Rheumatoid arthritis

RHEUMATOID ARTHRITIS

GUIDED BY:

MR. JAGAT UPADHYAY

ASST. PROFESSOR PHARMACEUTICAL

CHEMISTRY

PREPARED BY:

HARSH CHUNARA

ID NO: 10P008

ROLL NO: 08

YEAR : 4th year

FACULTY OF PHARMACY DHARMSINH DESAI UNIVERSITY, NADIAD.

04/08/2023DHARMSINH DESAI UNIVERSITY, NADIAD.

2 CONTENT Introduction

Signs and symptoms

Epidemiology Rheumatoid arthritis

Etiology of Rheumatoid arthritis

Drugs used in Rheumatoid arthritis

Mechanism of action

Treatment of Rheumatoid arthritis

References

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DHARMSINH DESAI UNIVERSITY, NADIAD.


4 What Is Rheumatiod Arthritis ? RA, is a form of inflammatory arthritis and an autoimmune

disease The immune system – is designed to protect our health by attacking

foreign cells such as viruses and bacteria – instead attacks the body’s own tissues, specifically the synovium, a thin membrane that lines the joints. As a result of the attack, fluid builds up in the joints, causing pain in the joints and inflamation that’s systemic – meaning it can\ occur throughput body.


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6 Sign & symptoms joints may feel warm to the touch and decreased range of motion, as

well as inflammation,

swelling and pain in the areas around the affected joints.

Stiffness

Malaises(feeling ill)

Muscle aches

Loss of appetite, which can lead to weight loss

pain


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8 Epidemiology More than 21% of American adults (over 46 million people) have arthritis

or another rheumatic condition diagnosed by a doctor.

Nearly two-thirds of arthritis patients are under 65 years old.

More than 60% of arthritis patients are women.By 2030, the number of people with arthritis is expected to rise to 67 million, reflecting a 40% increase.

RA Although it can occur at any age, the peak onset period is between the ages of 35 and 50. The disease may come on slowly or may appear suddenly.

The average age for being diagnosed with rheumatoid arthritis has steadily increased (from 63.3 to 66.8 years old), suggesting rheumatoid arthritis is becoming a disease of older adults.


9 Etiology Even though infectious agents such as viruses, bacteria, and fungi have

long been suspected as well as smoking, but none has been proven as the cause. It is believed that the tendency to develop rheumatoid arthritis may be genetically inherited.

Eg. the genetic marker HLA-DR4 has been identified in as many as 66% of patients with disease. This marker, which is present in white blood cells, plays a role in helping the immune system to distinguish between foreign cells (e.g., germs) and the body's own cells.

RA often is affected by pregnancy—symptoms improve before the infant is born and then worsen after delivery—it may be that hormones in the body influence disease development and progression.


10 Drugs used in Rheumatoid arthritis.

NSAIDs: (Nonsteroidal anti-inflammatorydrugs)

NSAIDs include such drugs as ibuprofen, ketoprofen ,and naproxen sodium,celecoxib.

Ibuprofen ketoprofen

The primary mechanism of action is inhibition of an enzyme called cyclooxygenase (COX). COX is an enzyme that is required in the conversion of arachidonic acid to prostaglandin H2 (PGH2) in the body.

The prostaglandins that are formed from PGH2 are important mediators of sensations such as pain and processes such as fever and inflammation.

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11 ibuprofen is a non-selective COX inhibitor. There are two forms of COX in the

body - COX-1,2.

The pain and inflammation reducing effects of NSAIDs are mediated through the inhibition COX-2, & COX-1 inhibition blocks the formation of thromboxane. The long-term blockage of COX-1 with chronic use of NSAID, however, may cause gastric toxicity, as COX-1 usually maintains the gastric mucosa

DHARMSINH DESAI UNIVERSITY, NADIAD.


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Disease-Modifying Antirheumatic drugs(DMARDs)

hydroxycholorquine,sulfasalazine,leflunomide.

Methotrexate also

M/A SULFASALASINE

The mode of action of Sulfasalazine or 5-aminosalicylic acid (5-ASA) and sulfapyridine

In ulcerative colitis, clinical studies utilizing rectal administration of Sulfasalazine,SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety.


13 Corticosteroids –

prednisone, prednisolone and methyprednisolone,

M/A:

Prednisone is a glucocorticoid receptor agonist. It is first metabolized in the liver to its active form, prednisolone. Prednisolone crosses cell membranes and binds with high affinity to specific cytoplasmic receptors.

the result includes inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of inflammatory response, suppression of humoral immune responses, and reduction in edema or scar tissue.


14 Biologic agents: There are currently nine such agents approved for rheumatoid arthritis:

abatacept , adalimumab , anakinra , certolizumab ,pegol etanercept , infliximab , golimumab and rituximab .

Each of the biologics blocks a specific step in the inflammation process. Cimzia, Enbrel, Humira, Remicade and Simponi block a cytokine called tumor necrosis factor-alpha (TNF), rituxan blocks b cells and therefore often are called TNF inhibitors.

rituximab

M/A:Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes.


15 CD20 regulates an early step(s) in the activation process for cell cycle initiation

and differentiation, and possibly functions as a calcium ion channel.

CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation.


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JAK inhibitors: tofacitinib

M/A:It is an inhibitor of the enzyme janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription


17 What is actual pathophysiology of RA? Preclinical phase

Several cell types and cytokines are involved in RA, and upregulation of cytokines, cytokine-related factors, and chemokines can pre-date the development of clinical symptoms.

