward, 5'-GCTGTTGGAGTTGCTTGTGG- 3'; PTRH2 reverse, 5'-AGGCTGAAACAGCAGCATGA-3 '; 18S forward, 5'- GTGGAGCGATTTGTCTGGTT-3 '; 18S reverse, 5'-CGCTGAGCCAGTCAGTGTAG-3 ' ; ACTB forward, 5'-CTGGAACGGTGAAGGTGACA-3 '; ACTB reverse, 5'- AAGGGACTTCCTGTAAC AATGCA-3 '; B2M forward, 5'- TGCTGTCTCCATGTTTGATGTATCT-3 '; B2M reverse, 5'- TCTCTGCTCCCCACCTCTAAGT-3 ' . Statistical and functional analysis Comparisons of clinical and biological data between R and NR at baseline were performed using Student's t-test for continuous variables. Comparisons of R or NR before and after treatment were performed with paired t-test. Identification of clinical parameters able to predict MTX/ABA responsiveness was performed with two different multivariate analyses: i) a logistic regression model with variable selection using Bayesian information criterion (BIC); ii) a linear discriminant analysis (LDA) which estimates a coefficient for each variable. Data from transcriptomic analysis were analyzed with GeneSpring GX V.13.0 (Agilent Technologies). Unpaired Student's t-test (p value < 0.05) with Benjamini Hochberg correction to check the False Discovery Rate (FDR) were used to determine the statistical significance in gene expression levels between R and NR. The GO analysis was used to investigate the biological processes, molecular function or cellular localization enriched in the transcripts list showing a significant gene expression fluctuation between R and NR. P value was computed by standard hypergeometric distribution. The GeneSpring Single Experiment Analysis (SEA) bio-informatics tool was used for computational analysis to identify potential curated canonical pathways which are enriched in the differentially expressed transcripts list, using WikiPathways database (http://www.wikipathways.org). The significance of the association between the genes and the pathways was measured by Fisher's exact test.

Results Characteristics of RA patients and their response to MTX/ABA Of the 104 RA patients included in the APPRAISE trial (25), clinical and biological data for subsequent analysis were available for 9 1 patients. Sixty-eight of whom were recruited to this present ancillary study based on RNA quality of samples (Fig.l). These 68 RA patients were split into two subsets at random: subset 1 (n=36) for the discovery of clinical or biological (including transcripts) markers associated with MTX/ABA responsiveness; subset 2 (n=32) for the validation of gene expression profile able to predict MTX/ABA responsiveness (Fig.l). After 6 months of treatment, RA patients were categorized according to their response (EULAR criteria) as responders (R: n=17 and 19 respectively in subsets 1 and 2) and non-responders (NR: n=19 and 13 respectively in subsets 1 and 2). Table 1 provides demographic and clinical information for these 68 RA patients at baseline and after 6 months of treatment. Table 1: Clinical and biological parameters of RA patients. Clinical and biological variables were collected before treatment and 6 months later. Response to methotrexate/abatacept was assessed by disease activity score 28 (DAS28) calculated with C reactive protein (CRP) at 6 months of treatment. Patients are categorized as indicated in material and methods. Values of parameters are expressed as mean ± standard error of the mean. Stars indicate significant comparisons between responders (R) and non-responders (NR) at baseline (* p<0.05; ** p<0.01). Dollars indicate significant comparisons in responders between baseline and 6 months ($$$ p<0.001). Pounds indicate significant comparisons in non-responders between baseline and 6 months (££ p<0.01; £££ p<0.001). All other comparisons are not significant. P values were determined by Student's t-test or paired t-test according to the comparisons. VAS: visual analog scale. The baseline characteristics of RA patients from subset 1 and 2 were comparable for all parameters suggesting absence of bias in randomization (Table 1). Whatever the subset, tender joint count (TJC), swollen joint count, global assessment of disease measured by the patient with visual analog scale (VAS), C reactive protein and disease activity score (DAS28- CRP) improved significantly after 6 months of treatment in R and in NR. The range of improvement was significantly higher in R than in NR for each parameter except global VAS and CRP (Table 1). In each subset, the comparison of clinical and biological parameters between R and NR showed statistical differences at baseline. Indeed, disease duration was longer in NR than in R (p<0.01) (Table 1). DAS28, patient assessment of disease and CRP were higher in NR than in R (p<0.05). These comparisons showed better response in RA patients with short disease duration and moderate disease activity. These observations raise the question of using clinical and biological parameters as predictors of responsiveness. Clinical and biological parameters not associated with MTX/ABA responsiveness Identification of clinical and/or biological parameters as predictors of responsiveness was performed by two different multivariate statistical approaches such as logistic regression and linear discriminant analysis. Logistic regression using more pertinent parameters such as MTX, TJC, disease duration and CRP identified in subset 1 did not allow us to predict accurately R or NR to MTX/ABA in subset 2 (sensitivity = 63%; specificity = 46%) (Fig.2A). Linear discriminant analysis which balanced each biological and clinical parameters was equally unable to predict effectively MTX/ABA responsiveness in subset 2 (sensitivity = 68%; specificity = 46%) (Fig.2B). In clinical practice, even if some individual parameters differed between R and NR at baseline, the rheumatologist did not use them to predict response to MTX/ABA 6 months later for a given RA patient. These observations lead us to identify predictors with another approach based on microarrays. Gene expression profiling to predict MTX/ABA responsiveness

