Pharmacotherapy of Autoimmune Disorders

Transcription

1 PHARMACY / MEDICAL POLICY POLICY RELATED POLICIES POLICY GUIDELINES DESCRIPTION SCOPE BENEFIT APPLICATION RATIONALE REFERENCES CODING APPENDIX HISTORY Pharmacotherapy of Autoimmune Disorders Number Effective Date December 8, 2015 Revision Date(s) 01/19/16; 01/04/16; 12/08/15; 07/14/15; 03/10/15; 01/13/15; 11/10/14; 08/11/14; 07/14/14 Replaces ; ; ; ; Policy [TOP] Index of Disease States, Drug Classes and Individual Drugs The medications in the following table are included in this policy: Disease Group Indication Therapeutic Drug Class First Line Individual Agents Second Line Ankylosing Spondylitis TNF- Antagonists adalimumab (Humira ) etanercept (Enbrel ) (both required) certolizumab (Cimzia ) golimumab (Simponi ) infliximab (Remicade ) Arthropathies Juvenile Idiopathic Arthritis Rheumatoid Arthritis IL-6 Inhibitors N/A tocilizumab (Actemra ) N/A adalimumab TNF- (Humira ) Antagonists etanercept (Enbrel ) (both required) T-cell Costimulation Modulators N/A abatacept (Orencia ) Anti-CD20 N/A rituximab (Rituxan ) IL-1 Inhibitors N/A anakinra (Kineret ) IL-6 Inhibitors N/A tocilizumab

2 (Actemra ) Janus Kinase Inhibitors T-cell Costimulation Modulators N/A tofacitinib (Xeljanz ) N/A abatacept (Orencia ) IBD Crohn's Colitis Ulcerative Colitis TNF- Antagonists TNF- Antagonists α4 Integrin Inhibitors TNF- Antagonists α4 Integrin Inhibitors N/A adalimumab (Humira ) etanercept (Enbrel ) (both required) adalimumab (Humira ) N/A adalimumab (Humira ) certolizumab (Cimzia ) golimumab (Simponi ) infliximab (Remicade ) certolizumab (Cimzia ) infliximab (Remicade ) natalizumab (Tysabri ) Vedolizumab (Entyvio ) golimumab (Simponi ) infliximab (Remicade ) Vedolizumab (Entyvio ) Lupus (SLE) Anti-CD20 rituximab (Rituxan ) N/A Miscellaneous Autoimmune Diseases Pyoderma Gangrenosum Wegener s Granulomatosis BLyS Inhibitors belimumab (Benlysta ) TNF- Antagonists adalimumab (Humira ) etanercept (Enbrel ) Anti-CD20 rituximab (Rituxan ) N/A infliximab (Remicade ) N/A Anti-CD52 Alemtuzumab (Lemtrada ) N/A Multiple Sclerosis Relapsing MS β-interferons interferon-β1a (Avonex, Rebif ) interferon-β1b (Betaseron, Extavia ) Copolymers glatiramer 20mg (generic) N/A Copaxone 40mg (no generic available for 40mg strength)

3 Dihydroorotate Dehydrogenase Inhibitor Nrf2 Pathway Activator Sphingosine 1- Phosphate Receptor Modulator α4 Integrin Inhibitors IL-12/23 inhibitors teriflunomide (Aubagio ) dimethyl fumarate (Tecfidera ) fingolimod (Gilenya ) N/A N/A N/A N/A natalizumab (Tysabri ) N/A ustekinumab (Stelara ) Psoriasis Thrombocytopenia Plaque Psoriasis Psoriatic Arthritis Hepatitis C- Induced Thrombocyt openia Immune Thrombocyt openia IL-17 inhibitors N/A secukinumab (Cosentyx ) Lymphocyte Activation Inhibitors TNF- Antagonists N/A alefacept (Amevive ) adalimumab (Humira ) etanercept (Enbrel ) (both required) infliximab (Remicade ) PDE4 Inhibitors N/A apremilast (Otezla ) IL-12/23 inhibitors N/A ustekinumab (Stelara ) PDE4 Inhibitors N/A apremilast (Otezla ) TNF- Antagonists Thrombopoietic Agents adalimumab (Humira ) etanercept (Enbrel ) (both required) eltrombopag (Promacta ) Anti-CD20 rituximab (Rituxan ) Thrombopoietic Agents Romiplostim (Nplate ) certolizumab (Cimzia ) golimumab (Simponi ) infliximab (Remicade ) N/A N/A N/A

4 Alphabetical Index BY GENERIC NAME abatacept (Orencia ) adalimumab (Humira ) alefacept (Amevive ) alemtuzumab (Lemtrada ) anakinra (Kineret ) apremilast (Otezla ) belimumab (Benlysta ) certolizumab pegol (Cimzia ) dimethyl fumarate (Tecfidera ) eltrombopag (Promacta ) etanercept (Enbrel ) glatiramer (Copaxone ) golimumab (Simponi ) infliximab (Remicade ) interferon-β1a (Rebif ) interferon-β1a (Avonex ) interferon-β1b (Betaseron ) interferon-β1b (Extavia ) natalizumab (Tysabri ) phosphodiesterase 4 Inhibitors rituximab (Rituxan ) romiplostim (Nplate ) secukinumab (Cosentyx ) teriflunomide (Aubagio ) tocilizumab (Actemra ) ustekinumab (Stelara ) vedolizumab (Entyvio ) BY BRAND NAME Actemra (tocilizumab) Amevive (alefacept) Aubagio (teriflunomide) Avonex (interferon β1a) Benlysta (belimumab) Betaseron (interferon β1b) Cimzia (certolizumab pegol) Copaxone (glatiramer) Cosentyx (secukinumab) Enbrel (etanercept) Entyvio (vedolizumab) Gilenya (fingolimod) Humira (adalimumab) Kineret (anakinra) Lemtrada (alemtuzumab) Nplate (romiplostim) Orencia (abatacept) Otezla (apremilast) Promacta (eltrombopag) Rebif (interferon β1a) Remicade (infliximab) Rituxan (rituximab) Simponi (golimumab) Stelara (ustekinumab) Tecfidera (dimethyl fumarate) Tysabri (natalizumab) Drugs by Therapeutic Drug Class Links to Drugs by Therapeutic Drug Class Alpha-4 integrin Inhibitors Anti-CD20 Monoclonal Antibodies Anti-CD52 Monoclonal Antibodies Beta-Interferons BLyS Inhibitors Copolymers Dihydroorotate Dehydrogenase Inhibitors IL-1 Inhibitors Drugs included within Drug Class natalizumab (Tysabri ) vedolizumab (Entyvio ) rituximab (Rituxan ) alemtuzumab (Lemtrada ) interferon-β1a (Avonex or Rebif ) interferon-β1b (Betaseron, Extavia ) belimumab (Benlysta ) glatiramer 20mg (generic form) Copaxone 40mg (available as brand only) teriflunomide (Aubagio ) anakinra (Kineret )

