therapeutic scenario in systemic lupus erythematosis (sle)

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THERAPEUTIC SCENARIO IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Dr. Pooja Hurkat Email:[email protected]

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Page 1: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

THERAPEUTIC SCENARIO IN SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE)

Dr. Pooja HurkatEmail:[email protected]

Page 2: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Agenda

What is SLE? Epidemiology Symptoms Aetiology Current standard of care and drawbacks Biologic therapy: A evolving approach Unmet Needs What’s Next?? Literature surveyed

Page 3: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

What is SLE

Systemic lupus erythematosus (SLE) is a severe, relapsing, remitting

multisystem autoimmune disease characterized by widespread

inflammation and production of auto antibodies.

The name SLE implies ~ almost any organ or system within the body

might be affected.

Onset can occur at any age however it most typically presents in young

adult females (female: male ratio of 9:1)

Page 4: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

5 million people with SLE 20 to 150 cases per 100,0001.5 million Americans 16,000 new US cases annually

Gender mostly affected

90% of cases occur in womenprevalence rates ~164 (white) to 406 (African American) per 100,000

Contributions from ethnicity

Incidence compared to Caucasians3X for Asians4X for African Americans (women) Estimated incidence rates are 1 to 25 per 100,000 in Americas, Europe and Asia Mortality compared to Caucasians2X for Asians 3X for African Americans (women)

Survival Rates ~90-95% in Western world

Danchenko et al., 2006; Lau et al. 2006; Pons-Estel et al., 2010; Ahmadpoor et al. 2014

Epidemiology

Page 5: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Symptoms

Elsevier Lupus Image Bank

Page 6: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Source : Fauci AS, Kasper DL, Braunwal d E, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison’s Priciples of Internal Medicine, 17th Edition: http://www.accessmedicine.com

Copyright © The McGraw- Hill Companies, Inc.

Aetiology

Page 7: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Goals of Therapy

Long-term survival

Lowest possible disease activity

Prevent organ damage

Minimize drug toxicity

Improve quality of life

Educate patients about their role in disease management

Individualized treatment of SLE based upon disease activity,

severity, and co-morbidities

Monitoring of disease

Multiorgan system involvement may require multidisciplinary

care

(van Vollenhoven et al., 2014; Bertsias et al., 2008; Wallace, 2008)

Page 8: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Medication Dose Range Drug Interaction Serious or common adverse effects

NSAIDs, salicylates

Doses toward upper limit of recommended

A2R.ACE inhibitors, glucocorticoid,flucon-azole, methotrexate

aseptic meningitis, decreased renal function, Vasculitis of skin, myocardial infarction, tinnitis, ototoxicity,GI events, dermatitis, dizziness, acute renal failure, edema, hypertention

Topical glucocorticoid

Mid potency for face, mid to high potency for other areas

None Known Atrophy of skin, contact dermatitis, folliculitis, hypopigmentation, infection

Topical sunscreen

SPF 15 atleast , 30+ preferred

None Known Contact dermatitis

Hydroxychloroquine

200-400 mg qd

None Known Retinal damage, agranulocytosis, aplastic anaemia, ataxia, cardiomyopathy, dizziness, myopathy, ototaxicity, peripheral neuropathy, pigmentation of skin, seizures, thrombocytopenia

Dehydroepiandrosterone

200mg qd unclear Acne, menstrual irregularities, high serum level of testosterone

Current standard of care & drawbacks

Harrison’s Internal Medicine . Part 13. Disorders of Immune systme, Connective tissue and Joints. Section 2. Disorders of Immune Mediated Injury. Chapter 313. Systemic Lupus Erythematosus. (New 17 th Edition)

A2R- Angiotensin 2 receptor,; ACE- Angiotesin converting enzyme;CHF-Congestive heart failure; CrCl- creatinine clearance; FDA- U.S. Food and Drug Administration; GI- Gastrointestinal;NSAIDs-Non steriodal anti inflammatory drugs;;SPF- Sun protection factor; VZV- Vericella zoster virus

