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Recent advances rheumatoid arthritis
- 1. Recent advances in treatment of Rheumatoid Arthritis Dr. Renu Yadav Resident Pharmacology
- 2. Definition and Introduction Pathophysiology ACR updated guidelines Anti-Rheumatoid drugs (conventional) Recent development Advances in drug delivery system Conclusion
- 3. Rheumatoid arthritis is an autoimmune disease that is characterized by inflammation of the joints and the subsequent destruction of cartilage and erosion of the bone.
- 5. In India, estimated prevalence rate of RA is 0.5%– 0.75% Three times more common in women. Globally, RA is the 42nd highest contributor to global disability measured in YLDs. U.K has the highest prevalence rate.
- 8. 1. NSAIDS 2. Corticosteroids 3. Non-biologic DMARDS : MTX, Leflunomide, Hydroxychloroquine, Sulfasalazine, Minocycline Tofacitinib
- 9. 4. Biologic DMARDS A. TNF antagonists (etanercept, infliximab, golimumab, adalimumab, certolizumab) B. Non- TNF Biologics Abatacept Rituximab Anakinra (IL-1 inhibitor) Tocilizumab (IL-6 inhibitors)
- 11. 1. Current treatment options fail to produce or produce only partial responses. 2. Possess severe side effects, higher doses, and frequent administration 3. Sustained remission is rarely achieved and requires ongoing therapy.
- 12. Drug MOA Dosage form FDA approved in Apremilast PDE4 inhibitor TAB March 2014 Celgene Ixekizumab Anti IL- 17A receptor antibody SC March 2016 Eli Lilly Sarilumab IL- 6 receptor antagonist SC May 2017 Sanofi Baricitinib Janus kinase (JAK) inhibitor TAB 31-May-2018 Eli Lilly and Company upadacitinib Janus kinase (JAK) inhibitor TAB 16-Aug-2019 AbbVie Inc
- 13. Drug MOA Dosage form FDA approved in Filgotinib PDE4 inhibitor September 24, 2020 Otilimab Monoclonal antibody Phase 3 clinical trial Peficitinib JAK -1/3 inhibitor FDA approval stage Sirukumab IL-6 inhibitor Iberiotoxin scorpion venom Early stages of dev ATI-450 selective p38-alpha MAPK inhibitor Phase II
- 14. Few examples for the biosimilars for the tumor necrosis factor (TNF) blockers Adalimumab biosimilars •Amjevita (adalimumab- atto) •Cyltezo (adalimumab- adbm) •Hyrimoz (adalimumab- adaz) Infliximab Biosimilars Inflectra (infliximab-dyyb) Renflexis (infliximab-abda) Etanercept Biosimilars Erelzi (etanercept-szzs) Eticovo (etanercept-ykro)
- 15. Therapeutic genes are generally delivered by 2 methods: in vivo and ex vivo. Generally, the intraarticular route is used for gene transfer in local in vivo strategies. eg ; IL-1Ra ART-102
- 16. Ex-vivo strategies include three steps: 1. Exclusion of synoviocytes from the affected area usually joint 2. In- vitro Transduction 3. Transduced cells are re-injected into the joints.
- 17. Scientists at Rush University Medical Center in Chicago are working on a vaccine that targets T cells. An RA vaccine is years away from approval for use in humans. But several types are in clinical trials or earlier phases of research
- 18. The drug is known as CEL-4000. A few years ago in Australia, researchers tested an RA vaccine called Rheumavax on 18 people. (TOL- DC)
- 19. Start patients on MTX and continue instead to rapidly switching to another DMARD Minimise use of glucocorticoids Add a biologic or a targeted synthetic DMARD instead of switching patients to triple therapy ( MTX, sulfasalazine, HSQS) Consider Tapering of drugs
- 20. 1 . Nanoparticles Eg : - Gold nanoparticles - Hyaluronic Acid conjugated MTX nanoparticles
- 21. 2. Liposomes Eg ; liposomal MTX
- 22. 3. Polymeric micelles 4. Microemulsion / nanoemulsion 5. Nanogels
- 23. Despite this enormous advancement in the methods of treatment of the disease, there is still a lot of scope for further research as there is no therapy available which can completely cure the disease. Presently, maximum therapies work on symptoms of the disease. Along with this, they show poor efficacy, severe side effects, high doses, greater frequency of administration and high cost.
Editor's Notes
- Articular – small joints, morning stiffness, swelling of joints, , popteal cyst Extra articular manifestation ; SKIN MANIFESTATIONS : Rheumatoid nodules, Ocular – keratoconj. Sicca, secondary Sjögren's syndrome Pleural effusions , atherosclerosis) Myocarditis, mesangial glomerulonephritis
- YLD- years living with disability
- In rheumatoid arthritis, Both the environmental factors and genetic factors are implicated - the immune responses influence The activation of dendritic cells, T cells, plasma cells, B cells, mast cells, macrophages, and angiogenesis cause synovitis. Proinflammatory cyctokines, TNF, IL, It starts at membranes of synovium and then progressively attacks the adjacent structures. Inflammed , proliferating synovium – pannus. Amongst these, persistently activated synovial macrophages are one of the leading factors for producing inflammation in RA
- A total score of ≥6 is needed to classify a patient as having definite RA.