5 IL-6 Inhibitors IL-12/23 Inhibitors IL-17 Inhibitors Janus Kinase Inhibitors Lymphocyte Activation Inhibitors Nrf2 Pathway Activators Phosphodiesterase 4 Inhibitors Sphingosine 1-Phosphate Receptor Modulators T-Cell Costimulation Modulators Thrombopoietic Agents TNF-α Antagonists tocilizumab (Actemra ) ustekinumab (Stelara ) secukinumab (Cosentyx ) tofacitinib (Xeljanz ) alefacept (Amevive ) dimethyl fumarate (Tecfidera ) apremilast (Otezla ) ingolimod (Gilenya ) abatacept (Orencia ) eltrombopag (Promacta ) romiplostim (Nplate ) adalimumab (Humira ) certolizumab pegol (Cimzia ) etanercept (Enbrel ) golimumab (Simponi or Simponi Aria ) infliximab (Remicade ) Alpha-4 Integrin Inhibitors natalizumab (Tysabri ) may be considered medically necessary as a second line agent for the treatment of patients with: Moderately to severely active Crohn s disease who have had inadequate response or intolerance to adalimumab (Humira ). Relapsing forms of multiple sclerosis when BOTH the following conditions are met: Patient must have an Expanded Disability Status Score (EDSS) of less than 6. Natalizumab is not to be used concurrently with other Multiple Sclerosis disease modifying drugs. All other uses of natalizumab are considered investigational. Due to safety concerns, access to Tysabri requires enrollment in the TOUCH registry maintained by the manufacturer. (See vedolizumab (Entyvio ) may be considered medically necessary as a second line agent for the treatment of patients with: Moderately to severely active Crohn s disease who have had inadequate response or intolerance to adalimumab (Humira ). Moderately to severely active ulcerative colitis who have had inadequate response or intolerance to adalimumab (Humira ). All other uses of vedolizumab are considered investigational. Anti-CD20 Monoclonal Antibodies rituximab (Rituxan ): See policy number Rituximab: Non-oncologic and Miscellaneous Uses. Use of rituximab to treat various types of cancer is covered in a separate medical policy Monoclonal Antibodies for the Treatment of B-Cell Malignancies. All other uses of rituximab not addressed in the above policies are considered investigational. Anti-CD52 Monoclonal Antibodies alemtuzumab (Lemtrada ), may be considered medically necessary for the treatment of relapsing multiple

6 sclerosis in patients in patients who have had an inadequate response to two or more disease modifying drugs indicated for the treatment of multiple sclerosis. Campath, the previously available form of alemtuzumab for the treatment of cancer, has been withdrawn voluntarily by the manufacturer and is no longer available. All other uses of alemtuzumab are considered investigational. Beta-Interferons interferon-β1a (Avonex or Rebif ), or interferon-β1b (Betaseron, Extavia ) may be considered medically necessary as first line agents for the treatment of relapsing forms of multiple sclerosis, when BOTH the following conditions are met: Patient must have an Expanded Disability Status Score (EDSS) of less than 6. Beta-interferons are not to be used concurrently with other Multiple Sclerosis disease modifying drugs. All other uses of beta-interferons are considered investigational. BLyS Inhibitors belimumab (Benlysta ) may be considered medically necessary for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) when BOTH the following conditions are met: Diagnosis of SLE is confirmed using either American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) criteria. Patient has failed a 6 month trial of standard induction therapy with mycophenolate, cyclophosphamide, azathioprine or other immunosuppressant, plus corticosteroid. All other uses of belimumab are considered investigational. Copolymers glatiramer 20mg (generic form) may be considered medically necessary as a first line agent for the treatment of relapsing forms of multiple sclerosis when BOTH the following conditions are met: Patient must have an Expanded Disability Status Score (EDSS) of less than 6. Glatiramer is not to be used concurrently with other Multiple Sclerosis disease modifying drugs. Copaxone 40mg (available as brand only) may be considered medically necessary as a second line agent for the treatment of relapsing forms of multiple sclerosis when BOTH the above conditions are AND and there has been documented inadequate response to or intolerance of the generic glatiramer 20mg. All other uses of glatiramer are considered investigational. Dihydroorotate Dehydrogenase Inhibitors teriflunomide (Aubagio ) may be considered medically necessary as a first line agent for the treatment of relapsing forms of multiple sclerosis when the following criteria are met: Patient must have an Expanded Disability Status Score (EDSS) of less than 6; Teriflunomide is not to be used concurrently with other Multiple Sclerosis disease modifying drugs. All other uses of teriflunomide are considered investigational. IL-1 Inhibitors anakinra (Kineret ) may be considered medically necessary as a second line agent for its FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an

7 inadequate response or intolerance to methotrexate, etanercept and adalimumab. All other uses of anakinra are considered investigational. IL-6 Inhibitors tocilizumab (Actemra ) may be considered medically necessary as a second line agent for the FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients that have inadequate response or intolerance to methotrexate, etanercept and adalimumab. All other uses of tocilizumab are considered investigational. IL-12/23 Inhibitors ustekinumab (Stelara ) and may be considered medically necessary as a second-line agent for the FDAapproved indications of: Treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy that have inadequate response or intolerance to etanercept and adalimumab, when the following criteria are met: Diagnosis of chronic plaque psoriasis involving 10% of the patient s body surface area (BSA). Exceptions may be granted for extensive recalcitrant facial involvement, pustular involvement of the hands or feet, and genital involvement which interferes with normal sexual function. History of an adequate trial and treatment failure with 1 approved systemic therapy (e.g., methotrexate, cyclosporine, acitretin [Soriatane ]) unless contraindicated or not tolerated. Treatment of adults with active psoriatic arthritis, either alone or with methotrexate, that have inadequate response or intolerance to etanercept and adalimumab, Quantity Limit: For patients weighing <100 kg (220 lbs.), the dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients weighing >100 kg (220 lbs.), the dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. If response is inadequate, dose may be increased to 90 mg every 12 weeks. Doses in excess of the above are not medically necessary. All other uses of ustekinumab are considered investigational. IL-17 Inhibitors Secukinumab (Cosentyx ) may be considered medically necessary as a second-line agent for the FDAapproved indication to treat adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy that have inadequate response or intolerance to etanercept and adalimumab. All other uses of secukinumab are considered investigational. Janus Kinase Inhibitors tofacitinib (Xeljanz ) may be considered medically necessary as a second line agent for its FDA-approved indication for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab. All other uses of tofacitinib are considered investigational. Lymphocyte Activation Inhibitors alefacept (Amevive ) may be considered a medically necessary second-line agent for its FDA-approved indication of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy that have inadequate response or intolerance to etanercept and adalimumab, when the following criteria are met:

