Treatment of Autoimmune Disease: Established Therapies

Treatment of Autoimmune Disease: Established Therapies

C H A P T E R 71 Treatment of Autoimmune Disease: Established Therapies Benedict K. Tiong, Bevra H. Hahn and Thanda Aung David Geffen School of Medic...

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C H A P T E R

71 Treatment of Autoimmune Disease: Established Therapies Benedict K. Tiong, Bevra H. Hahn and Thanda Aung David Geffen School of Medicine, Division of Rheumatology, University of California Los Angeles, Los Angeles, CA, United States

O U T L I N E Principles of Immune Suppression

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General Considerations

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Nonspecific Antiinflammatory Drugs Nonsteroidal Antiinflammatory Drugs Glucocorticoids

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Established Treatments of Rheumatic Diseases Antimalarials Sulfasalazine Leflunomide Methotrexate Cyclophosphamide Mycophenolate Mofetil (Cellcept) Azathioprine (Imuran) Calcineurin Inhibitors: Cyclosporin A, Tacrolimus, and Voclosporin

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Biologic Agents Cytokine-Targeted Therapies Tumor Necrosis Factor Inhibitors Tocilizumab (Anti-IL6R: Actemra)

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IL-1 Antagonists Secukinumab (Anti-IL17A: Cosentyx) Ustekinumab (Anti-p40 for IL-12 and IL-23 Signaling: Stelara) B-Cell-Targeted Therapies Rituximab (Rituxan) Belimumab (Anti-BLyS: Benlysta) T-Cell-Targeted Therapies

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Other Treatment Options Apremilast (Otezla) Tofacitinib (Inhibitor of Janus Kinase Activation Pathway: Xeljanz)

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Intravenous Immunoglobulin

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Comment Regarding Costs of Therapies: Biosimilars

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Moving Toward More Biological and Molecular Therapies

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References

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Rapid advances in immunology and greater understanding of disease etiology and pathogenesis have made the treatment of autoimmune diseases a dynamic and swiftly evolving field. Established therapies such as glucocorticoids (GCs), nonspecific immunosuppressive agents, and disease-modifying rheumatoid drugs (DMARD) are being supplemented or replaced by newer, more targeted biologic and molecular therapies. Progress in elucidation of basic mechanisms of autoimmune diseases has led to rapid development of targets on antigen-presenting cells (APCs), T/B lymphocytes, cytokines, and costimulatory molecules. In addition, improved measures of defining clinical response and identification of biomarkers reflecting clinical outcomes and prognosis have accelerated the development of treatment options for autoimmune diseases. The goal of this

The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00071-3

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Copyright © 2020 Elsevier Inc. All rights reserved.

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71. TREATMENT OF AUTOIMMUNE DISEASE: ESTABLISHED THERAPIES

chapter is to review established therapies of autoimmune diseases, with a focus on rheumatic diseases. We will highlight traditional therapies that form the foundation of current clinical practice (see Table 71.1), while laying out a context for which newer biologic and molecular targets are now incorporated into the current standard of care. TABLE 71.1 Drug

Established Immunosuppressive Treatments for Autoimmune Rheumatic Diseases Primary mechanism of action

Side effects

Indications

CONVENTIONAL DMARDS Antimalarials

Inhibition of TLR-3/7, raising of lysozyme pH affecting antigen processing

Retinopathy and gray skin/nails discoloration. Rarely headache, pruritus, rash, neuropathy, corneal deposition, peripheral myopathy, cardiomyopathy

Systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, Sjogren’s, juvenile dermatomyositis, palindromic rheumatism

Sulfasalazine

Inhibition of prostaglandin synthesis and cylcooxygenase, inhibition of NFκB transcription, reduction of TNF, suppression of B cells

Elevated liver enzymes, leukopenia, agranulocytosis, megaloblastic anemia, oligospermia, sperm dysmotility, GI or CNS side effects

Inflammatory bowel disease (ulcerative colitis), mild rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis

Leflunomide

Inhibits dihydroorotate dehydrogenase, affecting de novo pyrimidine synthesis

Elevated liver enzymes, diarrhea, rash, hair loss, hypertension, interstitial pneumonitis, class X teratogen

Rheumatoid arthritis

Methotrexate

Inhibits dihydrofolate reductase, interfering with purine and pyrimidine metabolism and amino acid synthesis

Elevated liver enzymes, oral ulcers, diarrhea, mild hair loss, pneumonitis, infections, bone marrow suppression

Rheumatoid arthritis, psoriasis and psoriatic arthritis, seronegative spondyloarthropathies, arthritic/skin manifestations of systemic lupus erythematosus, granulomatosis with polyangiitis, steroid sparing agent

Cyclophosphamide Alkylating agent that inhibits cell division by cross-linking DNA and reducing DNA synthesis

Infections, bladder toxicity with hemorrhagic cystitis or carcinoma, secondary malignancy, premature ovarian failure, infertility, neutropenia, hair loss, bone marrow suppression, oral ulcers

Systemic lupus erythematosus nephritis or other life-threatening manifestations, rheumatoid arthritis transverse myelitis, systemic sclerosis-related ILD, granulomatosis with polyangiitis, polyarteritis nodosa, rheumatoid vasculitis

Mycophenolate mofetil

Inhibits inosine monophosphate dehydrogenase, affecting de novo purine synthesis in activated lymphocytes

Diarrhea, abdominal cramps, nausea, infection, bone marrow suppression, neoplasia, rash, tremor

Systemic lupus erythematosus nephritis or other serious manifestations, myasthenia gravis, systemic vasculitis

Azathioprine

Purine antagonist, inhibits synthesis of DNA, RNA, proteins, cellular metabolism

Bone marrow suppression, infection, gastrointestinal upset, nausea, neoplasia

Maintenance therapy for systemic lupus erythematosus nephritis, treatment and/or maintenance for other manifestations of SLE, ulcerative colitis, Crohn’s disease rheumatoid arthritis, ANCA-positive vasculitis

Cyclosporine

Calcineurin inhibitors; inhibit transcription of IL-2 production, proliferation of T lymphocytes; inhibits production of IL2, IL-4, and CD40 ligand. Voclosporin is in clinical trials for lupus nephritis

Renal toxicity, hypertension, neurologic side effects, skin or lymphoproliferative disorders, significant drugdrug interactions

Refractory ocular and mucocutaneous Behc¸et’s disease, adult systemic lupus nephritis, systemic sclerosis, severe ulcerative colitis, myasthenia gravis; typically not first-line therapy

Infusion reactions to IV infliximab (but not to subcutaneous), rash, arthralgias, fatigue, infection, increased risk of lymphoma, skin cancers, neurologic disorders

Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis (inflix, etan, ada), juvenile idiopathic arthritis (etanercept and adalimumab), Crohn’s disease, and ulcerative colitis. Uveitis (adalimumab)

Tacrolimus Voclosporin

BIOLOGIC DMARDS Infliximab Adalimumab Golimumab Etanercept

Tumor necrosis factor inhibitor; downregulates inflammatory cytokines, inhibits immunoregulatory functions of TNF

Certolizumab (Continued)

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TABLE 71.1

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(Continued)

Drug

Primary mechanism of action

Side effects

Indications

Tocilizumab

IL-6R antagonist leading to reduced cytokine and proinflammatory pathways

Neutropenia, thrombocytopenia, elevated liver enzymes, GI perforation, infections, hyperlipidemia, rash

Rheumatoid arthritis, giant cell arteritis, systemic and polyarticular juvenile idiopathic arthritis

Anakinra

Antagonists of IL-1R, therefore inhibits inflammasome

Nausea, diarrhea, vomiting, eosinophilia, leukopenia, headache, infection

Rheumatoid arthritis, neonatal onset multisystem inflammatory disease (anakinra), systemic juvenile idiopathic arthritis, acute or uncontrolled gout. Canakinumab is approved for Familial Mediterranean Fever, cryopyrin-associated periodic syndromes, and TNF receptorassociated periodic syndromes

Rituximab

Anti-CD20 monoclonal antibody against B cells

Infusion reaction, infections. Reduced Rheumatoid arthritis, granulomatosis with vaccination response, mucocutaneous polyangiitis, microscopic polyangiitis, reactions, malignancy, rare PML due to systemic lupus erythematosus JC virus, cytopenias