Page 9: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Methotrexate b (for dermatitis,arthritis)

10-25 mg once a week, PO or SC, with folic acid, decrease dose if CrCl<60 mL/min

Acitretin, leflunomide, NSAIDs and salicylates, penicillins, probenecid, sulfonamides, trimethoprim

Anemia, bone marrow suppression, leucopenia, thrombocytopenia, hepatotoxicity, nephrotoxicity , infections, neurotoxicity, pulmonory fibrosis, pneumonitis, severe dermatitis, seizures

Glucocorticoids, oral

Prednisone; prednisolone; 0.5-1 mg/kg per day

A2R/ACE antagonists, antiarrhythmics class III,ß2,cyclosporine, NSAIDs and salicylates, phenothiazines, phenytoins, quinolones, rifampin, risperidone, thiazides, sulfonylureas

Infection, VZV infection, hypertention, hyperglycemia, hypokalemia, acne, allergic reactions, anxiety, aseptic necrosis of bone, cushingoid changes, CHF, fragile skin, insomnia, menstrual irregularities, mood swings, osteoporosis, psychosis

Mycophenolate mofetil

2-3 g/day PO; decrease dose if CrCl<25mL/min

Acyclovir,antacids, azathioprine, bile acid binding resins, ganciclovir, iron, salts, probenecid, oral contraceptives

Infection, leukopenia, anemia, thrombocytopenia, lymphoma, lympoproliferative disorders, malignancy, alopecia, cough, diarrhea, fever, GI symptoms,headache, hypercholestremia, hypertension, hyperkalemia,insomnia, peripheral edema, transaminitis, tremor, rash

Conti…..

Page 10: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Methylprednisolone sodium succinate, IVa (approved for lupus nephritis)

For severe disease , 1 g IV qd × 3 days

As for oral glucocorticoids

As for oral glucocorticoids (if used repeatedly); anaphylaxis

Cyclophosphamide b

IV

Oral

7-25 mg/ kg q month ×6;

Consider mesna administration with dose

1.5-3 mg/kg per day Decrease dose for CrCl < 25 mL/min

Allopurinol, bone marrow suppressants,colony stimulating factors, doxorubicin, rituximab, succinylcholine, zidovudine

VZV infection, bone marrow suppression, leukopenia, anemia, thrombocytopenia, hemorrhegic cystitis (less with IV), carcinoma of bladder, alopecia, nausea , diarrhoea, malaise, malignancy, ovarian and testicular failure

Mycophenolate mofetil

2-3 g/day PO; decrease dose if CrCl<25mL/min

Acyclovir,antacids, azathioprine, bile acid binding resins, ganciclovir, iron, salts, probenecid, oral contraceptives

leukopenia, anemia, thrombocytopenia, lymphoma, lympoproliferative disorders, malignancy, alopecia, cough, diarrhea, fever, headacheGIsymptoms,hypercholestremia, hypertension, hyperkalemia, insomnia, peripheral edema, transaminitis, tremor, rash

Azathioprine 2-3 mg/ kg per day PO; decrease frequency of dose if CrCl < 50mL/min

ACE inhibitors, allopurinol, bone marrow suppresants, interferone, mycophenolate mofetil, rituximab, warfarin, zidovudin

Infection, VZV infection, bone marrow suppresssion, leucopenia, anemia, thrombocytopenia, peancreatitis, hepatotoxicity, malignancy, alopecia, fever, flulike illness, GU symptoms

Conti…..