8 Diagnosis of chronic plaque psoriasis involving 10% of the patient s body surface area (BSA). Exceptions may be granted for extensive recalcitrant facial involvement, pustular involvement of the hands or feet, and genital involvement which interferes with normal sexual function. History of an adequate trial and treatment failure with 1 approved systemic therapy (e.g., methotrexate, cyclosporine, acitretin [Soriatane ]) unless contraindicated or not tolerated. All other uses of alefacept are considered investigational. Nrf2 Pathway Activators dimethyl fumarate (Tecfidera ) may be considered medically necessary for the treatment of relapsing/remitting multiple sclerosis when ALL of the following criteria are met. Patient must have an Expanded Disability Status Score (EDSS) of less than 6; and Dimethyl fumarate is not to be used concurrently with other Multiple Sclerosis disease modifying drugs. Quantity Limit: Quantity limited to 14 of the 120 mg capsules, to achieve a dosage of one 120 mg capsule twice daily for the first week. (Doses of 120mg 2 or 3 times daily may be approved up to 90 days on a case basis for patients having difficulty tolerating the full dose.) After the first week of therapy, 240mg capsules should be dispensed except as noted above, with quantity limited to 60 capsules per 30 day supply, to achieve a dosage of 240mg twice daily. Doses in excess of 480mg per day are considered not medically necessary. All other uses of dimethyl fumarate are considered investigational. Sphingosine 1-Phosphate Receptor Modulators fingolimod (Gilenya ) may be considered medically necessary for the treatment of relapsing/remitting multiple sclerosis when ALL of the following criteria are met. Patient must have an Expanded Disability Status Score (EDSS) of less than 6; and Fingolimod is not to be used concurrently with other Multiple Sclerosis disease modifying drugs. Quantity Limit: Quantity is limited to achieve a dosage of 0.5mg per day. All other uses of fingolimod are considered investigational. Phosphodiesterase 4 Inhibitors apremilast (Otezla ) may be considered medically necessary for the treatment of adult patients with moderate to severe plaque psoriasis or psoriatic arthritis when ALL of the following criteria are met. Patient meets all the requirements for approval of etanercept and adalimumab; and Patient has had an inadequate response or intolerance to etanercept and adalimumab. All other uses of apremilast are considered investigational. T-Cell Costimulation Modulators abatacept (Orencia ) IV infusion or subcutaneous injection may be considered medically necessary as a second line agent for its FDA-approved indications of: Treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate

9 response or intolerance to methotrexate, etanercept and adalimumab. Treatment of juvenile idiopathic arthritis in patients who have had an inadequate response or intolerance to etanercept and adalimumab. Quantity Limit: 125 mg every week. All other uses of abatacept are considered investigational. Thrombopoietic Agents eltrombopag (Promacta ) may be considered medically necessary for the treatment of idiopathic thrombocytopenic purpura (ITP) or hepatitis C induced thrombocytopenia when all the following criteria are met: A platelet count < 30,000/µL, AND Failure of corticosteroids, AND Failure of either intravenous immune globulin (IVIg) or splenectomy. All other uses of eltrombopag are considered investigational. romiplostim (Nplate ) may be considered medically necessary for the treatment of idiopathic thrombocytopenic purpura (ITP) when all the following criteria are met: A platelet count < 30,000/µL, AND Failure of corticosteroids, AND Failure of either intravenous immune globulin (IVIg) or splenectomy. All other uses of romiplostim are considered investigational. TNF-α Antagonists adalimumab (Humira ) may be considered a medically necessary first line TNF- antagonist for its FDAapproved indications of: Moderate to severe rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis when the following condition are met: o The patient has not responded to or does not tolerate methotrexate; or o Adalimumab is being added to the regimen after the patient has had an inadequate partial response to methotrexate monotherapy; or o The patient is being started on adalimumab concurrently with methotrexate. Moderate to severe ankylosing spondylitis. Adult patients with moderate to severe plaque psoriasis who meet the biologic response modifier initiation criteria below. Crohn s disease or ulcerative colitis in the moderately to severely active patient, who has had an inadequate response to conventional therapy (see below). Pyoderma gangrenosum that has not responded to standard non-biologic therapy (e.g., corticosteroids, immunosuppressants). Moderate to severe hidradenitis suppurativa. certolizumab pegol (Cimzia ) may be considered a medically necessary second line TNF- antagonist for its FDA-approved indications of: Moderate to severe rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab. Crohn s disease in the moderately to severely active patient, who has had an inadequate response or intolerance to conventional therapy (see below) and to adalimumab.

10 etanercept (Enbrel ) may be considered a medically necessary first line TNF- antagonist for its FDAapproved indications of: Moderate to severe rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis when the following conditions are met: o The patient has not responded to or does not tolerate methotrexate; or o Etanercept is being added to the regimen after the patient has had an inadequate partial response to methotrexate monotherapy; or o The patient is being started on etanercept concurrently with methotrexate. Moderate to severe ankylosing spondylitis. Adult patients with moderate to severe plaque psoriasis who meet the biologic response modifier initiation criteria below. Pyoderma gangrenosum that has not responded to standard non-biologic therapy (e.g., corticosteroids, immunosuppressants). golimumab (Simponi or Simponi Aria ) may be considered a medically necessary second line TNF- antagonist for its FDA-approved indications of: Moderate to severe rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab. Ulcerative colitis in the moderately to severely active patient, who has had an inadequate response or intolerance to conventional therapy (see below) and to adalimumab. infliximab (Remicade ), may be considered a medically necessary second line TNF- antagonist for its FDAapproved indications of: Moderate to severe rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, in patients who have had an inadequate response or intolerance to methotrexate, etanercept and adalimumab. Adult patients with moderate to severe plaque psoriasis who meet the biologic response modifier initiation criteria below and have had an inadequate response or intolerance to etanercept and adalimumab. (Note: infliximab may be considered medically necessary as emergent treatment for severe pustular, exfoliative or inflammatory psoriasis without prior use or failure/intolerance of a first line agent, in contrast to stable plaque psoriasis.) Crohn s disease or ulcerative colitis in the moderately to severely active patient, who has had an inadequate response or intolerance to conventional therapy (see below) and to adalimumab. Pyoderma gangrenosum that has not responded to standard non-biologic therapy (e.g., corticosteroids, immunosuppressants). Biologic response modifier initiation criteria for plaque psoriasis: Diagnosis of chronic plaque psoriasis involving 10% of the patient s body surface area (BSA). Exceptions may be granted for extensive recalcitrant facial involvement, pustular involvement of the hands or feet, and genital involvement which interferes with normal sexual function. History of an adequate trial and treatment failure with 1 approved systemic therapy (e.g., methotrexate, cyclosporine, acitretin [Soriatane ]) unless contraindicated or not tolerated. Conventional therapy for Crohn s disease: History of an adequate trial and treatment failure with at least two of the following: Corticosteroids (e.g., prednisone, prednisolone, dexamethasone, budesonide, etc.) Immunomodulatory drugs (e.g., azathioprine, mercaptopurine, cyclosporine) Antibiotics (e.g., metronidazole, Cipro, Floxin, Levaqin) Conventional therapy for Ulcerative Colitis: History of an adequate trial and treatment failure with at least three of the following: Corticosteroids (i.e., prednisone, prednisolone, dexamethasone, budesonide, etc.)

11 Sulfasalazine Immunomodulatory drugs (i.e., azathioprine, mercaptopurine, cyclosporine) Pentasa, Rowasa or Asacol Quantity Limits (If adequate response is not obtained at these doses, alternative drugs should be considered): adalimumab (Humira ) o Initial dose 80 mg, 40 mg second week, then 40 mg every other week. o Psoriasis patients not achieving adequate response after 12 weeks at 40 mg every other week may be approved for 40 mg weekly. certolizumab pegol (Cimzia ) o Loading dose is 400 mg at weeks 0, 2 and 4. Maintenance 400 mg every 4 weeks. etanercept (Enbrel ) o 50 mg twice weekly for up to 12 weeks, then maintenance dose 50 mg weekly. o Psoriasis patients who experience significant worsening of symptoms after the dose is lowered to 50mg/week may be approved for the higher dose on a case by case basis. golimumab (Simponi ) o Maximum 50 mg monthly. infliximab (Remicade ) o Loading doses at weeks 0, 2, and 6, then 3-5 mg/kg every 4-8 weeks maintenance. o Maintenance therapy with Remicade may be approved based on objective documentation of effectiveness. o Treatment at doses in excess of 5 mg/kg every 4 weeks or 10mg/kg every 8 weeks is not medically necessary. Use of TNF-α antagonists in patients with other arthropathies, autoimmune disorders or other conditions not listed above is considered investigational. Use for other rare conditions when all conventional therapies have been tried and failed or where they are clinically contraindicated may be considered on a case-by-case basis. Use of TNF-α antagonists to treat milder plaque psoriasis is considered investigational. However, use in patients whose plaque psoriasis is refractory to treatment with recognized conventional therapies may be considered on a case-by-case basis. Related Policies Monoclonal Antibodies for the Treatment of B-Cell Malignancies [TOP] Pharmacologic Treatment of Neuropathy, Fibromyalgia and Seizure Disorders Dalfampridine (Ampyra ) Rituximab: Non-oncologic and Miscellaneous Uses Immune Globulin Therapy Policy Guidelines For purposes of this policy, an adult is defined as anyone 18 years of age or older. [TOP]

