20160113 after the biologics where will you be

The day after Biologicswhere will you be?Taipei Medical University Shunang Ho hospitalRheumatology Dr. KaiLuen Tsai

1

outlineBiologics vs traditional DMARDIndication for Biologics in Rheumatic dzPost marketing risk managementRisk of infectionCancer concern

Nature Reviews Gastroenterology & Hepatology 12, 363368 (2015)

(DMARD) Hydroxychloroquin (Plaquenil, ; Geniquin )Sulfasalazine (Salazopyrin )Leflunomide (Arava,; Arheuma )D-penicillamine (Metalcaptase )Methotrexate (MTX )Azathioprine (Imuran )Cyclophosphamide (Cytoxan, Endoxan )Cyclosporine (Sandimmun Neoral , Equoral )Mycophenolate mofetil (Cellcept )Mycophenolic acid (Myfortic )

: Ancient time: legends: Aspirin, Colchicine : Middle age: Gold salt, penicillamine, salfazopyrine, hydroxychloroquine, NSAID: Renaissance : MTX 1951 Steroid 1948Modern : Biologics: Anti-TNF alpha 1980

: Renaisance: MTX 1951 Steroid 1948Modern : Biologics: Anti-TNF alpha 1980 -> remission induction, treat to target, risk management, target therpay6

Medication for JIANature Reviews Rheumatology 11, 290300 (2015)

steroid side effect/ ()/

Steroid dose is commonly characterised into:Low dose (e.g. 20mg/day of prednis(ol)one, sometimes more than 100mg/day).

56 10DAS28 7.24ESR 98 CRP 4.275 20DAS28 5.32ESR 65 CRP 5.2

56 ESR 78 CRP 4.2

NEJM 2001

NEJM, 2006.

NEJM 2012

rapid expansion of the therapeutic bioagents has the potential to dramatically improve RA patient care.12


http://speakingofresearch.com/tag/monoclonal-antibodies/

Nature Clinical Practice Neurology (2005) 1, 34-44MURINECIMETRICRECOMSTRUCTIVEHUMAN100%33%10%0%

1975198319881985/1990

Humira , an anti-TNF (Tumour Necrosis Factor) treatment for rheumatoid arthritis (RA), leads the way as the first commercial, fully-human monoclonal antibody drug. Marketed by Abbott, it first appeared in 2003.



(RA) (AS) (USpA) (Psor, PsA)(CD, UC) (SS) (SLE) (PSS or SSc) (Osteoporosis)/ (BA/AD)/ (Pemphigus, bullous pemphigoid) (Vasculitis)

2016/1/14Etanercept(Enbrel)TNFAdalimumsb(Humira)TNF

Golimumab(Simponi)TNF

Rituxtimab (MabTheRa)BCD20

Abatacept (Orencia )T

Tocilizumab (Actemra )IL-6

Ustekinumab(Stelara)IL-12/IL-23Belimumab(Benlysta)B

Omalizumab ( Xolair )IgE IgEDenosumab(Prolia)RANKLTofacitinib(XELJANZ)The JAK inhibitor tofacitinib

Rheumatoid arthritis

Chronic SystemicAutoimmune disease

Synovitis / ACCP / RF

The role of cytokinesCytokines are natural mediators of cell function.1 They transmit information between cells, mediate inflammatory reactions, and regulate cell growth and differentiation.1,2 Cytokines work either in synergy with other cytokines, promoting and supplementing their effects, or in opposition to them.1 Their targets may be the cells that produced them or adjacent cells.1 Some cytokines are capable of inducing production of other cytokines by binding to specific receptors on target cells. Once activated, these cells release more cytokines, setting up a cytokine cascade in the synovium.3 The cytokine network is largely self-regulating, with a balance of pro- and anti-inflammatory cytokines.4 As shown here, proinflammatory cytokines such as TNF induce inflammation by binding to appropriate cell-surface receptors. Serving as a counterbalance are anti-inflammatory cytokines such as soluble TNF-receptors, which intercept and neutralize TNF.5 References: 1. Arend WP, Dayer J. Cytokines and growth factors. In: Kelley WN, ed. Textbook of Rheumatology. Vol 1. 4th ed. Philadelphia, Pa: W.B. Saunders Company; 1993;227-247. 2. Carpenter AB. Immunology and inflammation. In: Wegener ST, ed. Clinical Care in the Rheumatic Diseases. Atlanta, Ga: American College of Rheumatology; 1996:9-14. 3. Baumgartner SW. Tumor necrosis factor inactivation in the management of rheumatoid arthritis. South Med J. 2000;93:753-759. 4. Arend WP. Mediators of inflammation, tissue destruction, and repair: growth factors and cytokines. In: Klippel JH, ed. Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation; 1997:39-64. 5. Moreland LW. Inhibitors of tumor necrosis factor: new treatment options for rheumatoid arthritis. Cleve Clin J Med. 1999;66:367-374.