Belimumab

Inhibits cytokine B lymphocyte stimulator protein (BLys, also called BAFF) necessary for B-cell proliferation, survival, and differentiation

Infections. Nausea, diarrhea, fever, insomnia, depression, leukopenia, angioedema, hypersensitivity to IV infusion. Recently available in the United States in subcutaneous injectable form

Mild-to-moderate autoantibody-positive SLE (has not completed testing in lupus nephritis and has not been used in patients with active central nervous system lupus)

Secukinumab

Inhibits IL-17A and the release of IL17-stimulated chemokines and proinflammatory cytokines

Infections. Neutropenia, nausea, diarrhea, anaphylaxis to IV doses, urticaria, can induce inflammatory bowel disease

Psoriasis, psoriatic arthritis, and ankylosing spondylitis

Ustekinumab

Inhibits IL-12 and IL-23-mediated cell signaling and cytokine production

Crohn’s disease, plaque psoriasis, and Infections. Nasopharyngitis, increased psoriatic arthritis risk of nonmelanoma skin cancers, injection site erythema, headache, reversible posterior leukoencephalopathy syndrome, arthralgia, headache, back pain, nausea, diarrhea

Abatacept

CTLA4Ig fusion protein: binds CD80 and 86, preventing their binding to CD28, thereby inhibiting T-cell activation

Infections. Headache, nausea, malignancy, may induce multiple sclerosis (very rare), vasculitis, nasopharyngitis, dizziness, back pain, extremity pain

Rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, lupus arthritis

Apremilast

Inhibits PDE4, results in increased intracellular cAMP levels

Headache, depression, diarrhea, nausea, decreased appetite, infection, rash, weight loss

Psoriasis, psoriatic arthritis

Tofacitinib Baricitinib

Inhibits JAK enzymes, preventing cytokine signaling of immune cells

Infection. Increased liver enzymes, infection, anemia, lymphopenia, hyperlipidemia, headache

Rheumatoid arthritis

Rate-related infusion reactions, headache, aseptic meningitis, acute renal failure, thrombosis, urticaria, anaphylaxis, especially in IgA-deficient patients

GuillainBarre´ syndrome, myasthenia gravis, autoimmune peripheral neuropathies, rheumatic hematologic autoimmune thrombocytopenia, or hemolytic anemia, refractory dermatomyositis or polymyositis, Kawasaki disease in children

Canakinumab

OTHER THERAPIES IVIG

Interference with Fc receptors, antiidiotypic antibodies, inhibition of reticuloendothelial clearance

US FDA has approved therapies for diseases listed in italics or are expected to soon do so. DMARD, Disease-modifying antirheumatic drugs; GI, gastrointestinal; ILD, interstitial lung disease; IL, Interleukin; IVIG, intravenous immuneglobulin; JC, John Cunningham virus; JAK, Janus kinase; NFκB, nuclear factor kappa B; PML, progressive multifocal leukoencephalopathy; TLR, Toll-like receptor; TNF, tumor necrosis factor.

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PRINCIPLES OF IMMUNE SUPPRESSION As with our oncology colleagues, the goals for physicians treating autoimmune diseases are to induce improvement (remission or low disease activity), while arresting irreversible organ damage and minimizing treatment side effects. Although definitive cure and restoration of permanent immunological tolerance would be ideal, most treatments now do not achieve that goal. Treatments are often nonspecifically antiinflammatory and/ or immunosuppressive. Thus the substantive side effects that accompany such treatments require balancing the risks of infection, bone marrow suppression, and other organ toxicity with potential efficacy. In recent years, the paradigm of “tight control” has emerged, in which goal-directed treatments are based on quantitative and disease-specific measurements that guide providers to rapidly achieve low disease activity or remission. Notably, “tight control” in rheumatoid arthritis (RA) was illustrated in the TICORA study (Grigor et al., 2004) in which 111 patients were randomly assigned to either an intensive or a routine management group. Intensive management consisted of monthly office visits, measurements of disease activity scores (DAS), steroid injections of swollen joints, and every 3 month escalation of treatment by a defined protocol if moderate or high disease activity persisted. In contrast, the routine management group was seen every 3 months, without DAS measurement, and steroid injections and treatment escalation were based on the clinical judgment of the clinician, in contrast to predefined formal targets. After 18 months, patients in the tight control/intensive group showed significantly improved disease activity, physical function, and quality of life, as well as less radiographic progression of arthritis—all at no additional cost compared to routinely managed patients. The BeST study (Goekoop-Ruiterman et al., 2007; Goekoop-Ruiterman et al., 2005) and others (Mottonen et al., 1999; Rantalaiho et al., 2009) similarly illustrated greater remission rates and earlier functional improvement in RA arthritis patients with early, goal-directed therapy emphasizing aggressive treatment to achieve tight control of disease. Given the clear advantages of intensive treatment, the tight control paradigm is reflected in the 2015 update of the American College of Rheumatology’s recommendations for the use of disease-modifying antirheumatic drugs (DMARD) and biologics in the treatment of RA (Singh et al., 2016). With greater integration of quantitative measurements and DAS to define targets for treatment remission, goal-directed therapy as demonstrated in RA may serve as a harbinger for tight control treatment algorithms under study in other autoimmune diseases. Already, there is interest in working groups for establishing similarly objective “tight control” measures for seronegative spondyloarthropathies, systemic lupus erythematosus (SLE), and others.

GENERAL CONSIDERATIONS For many autoimmune disorders, chronic inflammation can lead to a variety of nonspecific, constitutional symptoms that include fatigue, muscle pains, weight loss, and/or fever. In fact, 40%80% of the patients with SLE (lupus) experience such constitutional symptoms at any one time (Von Feldt, 1995). Furthermore, constitutional symptoms are present in a variety of other disorders such as multiple sclerosis, RA, multisystem autoimmune diseases, and vasculitis. General therapeutic principles focus on treating reversible causes of fatigue, weakness, and weight loss, such as anemia, drug toxicities, and ruling out other potential etiologies such as malignancy, infections, or thyroid/endocrine disorders. Proper muscle conditioning with appropriate aerobic exercise, good sleep management, and pain control may improve symptoms. Some studies have shown that stress may induce or exacerbate preexisting lupus symptoms (Blumenfield, 1978; Otto and Mackay, 1967), in which overall stress reduction may be beneficial (Greco et al., 2004). In addition, management of precipitating environmental factors such as sun exposure and tobacco smoke is important. UV light in SLE patients induces increased apoptosis in skin cells, thus enhancing self-antigenicity of keratinocytes to express self-antigens on their surface that may stimulate an inflammatory response and autoantibody production leading to photosensitivity, cutaneous SLE, and/or generalized flares (Casciola-Rosen et al., 1994; Jones, 1992). Furthermore, genetically prone RA patients that carry an epitope in the hypervariable region of the human leukocyte antigen-DR (HLA-DR) chain, known as the “shared epitope,” have a higher risk of developing RA if they smoke cigarettes (Padyukov et al., 2004). The relative risk for development of RA in current smokers is 2.35.6-fold higher than for nonsmokers. In another study, the relative risk for developing RA was 20-fold higher in those with two alleles of the shared epitope, a smoking history, and anticyclic citrullinated peptide (anti-CCP) antibodies (Klareskog et al., 2006). Smoking may also increase disease severity (Saag et al., 1997; Wolfe, 2000). The mechanism of interaction between smoking and the shared epitope may primarily affect

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NONSPECIFIC ANTIINFLAMMATORY DRUGS

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citrullination of proteins in inflamed synovial tissue. The association between smoking and RA was most robust in patients with anti-CCP autoantibodies detected in blood (Klareskog et al., 2006). Studies have shown an association with smoking and development of autoantibodies, such as antinuclear antibodies (ANA) (Regius et al., 1988). Smoking may also be associated with increased risk for development of SLE (Ghaussy et al., 2001) and Crohn’s disease, although it may lessen the risk of developing ulcerative colitis (UC) (Mahid et al., 2006; Tobin et al., 1987). Hence, simple but important lifestyle changes such as reducing sun exposure (for SLE) and avoiding tobacco (for RA, SLE, and Crohn’s disease) are important therapeutic considerations in management of autoimmune diseases.