With subset 1, the cRNA from 17 R and 19 NR were co-hybridized with a cRNA internal reference from 10 healthy subjects on whole human genome microarrays, by two color technology. After elimination of spikes and flagged probes, 19,620 probes were detected in all samples. From these 19,620 transcripts, we next identified 87 transcripts with statistically significant variation between R and NR according to a t-test with correction for multiple testing [false discovery rate (FDR), Benjamini Hochberg correction]. These transcripts are listed in Table 2 (69 transcripts are referenced with a Ref Seq accession number while 18 probes were unknown) (Table 2). Table 2 : List of transcripts differentially expressed in MTX/ABA responders (R) vs non-responders (NR). Only Agilent's probes with accession number (RefSeqAcc) are reported in this Table (69 out of 87 transcripts). Fold change (FC) is the ratio of relative abundance of transcripts in NR versus R. Positive FC means an up-regulation of the corresponding transcript in NR patients and conversely. P values were determined by t-test with Benjamini-Hochberg correction for false discovery rate estimation (p< 0.05).

Agilent probe P Gene FC GeneName RefSeqAcc ID (Corr) Symbol A_23_P 163025 0.00001 2.36 RNASE3 ribonuclease, RNase A family, 3 NM_002935 ribonuclease, RNase A family, 2 A_32_P1712 0.00001 2.39 RNASE2 (liver, eosinophil-derived neurotoxin) NM_002934 ribonuclease, RNase A family, 2 A_23_P151637 0.00003 2.44 RNASE2 (liver, eosinophil-derived neurotoxin) NM_002934 interferon, alpha-inducible A 24 P261929 0.019 1.43 IFI27L1 protein 27-like 1 NM_206949 ER membrane protein complex A_23_P78134 0.022 1.24 EMC6 subunit 6 NM_001 014764 heat shock factor binding A_23_P328511 0.022 1.40 HSBP1 protein 1 NM_001537 A_23_P78563 0.022 1.43 UBL5 ubiquitin-like 5 NM_024292 biogenesis of lysosomal A_23_P53298 0.022 1.48 BLOC1S1 organelles complex- 1, subunit 1 NM_001487 ribonuclease, RNase A family, 2 A_23_P4 17632 0.022 1.94 ECRP pseudogene NR_033909 membrane-spanning 4-domains, A_23_P75769 0.025 2.17 MS4A4A subfamily A, member 4A NM_024021 guanylate binding protein A_23_P 130642 0.027 GBP6 1.24 family, member 6 NM_1 98460 zinc finger, CCHC domain A_24_P88505 0.027 1.44 ZCCHC17 containing 17 NM_0 16505 LSM LSM1, U6 small nuclear RNA A_23_P20384 0.027 1.45 associated NM_0 14462 1 A_23_P76488 0.028 1.93 EMP1 epithelial membrane protein 1 NM_001423 N(alpha)-acetyltransferase 38, A_23_P358555 0.030 1.31 NAA38 NatC auxiliary subunit NM_032356

A_23_P209347 0.030 ANKRD44 ankyrin repeat domain 44 1.36 NM_1 53697 proteasome (prosome, A_23_P25735 0.030 1.56 PSMA6 macropain) subunit, alpha type, 6 NM_002791 cytochrome c oxidase subunit A 23 P81690 0.030 1.59 COX7A2 Vila polypeptide 2 (liver) NM_001865 NADH dehydrogenase A_32_P98313 0.030 1.79 NDUFA4 (ubiquinone) 1 alpha subcomplex, 4, 9kDa NM_002489

A_23_P52647 0.031 EHD1 EH-domain containing 1 1.27 NM_006795 ATP synthase, H+ transporting, A_23_P1 54832 0.031 1.47 ATP5J mitochondrial Fo complex, subunit F6 NM_00 1003703 vesicle transport through A_23_P425932 0.032 VTHA 1.27 interaction with t-SNAREs 1A XM_005269544 cytochrome c oxidase subunit A_32_P1 68247 0.032 1.34 COX6A1 Via polypeptide 1 NM_004373 A_23_P 15493 0.032 1.21 PTRH2 peptidyl-tRNA hydrolase 2 NM_0 16077 translocase of inner A_23_P98382 0.032 1.66 TIMM8B mitochondrial membrane 8 homolog B (yeast) NM_0 12459