Others: Tofacitinib(Xeljanz

CTLA4-Ig

1. Adapted from Waldburger JM et al. Arthritis Res Ther 2009;11:206. 2. Adapted from Shuai K et al. Nat Rev Immunol 2003;3:900911. 3. Adapted from Jiang JK et al. J Med Chem 2008;51:80128018.XEL-FM-1409007

DAS 28 (28DAS28 = 0.56 (TJC28) + 0.28 (SJC28) + 0.70 Ln (ESR) + 0.014 (GH)

: 28 (Disease Activity Score, DAS 28) 5.1 (DMARD) MTX base + DMARD ESR>

Nature Reviews Rheumatology 11, 276289 (2015)


??CV risk significant decreasedTuberculosisCOPD patient : treated with ORENCIA developed adverse events more frequently than those treated with placeboRA+CKD pt, associated with less renal function decline (Rheumatol Int.2015 Apr;35(4):727-34.HBV, HCVAnti-Il-6: bowel perforation risk Increase infection riskBase on which kind of biologics: IL6, JAK inhibitor -> dyslipidemiaDecrease steroid dose -> had benefit for blood sugar controlHema: Base on which kinds of biologicsOnco: Cancer risk +/-Biologics induce lupus

Anklyosing spondylitis

Nature Reviews Rheumatology 6, 75-81

Biologics for ASFurther:Anti-IL 17Anti-JAKAnti-WNT

Psoriasis (PsO) Psoriatic arthritis(PsA)2016/1/14

43 y/o F

4000110439 43 y/o

60 y/o f

4160 y/o 05843426

38 y/o m

4207249934 38 y/o m

in psoriatic lesionsinduces proliferation of keratinocytes

N Engl J Med 2009; 361:496-509

44

TN Engl J Med 2009; 361:496-509

45

Nature BiotechUstekinumab (Stelara)

AdalimumabEtanerceptInfiximabGolimumabUstekinumab 45/90

Ustekinumab47

For PsO and PsAAnti-TNFEtanerceptAdalimumabGolimumabAnti-IL12/23Ustekinumab

FutureIL 17 inhibitorAbatacept (CTLA4-Ig, Costimulation blockadeTofacitinib (JAK inhibitor)PDE4 inhibitorIL 6 ?Anti-CD 20 ?

Inflammation bowel diseaseCrohn's disease and ulcerative colitis

Nature Reviews Gastroenterology & Hepatology7,110-117(February 2010)

Biologics for IBD

Nature Reviews Gastroenterology & Hepatology12,537545(2015)

Systemic lupus erythematous

2016/1/14

Lupus pathway RituximabAbataceptBelimumabCD20

Regimen ? Rituximab for SLE refractory LN ( 30%~50% )Hemolytic anemia (50%~)

Two major clinical trials have not met their endpoints, but ACR and EULAR guidelines suggest consideration of rituximab for patients with active lupus nephritisrefractory to conventional therapies. By Lancet Vol 384 November 22, 2014

Regimen ? Lupus nephritis

For lupus nephritis, partial response was defined as 50% improvement in all renal parameters (serum creatinine level and proteinuria) with abnormal values at baseline, complete response was defined as a decrease in proteinuria to 0.5 gm/day,

partial response was defined as a hemoglobin level 10 gm/dl with at least a 2 gm/dl increase from the pretreatment level; complete response was defined as a hemoglobin level 11 gm/dl in women or 12 gm/dl in men without hemolysis

complete response was defined as a platelet count of at least 100 109/liter; response was defined as a platelet count of 30100 109/liter and at least a doubling ofthe baseline count; and no response was defined as a platelet count 30 109/liter or less than doubling of the baseline count 54

Belimumab is approved in the United States, Canada and Europe for treatment of SLE. However, the major phase III trials excluded the more severe cases of SLE with kidney and brain damage, so its effectiveness has not been demonstrated in those cases.