NONSPECIFIC ANTIINFLAMMATORY DRUGS Nonsteroidal Antiinflammatory Drugs Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used throughout the world either over the counter or via prescription. All major NSAID classes share the common mechanism of inhibiting cyclooxygenase, which metabolizes arachidonic acid to cyclic endoperoxidases to form prostaglandins. Prostaglandins’ role in inflammation includes induction of swelling, erythema, neutrophil trafficking, changes in vascular permeability, and inhibition of apoptosis (Harris, 2002; Lu et al., 1995). In addition, other nonprostaglandin mechanisms include NSAID inhibition of nuclear factor kappa B (NFκB)dependent transcription (Amin et al., 1995), thus decreasing nitric oxide that normally may lead to increased vascular permeability and immune cell trafficking. NSAIDs are used commonly in multisystem autoimmune diseases to treat constitutional symptoms, fever, arthritis, serositis, and headache. The potential adverse effects (AEs) of NSAIDs often limit their use, particularly induction of dyspepsia, peptic ulcer disease (often with bleeding), renal vasoconstriction with acute renal injury, and exacerbation of hypertension and heart failure (Solomon, 2012), with increased risk for myocardial infarction. Thus, for safety concerns, they are recommended most commonly for as-needed (for pain and/or joint inflammation) rather than continual use. According to Epocrates searched on March 2018, a monthly dose of ibuprofen (400 mg tid) costs $24.00.

Glucocorticoids GCs have a broad range of antiinflammatory and immunosuppressive effects on both the innate and adaptive immune system. GC binds to an intracellular receptor, where they can directly affect gene transcription, resulting in inhibition of production of inflammatory cytokines, and effects on posttranslational mRNA stability. Antiinflammatory effects include downregulation of nitric oxide synthesis resulting in reduced blood vessel permeability, decreased leukocyte migration to peripheral tissues, inhibition of inflammatory mediators such as eicosanoids, inhibition of collagenases, and suppression of inflammatory cytokines. Effects of GC on immune cells include inhibition of signaling for T-cell activation and interleukin (IL)-2 synthesis, downregulation of APCs via blockade of costimulatory molecules, immune deviation toward Th2 cytokines, and induction of T-cell apoptosis (Kirouka, 2007). GCs are often used to control acute manifestations of inflammatory and autoimmune disorders, dosed on a mg/kg basis depending on the severity of the disease. Typical dosing regimens may be divided as follows from most potent to least: (1) pulse intravenous (IV) therapy with methylprednisolone 5001000 mg/day, (2) very high-dose oral GC at 12 mg/kg/day prednisone or equivalent, (3) high-dose oral GC at 0.61 mg/kg/day prednisone or equivalent, (4) medium-dose GC at 0.1250.5 mg/kg/day prednisone or equivalent, or (5) low-dose GC at 0.125 mg/kg/day prednisone or equivalent (King and Hahn, 2007). Organ threatening manifestations of disease in SLE, dermatomyositis, large and small vessel vasculitis, and multiple sclerosis often require pulse IV steroids as part of the initial induction therapy for acute flare control. Other common indications include polymyalgia rheumatica, crystalline disease flares, active RA, and Sjo¨gren’s extrasalivary gland manifestations. GCs have numerous AEs on many organ systems, more common with use of GC in high doses or over a long period of time. Major AEs with high dose (prednisone .20 mg/day) include infection, mental disturbances, osteonecrosis, osteoporosis with fractures, and impact on safety with live vaccination. For use of prednisone doses .10 mg/day, there is increased risk of glucose intolerance, peptic ulcer disease, myopathy, glaucoma, and hypertension. Weight gain is found as a common side effect even with the low dose, prednisone .5 mg/day and osteoporosis risk with the doses $ 57.5 mg/day for 3 months (Saag et al., 2011). Recent data (Al Sawah et al., 2015) show that doses of prednisone $ 7.5 mg of prednisone daily are associated with measurable damage over

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time, but doses .20 mg a day cause damage at twice that rate. Most authorities recommend tapering to doses between 0 and 7.5 mg a day for this reason. According to Epocrates in March 2018, a monthly dose of prednisone 15 mg daily costs $48.00.

ESTABLISHED TREATMENTS OF RHEUMATIC DISEASES Antimalarials Antimalarial medications such as hydroxychloroquine, chloroquine, and quinacrine can be used to treat mild-to-moderate manifestations of SLE or RA and other rheumatic disorders. Various mechanisms of action may contribute to their utility in immune modulation, including (1) inhibition of activation of intracellular Tolllike receptor (TLR)-3 and TLR-7, (2) blockade of antigen processing by raising intracytoplasmic pH in lysozymes with resultant decreased lymphocyte proliferation, autoantibody production, and natural killer cells (NK) activity, and (3) inhibition of formation of immune complexes (Fox, 1993; Fox and Kang, 1993; Kyburz et al., 2006). In addition, antiinflammatory effects include inhibition of phospholipases, prostaglandins, blockade of superoxide secretion, suppression of destructive proteolytic enzymes by synoviocytes, and blockade of UV light to protect keratinocytes from increased antigenicity (Wallace, 2007). Hormonal actions may impair insulin release, antiproliferative effects may inhibit graft versus host disease, and intercalation with DNA may block synthesis to allow degradation of ribosomal RNA (Wallace, 2007). Hydroxychloroquine and chloroquine can also inhibit platelet aggregation and adhesion (Edwards et al., 1997; Ernst et al., 1984; Jancinova et al., 1994), adding to their utility for SLE patients with coexisting antiphospholipid syndrome and/or platelet abnormalities. In SLE, antimalarials are most useful in treating constitutional symptoms, skin lesions, and arthritis, and for reduction of disease flare. In addition, the 2007 LUMINA trial illustrated an association between hydroxychloroquine and improved survival (Alarcon et al., 2007). Pregnant mothers with anti-Ro may use hydroxychloroquine to reduce risk of antibody-associated cardiac neonatal lupus (Izmirly et al., 2010). In RA, antimalarials are typically used in combination with other disease-modifying agents, such as methotrexate (MTX) or sulfasalazine. A large observational study indicated reduced risk of diabetes mellitus among patients who were taking hydroxychloroquine for RA compared to those not taking the medication (Wasko et al., 2007). Antimalarials may also decrease antibody levels in Sjo€gren’s syndrome, as well as improve sicca symptoms by inhibiting glandular cholinesterase (Dawson et al., 2005). Hydroxychloroquine has also been used in systemic onset juvenile idiopathic arthritis (Still’s disease), juvenile dermatomyositis, and palindromic rheumatism. One study found that the use of antimalarials in palindromic rheumatism patients was associated with a 20% decreased risk of progression to RA or other connective tissue disease (Gonzalez-Lopez et al., 2000). Side effects vary with specific antimalarials (in general the highest risk of important AEs is associated with chloroquine). These side effects include neuromuscular and cardiac toxicity, skin changes (particularly hyperpigmentation with all, and yellow discoloration with quinacrine), aplastic anemia (quinacrine), and rare ocular effects, including macular damage. Regular ocular screening of patients treated for more than 6 months with chloroquine or hydroxychloroquine is recommended (Marmor et al., 2011). For maximal safety regarding retinal toxicity, doses of hydroxychloroquine should not exceed 5 mg/kg daily (real weight); and risk for retinal toxicity increases after a total cumulative dose of 1000 g. According to Epocrates searched on March 2018, a monthly dose of hydroxychloroquine (400 mg daily) costs $240.00.