- NSAIDS - They are generally used for the symptomatic relief of the disease and do not have any effect on ds modification. An es-tablished Guideline for RA known as “National Institute for Health and Clinical Excellence (NICE)” states that cor-ticosteroids should be used only after the application of all other treatment options Traditionally DMARDs have been used since the 1920s are mainly non-biologic. Methotrexate (MTX) still remains the drug of choice Tofacitinib carries black box warning – seious infection, lymphoma, malignancy, pt shld b tested for latent TB.
- Biologic agents are genetically engineered proteins molecules that block the proinflammatory cyctokines TNF alpha These are effective when non biologic drugs fail to achieve clinical reponse- more expensive, Tuberculin testing is mandatory before starting biologics. Other than anakinra , and tocilizumab they require no monitoring,- small risk of inc infection. Etarnacept – SC, slows erosive ds progression greater than mtx Infliximab – IV, infusion reaction, Adalimumab- less antigenic, SC, Abatacept – co-stimulation modulator. It binds to CD80/86 receptors on APC- inhibits interaction between APC and T-cells ….. IV infusion, Rituximab- monoclonal antibody, binds to B cell leading to complete depletion of peripheral b cell, Anakinra – limited use, less effective Tocili – approved for mod- severe active RA, who failed to response to one or more anti – TNF biologics S/e inc infection, lipids , liver enzymes, GI perforation,
- Apremilast - Glenmark is the first company to receive the DCGI approval and marketing authorization for Apremilast in India now mainly for psoriatic arthritis. Apremilast, an oral phosphodiesterase-4 inhibitor that modulates anti- and pro-inflammatory cytokines Ixekizumab - Ixekizumab blocks the inflammatory protein IL-17A. This improves joint pain and swelling from arthritis and rash from psoriasis. Ixekizumab should not be given in combination with another biologic drug. Sarilumab - Sarilumab plus methotrexate inhibited the progression of structural damage in patients who had inadequately responded to methotrexate. As monotherapy in patients who were inappropriate for continued treatment with methotrexate, sarilumab was more effective than adalimumab in reducing the signs and symptoms of RA.. sarilumab extends the available treatment options for adults with moderately to severely active RA who have responded inadequately to, or are intolerant of, at least one DMARD. Baricitinib - oral, targeted synthetic DMARD that inhibits JAK1 and JAK2,… This novel, small molecule is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. Upadacitinib - inhibited radiographic progression and displayed rapid and sustained clinical and functional efficacy in RA when in combination with methotrexate (MTX), upadacitinib was superior to placebo in MTX-Inadequate Responders (IRs) and biologic disease modifying antirheumatic drugs-IRs while as monotherapy
- However, latest biologic DMARDs under investigation are phospholipase A2 (PLA2) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, chemokines blocker, colony stimulating factor” (CSF) inhibitors and others
- Biologics or biologic drugs are products made from living organisms or contain components of living organisms Biosimilars are not new drugs, but rather they are copies of biologic drugs that have been used to treat many diseases and conditions
- The systemic gene therapy consists of the transfer of genes to the cells and these cells synthesize the gene product. Which are then secreted into the circulation. This approach is beneficial as rheumatoid arthritis has its systemic nature and it has the capacity to target more than one joint simultaneously ART-102 : It's a gene therapy medication that may reduce interferon-beta (IFN-β), which produces proteins that promote the development of RA.
- .
- Because it isn’t a biologic, researchers say it may cost less and be easier to make than biologics. They also say it likely won’t weaken your immune system the way current biologics can. But for now, these are just theories. CEL-4000 hasn’t been tested in humans. Doctors took samples of their blood and separated out certain cells called dendritic cells. These are inflammatory cells of the immune system. Those cells were "tolerized." That means they were modified in a lab to react differently to anti-CCP (a substance that can trigger RA). Then, the tolerized dendritic cells, or tolDC, were injected back into the patients. Australian researchers aren’t the only ones testing tolDC therapy for RA. In the U.K., researchers found tolDC to be a safe, acceptable treatment option for knee symptoms in a group of people with inflammatory arthritis.
- Nanoparticles are the particles microscopic in size and smaller than 1micron. They generally measure approximately 1 – 1000 nm in size Nanoparticles also enhance the solubility and bioavailability of poorly soluble drugs These nanocarrier systems also have properties of the high surface to volume ratio, enhanced permeability and retention effect, sustained action
- Liposomes are extensively used as drug carriers for rheumatoid arthritis treatment. They are basically vesicular concentric lipid bilayers. Many drugs used for the treatment that RA possesses low bioavailability, limited selectivity, high clearance, etc. And that’s why to require frequent and high dosing to maintain the therapeutic effect. High doses are also the cause of side effects. Liposomes are the solution for these drawbacks.
- Despite this enormous advancement in the methods of treatment of the disease, there is still a lot of scope for further research as there is no therapy available which can completely cure the disease. Presently, maximum therapies work on symptoms of the disease. Along with this, they show poor efficacy, severe side effects, high doses, greater frequency of administration and high cost.