A_23_P74114 0.034 ZNF713 zinc finger protein 713 1.22 NM_1 82633 interferon, alpha-inducible A 23 P140146 0.034 1.47 IFI27L2 protein 27-like 2 NM_032036 cytochrome c oxidase subunit A_23_P1 59650 0.035 2.01 COX7B Vllb NM_001866 glutathione S-transferase omega A_23_P1254 0.036 1.35 GSTOl 1 NM_004832

A_24_P1 13815 0.036 - SLC35E2 solute carrier family 35, member NM_1 82838 1.36 E2 neutral cholesterol ester A_23_P1 32644 0.036 1.40 NCEH1 hydrolase 1 NM_020792 A 23 P41114 0.036 2.08 CSTA cystatin A (stefin A) NM_005213 A_32_P131377 0.037 1.26 REEP5 receptor accessory protein 5 NM_005669 DCN1, defective in cullin

A_23_P127533 0.037 1.39 DCUN1D5 neddylation 1, domain containing 5 NM_032299 A_24_P1 86379 0.037 1.34 FUOM fucose mutarotase NM_1 98472 NADH dehydrogenase A_23_P145777 0.038 1.76 NDUFA4 (ubiquinone) 1 alpha subcomplex, 4, 9kDa NM_002489 proteasome (prosome, A_32_P43217 0.038 1.52 PSMA6 macropain) subunit, alpha type, 6 NM_002791 ubiquinol-cytochrome c A_23_P213718 0.038 1.77 UQCRQ reductase, complexIII NM_0 14402 glutathione S-transferase omega A_24_P3 04051 0.039 1.35 GSTOl 1 NM_004832

A_23_P 170233 0.039 1.91 CSTA cystatin A (stefin A) NM_005213 fatty acid binding protein 5 A_23_P59877 0.039 1.49 FABP5 (psoriasis-associated) NM_001444 transcriptional regulating factor A_23_P59022 0.040 TRERF1 1.20 1 NM_033502 Ras association (RalGDS/AF-6) A_23_P201497 0.040 RASSF5 1.43 domain family member 5 NM_1 82663 enhancer of rudimentary A_23_P128734 0.040 1.47 ERH homolog (Drosophila) NM_004450 A_32_P205553 0.040 1.51 RPL26L1 ribosomal protein L26-like 1 NM_0 16093 thioredoxin domain containing A_23_P3 80848 0.040 1.54 TXNDC17 17 NM_032731 myosin, light chain 6, alkali, A_23_P344973 0.040 1.55 MYL6 smooth muscle and non-muscle NM_079423 A_23_P326080 0.040 4.47 DEFA4 defensin, alpha 4, corticostatin NM_001925

A_23_P26413 0.040 RBL2 retinoblastoma-like 2 1.32 NM_005611 nuclear pore complex interacting A_32_P1 87827 0.040 NPIPB9 1.38 protein family, member B9 NM_00 1287251 A 23 P79199 0.040 1.64 DBI diazepam binding inhibitor NM_020548 A 23 P114929 0.041 1.18 MPC2 mitochondrial pyruvate carrier 2 NM_015415 eukaryotic translation initiation A_23_P 127467 0.041 1.22 EIF1AD factor 1A domain containing NM_032325 malignant T cell amplified A_23_P1 14282 0.041 1.47 MCTS1 sequence 1 NM_0 14060 calcium channel, voltage- A_23_P353014 0.041 1.37 CACNA2D4 dependent, alpha 2/delta subunit 4 NM_1 72364 coiled-coil-helix-coiled-coil- A_23_P371613 0.041 1.32 CHCHD1 helix domain containing 1 NM_203298 carcinoembryonic antigen- A_23_P3 80240 0.041 3.85 CEACAM8 related cell adhesion molecule 8 NM_001816 RAB32, member RAS oncogene A_23_P42375 0.043 1.26 RAB32 family NM_006834 proteasome (prosome, A_23_P15705 0.043 1.32 PSMB6 macropain) subunit, beta type, 6 NM_002798 A_23_P71148 0.044 1.42 BLVRA biliverdin reductase A NM_000712 NADH dehydrogenase A_24_P23245 0.044 1.57 NDUFA6 (ubiquinone) 1 alpha subcomplex, 6, 14kDa NM_002490 A_23_P54179 0.045 1.15 ZNF410 zinc finger protein 410 NM_021188 A_23_P1 03282 0.048 1.22 TMEM59 transmembrane protein 59 NM_004872 CTBP1 antisense RNA 2 (head A_23_P7087 0.048 CTBP1-AS2 1.14 to head) NR_033339 calmodulin 2 (phosphorylase A_23_P326170 0.048 1.28 CALM2 kinase, delta) NM_001743 TAF12 RNA polymerase II, A_23_P63178 0.049 1.26 TAF12 TATA box binding protein (TBP)-associated factor NM_005644 A_23_P7697 0.049 1.28 SNX2 sorting nexin 2 NM_003100