Sulfasalazine Sulfasalazine (azulfidine) was originally proposed for use in RA, although ultimately great benefit was seen in treatment for inflammatory bowel disease (IBD). After oral ingestion, the majority of the intact drug reaches the large intestine and is reduced to sulfapyridine and 5-aminosalicylic acid (5-ASA). For IBD, and specifically UC, 5-ASA acts locally in the colon to decrease inflammatory responses via inhibition of prostaglandin synthesis. Interestingly, in contrast to UC, the active metabolite in RA patients is sulfapyridine, although the exact mechanism of action has not been clearly identified. Patients with mild/moderate UC treated with azulfidine or 5-ASA have 50%65% response rates (MacDermott, 2017). Patients with RA show approximately 50% response rates (20% improvement or better) to sulfasalazine alone, and better response rates (nearly 80%) for triple therapy with sulfasalazine plus MTX plus hydroxychloroquine (Weisman and Rinaldi, 2017). In addition, studies suggest that the parent sulfasalazine drug inhibits NFκB transcription, may inhibit tumor necrosis factor (TNF)-α in

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macrophages by inducing apoptosis, and may suppress B-cell function (Hirohata et al., 2002; Lee et al., 2004; Rodenburg et al., 2000; Wahl et al., 1998). In RA, sulfasalazine is often used in combination therapy with other DMARDs for optimal treatment. AEs include elevated liver function tests, leukopenia, agranulocytosis, megaloblastic anemia, and gastrointestinal or central nervous system effects. In men, transient infertility has been observed with qualitative and quantitative abnormalities in sperm including oligospermia and sperm dysmotility. These effects were reversible 13 months after discontinuation of sulfasalazine (Ostensen, 2017; Sands et al., 2015). According to Epocrates searched on March 2018, the monthly cost of sulfasalazine at 1 g bid is $41.00. The monthly cost of triple therapy with sulfasalazine plus MTX at 15 mg a week orally plus hydroxychloroquine at 400 mg daily is approximately $300.00, which is considerably less expensive than the widely used MTX-plusadalimumab (biologic inhibitor of TNF-α which is given 40 mg subcutaneously every 2 weeks which costs approximately $5000 per month), a combination which costs approximately $5125.00 per month.

Leflunomide Leflunomide (LF) is an oral medication that, once absorbed, is metabolized into its active form known as teriflunomide. The main mechanism of action of teriflunomide is to inhibit the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which is an enzyme involved in the de novo pyrimidine synthesis pathway of ribonucleotide uridine monophosphate pyrimidine. Disruption of DHODH prevents activated lymphocytes from moving from the G1 to S phase (Fox, 1998). In addition, the immunomodulatory effects of LF are broad, including inhibition of leukocyte adhesion to endothelial cells and infiltration into synovium, which may be of particular importance in RA (Dimitrijevic and Bartlett, 1996; Grisar et al., 2004; Salmi et al., 1997). In addition, LF preferentially inhibits memory self-reactive lymphocytes, affects dendritic cell antigen presentation, and blocks NFκB activation (Manna and Aggarwal, 1999; Zhang et al., 1997). LF blocks protein tyrosine kinases Jak1 and Jak3, which affect T-cell stimulation via IL-2 receptor activation (Siemasko et al., 1998). LF may also increase the production of transforming growth factor beta, which is a known antiinflammatory cytokine (Cao et al., 1996). In patients with RA, LF is similar in efficacy to MTX; each treatment used alone results in 20% or greater improvement in approximately 50% of the patients. Common side effects include diarrhea, rash, hair loss, and elevated liver enzymes. Less common side effects include hypertension, interstitial pneumonitis, leukopenia, hematologic toxicities, and peripheral neuropathy. LF is contraindicated in pregnant and nursing women and in patients with preexisting liver disease. LF is approved by the United States Food and Drug Administration (US FDA) for the treatment of RA. In RA, trials have demonstrated efficacy of LF as monotherapy, with comparable outcomes to those of MTX or sulfasalazine monotherapy (Emery et al., 2000; Smolen et al., 1999). Other trials have shown efficacy in psoriatic arthritis (PsA), juvenile polyarthritis, and resistant dermatomyositis, but not ankylosing spondylitis (AS). In www.goodrx.com searched on March 2018, a month supply of LF at a dose of 20 mg daily orally costs $200400.

Methotrexate MTX is a folate antagonist that has been used effectively in a variety of autoimmune conditions. Competitive binding blocks the enzyme dihydrofolate reductase from reducing dihydrofolic acid to folinic acid, the active intracellular metabolite involved in purine/pyrimidine metabolism, and amino acid/polyamine synthesis. However, at the doses used in rheumatic conditions, which are often lower than in oncologic chemotherapeutic regimens, the exact mechanism of action is uncertain. Animal models suggest that MTX increases extracellular concentrations of adenosine in inflammatory tissue, which has antiinflammatory effects via dephosphorylation of adenine nucleotides (Cronstein, 1996; Morabito et al., 1998). Other possible mechanisms include inhibition of DNA methylation necessary for cell proliferation, induction of apoptosis of activated peripheral T cells, regulation of IL-1β, increased IL-10 synthesis, inhibition of leukotriene B2 formation and cyclooxygenase-2, and interference with neutrophil function (Cronstein, 1996; Genestier et al., 1998; Mello et al., 2000; Seitz et al., 2001). MTX can be taken orally, subcutaneously, or intramuscularly. In RA, approximately 50% of the patients with RA show 20% or better improvement in joint scores. Side effects include elevation of liver enzymes, especially when concurrently ingesting alcohol, oral ulcers, postingestion nausea, diarrhea, and hair loss. More severe complications include pneumonitis, infections due to immune suppression, bone marrow suppression, and hepatic fibrosis. Folic or folinic acid is often used as supplementation to reduce hematologic and other side effects, although folinic acid may interfere with efficacy. Pregnancy should be avoided, as MTX is a known teratogen.

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MTX is used in a variety of rheumatic conditions, most prominently in RA, but also in psoriasis/PsA, peripheral joint disease in spondyloarthropathies, SLE, granulomatosis with polyangiitis (GPA) (formerly called Wegener’s granulomatosis), and other large vessel vasculitides. Barring contraindications or allergy, MTX can be considered one of the cornerstones of DMARDs for the treatment of RA. Studies have shown both short-term and long-term efficacy in RA disease measurements, such as joint pain and swelling, quality of life, objective laboratory markers of inflammation, and radiologic progression of disease (Rich et al., 1999; Weinblatt et al., 1992, 1994), as well as possible improvement in survival (Choi et al., 2002). MTX monotherapy is first-line treatment for RA. If there is not adequate improvement in disease activity after several weeks, it is used in combination therapy with other DMARDs, such as sulfasalazine or hydroxychloroquine, or biologics (O’Dell et al., 1996; Weinblatt, 2013). Numerous trials have demonstrated the value of MTX in combination therapy on disease activity measures, reduction of radiographic progression, and functionality. MTX is often used in other disorders to treat peripheral joint arthritis symptoms, such as in psoriasis (35%40% have 75% or greater clearing of skin lesions), seronegative spondylarthritis disorders, and joint manifestations in lupus patients. In vasculitides such as GPA, oral MTX can be used as initial therapy for nonorgan threatening, nonrenal disease, although its use is associated with a higher relapse rate compared to cyclophosphamide (CYC). Thus MTX is a reasonable alternative for patients who cannot tolerate other more toxic (but more effective) treatment regimens (De Groot et al., 2005; Mukhtyar et al., 2009). In addition, MTX may be used as a steroid-sparing agent in the large vessel vasculitis in giant cell arteritis, although there is conflicting evidence of its efficacy in this setting (Hoffman et al., 2002; Jover et al., 2001). According to Epocrates searched on March 2018, the monthly cost of 15 mg daily of MTX once a week orally is approximately $22.00.

