Rheumatoid Arthritis

Disease Characteristics

Incidence

Anthony's Section

United States

incidence of Americans based on study from Olmsted County, Minnesota (Myasoedova,2010)

Female

321/100,000

Male

145/100,000

Worldwide

Depicts worldwide incidence of Rheumatoid Arthritis as well as costs(Kvien, 2004)

2-3 times higher in women than men

(Ahlmen, 2010)

higher in pregnant women

Worldwide distribution 1-2%

Prevalence increases with age

5% in women over 55

Percentages vary for age groups and genders. Refer to paper for other percentages with age and gender.

Incidence of Rheumatoid Arthritis in the UK(Symmons, 1994)

Males

10-11/100,000

Females

27-30/100,000

It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century.

(Firestein 2003)

Geography

Anthony's Section

More prevalent in some subsets of Native Americans

Also in incidence section

Worldwide distribution

Symptoms

Anthony's Section

Symptoms

Signs and symptoms of Rheumatoid Arthritis (Source: 2014, http://www.niams.nih.gov/Health_Info/Rheumatic_Disease/)

Nodules under skin

Numbness/tingling

Red inflamed eyes/discharge from eyes

high fever/signs of infection

bone fracture

Tendency to bruise

Difficulty Breathing/Chest pain

Loss of range of motion

Joint pain

Morning Stiffness

Risk Factors

Steve's Section

50% Genetic factor

60% of cases of RA in US carry shared epitope of leukocyte antigen HLA-DR4 cluster. (Barton, 2009)

Sex, age, family

Increases with age 35-50

(Temprano, 2014)

Relatives have 2-3x increase chance of RA

(Ahlmen, 2010)

Women are affected 3x more than men

RA in sex differences diminish as age increases. Danish study - rate higher for women with 1 childbirth than 2 or 3. Reduced immune adaptability may exist for women predisposed to RA (Ahlmen, 2010)

environment

Infection by P. gingivalis

Synovial fluid of patients contain oral anaerobic bacterial antibodies associated with P. gingivalis. Other indirect studies with Mycoplasma, EBV, and rubella. (Hitchon, 2010)

Growing up under drug-alcohol addicted parents

Fuller-Thomson, 2014

Smoking

Strongest and consistent data. Modest to moderate risk (1.3-2.4x) (Carlens, 2010)

Reproductive Hormone

Oral contraceptives, Hormone replace therapy, live birth history, menstrual history (Barrett, 1999)

Current Treatment

Financial review

Sumithra's section

Direct costs

Direct costs include medical costs such as treatment,hospital and medication costs. These are worth US$ 5720 annually.Economic burden of rheumatoid arthritis: a systematic review(N.J.Cooper, 2000)\

Treatment cost

Cost of using DMARDs (CyA, Methotrexate, sulphasalazine)

Usage of DMARDs have been proved to be cost effective at the time of disease onset.Cost Effectiveness analysis of Disease-Modifying Anti-rheumatic Drugs in rheumatoid arthritis. A systematic Review Literature.(Maurizio Benucci, 2011)

TNF blocking agents though comparatively higher in cost.

TNF blocking agents (Etanercept, Infliximab)though comparatively higher in cost, is both efficient and cost effective when standard dosing regimens are used.Cost Effectiveness analysis of Disease-Modifying Anti-rheumatic Drugs in rheumatoid arthritis. A systematic Review Literature.(Maurizio Benucci, 2011)

Genetically engineered drugs on an average cost about $1000-$3000 per month depending on the stage of RA.

The cost of rheumatoid arthritis.(E.McINTOSH, 1996)

Cost of diagnosis and laboratory tests

Hospital visits- these account for about US$1855 to US$4944

Economic burden of rheumatoid arthritis: a systematic review.(N.J.Cooper)

ESR, RF test and X rays- These lab tests cost $25- $30 each on an average. Multiple tests need to be conducted, hence COI (Cost of Illness) rises in the long run.

The cost of rheumatoid arthritis.( E.McINTOSH, 1996)

Indirect costs

Indirect costs are costs where resources are lost.An average of US$ 37,501 annually.Economic burden of rheumatoid arthritis: a systematic review.(N.J.Cooper,2000)

Morbidity - Losses due to restriction from illness.

Economic burden of rheumatoid arthritis: a systematic review.(N.J.Cooper,2000)

Morality cost- Calculated present value of lost production due to death caused by RA.

Economic burden of rheumatoid arthritis: a systematic review.(N.J.Cooper,2000)

Current Treatments

JoleneClifton, Ruffing. November 28, 2012

NSAIDs

Non Steroidal Anti Inflammatory Drugs reduce acute infection, decrease pain, and improve function. They do not however, change the course of the disease.

Corticosteroids

Corticosteroids have both anti-inflammatory and immunoregulatory activity. They can be administered orally, IM, IV and are useful in early stages of the disease.

Prednisone, Methylprenisolone, Medrol

DMARDs

Disease Modifying Anti-Rheumatic Drugs (DMARDs) improve symptoms and can change the course of the disease and can improve radiographic outcomes.

Methotrexate, Hydroxychloroquine,Sulfasalazine, Leflunomide, Tumor Necrosis Factor Inhibitor, T Cell Costimulatory Blocking Agents, B cell depleting agents, Interleukin-1 (IL-1) Receptor Antagonist Therapy, Intramuscular Gold

Biologics

Biologics are designed to inhibit certain components of the immune system, such as those that are responsible for inflammation. They are one of the only treatment options that slow the progression of RA.