A_23_P97005 0.049 JAK1 1 1.42 NM_002227 A_23_P205281 0.050 1.39 C14orf2 chromosome 14 open reading NM_004894 Finally, we performed a hierarchical clustering of the 36 patients above (subset 1) based on the levels of the 87 transcripts indicated above, resulting in an almost perfect separation of the R and NR into two major clusters. Indeed, only one R patient was misclassified on the patient's dendrogram. We wished to confirm that a combination of the above transcript levels could be used as a predictor of responsiveness. For this purpose, we used a linear discriminant analysis to select a minimal combination of transcripts from training subset 1 transcriptomic data able to classify correctly RA patients from validation subset 2. Among these 87 mRNA, 4 transcripts {BLOC1SI, RNASE3, COX6A1, PTRH2) were retained by linear discriminant analysis although they did not have the smallest P value (Table 2). Hierarchical clustering of the 32 patients from subset 2, based on these 4 transcript levels measured by qRT-PCR, resulted in two major clusters of R versus NR, with 26 well classified patients (data not shown). This procedure identified six misclassified patients and indicated that this set of 4 transcripts provides 75% sensitivity, 85% specificity, and 85% negative predictive value and 75% positive predictive value for identification of future R and NR to MTX/ABA. To ascertain if this signature was specific to ABA, we used these combinations of 87 mRNA to predict drug responsiveness in an independent cohort of RA patients, with the same level of disease activity, treated by TNFa blocking agents such as etanercept or adalimumab, both associated with MTX. These combinations were unable to classify correctly R and NR to TNFa blocking agents whatever the molecular structure (fusion protein or monoclonal antibody directed against TNFa) suggesting a specificity of this signature for MTX/ABA. This combination of 87 predictors also raised the question of understanding the biological signification of these genes in response to MTX/ABA or RA pathophysiology. Pre-silencing of electron transport chain pathway associated with MTX/ABA responsiveness Different approaches were used to understand the involvement of this signature (87 mRNA) in biological processes. These 87 mRNA were submitted to gene ontology analysis leading us to discover an enrichment (from 6x to 49x more) of 18 Gene Ontology (GO) classes in these 87 mRNA compared to the whole human genome Table 3). Table 3. Gene ontology analysis with the 87 dysregulated transcripts between responders and non responders to methotrexate /abatacept. Corrected P values were determined by a standard hypergeometric distribution. Count % in Count % in GO P- in 87 87 in GO Term human Enrichment ACCESSION value mRNA mRNA human genome list list genome Biological process hydrogen ion GO: 1902600 transmembrane 0.0011 6 10.17 93 0.55 18.38 transport respiratory electron GO:0022904 0.0011 6 10.17 99 0.59 17.26 transport chain electron transport GO:0022900 0.0011 6 10.17 101 0.60 16.92 chain GO:0045333 cellular respiration 0.0011 7 11.86 146 0.87 13.66 GO:0015992 proton transport 0.0019 6 10.17 115 0.68 14.86 GO:0006818 hydrogen transport 0.0019 6 10.17 117 0.70 14.61 Molecular function heme-copper GO:0015002 terminal oxidase 0.0011 4 6.78 23 0.14 49.54 activity cytochrome-c GO:0004129 0.0011 4 6.78 23 0.14 49.54 oxidase activity oxidoreductase activity, acting on a GO:0016676 heme group of 0.0011 4 6.78 23 0.14 49.54 donors, oxygen as acceptor oxidoreductase activity, acting on a GO:0016675 0.0011 4 6.78 24 0.14 47.47 heme group of donors hydrogen ion GO:0015078 transmembrane 0.0011 6 10.17 88 0.52 19.42 transporter activity Cellular localization GO:0070469 respiratory chain 0.0011 6 10.17 68 0.40 25.13 mitochondrial GO:0044455 0.0011 7 11.86 144 0.86 13.85 membrane part mitochondrial inner GO:0005743 0.0011 10 16.95 350 2.08 8.14 membrane organelle inner GO:0019866 0.0011 10 16.95 390 2.32 7.30 membrane mitochondrial GO:0005746 0.0017 5 8.47 62 0.37 22.97 respiratory chain mitochondrial GO:0005740 0.0017 1 1 18.64 544 3.24 5.76 envelope GO:0031966 mitochondrial 0.0053 10 16.95 508 3.02 5.61 membrane