Cyclophosphamide CYC is a potent alkylating agent, used most often to treat life-threatening or organ-threatening manifestations of autoimmune and inflammatory diseases. It can be administered orally or intravenously and is metabolized by the liver mitochondrial P-450 enzyme into several active metabolites with both therapeutic and toxic effects. CYC has direct effects on DNA resulting in cell death and modulates T-cell activation (Fox and McCune, 1994; McCune and Fox, 1989). Significant side effects often limit more widespread use and include an increased risk for opportunistic infections such as Pneumocystis jiroveci pneumonia and fungal infections, bladder toxicity with hemorrhagic cystitis and carcinoma of the bladder, neutropenia, increased risk of infertility or premature ovarian failure, and development of malignancy. Short-term therapeutic use of CYC aims for rapid control of the underlying inflammatory process (over a period of a few weeks to months), while seeking replacement of CYC when possible with an acceptable alternative to avoid the significant long-term toxicities. CYC has been used effectively in the treatment of lupus nephritis, interstitial lung disease in multisystem autoimmune disease, and medium and small vessel vasculitis. In patients with severe lupus nephritis, initial landmark trials from the National Institute of Health demonstrated the superiority of monthly high-dose IV CYC (5001000 mg/m2) for 6 months, followed by two quarterly pulses with GCs, versus GC therapy alone in preserving renal function (Austin et al., 1986; Boumpas et al., 1992; Gourley et al., 1996; Illei et al., 2001). Subsequent studies have investigated the role of low-dose CYC regimens (500 mg IV every 2 weeks for 36 months) and found that this regimen compared to the higher dose CYC produces similar rates of renal remission in European patients—for up to 10 years (Houssiau et al., 2010b, 2002). It is not known whether the low-dose regimen is effective in African Americans, Asians, or Latinos with lupus nephritis. Small studies suggest a role for CYC in treatment of central nervous system manifestations of SLE, such as transverse myelitis (Barile and Lavalle, 1992; Kovacs et al., 2000; Neuwelt et al., 1995). CYC has also demonstrated improvement in pulmonary function, dyspnea, skin thickening, and health-related quality of life in patients with symptomatic systemic sclerosisrelated interstitial lung disease (Tashkin et al., 2006). CYC is a second-line agent alternative to mycophenolate for most cases of systemic sclerosis-related interstitial lung disease due to its AEs (Tashkin et al., 2016). Systemic vasculitides such as GPA, microscopic polyangiitis, anti-neutrophilic-cytoplasm antibody (ANCA)-positive vasculitis, rheumatoid vasculitis, polyarteritis nodosa, autoimmune-associated mononeuritis multiplex, and optic neuritis are other indications for CYC in which significant clinical improvement and/or survival benefits have been shown (Galindo-Rodriguez et al., 1999; Ribi et al., 2010; Scott and Bacon, 1984; Stone, 2010). CYC may be administered IV at 34 week intervals (or longer) or orally on a daily basis: the incidence of urinary bladder toxicity is probably higher with daily oral dosing. Medicare reimbursement for a 1 g/kg dose of CYC IV is approximately $1200.00 (Afifi et al., 2016).

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Mycophenolate Mofetil (Cellcept) Mycophenolate mofetil (MMF) was used initially in the 1990s for the prevention of allograft rejection in renal transplantation. In the past decade, MMF has been shown to be an effective therapy in both induction and maintenance of improvement in SLE nephritis, thus allowing for use of an alternative regimen to CYC. MMF reversibly inhibits the enzyme inosine monophosphate dehydrogenase, which is necessary for de novo purine synthesis in activated lymphocytes. Blockade with MMF results in reduced T- and B-cell proliferation, less antibody production, induction of apoptosis of activated T lymphocytes, and hindrance of production and function of adhesion molecules important for lymphocyte migration to inflammatory tissues (Allison and Eugui, 2000). Side effects include diarrhea, nausea, gastrointestinal upset, infections, bone marrow toxicity, neoplasia, and rash. MMF compared to CYC is less likely to cause alopecia and amenorrhea, but rates of infection, serious infection, and death are similar with the two treatments (Touma et al., 2011). MMF is teratogenic and should be stopped if pregnancy is being considered. The use of MMF has profoundly changed the outcomes and therapeutic landscape in induction therapy of improvement in diffuse proliferative and membranous serious SLE-related glomerulonephritis. Initial studies in Chinese patients suggested that MMF was an effective alternative to CYC (Chan et al., 2000; Hu et al., 2002). Subsequent clinical trials compared CYC to MMF. A recent international, randomized controlled trial (ALMS trial) of 370 SLE patients with active nephritis compared MMF (23 g/day) to IV CYC (0.51 g/m2) monthly for 6 months. This induction therapy showed similar efficacy between the two treatments (Appel et al., 2009). Interestingly, however, proportions of African-Americans and Latino Americans responding to CYC were lower compared to Caucasians and Asians, whereas responses in all four racial groups to MMF were similar (Isenberg et al., 2010). A subsequent metaanalysis confirmed MMF and CYC to be equivalent in efficacy and side-effect profiles (Touma et al., 2011), although MMF was not superior to CYC as suggested by an earlier randomized but not blinded clinical trial (Ginzler et al., 2005). A follow-up analysis from the ALMS trial examining nonrenal lupus activity in the same nephritis patients showed similar efficacy between MMF and CYC on nonrenal manifestations, thus suggesting MMF as a reasonable alternative to CYC for renal and nonrenal SLE (Ginzler et al., 2010). Furthermore, in addition to the above trials demonstrating MMF’s utility in induction therapy in SLE, a recent study has demonstrated MMF’s superiority in safety and efficacy as maintenance therapy for SLE nephritis compared to CYC (Contreras et al., 2004) and azathioprine (AZA) (Dooley et al., 2011; Houssiau, 2016). The American College of Rheumatology’s 2012 guidelines for treatment and management of classes III, IV, and V glomerulonephritis reflect the current state of the art regarding use of MMF (Hahn et al., 2012). It is a first choice for induction therapy (with GCs) and maintenance therapy in lupus nephritis patients who are not Caucasian or Asian, since similar proportions respond in all racial groups. Short-term therapy (6 months) with IV CYC can be chosen instead; higher proportions of Caucasians and Asians respond compared to Blacks and Latinas, but there are good responders in all groups. MMF has been successfully used for treating systemic sclerosis, myositis, uveitis, and vasculitis (GPA maintenance therapy). Because of its antilymphocyte and antifibrotic effects, it has been effective in treating interstitial lung disease associated with many rheumatic diseases (Fischer et al., 2013; Morganroth et al., 2010). MMF has also been used as a steroid-sparing agent for the treatment of other rheumatic diseases and for the treatment of autoimmune hepatitis. MMF is approved by the FDA in adults and children for maintenance of renal, liver, and heart transplants. An induction dose of MMF, 3 g orally daily, costs approximately $1300 per month according to Epocrates, searched on March 2018.

Azathioprine (Imuran) AZA is a prodrug that is metabolized to its active component 6-mercaptopurine (6-MP), a purine antagonist that inhibits DNA synthesis that leads to both cytotoxicity and decreased cellular proliferation. Intracellular metabolism of 6-MP results in decreased numbers of circulating lymphocytes, IL-2 secretion, and immunoglobulin production (Wilke, 2010). It is approved by the US FDA for prevention of renal transplant rejection and the treatment of RA; however, off-label use is common for remission maintenance of many rheumatic diseases such as SLE, polymyositis/dermatomyositis, Behc¸et’s disease, ANCA-associated vasculitis, or as a steroid-sparing agent in many other rheumatic diseases. AEs include nausea, vomiting, bone marrow suppression (particularly anemia), increased risk of infection, and malignancy. Individuals with a homozygous genetic polymorphism of the enzyme thiopurine methyltransferase that reduces the metabolism of AZA may be at greater risk for AZA bone marrow toxicity. Some authorities recommend checking for this genetic polymorphism prior to initiation of therapy. A number of studies have shown efficacy of AZA over placebo in the

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treatment of RA (Cade et al., 1976; Urowitz et al., 1973; Woodland et al., 1981), although more recent combination therapies of MTX plus biologics or other DMARDs are better. Recent data in RA suggested combined MTX and AZA had statistically more withdrawals due to adverse events than oral MTX alone (Hazlewood et al., 2016). In addition, AZA can be used for effective maintenance therapy in lupus nephritis (Contreras et al., 2004; Houssiau et al., 2010a), UC and Crohn’s bowel disease (Prefontaine et al., 2009; Timmer et al., 2007), ANCA-positive vasculitis (Pagnoux et al., 2008), and autoimmune hepatitis. According to Epocrates, searched on March 2018, a dose of 150 mg daily of AZA costs approximately $110.00 a month.