Muco-cutanous

mucocutanous55

Anti-dsDNA, median % changeanti-CD 20+ B cell, median % changeBelimumab

Belimumab56

Abatacept(CTLA4-Ig

Abatacept(CTLA4-Ig57

To be continuous.


An easy-to-fail endpoint and aggressive back ground meds

()

B Cell-targeted Therapies seems effect in Sjogren syndrome

Rheumatology (2015) 54 (2): 219-230.


61

JAMA, August 8, 2007Vol 298, No. 6 (

Nature Reviews Rheumatology 10, 502510 (2014) potential therapeutic targets in AAV and LVV,

Osteoporosis

2016/1/14

2016/1/14

2016/1/14

RANKL

Osteoarthritis

Osteoarthritis

-nerve growth factor (-NGF), IL-1 or TNF?Hyaluronic acidPlatelet-rich plasmaStem cells

Ann. Rheum. Dis. 71, 891898 (2012).

Erosions were measured 1 year after biweekly subcutaneous injections with either placebo or adalimumab. Patients with interphalangeal joint swelling at baseline had fewer new erosions when treated with adalimumab (P= 0.009).68

Even brain, may be the further targetNature Reviews Immunology 16, 2234 (2016)


Anti-TNF alpha

Volume 8, No. 10, p601611, October 2008

Kalb R, et al. G2C 2014. P1643 Cumulative Incidence Rates of Serious Infections per 100 Patient-years, Overall Population

Abatacept

Figure 3

The Lancet2015 386, 258-265DOI: (10.1016/S0140-6736(14)61704-9)

74Traditional meta-analysis and network meta-analysis

Risk of serious infection among specified populations of patients compared with patients receiving traditional DMARD monotherapy. Data for the traditional meta-analysis are OR (95% CI) and data for the network meta-analysis are OR (95% Crl). OR=odds ratio. CrI=credible interval. DMARD=disease-modifying antirheumatic drugs.

Histoplasmosis, coccidioidomycosis, blastomycocis Pulmonary aspergillosis Listeriosis PcP Strongyloidiasis PML Hepatitis B reactivation MOTT (atypical mycobacterias) TuberculosisInfectious considerations ofbiologic DMARDs

The cytokine TNF plays an important role in defense against TB infection through several mechanisms, including macrophage activation and formation of granulomas.

Volume 3, No. 3, p148155, March 2003

Volume 8, No. 10, p601611, October 2008Progression of M tuberculosis infection

It is important to remember that >50% of reported TB cases associated with anti-TNF therapy are extrapulmonary.

Ann Rheum Dis 2010;69:522528UKHigher numbers of patients are at risk of developing TB with anti-TNF-a therapy in Asia compared with Western Europe and North America. International Journal of Rheumatic Diseases 2014; 17: 291298

The question?

XQuantiFERON

Base surveyXQuantiFERON

Half year

83

Question ? 1. LTBI INH anti-TNF ? ?2. TB reactivationanti-TNF? 3. INH?9TB? 4. INH ? Liver toxicity ?

Non cases of LTBI(latent TB infection) re-activeation were observed inpatients receiving concomitant INH prophylaxis for LTBI.

Hepatitis B and Hepatitis C

Risk of cancerAnti-TNF alpha:Clinical data on the risk of lymphomas, leukemias, and solid malignancies, as well as the overall risk of malignancy stemming from the use of TNF inhibitors, are mixed.The risk of melanoma is uncertain but may also be increased.Taiwan data: the risk of cancer was significantly reduced in biologic users compared with DMARD-only patients (HR 0.63, 95% CI 0.49-0.80,P

20160113 after the biologics where will you be

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