All these 18 GO classes, based on the 87 mRNA, were relative to mitochondrial respiratory chain located in the inner membrane of mitochondria (corrected p value < 0.005). For instance, 6/87 mRNA of genes linked to electron transport chain (GO: 0022900) were included in our signature while 101 genes from the whole human genome are known to be relative to this same GO class (corrected p value = 0.001). The fold enrichment in this GO term is 16x (Table 3). Moreover, these 87 mRNA were submitted to WikiPathways via Single Experiment Analysis (SEA) tool from GeneSpring software leading us to find an enrichment of 4 signaling pathways: Electron Transport Chain (ETC) WP1 11 4 1171 (P value = 1.6. 10 9),

Oxidative Phosphorylation WP623 45305 (P value = 2.5. 10 4 ), Proteasome Degradation WP183 45274 (P value = 0.008) and TSH signaling pathway WP2032 44635 (P value = 0.008). GO analysis and SEA were in agreement since the ETC pathway localized in mitochondria was found with these two tools. The ETC pathway includes 104 proteins split up into five complexes of electron transport chain, embedded in the inner membrane of mitochondria. Among the 87 mRNA of our signature, 7 transcripts from the ETC pathway (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) covering 4 out of 5 complexes of this pathway, were significantly (P value< 0.05) down-regulated in 17 R compared to 19 NR to MTX/ABA. This differential gene expression profile including these 7 genes suggested a reduced expression of mitochondrial respiratory chain pathway in R before ABA administration. In addition, taking into account gene expression profiling from the whole ETC pathway (n=104 genes), principal component analysis correctly separated R from NR before treatment even if all the transcripts from this pathway were not significantly dysregulated between R and NR. Moreover, this separation between R and NR to MTX/ABA observed with the transcripts (7 or 104 transcripts) from ETC pathway was not checked in 3 1 RA patients treated with TNFa blocking agents [adalimumab (n=20) or etanercept (n=l l)] suggesting an ABA specificity. The dysregulation of these transcripts could be linked to the more elevated CRP observed in NR compared to R at baseline (Table 1). Correlations between each significant transcript level from ETC pathway (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) and CRP or DAS28(CRP) were performed to discard a CRP or disease activity effect on the gene expression levels from this signature linked to a supposedly more pronounced mitochondrial activity in the inflammatory state. A very low positive coefficient of correlation (R) and coefficient of determination (R2) between CRP (0.2 < R < 0.4; 0.04 < R2 < 0.16) or DAS28(CRP) (0.3 < R < 0.4; 0.09 < R2 < 0.16) and gene expression level was observed leading us to discard the impact of CRP or disease activity on the ETC pathway at baseline. Finally, we measured gene expression fluctuation in an independent transcriptomic analysis between baseline and 6 months of treatment by MTX/ABA in R and NR. Only 5 genes (COX7B, COX11, UQCRC2, NDUFU3, NDUFS1) among the 104 genes involved in the ETC pathway were significantly up-regulated in R after 6 months of treatment while these genes were invariant in NR to MTX/ABA (data not shown). This observation suggests that ABA increased gene expression levels of some genes from ETC pathway only in R and not in NR independently of the disease activity which decreased whatever the response to MTX/ABA. Overall, these results suggest that these gene levels were not related to disease but are genes of susceptibility to ABA and that a silent expression of ETC signature is more associated with MTX/ABA response. Discussion: In this ancillary study, we identified 87 transcripts whose relative abundance was able to separate R and NR to MTX/ABA in 36 RA patients before treatment (Table 2). Next, we validated a minimal combination of 4 transcripts to predict for the first time MTX/ABA responsiveness in an independent subset of 32 RA patients (Fig.4). According to GO and WikiPathways analysis, we showed an enrichment of 7 genes among the previous 87 belonging to the ETC pathway, suggesting a specific signature of response (Fig.5). Indeed, RA patients with pre-silencing of ETC pathway before treatment are those most susceptible to responding to MTX/ABA 6 months later. In RA and in a context of personalized medicine, the major current challenge is the optimization of drug prescription only to patients susceptible of responding to them and avoiding side effects, thus justifying the identification of predictive biomarkers of drug responsiveness. To date, only two biomarkers are known to be associated with MTX/ABA responsiveness in RA: anti-CCP positivity and low baseline number of CD8+CD28- T cells (26-29). Notwithstanding, there is no clinical and/or biological biomarker used in routinely known to be able to predict MTX/ABA responsiveness prior to treatment initiation for any given RA patient. Indeed, in our study, two statistical approaches of multivariate analysis were unable to identify predictive clinical or biological parameters of MTX/ABA responsiveness, even if disease duration, CRP, global patient assessment of disease and DAS28(CRP) were significantly different between R and NR at baseline (Table 1 and Fig.2). The difficulties we faced in prediction of drug responsiveness with clinical and/or biological parameters lead us to use functional genomic global approach without a priori to identify a predictive signature to MTX/ABA responsiveness. The transcriptomic approach based on the whole genome allowed to identify a signature able to separate R from NR to several drugs (infliximab, tocilizumab, rituximab) used in RA (19-24). For ABA, only one study has previously measured the type-I interferon- regulated transcripts from peripheral blood mononuclear cells in RA patients independently of response to ABA (30). In our study, we identified and validated a gene signature predictive of MTX/ABA responsiveness. This signature included 87 genes variously involved in ETC, proteasome, interferon, RNA processes, etc. This combination of 87 genes is also specific to ABA since it was not able to predict TNFa blocking agent response. Next, we validated this signature with an independent subset of 32 RA patients by means of a minimal combination of 4 genes whose gene expression levels were measured by qRT-PCR, more easily usable in routine practice than microarrays. This signature is the optimized combination of genes able to predict drug responsiveness with good accuracy, since it correctly predicted the future response in 81% of RA patients (75% sensitivity, 85% specificity, and 85% negative predictive value and 75% positive predictive value) prior to treatment (Fig.4). Each gene taken separately was unable to predict drug responsiveness (data not shown) but all genes together predicted MTX/ABA responsiveness with good accuracy. Of these 4 genes, RNAselll gene codes for the RNAselll enzyme which specifically cleaves double-stranded RNA and is involved in the processing of ribosomal RNA precursors of some mRNAs (31). BLOC1S1 (Biogenesis of lysosomal organelles complex-1, subunit 1) codes for the protein BLOC1S1, also known as GCN5L1, is an essential component of the mitochondrial acetyltransferase machinery, and modulates mitochondrial respiration via acetylation of ETC proteins (32). COX6A1 codes for the mitochondrial protein cytochrome c oxidase subunit 6A1 (COX6A1) located in the complex IV. This is the last enzyme in the mitochondrial ETC which drives ATP synthesis (33). PTRH2 codes for the peptidyl-tRNA hydrolase 2 which is a mitochondrial protein released from the mitochondria to the cytoplasm during apoptosis.