12 Description [TOP] The term autoimmune disorders covers a wide range of syndromes often involving damage to multiple organ systems. Since the advent of biologics and small molecule targeted therapies, a variety of pathways and specific points of intervention have been identified and drugs developed to modify the pathology that is damaging the patient. Since multiple diseases share common signaling pathways, it is not surprising that drugs and diseases often overlap, leading to the complex web of alternative therapies that are now available to physicians. This policy is an attempt to aggregate them all in a format that permits users to access and cross-reference the drugs in question by brand and generic name, target disease and pharmacologic drug class. The diseases include a variety of inflammatory arthropathies such as rheumatoid and psoriatic arthritis and ankylosing spondylitis. Psoriasis, multiple sclerosis, and a large number of ultra-orphan diseases fall in this general category. The ones with large populations now have multiple drugs to choose from, while the orphans often lack a single FDA-approved therapeutic option. This poses a challenge to maintaining and updating medical policies. Inflammatory arthropathies are a group of heterogeneous connective tissue disorders affecting the joints, which share certain common features such as inflammation and altered patterns of immune regulation. Those conditions at focus in this policy include rheumatoid arthritis (RA); and the spondyloarthropathies, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Rheumatoid Arthritis (RA) RA is a chronic, progressive, inflammatory, autoimmune disease affecting about 1% of the US adult population and occurs approximately 3 times more frequently in women than in men (ACR Subcommittee on Rheumatoid Arthritis Guidelines, 2002). Almost 80% of RA cases occur in patients between 35 and 50 years of age (Kavanaugh and Lipsky, 1996); usually a time of peak social productivity. The underlying cause of RA is unknown, but the disease is characterized by persistent inflammation of the synovium, cartilage loss, and bone erosion in peripheral joints, usually in a symmetric fashion. This inflammation is believed to be mediated by both B- and T-cells and a variety of cytokines (messenger proteins), including tumor necrosis factor-alpha (TNF-). Research has shown that joint damage occurs within the first 2 years of symptoms and diagnosis and progresses rapidly if not treated. Although RA primarily affects the joints, it is a systemic disease and does cause systemic and extra-articular clinical features (e.g., fever, fatigue, anorexia, weight loss, and anemia), which contribute to the significant work disability and impaired quality of life which occur. Patients with RA also have earlier mortality than the general population averaging 7-10 years, primarily due to an increased risk of cardiovascular disease, infection, and lymphoma associated with more severe inflammation. Psoriatic Arthritis (PsA) PsA is characterized as a spondyloarthropathy associated with psoriasis. The true incidence is unknown, and is variably reported to occur in 6-42% (25% is considered a reasonable estimate) of patients with psoriasis, an immunologic skin disease which occurs in 2-3% of the general population. There is similarity in the histopathogenesis of PsA and RA, including the role of cytokines such as tumor necrosis factor alpha (TNF-), although there are important differences as well. Several subsets of PsA have also been described. PsA is characterized by stiffness, both peripheral and spine inflammation and pain, joint deformities related to joint destruction, dactylitis, enthesitis (inflammation at insertion sites of tendons, ligaments, and joint capsule fibers), and psoriasis skin plaques. The course of PsA is variable, but the majority of patients develop a chronic progressive form of the disease resulting in joint destruction, unless treated effectively. Although less well characterized than in RA, similar levels of disability, decreased quality of life, increased co-morbidities, and premature mortality are now being noted in long term registry studies. Other Spondloarthropathies (SpAs) The spondyloarthropathies are a heterogeneous set of disorders characterized by axial skeletal involvement and frequent association with the HLA-B27 antigen. Ankylosing spondylitis (AS) is probably the most familiar spondyloarthropathy, which is characterized predominantly by progressive vertebral enthesitis and facet joint inflammation of the spine and sacroiliac joints, leading to eventual spine fusion and decreased range of motion, as well as peripheral joint synovitis, although much less than is seen in RA. Variations in incidence among

13 different racial groups support the hypothesis of a genetic role in AS, as is also postulated in other arthropathies. In the United States, AS is believed to affect approximately 1-3 persons/1000, or about 350,000 to 1 million individuals. While peripheral arthritis is commonly seen in association with psoriasis, approximately 20-40% of patients with PsA may have some degree of sacroiliitis with paravertebral ossification. The skin manifestations associated with the arthropathy are not necessarily widespread and may be localized. About 20% of patients with inflammatory bowel disease may have evidence of sacroiliitis and some 20% of these patients may progress to spondylitis. The course of the spondylitis does not necessarily correlate with bowel inflammatory activity. Psoriasis Psoriasis is a chronic, multifactorial, noncontagious skin disorder that affects about 2.1% of the U.S. population and 1-3% of persons worldwide. About 4.5 million, or 1 in 65, Americans have psoriasis. Onset is typically between the ages of 15 and 35 and prevalence is slightly greater in women. It is also more common in some ethnic groups (Caucasians) than others (African American or Asians). A genetic component has also been identified. There are several forms of psoriasis, but plaque psoriasis (or psoriasis vulgaris) is the most common form of the disease, affecting about 80% of psoriatic patients. About 20-30% of people with psoriasis have cases that are considered moderate to severe (covering more than 3% of their body). Although not typically life-threatening, psoriasis can have a large impact on quality of life. Seventy-five percent of people with moderate to severe psoriasis report their disease has a moderate to large impact on their everyday lives. Patients with palmar-plantar disease may have less than 3% involvement, but often have debilitating and recalcitrant disease. Further, approximately 7% of psoriatic patients have concurrent arthritis (which may be particularly relevant to one s choice of therapy). Psoriasis is a chronic immune-mediated inflammatory disease characterized by T-cell activation and accumulation in the epidermis and dermis, leading to abnormal differentiation and hyperproliferation of keratinocytes. Recent advances in the understanding of the cellular mechanisms underlying psoriasis have given rise to a generation of highly targeted biotechnologies for this indication. As the severity of psoriasis ranges from mild to severe, with or without concurrent arthritis, available treatments lie along a spectrum from minimally invasive with a low risk of systemic side effects, to systemic therapy with a risk of potentially severe side effects. Non-invasive, topical treatments may also have significant side effects; for example, topical corticosteroids applied to large areas of skin may result in significant levels of systemic absorption. Many treatments have a cumulative toxicity potential, but the benefit of prolonged remissions makes the use of the more potent treatments relatively attractive. Inflammatory Bowel Diseases (IBD) This diagnosis grouping includes Crohn s disease (CD) and ulcerative colitis (UC). Unlike UC, CD is not limited to the colon and can manifest anywhere in the GI tract. Therefore, while UC can be eliminated by performing total colectomy, CD cannot. CD is an idiopathic, chronic inflammatory disease of the gastrointestinal tract affecting primarily the small and large intestine. CD is caused by a dysregulation of the normal gut immune response, ultimately creating a chronic inflammatory state. TNF- is thought to be at the center of a complex cascade of immune mediated events that result in the pathological manifestations of the disease. The main presenting symptoms of CD include: abdominal pain, diarrhea, rectal bleeding, malaise, fever, weight loss, and right-lowerquadrant pain and tenderness. Severe complications of the condition include fistulas, strictures, intra-abdominal abscesses, and nutrient malabsorption. CD and UC have overlapping features and as such are collectively known as inflammatory bowel diseases. Although the presentation of UC is usually different than CD because it is limited to the rectum and colon, their overlapping characteristics can make differential diagnosis very difficult. However, it is important to note the differences, since treatments that are successful in UC will not necessarily work as well in CD. Miscellaneous Autoimmune Diseases TNF inhibitors, rituximab and various other agents have been used off-label to treat a variety of autoimmune