Page 11: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Despite the broad biological and clinical heterogeneity of SLE specific pathways of immune dysregulation have been well characterized and are known to be relevant to significant subsets of patients.Selective targeting of key immune regulatory molecules seems to offer promise for effective disease management with lower toxicity than current therapies

Biologic treatments for SLE: Targets and mode of action. The numbers of therapeutic agents are designated in text. pDC: plasmacytoid DC; Mac: macrophages; Mon: monocytes

Biologic Therapy: A evolving Approach

Page 12: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Innate Immune pathway targeting agents in development of SLE

Page 13: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

B Cell pathway targeting agents in development of SLE

Page 14: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

T cell pathway targeting agent in development for SLE

Page 15: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Algorithm for treatment of SLE

CLE,-Cutaneous Lupus erhythematosus; CVD- Cardiovascular disease;IVIG-Intravenous Immunoglobulin; MMF-Mycophenolate Mofetil

Wen Xiong and Robert G. Lahita. Pragmatic approaches to therapy for sytemic lupus erythematosus. 2013. Nature Reviews: Rheumatology. Advance Online Publication. Pg 1 to 12

Page 16: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Potential insight to improved trial design from SLE trials

Page 17: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

UNMET NEEDS

Page 18: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

WHATS NEXT??

The next phase of research will see the development of numerous molecules and

immunomodulators such as peptide-based agents that are currently in pre-clinical and early

phase trials.

Given the heterogeneity in clinical phenotype and immunopathogenesis, it may be that there is

no one-size-fits-all therapy for systemic lupus erythematosus. Alternatively, combination

therapy may be effective as evidenced from treatment in B cell malignancies.

The patents of older biologics including rituximab will soon expire and will lose exclusivity in

the USA by 2018. Thus, the development and licensing of ‘biosimilars’ that seek to imitate

originator biologics as closely as possible in the next few years may greatly influence the cost

effectiveness of therapies.

Biomarkers that may allow prediction of active disease, prognosis and/or response to therapy

are lacking but are likely to emerge with new the application of new technologies.

The future research agenda will focus on better trial design including the use of composite

disease activity index as end points, combination therapies, biomarkers and the development

and licensing of biosimilars.

Finally, the introduction of the treat-to-target concept in systemic lupus erythematosus provides

a new personalized approach for managing patients. The target of achieving low disease active

or remission with reduction in oral corticosteroid is attainable (van Vollenhoven et al, 2014).

Page 19: Therapeutic Scenario in Systemic Lupus Erythematosis (SLE)

Literature Surveyed

Pons-Estel GJ, Alarcón GS, Scofield L, et al. Understanding the epidemiology and progression of systemic

lupus erythematosus. Semin Arthritis Rheum 2010; 39:257

Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a comparison of

worldwide disease burden. Lupus 2006; 15:308.

Rus V, Maury EE, Hochberg MC. The epidemiology of systemic lupus erythematosus. In: Dubois' Lupus

Erythematosus, Wallace DJ, Hahn BH (Eds), Lippincott Williams and Wilkins, Philadelphia 2002.

Peschken CA, Esdaile M. Rheumatic diseases in North America's indigenous peoples. Semin Arthritis

Rheum 1999; 28:368.

van Vollenhoven RF, Mosca M, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus:

recommendations from an international task force. Ann Rheum Dis 2014; 73:958.

Bertsias G, Ioannidis JP, Boletis J, et al. EULAR recommendations for the management of systemic lupus

erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies

Including Therapeutics. Ann Rheum Dis 2008; 67:195.

Wallace DJ. Improving the prognosis of SLE without prescribing lupus drugs and the primary care paradox.

Lupus 2008; 17:91. Alkaterini Thanou and Joan T. 2013.

Merrill. Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys. Advance

online publication. Nature. Pg 1-12

Alkaterini Thanou and Joan T. 2013. Merrill. Treatment of systemic lupus erythematosus: new therapeutic

avenues and blind alleys. Advance online publication. Nature. Pg 1-12

Md Yusof MY, Vital EM, Emery P. Biologics in systemic lupus erythematosus: current options and future

perspectives. Br J Hosp Med (Lond). 2014 Aug;75(8):440, 442-7. doi: 10.12968/hmed.2014.75.8.440.