Calcineurin Inhibitors: Cyclosporin A, Tacrolimus, and Voclosporin Cyclosporin A (CSA) is a cyclic peptide of 11 amino acids that binds with high affinity to cyclophilins, which competitively bind to calcineurin. This leads to inhibition of translocation of transcription factors, NF-AT, thus reducing transcription of early cytokine genes that encode IL-2, TNF-α, interferon (IFN)-γ, IL-3, IL-4, CD40, and granulocyte-macrophage colony-stimulating factor (Schreiber and Crabtree, 1992; Timmerman et al., 1996; Wiederrecht et al., 1993). Furthermore, CSA interferes with antigen presentation by APCs. The ultimate net effect is reduction of lymphocyte proliferation. CSA is metabolized by the cytochrome P450 3A4 liver enzymes and has a variety of drugdrug interactions that may interfere with blood concentration levels, thus requiring monitoring of CSA levels. Side effects include renal toxicity, hypertension, neurologic side effects such as tremor, encephalopathy, increased risk of skin or lymphoproliferative malignancies, and heightened risk for infection. However, unlike many alkylating agents and purine antagonists, CSA lacks clinically significant bone marrow suppression. CSA has been used in a variety of established and suspected autoimmune disorders, including RA, PsA, ocular and mucocutaneous Behcet’s disease, adult lupus membranous nephritis, systemic sclerosis, atopic dermatitis, severe UC, pemphigus vulgaris, and myasthenia gravis (Magee, 2012). However, concern over long-term side effects, especially of renal toxicity, hypertension, and a myriad of drug interactions, has limited utility in chronic autoimmune diseases, except in patients who have failed more conventional therapies. Tacrolimus, another oral medication that inhibits T lymphocyte activation similarly to cyclosporine, is used widely for prevention of allograft rejection, because its potential AEs are slightly less than those of cyclosporine, with fewer hypertensive effects. Further, in vivo, the immunosuppressive effects are 1020 times greater than cyclosporine. It is being used for some autoimmune diseases, including induction and maintenance therapy for lupus nephritis, RA, and autoimmune hepatitis (Lee et al., 2011; Li et al., 2012). In Chinese and Japanese studies, tacrolimus was equivalent to high-dose IV CYC in lupus nephritis (Wang et al., 2012) and in combination with low-dose mycophenolate was very effective in inducing partial or complete remissions (in 83% compared to 63% on IV CYC) (Liu et al., 2015). A dose of 5 mg daily costs approximately $3000 per month according to Epocrates, searched on March 2018. Voclosporin, another calcineurin inhibitor, is part of the next generation of treatments in this class of drugs. Previously known by other names, including ISA247, its structure is the same as cyclosporine except at the amino acid-1 residue. This difference allows for higher binding to calcineurin, and higher potency compared to cyclosporine (Papp et al., 2008). The AEs are similar to other calcineurin inhibitors, including headache, hypertension, diarrhea, and respiratory infections. Voclosporin has been used as therapy in plaque psoriasis, noninfectious uveitis, and renal allograft rejection (Schultz, 2013). There are ongoing studies for its use in lupus nephritis.

BIOLOGIC AGENTS With increasing understanding of the pathogenesis of autoimmune rheumatic diseases, several biologic agents have been developed. They can be classified based on their mechanism of actions, cytokine-targeted therapies, B-cell-targeted therapies, and T-cell-targeted therapies.

Cytokine-Targeted Therapies Therapies interfering with TNF, IL 1, IL6, IL 12, IL 23 are currently available for rheumatic diseases particularly for RA, AS, juvenile chronic arthritis, psoriasis, and PsA.

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Tumor Necrosis Factor Inhibitors TNF inhibitors are a class of biologic drugs utilizing monoclonal antibodies (mABs) or TNF-binding fusion proteins to neutralize and block various proteins in autoimmune disease processes. The target protein of these therapeutic mAbs is TNF-α, a pleiotropic cytokine with proinflammatory and immunoregulatory functions. TNFα interacts with two receptors, either p55 (TNF receptor 1) or p75 (TNF receptor 2), resulting in various downstream signaling pathways as part of this inflammatory process (Taylor, 2010). TNF inhibitors have a structure based on the immunoglobulin molecule, including two identical heavy chains and two identical light chains. There are two functional regions in each antibody: the variable region (Fab) and the constant region (Fc). Interaction of the Fc receptors with the Fc portion of the mAb results in blocking the interaction between TNF-α and its receptors as the therapeutic target of this class of molecules. Currently, there are five FDA-approved TNF inhibitors in the United States. Infliximab is a chimeric IgG1 mAb made of a murine Fab region linked to a human IgG1 kappa constant region. Adalimumab is a fully human recombinant Fab with a human IgG1 kappa constant region. Golimumab also is fully humanized with a human IgG1 kappa constant region. Etanercept is a recombinant fusion protein consisting of the TNF receptor 2 and the Fc fraction of a human IgG1 constant region. Certolizumab is a humanized IgG4 Fab fragment linked to polyethylene glycol. They are administered intravenously or subcutaneously. TNF inhibitors are indicated for autoimmune disease including RA, PsA, AS, plaque psoriasis, juvenile idiopathic arthritis, Crohn’s disease, and UC (Willrich et al., 2015). In RA, the TNFi usually used with MTX results in at least 20% improvement in 60%70% of the patients, 50% improvement in 40%50%, and 70% improvement in 20%30%. Placebos result in improvement rates of 1%12%. In RA, TNFi are better than MTX alone; most TNFi work better when combined with MTX. In patients with early disease (less than 3 years), remissions (defined as very low disease activity using international standard measures) occur in as many as 50% with etanercept plus MTX. They also reduce the damage that RA causes in joints (erosions and cartilage loss) (Schur, 2017). For treatment of psoriasis, the mAb anti-TNFs are more effective than the fusion protein (etanercept). The most common AEs of TNFi include acute and delayed infusion/injection reactions such as rash, arthralgias, fatigue, and myalgias. Infection with bacteria, fungus, and viruses also occurs due to blockage of the immune response, with a notable increased incidence in mycobacterial tuberculosis infections. In fact, the physician must rule out active tuberculosis before administering any of the TNF inhibitors. Other less common AEs include an increased risk of malignancy and neurological disorders. TNF inhibitors should be avoided in patients with known demyelinating disease. The monthly costs of TNFi are high. According to www.goodrx.com searched on March 2018, approximate monthly cost of etanercept usual dose of 50 mg a week subcutaneous (autoinjector) is $5400, adalimumab 40 mg every 2 weeks sc is $5000, remicaid IV at 10 mg/kg (given at 68 week intervals) is $6000, and certolizumab (preferred for patients during pregnancy) is $4000.

Tocilizumab (Anti-IL6R: Actemra) Tocilizumab is a humanized anti-IL-6 receptor mAB targeting the IL-6 pathway. IL-6, a pleiotropic cytokine, is important in the pathogenesis of RA, and other autoimmune diseases. There are two different IL-6-mediated signaling pathways (Calabrese and Rose-John, 2014). In classical signaling, IL-6 binds to the membrane bound receptor (mIL-6R) via the signal transduction protein gp130, leading to dimerization and further intracellular signaling. The second pathway relies on the proteolytic cleavage of mIL-6R, leading to the generation of soluble receptor for IL-6 (sIL-6R). Tocilizumab competitively inhibits IL-6 binding to mIL-6R and sIL-6R thereby blunting downstream proinflammatory effects. A recent clinical trial in giant cell arteritis showed tocilizumab treatment induced improvement in 56% compared to 14% on placebo, at both 6 and 12 months of treatment (Stone et al., 2017). In patients with RA, tocilizumab used in combination with MTX has been studied in randomized controlled trials compared to placebo. Findings showed the efficacy of tocilizumab in combination with MTX compared to placebo, as remission of disease based on 20%, 50%, and 70% improvement was 2.5, 3.2, and 6 times higher, respectively, in this group (Singh et al., 2011). In patients with RA, tocilizumab as monotherapy was studied in a randomized clinical trial compared to MTX, yielding 69% with 20% improvement, 44% with 50% improvement, and 28% with 70% improvement (Jones et al., 2010a). The AEs most commonly reported have been infections including pneumonia, cellulitis, herpes zoster, gastroenteritis, and diverticulitis. Other side effects include an elevation in lipid levels and cytopenias. Effective blockade of IL-6R can also decrease hepcidin levels and result in an elevation in hemoglobin production (Navarro-Millan et al., 2012). In addition to use in RA, tocilizumab has been recently approved by the US FDA for giant cell arteritis. It may also be used in other forms of

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vasculitis, and in systemic and polyarticular juvenile idiopathic arthritis. Dosed at 162 mg subcutaneously every 2 weeks (prefilled syringe), the price of a 1 month supply is approximately $2200 according to www.goodrx.com searched on March 2018.