14 diseases. Most of these represent significant unmet medical needs. Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is a chronic, complicated, progressive autoimmune disease impacting multiple organ systems. It is a condition characterized by auto-reactive b-cells. Autoantibody production from such abnormal b lymphocyte function leads to chronic inflammation and cellular, tissue and organ damage. Diverse in presentation, patients with SLE experience mild to life-threatening manifestations and unpredictable clinical course of exacerbations and remissions. As symptoms are non-specific, the identification of SLE is often-times delayed. It has been reported that patients visit a mean of three different physicians and an average of 4 years after the onset of symptoms before a correct diagnosis is reached. The mucocutaneous (rash), articular (arthritis), serosal (pleuritis, pericarditis), renal (proteinuria) and neurologic (seizures, psychosis) clinical features, as well as hematologic and immunologic laboratory findings, incorporated in the American College of Rheumatology SLE diagnosis classification criteria reflects the heterogeneity of the disease. Most commonly involved organs include the skin, musculoskeletal, renal, nervous cardiovascular and pulmonary systems. Over 75% of SLE patients have debilitating, generally non-fatal mucocutaneous (rash) and musculoskeletal involvement (arthritis). A smaller SLE population (50%-66%) is afflicted with renal disorders, and is associated with poorer outcome and mortality. About 2/3 of SLE patients also present with varying severity of neuropsychiatric manifestations ranging from mood disorders, anxiety, psychosis to seizures. Other less common but serious manifestations include serositis (16 to 64%), neurological disorders (9 to 36%), and immune-mediated cytopenias (4 to 43%). Depression is common among people with chronic autoimmune disease. Overall, SLE patients have a 2-5 times greater mortality rate. As endogenous female sex hormone is identified to have a role in SLE development, SLE is found primarily in women (90% of SLE population are female, 6-10 female:1 male), typically years of age. In the US, more than 300,000 people have SLE and an annual incident rate of 15, million people are impacted worldwide. While SLE patients have at least twice the mortality risk relative to the general population, survival rate at 15 years improved dramatically from 50% in the 1950s to currently greater than 80%. Most common causes of death are cardiovascular disease, infections, renal disease and complications due to SLE disease activity. In addition to gender, ethnicity has an influence on the development of SLE. Mestizo, indigenous Americans, Blacks and Asians have more severe SLE disease and poorer clinical progression. Blacks are three times more likely than Caucasians to have SLE. Asian and African American SLE patients develop renal disease more frequently than those of European descent (60-70%, 50%, 20-30%, respectively). Systemic Lupus Erythematosus (SLE) is characterized by auto-reactive B-cells. Autoantibody production from such abnormal B lymphocyte function leads to chronic inflammation. Autoantibody complex, cytokines and complement activation represent mediators of tissue damage in SLE patients. Anti-nuclear antibody (ANA) is found present in more than 90% of patients. Those positive are more likely to have active lupus associated with B cell dysfunction. Anti-dsDNA, a type of anti-nuclear antibody (ANA), is one of the diagnosis criteria established by the American College of Rheumatology and is monitored as gauge of SLE disease response to treatment. Consistent with existing pathophysiology, inhibition of BLyS, an endogenous protein responsible for B-cell homeostatsis, decreases autoreactive B-cell activity and serological changes. Transgenic animals overexpressing BLyS have lupus-like syndrome, increased immunoglobulins and immune complex depositions. BLyS is also found elevated in human autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Sijogen s. Most patients present with generalized symptoms of fatigue, fever, anorexia, weight loss, photosensitivity, malar rash, oral ulcers, arthralgia and hair loss. Incompletely controlled SLE can progress to end-stage organ involvement; SLE activity of 60% of SLE patients is found to worsen within 2-7 years of diagnosis. Irreversible cellular and tissue damages can accumulate to result in life-threatening renal, cardiac, pulmonary, CNS and hematological system toxicities. The subsequent development of pleuritis, pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia and other blood dyscrasias present significant mortality and morbidity risks. Aside from these autoimmune mediated disease manifestations, SLE patient are in high risk for infections of the respiratory and urinary systems, cardiovascular diseases, hematological and solid tumors, maternal and fetal morbidity and mortality (spontaneous abortions, pre-eclampsia, intrauterine growth impairment, premature birth). Most common causes of death are infections, renal disease, cardiovascular disease and complications due to