Three out of these 4 transcripts (BLOC1S1, COX6A1 and PTRH2) and 13 probes out of 87 encodes for proteins located in mitochondria. In addition, some of them are involved in ETC pathway suggesting implication of mitochondrial metabolism in MTX/ABA responsiveness prediction. ETC is a series of 5 complexes anchored to the inner membrane of mitochondria that transfer electrons via redox reactions that drives ATP synthesis generating reactive oxygen species (ROS) and subsequent oxidative stress (34). Redox balance in mitochondria is a critical component in T cell activation and proliferation (35). The production of ROS by the ETC complex III conducts to large amount of ATP to enhance activity of proliferating T cell after TCR cross-linking (36-39). In our study, ETC genes were down-regulated in R compared to NR suggesting low level of ROS production and less T cell activation before treatment. Besides, a previous study suggested it will be interesting to determine whether ROS production in T cells may be a predictor of clinical response to ABA (40). Our results are consistent with hypothesis of the involvement of ROS in the pathophysiological processes of ABA response. Moreover, this signature included also RASSF5 which was significantly up-regulated in R compared to NR. RASSF5, also known as RAPL, is the effector of Rapl. Rapl plays a central role in T cell response through TCR and costimulation signals. Indeed, a model was drawn in which inactivation of Rapl plays a central role in establishing oxidative stress and can influence the T cell response in RA (40, 41). So, since RASSF5 was upregulated in future R, we could speculate that Rapl is overexpressed suggesting low level of ROS and subsequent less T cell activation and proliferation in R. Furthermore, we found that CACNA2D4 (member of the alpha-2/delta subunit family from the voltage-dependent calcium channel complex) and CALM2 (calcium sensor and signal transducer by binding calcium) were both down-regulated in R compared to NR (Table 2). During T cell activation, mitochondria localize close to the immunological synapse and regulate local calcium homeostasis to generate subsequent ROS production (42). CACNA2D4 and CALM2 are involved in calcium homeostasis suggesting impaired calcium trafficking in R which is consistent with the low level of ETC gene expression behind the low level of ROS in R. All together, these data are consistent with a dysregulation of mitochondria metabolism in future R compared to future NR before treatment. These data suggest less oxidative stress in future responders to ABA while the NR present high expression of genes from ETC pathway showing oxidative stress. After 6 months of treatment by ABA, we showed that 5 genes (COX7B, COX1 1, UQCRC2, NDUFU3, NDUFS1) involved in the ETC pathway were significantly up-regulated in R while these genes were invariant in NR to MTX/ABA. So, whereas ABA seems not to affect oxidative state in NR, it seems to modulate oxidative stress in R since genes from ETC pathway were up-regulated under ABA. Actually, genes from ETC pathway were downregulated in R compared to NR but they were also down-regulated in R compared to healthy subject. Yet, low levels of ROS in T cell are useful and slight increase of their level is not harmful for T cells because of detoxication by antioxydants whereas high increase of ROS rates induce oxidative damage and subsequent apoptosis (43). ABA could restore the redox balance from mitochondria and improve T cell activation and proliferation. In addition, since there was enhanced mitochondrial ROS production in RA patients with inflammation state and since CRP was higher in NR compared to R at baseline, we ensured the absence of correlation between gene expression levels of NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1 and CRP or DAS28(CRP) to make sure that the 87 genes combination was associated with responsiveness prediction. These results support a model in which reduced expression of mitochondrial ETC proteins in future R is independent of inflammation and has a strong impact on response to MTX/ABA treatment. Reduction in the level of ETC genes resulting in defective mitochondria seems increase the sensitivity of RA patients to MTX/ABA. This model has already been highlighted in oesophageal adenocarcinoma and colorectal cancer treated by (44, 45). Indeed, ATP5J and COX7A2 included in our combination were also found to be down-regulated and associated with response to chemotherapy respectively in colorectal cancer and oesophageal adenocarcinoma (44, 45). Like in cancer, pre-treatment conditions targeting mitochondrial metabolism might be a determinant of susceptibility to MTX/ABA (46). Finally, ROS induce also proteasome instability resulting as refolding or degradation of damaged proteins through immuneproteasome activation (34). Three genes (UBL5, PSMA6, PSMB6) of the signature were involved in proteasome degradation. Indeed, PSMA6 or PSMB6 were downregulated in R compared to NR suggesting less proteasome activation in future R to ABA. In summary, we identified and validated a gene expression signature able to predict MTX/ABA responsiveness. This signature involved genes from ETC pathway whose pre- silencing could be a specific determinant of susceptibility to MTX/ABA. The down- regulation of these genes reflected the imbalance of the redox balance observed in R. The intracellular redox balance is crucial for the antigenic response of T cells. After 6 months of treatment, ABA significantly up-regulated some ETC genes in R conducting probably to a slight increase of ROS, restoring the redox balance and improving the T cells response. Further studies are necessary for large scale validation of this signature before evaluating its pertinence in clinical practice and further investigations will be necessary to check the ROS levels in ABA/MTX R and NR.

REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

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1. A method of predicting whether a patient suffering from an autoimmune inflammatory disease will achieve a response with an agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway comprising i) determining the expression level of at least one gene selected from the group consisting of RNASE3, BLOC1S1, COX6A1 and PTRH2 ii) comparing the expression level determined at step i) with a predetermined reference value and iii) concluding that there is probability that the patient will achieve a response when the level determined at step i) is lower than the predetermined reference value or concluding that there is probability that the patient will not achieve a response when the level determined at step i) is higher than the predetermined reference value.

2. The method of claim 1 wherein the patient suffers from an autoimmune inflammatory disease selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic dermatitis, x-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma, systemic scleroderma, sclerosis, systemic sclerosis, multiple sclerosis (MS), spino-optical MS, primary progressive MS (PPMS), relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, and ataxic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, transmural colitis, autoimmune inflammatory bowel disease, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome, adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis, Rasmussen's encephalitis, limbic and/or brainstem encephalitis, uveitis, anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, autoimmune uveitis, glomerulonephritis (GN), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), rapidly progressive GN, allergic conditions, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematodes such as cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), lupus erythematosus disseminatus, lupus (including nephritis, cerebritis, pediatric, non-renal, extra-renal, discoid, alopecia), juvenile onset (Type I) diabetes mellitus, including pediatric insulin- dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis, lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large vessel vasculitis, polymyalgia rheumatica, giant cell (Takayasu's) arteritis, medium vessel vasculitis, Kawasaki's disease, polyarteritis nodosa, microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Bechet's or Behcet's disease, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus, optionally pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, pemphigus erythematosus, autoimmune polyendocrinopathies, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathies, chronic neuropathy, IgM polyneuropathies, IgM-mediated neuropathy, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis); subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, allergic encephalomyelitis, experimental allergic encephalomyelitis (EAE), myasthenia gravis, thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis, bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac disease, Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AGED), autoimmune hearing loss, opsoclonus myoclonus syndrome (OMS), polychondritis such as refractory or relapsed polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis, optionally benign monoclonal gammopathy or monoclonal garnmopathy of undetermined significance, MGUS, peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressler's syndrome, alopecia greata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post- cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant cell polymyalgia, endocrine ophthamopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired splenic atrophy, infertility due to antispermatozoan antobodies, non-malignant thymoma, vitiligo, SCID and Epstein- Barr virus-associated diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Lesihmania, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, ischemic re-perfusion disorder, reduction in blood pressure response, vascular dysfunction, antgiectasis, tissue injury, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, reperfusion injury of myocardial or other tissues, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, acute serious inflammation, chronic intractable inflammation, pyelitis, pneumonocirrhosis, diabetic retinopathy, diabetic large-artery disorder, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis.