IL-1 Antagonists IL-1 is one of the proinflammatory cytokines underlying the inflammatory symptoms of RA, systemic juvenile inflammatory arthritis (JIA), and autoinflammatory diseases. Anakinra (Kineret), rilonacept (Arcalyst), and canakinumab (Ilaris) are currently available IL-1 antagonists. Anakinra is a recombinant human IL-1 receptor antagonist; it blocks IL-1 activity by competitively inhibiting IL-1 binding to the IL-1 receptor (IL-1R). Blocking IL1 also serves to inhibit clinical response to inflammasome activation; thus these agents can be useful in inflammasomemediated conditions such as acute gout. Rilonacept is dimeric fusion protein that incorporates in extracellular domains of both IL-1R and IL-1 R accessory protein fused to the Fc portion of an IgG molecule. Canakinumab is a human mAB that targets IL-1 β. All these agents are administered by subcutaneous injection. Anakinra is effective in systemic JIAs (Nigrovic et al., 2011; Vastert et al., 2014). Anakinra can be used in combination with MTX. However, it is less effective than other biologic DMARDs in adult RA (Singh et al., 2009). Increasing data suggest that IL-1 inhibition is an effective alternative for patients with familial Mediterranean fever who do not respond to or cannot tolerate colchicine (Gul et al., 2015; Hashkes et al., 2012; van der Hilst et al., 2016). The choice of IL-1 inhibitor depends upon a combination of factors including regulatory or insurance requirements, route of administration, and cost. Canakinumab may be preferred due to its efficacy and convenience since it is given every 48 weeks. Beneficial effects of IL-1 inhibition were seen in patients with acute gout in open-label pilot studies using anakinra, 100 mg daily given subcutaneously until symptoms of acute gouty arthritis improved (So et al., 2007). Rilonacept and canakinumab are approved by the US FDA for the treatment of cryopyrin-associated periodic syndromes or catastrophic antiphospolipid syndrome (CAPS). Anakinra was also used off-label with success in CAPS. AEs include anaphylaxis/hypersensitivity reactions, infections, injection site reaction, and neutropenia. Canakinumab can also cause nasopharyngitis, headache, vertigo, and diarrhea. The monthly cost of Anakinra dosed at 100 mg subcutaneously daily is $4156 according to www.goodrx.com searched on March 2018.

Secukinumab (Anti-IL17A: Cosentyx) Secukinumab is a fully humanized (IgG1κ) mAB directed against IL-17A. IL-17A is a cytokine and the primary effector of Th-17 cells as part of the pathogenesis of several autoimmune diseases including psoriasis, PsA, and AS. More specifically, IL-17A has several functions in these diseases such as keratinocyte trafficking, acting on chemokines such as CCL20 and CXCLs (Maldonado-Ficco et al., 2016). Selective blocking of IL-17A by secukinumab has demonstrated efficacy in these autoimmune diseases. For example, secukinumab in patients with moderate-tosevere plaque psoriasis induced 75% or greater improvement in the surface area of plaques in almost 80% of the individuals, compared to 44% with etanercept and 5% on placebo (using the psoriasis activity scoring index (PASI) score, a standard measurement of extent of psoriasis). The efficacy of secukinumab (and other IL17 inhibitors that are currently available) in plaque psoriasis is probably the best to date among the biologics (Feldman, 2017). Secukinumab showed significant but not dramatic response in patients with PsA in previous clinical trials with 20% improvement noted in 54% and 51% of the 300 and 150 mg dosed groups, respectively, as compared to placebo (McInnes et al., 2015). AEs of secukinumab include neutropenia, and infections notable for candidiasis (Baeten et al., 2015). According to www.goodrx.com (searched on April 2018), a monthly dose of secukinumab at 150 mg subcutaneously weekly costs $4700. However, the biologic can be withheld for a few weeks after the first 5 weeks if there is good response, so the high monthly cost may be intermittent.

Ustekinumab (Anti-p40 for IL-12 and IL-23 Signaling: Stelara) Ustekinumab binds to the p40 subunit of IL-12 and IL-23. This then prevents binding to the IL-12 and IL-23 receptors, inhibiting IL-12 and IL-23-mediated cell signaling, activation, and cytokine production, including Th1 and Th17 production of IFN-γ, IL-17, and IL-22 (Yeilding et al., 2012). In patients with active PsA, multicenter placebo-controlled trials showed significant improvement compared to placebo at doses of 45 and 90 mg with 42% and 49%, respectively, achieving 20% improvement, compared to 22% on placebo with 20% improvement

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(McInnes et al., 2013). In psoriasis, ustekinumab treatment of moderate-to-severe plaque disease results in 67% of the patients achieving 75% or greater reduction of total skin involved (PASI score) (Feldman, 2017). AEs include infections, such as nasopharyngitis. There is also increased risk of nonmelanoma skin cancers as demonstrated in postmarketing data (Baker and Isaacs, 2017). Ustekinumab has been FDA-approved for use in Crohn’s disease, plaque psoriasis, and PsA. A single injection of ustekinumab subcutaneous is approximately $10,600, but it is given once every 12 weeks for psoriasis and PsA, making the monthly cost $3533 (www.goodrx.com searched on April 2018).

B-Cell-Targeted Therapies Targeting autoreactive B cells or B-cell maturation signals has become successful therapy for autoimmune rheumatic conditions and will be discussed briefly here and in further detail in the next chapter.

Rituximab (Rituxan) Rituximab is a chimeric anti-CD20 mAB, which causes depletion of B cells via various mechanisms, including Fc gamma receptor-mediated antibody-dependent cytotoxicity, antibody-dependent complement-mediated cell lysis, and B-cell apoptosis (Cragg et al., 2005). Rituximab selectively depletes CD20 1 B cells, which play a role in autoantibody-mediated diseases including the chronic synovitis associated with RA (Tsokos, 2004). Results of the RAVE and RITUXVAS trials in patients with ANCA vasculitis show that rituximab is an effective and safer alternative to CYC, especially in patients with relapsing disease (Jones et al., 2010b; Stone et al., 2010). Of note, in prospective, controlled randomized trials, rituximab was not shown to be superior to placebo for treatment of SLE patients with active disease (renal or nonrenal) who were receiving GC plus hydroxychloroquine plus an immunosuppressive drug (Merrill et al., 2010; Rovin et al., 2012). However, many open-label studies attest to the efficacy of rituximab in SLE. In addition, there may be patients with lupus nephritis who respond to rituximab infusions in combination with MMF, without additional daily GCs (Beckwith and Lightstone, 2014). Prospective trials are in progress. The US FDA has approved rituximab for non-Hodgkin’s lymphoma, B-cell chronic lymphocytic leukemia, RA, GPA, and microscopic polyangiitis. Adverse reactions include infusion reaction, infections, hypogammaglobulinemia, and late onset neutropenia. A “round” of rituximab which consists of once-a-weekfor-4-weeks or the same total dose given once every 2 weeks during the 4 weeks is approximately $38,000 (not including infusion costs). Some patients maintain improvement for many months or years and do not need a second dose; in many rheumatic disease patients, the round is repeated every 6 months.