15 SLE disease activity. Idiopathic Thrombocytopenic Purpura (ITP) Idiopathic Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by destruction of normal platelets due to unknown stimulus and a resulting risk of severe bleeding complications. Recent update by International Working Group (IWG) consensus panel set the platelet count threshold as less than 100,000 per µl. The initiating event of ITP is unclear and various mechanisms of platelet destruction may be important. IgG autoantibodies on the platelet surface can cause platelet uptake and destruction by reticuloendothelial phagocytes. T-cell mediated cytotoxicity against megakaryocytes and platelets may cause thrombocytopenia. In addition to increased platelet destruction, the production of platelets is often decreased in ITP. Adult ITP has an annual incidence of approximately two cases per 100,000. It is estimated in the United States there are 100 patients with ITP per one million people or approximately 30,000 total and 15,000 with a chronic form of ITP assuming the population is 300 million. Adult ITP is more likely than childhood ITP to be chronic. Spontaneous remission occurs in more than 80% of cases in children but is uncommon in adults. As a result, evidence based treatment guidelines differ between adult and children. For specific treatment recommendations in children with ITP, please refer to the ASH 2011 guideline Section 1: ITP in children. The incidence rate appears to increase with age, with the highest age-specific incidence in patients older than 60 years of age. The female-to-male ratio of ITP patients is bimodal, being 1.9 women for each man in ages less than 50 and 1.2:1 in ages 65 and older. There is no apparent prevalence difference between African Americans and whites. Intracranial hemorrhage represents the most serious complication of ITP. The mortality rate from hemorrhage is approximately 1% in children and 5% in adults. In patients with severe thrombocytopenia, predicted five-year mortality rates from bleeding are significantly raised in patients older than 60 years versus patients younger than 40 years, 47.8% versus 2.2%, respectively. Pyoderma Gangrenosum Pyoderma gangrenosum is an inflammatory disease with dermatologic manifestations including painful ulcerations with erythematous borders. It is presumed to be autoimmune in origin, though the mechanism is not well understood. Lesions usually develop at sites of minor skin injury, usually on the lower extremities. These lesions can grow in size and become necrotic. Underlying fasciitis may occasionally develop from them. Some patients develop pustular, bullous or vegetative lesions. Other common sites are colostomies and paraneoplastic lesions in patients with hematologic malignancies. Progress of the lesions is highly variable, and patient response to treatment is heterogeneous. Obesity, diabetes or edema may be contributing factors. Due to the infrequent occurrence and heterogeneity of pyoderma gangrenosum, the treatment approach is empiric and patient-specific. First-line options include topical tacrolimus, nicotine, and 5-ASA, systemic corticosteroids and immunosuppressant agents such as azathioprine, cyclosporine, methotrexate and mycophenolate. When these approaches fail, biologic therapy is usually tried. Successful treatment with TNF inhibitors (etanercept, adalimumab, infliximab) has been reported. Response to ustekinumab and various investigational interleukin inhibitors has also been reported. Surgical management is another option. Hidradenitis Suppurativa Hidradenitis Suppurativa (HS) is an inflammatory skin disease affecting an estimated 1 to 4% of the world population. The main features of HS include painful and chronically recurring, deep-seated follicular nodules, papules, pustules, and abscesses, scarring, sinus tracts, and recurrent discharge. The areas most commonly affected are under the arms, groin, buttocks, and under the breasts. The disease is variable and recurrent. It may occur as solitary or multiple lesions in one area, or in many areas. In more severe cases, there may be large areas of skin affected by recurrent, draining lesions. The U.S. Food and Drug Administration (FDA) approved adalimumab to treat patients with HS. Wegener s Granulomatosis and Microscopic Polyangitis Wegener s granulomatosis (WG) is an autoimmune vasculitis that may affect various internal organs and can be potentially life-threatening. Symptoms vary and can mimic a variety of other diseases, making it difficult to diagnose. These include rhinitis, glomerulonephritis, pulmonary nodules and hemorrhage, neuropathies,

16 gastrointestinal symptoms and various other inflammatory manifestations. The disease can occur at any age, usually in adults. WG can be recognized by the distinctive triad of granulomatous inflammation, necrosis, and vasculitis of the respiratory tract. Vasculitis in other regions is also common. It can follow a varied clinical course that is strongly influenced by treatment. Untreated, generalized WG is usually lethal. Historically, treatment with immunosuppressants has been used. Glucocorticoids and cyclophosphamide have been a standard therapy, but this is limited by cyclophosphamide toxicity. If remission is achieved, less toxic agents such as azathioprine may be employed for maintenance. The U.S. Food and Drug Administration (FDA) has approved rituximab in combination with glucocorticoids, to treat patients with WG and microscopic polyangiitis (MPA). Both of these diseases affect people of all ages and ethnicities, and both genders. The causes of these disorders are unknown, and both are considered orphan diseases because they each affect less than 200,000 people in the United States. Multiple Sclerosis It is currently thought that multiple sclerosis (MS) is the result of a combination of factors including immune response, genetics, infection, and environmental issues. MS is characterized by the destruction of the myelin sheath that surrounds axons of the central nervous system (CNS) and eventual axonal damage. This is believed to be an autoimmune attack against myelin and the myelin-producing oligodendrocytes. There is an associated inflammatory response involving B-cells, T-cells, macrophages, antibodies, and complement. The myelin sheath is replaced by sclerotic plaques. The damage to the myelin sheath can delay or halt nerve impulses. Axonal damage leads to loss of nerve impulses. An estimated 250,000 to 400,000 cases exist in the United States. In 2000, the estimated prevalence was 191/100,000 Caucasians in the United States, with an incidence rate of 7.3/100,000 person-years at risk. Diagnosis usually occurs when patients are between 20 and 50 years of age. The disease is more prevalent: 1) further away from the equator; 2) in Caucasians; and 3) in women. Other risk factors include Epstein-Barr virus exposure, vitamin D deficiency, and smoking. MS usually follows one of the following four disease courses, but individual presentation can vary quite widely. 1. Relapsing-remitting MS (RRMS): clearly defined acute attacks followed by periods of partial or full recovery. This is the most common course of the disease describing approximately 85% of MS patients. 2. Primary-progressive MS (PPMS): the disease steadily progresses although there may be occasional plateaus or remissions. The patient does not experience acute attacks. Approximately 10% of MS patients have PPMS. 3. Secondary-progressive MS (SPMS): often follows RRMS. Patient experiences acute attacks similar to RRMS, but with progressively less recovery after acute attacks and progressively worsening function between attacks. As with PPMS, there may be occasional plateaus or remissions. Progressive-relapsing MS (PRMS): initially presents as PPMS with steady disease progression, but later experiences acute attacks with followed by partial recovery. This is only seen in approximately 5% of MS patients. Scope [TOP] Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage. Benefit Application

17 N/A [TOP] Rationale [TOP] Rheumatoid Arthritis The American College of Rheumatology (ACR) has established clinical guidelines for the treatment of rheumatoid arthritis (RA). While both non-pharmacologic (e.g., patient education, exercise, and physical and occupational therapy) and pharmacologic therapies are recommended, the mainstay of RA treatment is pharmacologic therapy. Pharmacologic management often consists of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs) (including biologic response modifiers/cytokine antagonists), and/or corticosteroids. Because of the evidence showing that joint damage can occur early in the disease process, physicians are now encouraged to treat patients more aggressively earlier by initiating a DMARD (or combinations of DMARDs) within 3 months of diagnosis. Emerging evidence also suggests that the DMARD subclass of tumor necrosis factor-alpha (TNF-) antagonists retard radiographic progression of the disease better than methotrexate (MTX), particularly in patients with rapidly progressive disease. The predictive risk factor found to be most associated with this subset of patients was a CRP 4.1 mg/dl. Other predictors are currently being investigated. This should lead to improved ability for the clinician to determine the best DMARD for an individual patient; however, the choice will continue to be influenced by numerous factors, including but not limited to relative efficacy, convenience of administration, adverse effects, monitoring requirements, comorbidities, and cost. Abatacept and rituximab have also gained labeling regarding ability to inhibit progressive structural damage. Psoriatic Arthritis Pharmacologic therapy combined with a physical rehabilitation program is the most effective available treatment for psoriatic arthritis (PsA). As with RA, early initiation of pharmacologic therapy is needed to avoid joint damage and disability. NSAIDs have customarily been used in milder disease along with corticosteroids or traditional DMARDs. Moderate to severe disease requires the use of traditional DMARDs such as MTX, sulfasalazine, or the anti-tnf agents. Azathioprine and cyclosporine are rarely used. Retinoids, phototherapy, and topical and systemic corticosteroids have also been used to treat the skin manifestations of PsA. In January 2002, etanercept, a TNF- inhibitor became the first therapy to be approved for the indication. Adalimumab has also recently received FDAapproval for this indication. Additionally, infliximab has been demonstrated effective for this condition in at least one randomized, double-blind, controlled clinical trial. FDA has since approved the newer TNF- inhibitors certolizumab pegol and golimumab for this indication. More recently, the IL12/IL23 inihbitor ustekinumab and the phosphodiesterase 4 inhibitor apremilast are now approved. Other Arthropathies Treatment of mild spondyloarthropathy may be benefited by symptomatic therapy with NSAIDs, corticosteroids, or sulfasalazine. These agents have shown to have little clinical benefit in patients with moderate to severe or progressive disease. The paucity of treatment options contrasts with the treatment of RA where there are several different categories of DMARDs (disease-modifying anti-rheumatic drugs) that are used alone or in combination to try and alter the natural history of the disease. Like PsA, etanercept became the first therapy approved by the FDA for the treatment of AS, followed by infliximab and adalimumab. Psoriasis Topical therapy, usually corticosteroids, is recommended as first-line treatment in psoriasis because these products are easy to administer, inexpensive, and safe. However, application to large areas of involvement can be time-consuming, expensive, and messy. Most patients with moderate to severe disease will not achieve clearance or long-term remission. Tachyphylaxis may also develop with long-term use of topical corticosteroids. In