Actemra,Cimzia,Enbrel,Humira,Kineret, Orencia, Remicade, Rituxan, Simponi

Surgical treatment

In cases of extreme pain, patients can opt for surgical intervention that will prevent further impairment and decrease pain.

Synovectomy, Arthrodesis, Arthroplasty

Diagnosis

Agnes Section

no definitive lab test that diagnoses

No laboratory test will definitively confirm a diagnosis of rheumatoid arthritis.(Ruffing & Bingham 2012)

Genetic Predisposition

(Am J Hum, 2004)

Candidate Genes with SNPs Linked to RA and Their Potential Function
in Pathogenesis

Table 1(McInnes 2011)

Positive rheumatoid factor 70-80%

(Ruffing & Bingham 2012)

Baseline X-Rays (hands, feet, affected joints, and sometimes a baseline chest X-Ray)

(Ruffing & Bingham 2012)

2010 ACR/EULAR criteria

Criteria clearly allows earlier diagnosis of RA, although the clinical picture is slightly different on the group level. RA may be falsely diagnosed in some patients with self-limiting disease.(de Hair 2012)

Cytokine profile

cytokine profile at the earliest time points after onset of symptomscould identify novel targets that prevent progression to chronic arthritis.(Firestein 2005)

Molecular Basis

Amy Vu's Section

RA Synovial Fibroblasts (RASF) - prime player in joint destruction of RA patients

"Mechanism of Disease: the molecular and cellular basis of joint destruction in RA"(Muller-Ladner, 2005)

IL-15 = proinflammatory cytokine produced by RASF

Positive-feedback loop through activation of T cells which activate more RASF

Toll-like receptors (TLRs) involved in initial onset of innate immune response of inflammation

"Synovial Fibroblasts: key Players in RA"(Huber 2006)

A3AR receptor activation leads to apoptosis of inflammatory cells

"RA: History, Molecular Mechanisms, and Therapeutic Applications" (Fishman 2010)

A3AR agonists = proliferation of fibroblast-like synoviocytes

inhibition of pro-inflammatory cytokines

transcription factors such as nuclear factor κB, cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules.

Deleterious process of joint destruction mediated by intracellular signaling pathways involving (Müller-Ladner 2005)

Cytokine-independent pathways responsible for maintaining basic disease activity

Cytokine-independent pathways appear to be responsible for maintaining basic disease activity that is not affected by currently available therapies.(Müller-Ladner 2005)

Currently Used Biomarkers

Amy Vu's SectionBiomarkers in Rheumatoid Arthritis editorial by Hindawi Journals(Goëb 2014)

MiRNAs

1) Plasma miR-132 test at a cutoff value of 67.8 pmol/l could detect individuals with RA at 83.8% of sensitivity and 80.7% of specificity.(Murata 2010.)2) Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis(Duroux 2013.)

Different concentrations of miRNAs found in synovial fluid of RA individuals

miRNA-125 levels at onset of RA is indicative of effectiveness of treatment with rituximab

Cytokines

Cytokine biomarkers and the promise of personalized therapy in rheumatoid arthritis(Davis 2014)

ability to check cytokine levels throughout treatment as a way of observing disease prognosis

Urinary Peptide Markers

A panel of urinary biomarkers were determined to be characteristic of early onset RA with a sensitivity of 88% and specificity of 93%. (Stalmach 2014.)

ID of 39 peptides that were significantly different in cases of RA versus controls

Proposed Treatment

Unmet Needs

Tayler's Section

Current conventional and biologic disease- modifying therapies fail/produce partial responses

(McInnes 2011)

Molecular remission & reestablishing immunologic tolerance

Molecular remission and the capacity to reestablish immunologic tolerance remain elusive.(McInnes 2011)

Predictive biomarkers (prognosis, therapeutic response, and toxicity) lacking

Reliable predictive biomarkers of prognosis, therapeutic response, and toxicity are lacking(McInnes 2011)

Sustained remission rare; requires ongoing pharmacologic therapy

Sustained remission is rarely achieved and requires ongoing pharmacologic therapy(McInnes 2011)

Pathogenic mechanisms that initiate and perpetuate rheumatoid arthritis needs clarification

Elucidation of the pathogenic mechanisms that initiate andperpetuate rheumatoid arthritis offers the promise of progress in each of thesedomains. (McInnes 2011)

Early Diagnosis

Urine

Kang et al. 2014Using urine gives higher predictive power for disease activity than conventional serum analysis. Levels of urinary soluble CD14 were abundant in patients with RA and used as new biomarkers.

Possible early rheumatoid arthritis biomarkers

Describes Biomarkers (increased TC,LDL-C, nonHDL-C and triglyceride serum levels and reduction in HDL-C levels) that may be used to diagnose RA(Georgiadis, 2006)

Combination therapy

Methotrexate monotherapy vs triple DMARDS

Etanerept plus methotrexate

Using biologic agents with a DMARD is not superior to using multiple DMARDs

Approved Immune-Targeted Therapies

Table 3(McInnes 2011)

The Pathogenesis of Rheumatoid Arthritis

Figure 2, Table 2(McInnes 2011)