3. The method of claim 1wherein the patient suffers from rheumatoid arthritis.

4. The method of claim 1 wherein the expression of at least 1, 2, 3, 4, or more genes are determined in the blood sample obtained from the patient.

5. The method of claim 1 wherein the expression levels of RNASE3, BLOC1S1, COX6A1 and PTRH2 are determined in the blood sample obtained from the patient.

6. The method of claim 1wherein the expression level of the gene is determined by PCR.

7. The method of claim 1 wherein the agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway is a CTLA-4 molecule.

8. The method of claim 7 wherein the CTLA-4 molecule contains at least a portion of an immunoglobulin, such as the Fc portion of an immunoglobulin fused to the extracellular domain of CTLA-4.

9. The method of claim 7 wherein the CTLA-4 molecule is abatacept.

10. The method of claim 7 wherein the CTA-4 molecule is belatacept.

11. The method of claim 1 wherein the agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway is administered in combination with methotrexate.

12. A method of treating an inflammatory autoimmune disease in a patient in need thereof comprising i) predicting whether the patient will achieve a response with an agent that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway by perfoming the method of claim 1 ii) and administering the agent when it is concluded that there is probability that the patient will achieve a response.

13. The method of claim 12 wherein when it is concluded that there is a probability that the patient will not achieve a response, the patient is administered with an antibody having specificity for a cytokine selected from the group consisting of TNFa, IL- lbeta, IL-6, IL-15, IL-17, IL-18, and IL-23. 14. The method of claim 1 wherein when it is concluded that there is a probability the patient will not achieve a response, the patient is administered with a TNF-a blocking agent (TBA).

15. The method of claim 12 wherein the TBA is selected in the group consisting of Etanercept, Infliximab, Adalimumab, Certolizumab pegol, and golimumab.

A . CLASSIFICATION O F SUBJECT MATTER INV. C12Q1/68 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C12Q

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , BIOSIS, EMBASE, WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

LEQUERRE, T: "Gene Expressi on I n Whol e 1-15 Bl ood Predi cts The Abatacept-Methotrexate Combi nati on Responsi veness I n Rheumatoi d Arthri t i s: Prel imi nary Resul t s From The Power Doppl er Ul trasonography Ι Μ1Θ1- 179 Study" , ARTHRITIS & RHEUMATISM, vol . 65 , no. Suppl . 10, Sp. I ss . SI . 1904, October 2013 (2013-10) , page S811 , XP055266126, 77TH ANNUAL MEETING OF THE AMERICAN -CO LLEGE-OF- RHEUMATOLOGY / 48TH ANNUAL MEETING OF THE ASSOCIATION ; SAN DI EGO, CA, USA; OCTOBER 25 -30, 2013 abstract -/-

X| Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

5 Apri l 2017 20/04/2017

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Bradbrook, Derek C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

A N BURSKA ET AL: "Gene expressi on 1-15 analysi s i n RA: towards personal i zed medi c i ne" , PHARMACOGENOMICS JOURNAL, vol . 14, no. 2 , 1 Apri l 2014 (2014-04-01) , pages 93-106, XP055266132 , GB ISSN : 1470-269X, D0I : 10. 1038/tpj .2013 .48 c i ted i n the appl i cati on the whol e document

M H BUCH ET AL: "Mode of acti on of 1-15 abatacept i n rheumatoi d arthri t i s pati ents havi ng fai l ed tumour necrosi s factor bl ockade: a hi stol ogi cal , gene expressi on and dynami c magneti c resonance imagi ng pi l ot study" , ANNALS OF THE RHEUMATIC DISEASES, vol . 68, no. 7 , 4 September 2008 (2008-09-04) , pages 1220-1227 , XP055266133 , GB ISSN : 0003-4967 , D0I : 10. 1136/ard. 2008. 091876 abstract

0 2012/101183 A2 (TC LAND EXPRESSION 1-15 [FR] ; CERVINO ALESSANDRA [FR] ; POPA-NITA 0ANA [FR] ; ) 2 August 2012 (2012-08-02) c l aims 1-18; exampl es 1-5 Patent document Publication Patent family Publication cited in search report date member(s) date

WO 2012101183 A2 02-08-2012 2668287 A2 04-12-2013 2015240304 Al 27-08-2015 2012101183 A2 02-08-2012