18 patients whose moderate to severe psoriasis fails topical therapy, the therapeutic options that remain are systemic agents, phototherapy and biologics. Approved systemic agents (methotrexate, cyclosporine, and acitretin) are highly effective in the treatment of psoriasis; however, these therapies have limitations due to serious toxicities that require monitoring. Methotrexate can cause hepatotoxicity. Methotrexate is also associated with bone marrow toxicity, severe pulmonary toxicity, and serious drug-drug interactions (e.g., trimethoprim-sulfamethoxazole). Cyclosporine is nephrotoxic, and can cause interstitial fibrosis and renal tubular atrophy in patients treated for more than 2 years. Hypertension, laboratory abnormalities (electrolytes, liver function tests, lipids), and numerous drug-drug interactions are also among the problems associated with cyclosporine. Because methotrexate and cyclosporine are potent immunosuppressive drugs, patients are at increased risk of infections and malignancies, including skin cancers and lymphoproliferative disorders. Like all retinoids, acitretin is highly teratogenic, posing a long-lasting risk (up to 3 years) in women of childbearing potential. Elevation in liver function tests, hyperlipidemia, and mucocutaneous reactions are additional adverse events associated with acitretin. Systemic corticosteroids are generally avoided as they may be associated with severe exacerbations, both during and after treatment. Phototherapy (e.g., UVB, narrowband UVB, PUVA) is used for patients who fail topicals or those with disease too extensive for topical therapy. Phototherapy can be effective for many patients, but it is inconvenient and timeconsuming, as frequent office or clinic visits are required and the availability of specialized phototherapy clinics may be limited. Cumulative exposure to PUVA is associated with an increased risk of squamous cell carcinoma and malignant melanoma. Various other strategies using traditional therapies have also been used to maintain remission and decrease the risk of cumulative end-organ toxicities. Rotational therapy involves the use of a therapy for some time and then switching to another form of therapy. Combination therapy uses low-dosages of different treatments concurrently to minimize toxicity and enhance efficacy. Traditionally, these strategies usually involve topicals, phototherapy, and systemics in various combinations. Biologic agents have been shown effective for many patients in randomized, double-blind, placebo-controlled clinical trials, but there are few head-to-head clinical trials comparing these agents with traditional therapies. NBUVB continues to appear a very effective therapy in terms of achievement of 75% response, global assessment ( clear or almost clear ), and length of remission. While the long-term risks of PUVA, methotrexate, and cyclosporine use in psoriatic patients have become more clearly identified, these data are not available for the biologics in this population. The new biologic agents are clearly more widely available and convenient than the mainstay of psoriasis therapy, NBUVB, which may require anywhere from outpatient visits to specialized facilities per year. On the other hand, biologics are all administered by injection, making them less convenient than systemic oral therapy. Infliximab (Remicade ) is approved for the treatment of adults with chronic severe plaque psoriasis who are candidates for systemic therapies and clinical trial results for adalimumab (Humira ), Remicade and etanercept (Enbrel ) have been published. Of these, three Humira studies added enough new information to warrant offlabel use consideration. In the first multicenter, randomized, double-blind, placebo-controlled study, 147 patients received Humira 80 mg at week 0, then 40 mg every other week beginning week 1, Humira 80 mg at week 0 and 1, then 40 mg every week beginning at week 1, or placebo for 12 weeks, after which placebo patients were crossed over to Humira 40 mg every other week in a 48-week open label extension trial. At week 12, 53% of patients taking Humira every other week, 80% of patients taking Humira weekly, and 4% of patients taking placebo achieved 75% improvement in Psoriasis Area and Severity Index score (P<0.001). Responses were sustained for 60 weeks. Humira was safe and well tolerated in this population. In the Phase III REVEAL study (Randomized Controlled Evaluation of adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis TriAL), 1,212 patients with moderate to severe chronic plaque psoriasis were randomized to treatment with Humira 80 mg at week 0, then 40 mg every other week beginning at week 1 or placebo. The trial was comprised of 3 periods, a 16-week, double-blind period for assessment of initial response; a 17-week open-label sustained response period, in which responders to either treatment (those achieving a PASI-75) received Humira 40 mg every other week; and a final 19-week, double-blind loss of response period, in which patients receiving Humira throughout the previous 2 study periods were re-randomized to either Humira every other week or placebo. In the initial response phase, more Humira-treated patients achieved a PASI-75 compared to those receiving placebo beginning at week 4 and at every visit throughout the 16-week evaluation period. At week 16, 71% of Humira- and 6.5% of placebo-treated patients achieved a PASI-75 (P<0.001). In Humira responders, mean PASI scores were maintained throughout the subsequent maintenance of response

