therapeutic scenario in systemic lupus erythematosis (sle)
TRANSCRIPT
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
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)
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
Symptoms
Elsevier Lupus Image Bank
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
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)
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
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…..
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…..
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
Innate Immune pathway targeting agents in development of SLE
B Cell pathway targeting agents in development of SLE
T cell pathway targeting agent in development for 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
Potential insight to improved trial design from SLE trials
UNMET NEEDS
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).
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.