Belimumab (Anti-BLyS: Benlysta) Belimumab is a fully human mAB directed against soluble B lymphocyte stimulator protein (BLyS)/B-cell activating factor (also called B cell-activating-factor (BAFF)); hence, it depletes maturing B cells by inhibition of BLyS, which is required for survival and maturation of most B-cell subsets. In 2011, belimumab became the first drug in 50 years to be approved for the treatment of active SLE (excluding patients with active renal or central nervous system (CNS) disease( (Furie et al., 2011; Hahn, 2013; Navarra et al., 2011). Of note, belimumab is meant for lupus patients who are antinuclear antibody or anti-double stranded DNA positive and interestingly showed less response in African-American patients. A recent study showed that responses are durable for a 4-year period—the follow-up period of the study (Merrill et al., 2012). AEs with belimumab include infusion reactions to the IV biologic (a subcutaneous version has just become available in 2017), infections, and depression. To date, blockade of both soluble and cell-bound BLyS and of the April receptor for BlyS plus the BAFF receptor have not been effective and/or safe enough to replace belimumab. The cost of IV belimumab once a month is approximately $4070 (www.goodrx.com, searched on April 2018). Prices were not available at the time of this writing for the subcutaneous form, which will probably come into wide usage.

T-Cell-Targeted Therapies Abatacept (CTLA4-Ig Blocks Second Signals: Orencia) Abatacept (CTLA4-Ig) is a fully human soluble fusion protein that is effective for the treatment of RA. It consists of the extracellular domain of CTLA4 and the Fc portion of IgG1. CTLA4-Ig binds CD80 (B7-1) and

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CD86 (B7-2) on APCs preventing these molecules from binding to their ligand, CD28, on T cells. This interferes with optimal T-cell activation resulting in decreased production of proinflammatory cytokines (Lenschow et al., 1996). Abatacept is effective, safe and produced statistically significantly less radiographic progression in RA. The US FDA has approved it for use in RA and polyarticular JIA patients who are inadequate responders to DMARDs (Maxwell and Singh, 2010). Abatacept may be used as an alternative to a TNF inhibitor. Abatacept can be administered intravenously every 4 weeks or it can be administered subcutaneously weekly. AEs include infusion reactions, infections, and headache. According to www.goodrx.com searched on April 2018, the monthly cost of abatacept 125 mg subcutaneously weekly is $4200.

OTHER TREATMENT OPTIONS Apremilast (Otezla) Apremilast is an orally available small molecule that specifically targets phosphodiesterase (PDE4) which results in an increased level of cAMP intracellularly in multiple cell types (T cells, mononuclear cells, others). Consequently, the increase in intracellular cAMP decreases the production of several proinflammatory mediators (TNF-α, IL-12, IL-23, IFN-γ, and inducible nitric oxide synthase), and it increases the production of antiinflammatory cytokines (IL-10) (Schafer et al., 2010). This compound is effective in psoriasis and PsA and is US FDA approved for the treatment of active PsA or plaque psoriasis (moderate to severe), and/or PsA (Edwards et al., 2016). Apremilast is started at low dose with titration up to 30 mg twice daily. Modest efficacy has been shown in AS in a double-blind, placebo-controlled unpowered phase II study, but there was no statistical significance (Pathan et al., 2013). Its efficacy was also demonstrated in Behc¸et’s disease (oral and genital ulcers) (Hatemi et al., 2015). The drug is well tolerated with diarrhea, nausea, headache, and weight loss being the most common side effects. No specific lab monitoring is required. The monthly cost of Apremilast at 30 mg bid orally is $3100 according to www.goodrx.com searched on April 2018.

Tofacitinib (Inhibitor of Janus Kinase Activation Pathway: Xeljanz) Tofacitinib is a novel orally administered disease-modifying agent which inhibits Janus kinase (JAK) enzymes, therefore decreasing signaling by a number of cytokine and growth factor receptors, resulting in reduction of a variety of inflammatory mediators. Tofacitinib was shown to be effective and can be used as monotherapy or combined with MTX (our usual approach) or other nonbiologic DMARDs in patients with moderately to severely active RA who have had an inadequate response to MTX (Fleischmann et al., 2012; Kremer et al., 2013). It is taken in a dose of 5 mg twice daily or 11 mg extended release daily. The relative safety of tofacitinib appeared similar to that of other biologic disease modifying agents, including increased risk of infection and abnormal liver function tests. Other side effects include neutropenia, lymphopenia, hyperlipidemia, and, possibly, increased serum creatinine and gastrointestinal perforations. The ACR recommends that tofacitinib be used in patients with RA who have failed to respond adequately to MTX plus a TNF-inhibiting or non-TNF-inhibiting biologic (including abatacept, rituximab, tocilizumab) (Singh et al., 2016). Thus it is not yet viewed as first-line therapy for most patients with RA. Several additional JakStat inhibitors, some more specific for molecules that do not inhibit hematopoiesis, are in development. Baricitinib has recently been approved by the FDA for treatment of RA. According to www.goodrx.com searched on April 2018, the monthly cost of tofacitinib at 5 mg bid orally is $4100.

INTRAVENOUS IMMUNOGLOBULIN The use of intravenous IV immuneglobulin (IVIG) in autoimmune diseases has several possible mechanisms of action in suppression of inflammatory and autoimmune processes, including interference with Fc receptors on effector cells, supply of antiidiotypic antibody activity against serum autoantibodies, inhibition of reticuloendothelial clearance of antibody-covered platelets via Fc receptors, and regulation of expression of proinflammatory cytokines and blockade of adhesion molecules in inflammatory states (Silvergleid and Berger, 2011). In addition, other effects of IVIG include solubilization and clearance of immune complexes, altered T-cell subsets, and increased T regulatory cells. IVIG is useful in a wide range of autoimmune and autoinflammatory diseases such as GuillainBarre´ syndrome, myasthenia gravis, autoimmune peripheral neuropathies, Kawasaki disease,

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hematologic conditions such as autoimmune thrombocytopenia, hemolytic anemia or neutropenia, and antibodymediated CNS diseases resulting from interference with neurotransmitter function. Small studies have shown that IVIG is a reasonable second-line therapy for refractory dermatomyositis or polymyositis (Cherin et al., 2002; Dalakas et al., 1993). AEs of IVIG treatment include allergic reactions, including anaphylaxis (particularly in males who are IgA deficient), headache, nausea, chills or flushing, aseptic meningitis, thrombosis, and renal dysfunction. Most of these reactions are mild and transient, reversible events. Serious reactions are rare (Silvergleid and Berger, 2011). According to Epocrates, searched on April 2018, the cost of a single “round” of IV Ig varies from $3500 to $8000, depending on the dose and the supplier. This does not include infusion costs.

COMMENT REGARDING COSTS OF THERAPIES: BIOSIMILARS As shown above, the cost of medications for treatment of a common inflammatory rheumatic disease, RA, can vary from $300 to $5000 per month. All of the recently developed treatments—biologics and small molecules— are on that expensive side. The costs are also quite variable depending on what contract has been made between the payer, the pharmacy provider, and the pharmacy benefits manager companies. Biosimilars have been developed which USA and European oversight bodies have approved for patient use. To date, biosimilars do not differ from the biologic they mimic in efficacy or toxicity (Cohen et al., 2017). Now the question becomes can they be priced to an advantage for the patients and providers—perhaps 30% less in cost? The answer appears complex, with a small number of European countries paying for only one biosimilar and not the original biologic for patients with RA. A recent study from the United Kingdom showed that using infliximab and etanercept biosimilars (in rheumatic diseases) saved the National Health Service 38.8 million pounds over 2 years (Aladel et al., 2017). In the United States, there is friction between choice, profit, and affordability, with some issues being decided in part by the legal system. Somewhere in the not-too-distant future, a compromise will have to be reached that allows care to be increasingly excellent but more affordable for patients, providers, and societies.

MOVING TOWARD MORE BIOLOGICAL AND MOLECULAR THERAPIES Over the past few decades, progressive advancement in our understandings of immunopathogenesis has led to a significant expansion of potential therapeutic targets. This scientific progress has ushered in widespread use of new biologic and molecular treatments specifically targeting B and T cells, costimulation and signal transduction molecules, maturation factors, cytokines, and TLRs on APCs. For example, anti-TNF therapy is now routinely used in RA and seronegative spondyloarthritides, as monotherapy or in combination therapy with traditional DMARDs as discussed above (Singh et al., 2016). Such new therapeutic targets are the subject of the next chapter and continue to improve the standard treatments and outcomes for many autoimmune diseases.

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