19 period (weeks 16-33) of the study. In the last period of the study examining loss of response, 28.4% of patients re-randomized to placebo lost response by week 52 compared to 4.9% of patients maintaining Humira (P<0.001). Humira was generally well tolerated and no unexpected adverse events were observed over the 52 weeks of the trial. In a second Phase III trial, CHAMPION (Comparative Study of HUMIRA vs. Methotrexate vs. Placebo In PsOriasis Patients), 271 patients were randomized to treatment with Humira 80 mg at week 0, then 40 mg every other week beginning at week 1 (n=108), methotrexate 7.5 mg x 2 weeks, 10 mg x 2 weeks, then 15 mg orally (n=110), or placebo (n=53) for a total of 16 weeks. At week 16, more Humira-treated patients achieved a PASI-75 response (80%) than patients receiving either methotrexate (36%, P<0.001) or placebo (19%, P<0.001). Similar results were observed for PASI-90 response and PGA clear or minimal response. Humira was generally welltolerated, with a safety profile similar to that known for an arthritis population. In September 2009, the FDA approved the use of ustekinumab to treat plaque psoriasis. Ustekinumab is a human IgG1қ monoclonal antibody that binds to the shared p40 subunit of interleukins 12 and 23, blocking signaling of their cognate receptors. It is known that IL-12 and IL-23 plays important roles in the pathogenesis of psoriasis. IL- 12 causes differentiation of CD4+ T cells to interferon-gamma (IFN-gamma)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12 β1 The evidence of efficacy consists mainly of two pivotal trials (PHOENIX I and PHOENIX II) submitted for FDA approval. Both studies showed robust clinical result against placebo. The primary endpoint for both studies was the proportion of patients achieving a PASI 75 in the 12 week placebo-controlled trial. Both the 45mg and 90 mg groups achieved statistically significantly higher PASI 75 rate compared to placebo (67.1%, 66.4%, 3.1%, respectively; each p< vs. placebo). Both studies also showed favorable secondary endpoint results for PGA score and DLQI vs. placebo. Ustekinumab was found more efficacious compared to etanercept during a Phase III, multi-center, active controlled trial with 930 patients (ACCEPT trial). For the primary efficacy endpoint of PASI 75 at week 12, a greater proportion of patients treated with ustekinumab 45mg and 90mg achieved a PASI 75 compared to those receiving etanercept 50mg. More recently, phosphodiesterase 4 inhibitor apremilast has been now approved for moderate to severe plaque psoriasis. Two multicenter, randomized, double-blind, placebo-controlled trials (PSOR-1 and PSOR-2) enrolled a total of 1257 subjects with moderate to severe plaque psoriasis. In both studies, subjects were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks. Primary endpoints were the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a spga score of clear (0) or almost clear (1) at Week 16. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis. Approximately 33% of patients receiving apremilast in PSOR-1 achieved a PASI-75 (vs. 5% on placebo), and 29% of apremilast patients in PSOR-2 (vs. 6% on placebo). In all groups, approximately 2/3 of patients achieving PASI-75 also had spga scores of clear (0) or almost clear (1). Crohn s Disease (CD) The American College of Gastroenterology indicates current therapeutic recommendations depend on disease location, disease severity, and the presence of disease-associated complications. Pharmacologic approaches include various 5-aminosalicylates (5-ASAs), corticosteroids, and immunosuppressants. While the effectiveness of the 5-ASAs is less than corticosteroids, their side effect profile is more favorable. Azathioprine and sulfasalazine are also associated with clinically significant long-term toxicity, according to the National Cooperative Crohn s Disease Study. Azathioprine, sulfasalazine, and prednisone have not been demonstrated to prevent recurrence of disease flares. Surgical resection is a common occurrence in CD, with up to 57% of patients requiring at least one surgery in any given year. Within 10 years of disease onset, 71% of patients undergo this therapy. Clinical trials with infliximab (Remicade) in patients with moderate to severe CD have shown that Remicade significantly reduces symptoms, improves quality of life, provides endoscopic evidence of mucosal healing, and reduces recurrence rates allowing for fewer hospitalizations and invasive procedures. Additionally, patients with

20 fistulizing disease were able to achieve a reduction in the number of draining enterocutaneous and rectovaginal fistulas. The safety and efficacy of adalimumab (Humira) for the induction and/or maintenance of remission in patients with moderately to severely active CD (Crohn s Disease Activity Index [CDAI] 220 and 450) was evaluated in four randomized placebo-controlled studies. Two of these studies evaluated Humira for induction of remission (defined as a CDAI <150), one study in patients who were TNF antagonist naïve (CLASSIC-I) and the other in patients who had lost response or were intolerant to Remicade (GAIN). Two of these studies evaluated Humira for maintenance of remission, both studies in patients who were TNF antagonist naïve (CLASSIC-II and CHARM). In CLASSIC-I, 299 patients with moderately to severely active CD, including patients with draining fistulas, were randomized to two subcutaneous injections at Weeks 0 and 2 with Humira 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. Enrollees were also able to maintain existing therapy with immunomodulatory agents, corticosteroids, and/or aminosalicylates. The primary efficacy endpoint was induction of remission (CDAI <150) at Week 4. The rate of remission was significantly higher in the 160 mg/80 mg group (36%, p=0.001), but not for the 40 mg/20 mg (18%, p=0.36) or 80 mg/40 mg (24%, p=0.06) groups compared with placebo (12%). Injection site reactions occurred more frequently in Humira-treated patients, otherwise adverse events occurred at similar frequencies in all four treatment groups. In GAIN, 325 patients with moderately to severely active CD who were intolerant of, who had lost response, or who had an inadequate response to Remicade were randomized to two subcutaneous injections at Weeks 0 and 2 with Humira 160 mg/80 mg or placebo. Primary efficacy endpoint was induction of remission (CDAI <150) at Week 4. Clinical response (decrease in CDAI score 70 or 100) at Week 4 was also assessed. More Humiratreated patients (21%, p<0.001) achieved clinical remission compared to those treated with placebo (7%). More Humira-treated patients (52%, p<0.01) achieved a clinical response-70 compared with the placebo group (34%). A total of 276 patients participating in CLASSIC-I enrolled in CLASSIC-II and received open-label Humira 40 mg subcutaneously at Weeks 0 (Week 4 of CLASSIC-I) and 2. Those patients (n=55) in remission at both Week 0 and Week 4 were re-randomized to Humira 40 mg QOW, 40 mg QW, or placebo for 52 additional weeks. Patients who were not in remission at both Weeks 0 and 4 were treated with open-label Humira 40 mg QOW. These patients were allowed to have their dose increase to 40 mg QW for non-response or disease flare. The rerandomized patients were also allowed to escape into this open-label arm with disease flare. The primary efficacy endpoint was maintenance of remission (CDAI <150) in randomized patients through week 56. Of the 55 patients randomized at Week 4, a greater proportion receiving Humira (79% of the Humira 40 mg QOW group and 83% of the 40 mg QW group, both p<0.05) were in remission compared to the placebo group (44%). Of 204 patients entering the open-label arm, 46% were in remission at Week 56. Humira was generally well-tolerated. In CHARM, a total of 854 patients with moderately to severely active CD were treated with open-label Humira 80 mg at Week 0 followed by 40 mg at Week 2 as induction therapy. At Week 4, patients were stratified by clinical response (decrease of CDAI 70) and randomized to double-blind treatment with subcutaneous Humira 40 mg QOW, Humira 40 mg QW, or placebo weekly for 52 additional weeks. The proportion of randomized clinical responders achieving clinical remission at Week 26 and 56 were coprimary endpoints. At Week 4, 499/854 (58%) of patients achieved a clinical response-70 and were randomized to Humira or placebo. The percentage of randomized responders in remission was significantly greater in the Humira 40 mg QOW and 40 mg QW groups compared to the placebo group at Week 26 (40%, 47%, and 17%, respectively; p<0.001) and at Week 56 (36%, 41%, and 12%, respectively; p<0.001). No significant differences in efficacy were observed between the two active treatment groups. Patients who did not achieve clinical response after 12 weeks were unlikely to achieve response. The safety profile for Humira was consistent with previous experience with the drug. More patients receiving placebo (13.4%) discontinued treatment for an adverse event than those receiving Humira (6.9% in the 40 mg QOW and 4.7% in the 40 mg QW group). Two randomized controlled Phase III trials, PRECiSE 1 and PRECiSE 2, demonstrated the safety and efficacy of Cimzia 400 mg SC at Weeks 0, 2, 4 and then every four weeks versus placebo for up to 24 weeks. In the induction study, patients who had C-reactive protein (CRP) levels >10 mg/l at baseline who were treated with certolizumab had higher response rates than placebo-treated patients (37% versus 26%; p=0.04) at Week 6. In the overall population, response rates were significantly higher with certolizumab vs. placebo (23% versus 16%; p=0.02). There were no significant differences in remission rates at Week 6 or 26 between certolizumab and placebo. Overall, certolizumab was well tolerated. The other trial investigated the efficacy of maintenance therapy in patients that had completed a standard induction course. In this study 64% of all initially enrolled patients achieved a clinical response (decrease in CDAI 150) at 6-weeks. Certolizumab produced significantly better