Anti-citrullinated protein antibodies (ACPAs), which include include perinuclear factor (APF), antikeratin antibodies (AKA), anti-Sa antibodies, and anticyclic citrullinated peptide antibodies (anti-CCP), are sensitive and specific serological markers of RA, offering predictive value for a diagnosis of RA

Clinical phase

The macrophages are activated by Th1 cytokines, including interferong (IFN-g), interleukin 12 (IL-12), and IL-18, which are released following activation of T cells by antigen-presenting cells. Macrophages may also be activated by direct contact with T cells, or by immune complexes or bacterial products in the synovial fluidsOnce activated, macrophages release multiple cytokines and other inflammatory mediators. Key cytokines involved in the pathogenesis of RA include several interleukins, tumor necrosis factor (TNF), transforming growth factor-β (TGF-β), & interferons (IFNα and IFNβ). Each cytokine may have multiple pleiotropic actions, but in patients with RA, the balance swings in favour of the proinflammatory cytokines.


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Cytokines play key roles in controlling cell growth and the immune response. Many cytokines function by binding to and activating type I and type II cytokine receptors. These receptors in turn rely on the Janus kinase (JAK) family of enzymes for signal transduction. Hence drugs that inhibit the activity of these Janus kinases block cytokine signaling.More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptor in turn recruit STAT transcription factors which modulate gene transcription.


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21Therapy of Rheumatoid arthritis

Corticosteroid Therapy medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function.

for short periods during severe flares of disease activity or when the disease is not responding to NSAIDs. However, corticosteroids can have serious side effects, especially when given in high doses for long periods of time.

Corticosteroid Therapy These side effects include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, risk of infection, muscle wasting, and destruction of large joints, such as the hips.


22 Diagnosis; Corticosteroid Therapy medications can be given orally or injected directly into

tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function.

These side effects include weight gain, facial puffiness, thinning of the skin and bone, easy bruising, cataracts, risk of infection, muscle wasting, and destruction of large joints, such as the hips.

Diagnosis of RA depends on the symptoms and results of a physical exam, such as warmth, swelling and pain in the joints. Some blood tests also can help confirm RA. Telltale signs include:

Anemia (a low red blood cell count)

Rheumatoid factor (an antibody, or blood protein, found in about 80% of patients with RA in time, but in as few as 30% at the start of arthritis)

Antibodies to cyclic citrullinated peptides (pieces of proteins), or anti-CCP for short (found in 60–70% of patients with RA)

Elevated erythrocyte sedimentation rate (a blood test that, in most patients with RA, confirms the amount of inflammation in the joints)


23 X-rays can help in detecting RA, but may not show anything abnormal in early arthritis. Even so, these first X-rays may be useful later to show if the disease is progressing. Often, MRI and ultrasound scanning are done to help judge the severity of RA.


24 Reference: Landre-Beauvais AJ. The first description of rheumatoid arthritis. Unabridged text of the doctoral

dissertation presented in 1800. Joint Bone Spine. 2001;68:130–143.

Dequeker J, Rico H. Rheumatoid arthritis-like deformities in an early 16th-century painting of the Flemish-Dutch school. JAMA. 1992;268: 249–251.

Sangha O. Epidemiology of rheumatic diseases. Rheumatology (Oxford). 2000;39(Suppl 2):3–12.

Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15–25.

Albani S, Carson DA (1997) Etiology and pathogenesis of rheumatoid arthritis. In: Koopman WJ (ed) Arthritis and allied conditions. Lippincott Williams & Wilkins, Baltimore, MD, 979 p

Graudal NA, Jurik AG, de Carvalho A, Graudal HK. Radiographic progression in rheumatoid arthritis: a long-term prospective study of 109 patients. Arthritis and rheumatism. 1998 Aug;41(8):1470-80.

Masi AT, Maldonado-Cocco JA, Kaplan SB, Feigenbaum SL, Chandler RW. Prospective study of the early course of rheumatoid arthritis in young adults: comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum. 1976 May.


25 Bowes J, Barton A. Recent advances in the genetics of RA susceptibility. Rheumatology

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Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4(Suppl 3):S265–S272.

Brooks PM. The burden of musculoskeletal disease--a global perspective. Clin Rheumatol. 2006 Nov;25(6):778-81.

Silman AJ, Hochberg MC. Epidemiology of the Rheumatic Diseases. 2nd ed. New York: Oxford University Press; 2001.

Pincus T, Callahan LF. What is the natural history of rheumatoid arthritis? Rheum Dis Clin North Am. 1993 Feb;19(1):123-51.

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anti-inflammatory effect of A3 adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis. Expert Opin Inves Drugs 16(10):1601–1613

Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 1(11):529–543


26 Camussi G, Lupia E (1998) The future role of anti-tumor necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs 55(5):613–620

Lee AN, Beck CE, Hall M. Rheumatoid factor and anti-CCP autoantibodiesin rheumatoid arthritis: a review. Clin Lab Sci. 2008;21:15–18.

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Bowes J, Barton A. Recent advances in the genetics of RA susceptibility. Rheumatology (Oxford). 2008;47:399–402.

Genovese MC (2009). Treatment of rheumatoid arthritis. In GS Firestein et al., eds., Kelley’s Textbook of Rheumatology, 8th ed., vol. 2, pp. 1119-1143. Philadelphia: Saunders Elsevier.

Nicola PJ, et al. (2005). The risk of congestive heart failure in rheumatoid arthritis: A population-based study over 46 years.Arthritis and Rheumatism, 52(2): 412-42009

Yocum DE, et al. (2003). Efficacy and safety of tacrolimus in patients with rheumatoid arthritis. Arthritis and Rheumatism, 48(12): 3328-3337.

Murray MT, Pizzorno JE (2006). Rheumatoid arthritis. In JE Pizzorno, MT Murray, eds., Textbook of Natural Medicine, 3rd ed., vol. 2, pp. 2089-2108. St. Louis: Churchill Livingstone Elsevier.

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Rheumatoid arthritis

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