Rheumatoid arthritis


Chronic systemic disease with articular and extra-articular manifestations.

A chronic inflammation of the synovial membrane, which can destroy articular cartilage and juxtaarticular bone.

Hallmark is symmetrical inflammatory polyarthritis affecting small proximal diarthrodial joints.

Characterized by symmetric, polyarticular pain and swelling, and  it typically involves the small joints of the hands and feet.

Most common cause of adult inflammatory arthritis.

Affects approximately .5% of adults in the US and 0.5-1% in Europe.

Joint damage accumulates with time, leading to disability and mortality.

Major target of disease is the synovium.

Rheumatoid arthritis involves chronic inflammation of synovial membranes, which leads to degradation of articular cartilage and the juxta-articular bone.

Inflammation is caused by T cells, B cells, and monocytes when endothelial cells are activated. 

Neovascularization, the growth of new blood vessels, serves as an additional marker for rheumatoid arthritis. 

A hyperplastic synovial lining layer can be caused by the expansion of synovial fibroblast and macrophage cells.

This expansion of the synovial membrane, sometimes referred to as “pannus”, can lead to bony erosions and cartilage degradation at the site of the cartilage-bone junction in the periarticular bone.

It is a systemic disease associated with multiple call, existing conditions and extra-articular manifestations.

The pre-clinical stages of seropositive RA are characterized by disordered immunity, often associated with mucosal surfaces, including the oral cavity, lungs, and G.I. tract, and by local and systemic generation of anti-citrullinated protein antibodies (ACPAs).

These autoantibodies can be detected in the blood a median of 4.5 years before the onset of arthritis.

The risk of RA increases overtime as autoantibody levels increase.

Onset of the inflammatory synovitis is a result of interactions of genetic and specific environmental exposures.

Rheumatoid arthritis begins years before it is clinically apparent and manifests as a continuum from asymptomatic immune dysfunction and progresses through various stages until it can be classified as RA.

RA is marked by the presence of autoantibodies to post translationally modified proteins, including anti-citrrullated protein antibodies, less specific autoantibodies, known as rheumatoid factors, that bind  the Fc portion of immunoglobulin; or both antibody types.

The synovial membrane is infiltrated in multiple joints with T cells, B cells, and monocytes.

Immune dysfunction that encompasses the PD-1 pathway is thought to be involved in the pathogenesis of rheumatoid arthritis.

Increased expression of PD-1 occurs on synovial T cells, decreased binding of PD-1 by PD-L1 may cause inadequate down regulation of pathogenic immune responses.

Activation of endothelial cells with neovascularization is also a hallmark of Rheumatoid Arthritis synovitis.

Synovial membrane expansion of fibroblast like and macrophage like cells leads to a hyperplastic synovial lining layer, termed pannus, that invades the periarticular bone at the Cartilage-bone Junction and leads to bony erosions and cartilage degradation.

Molecules such as nuclear factor kB ligand (RANKL), prostaglandins, matrix metalloproteinases are induced by pro inflammatory cytokines, including tumor necrosis factor and interleukin-6 and mediate signs and symptoms of disease, including pain and swelling, and degradation of Cartilage and bones.

Rheumatoid arthritis is the only immune mediated disease that shows combined TNF-alpha and interleukin 6 dependency.
Cytokines are critical drivers of inflammation and rheumatoid arthritis.
Symptoms are highly dynamic, manifesting with periods of stability interrupted by flares of disease activity which is characteristic of many autoimmune disorders.
Molecular markers or predictive of imminent flares and these markers represent the activation of naïve B cells, which increase in the blood approximately two weeks before a flare.
Identification of these cells are termed pre-inflammatory mesenchymal or PRIME cells.
These fibroblast like PRIME cells are CD45.
Synovial fibroblasts contribute to the pathogenesis of RA, as the cells perpetuate chronic inflammation  and promote the degradation of jointcartilage and bone.
Synovial fibroblasts can migrate and spread destructive arthritis between joints.
Fibroblast-like PRIME cells traffic to inflamed synovium and represent the circulating precursor of inflammatory synovial fibroblasts.

Stimulation by RANKL, TNF and IL-6 generates osteoclasts within the synovial membrane and promotes bony damage.

The immune system mistakenly attacks healthy cells, causing inflammation in the affected parts of the body.

Current rheumatoid arthritis patients have more comorbidities then matched counterparts without rheumatoid arthritis.

Autoimmune disease is in epilepsy may predispose to the development of RA.

Heart disease, venoidthromboembolic disease and osteoarthritis might develop as a result of RA.

RA mainly attacks the joints, usually, many at once-the hands, wrists, and knees.

In an RA-afflicted joint, the lining becomes inflamed, causing tissue damage that can result in long-lasting or chronic pain, loss of balance, and deformity.

Joint pain, tenderness, swelling, or stiffness lasting 6 weeks or longer.

Joint damage is intrinsically associated with joint swelling.

Morning stiffness that lasts 30 minutes or longer.

Multiple joints affected.

Small joints, such as wrists and hands affected.

Same joints on both sides of the body affected.

Same symptoms on both sides of the body.

Weight loss.




MRI is a more sensitive measure of joint inflammation and joint damage than clinical examination or x-rays.

MRI detected synovitis and particular bone marrow edema, which histlogically represents osteotis, are associated with subsequent bone damage progression in patients with active RA and in patients with RA who are in remission.

Individuals who have a specific genetic marker known as the HLA shared epitope have a 5-fold increased chance of developing RA than those who lack the genetic marker.

Other genes associated with the development of RA include STAT4, which is involved in the regulation and activation of the immune system.

TRAF1 and C5 are genes which play a role in chronic inflammation.

PTPN22, has been linked to RA development and progression.

B1 genes in the human genome contain an increased concentration of HLA-DRB1 alleles that are most commonly seen in RA patients.

Having or lacking these genes does not necessarily mean an individual will develop or be safe from developing RA.

RA predominantly affects females, with nearly 3 times as many women as men among the approximately 1.5 million people in the United States diagnosed with RA.

The disease typically manifests in women between ages 30 and 60 years; among men, it typically appears later in life.

Although familial history has been found to increase the chance of developing the disease, most people with RA do not have any family history of it.

Conventional radiography is the standard measure of structural joint damage.

Characteristic laboratory abnormality is a positive rheumatoid factor, a circulating autoantibody against the Fc fragment of immunoglobulin G (IgG).

Affects 1 in every 100 people.

Associated with increased comorbidity and premature mortality.

Women:male 3:1.

Affects about 1% of the U.S. population.

Affects approximately 2 million Americans, 

Worldwide prevalence about 5 per 1000 adults.(0.5-1.0%).

Increased incidence in women related to increased prevalence before menopause:2 to 3 times is common among women, as it is is among men.

Peak incidence is in the 3rd to 5th decades of life.

About 70% of patients women.

Predominately affects women and the elderly people.

Smoking a risk factor, and a predictor of disease severity.

Susceptibility linked with a region on chromosome 2q.

Arg620→Trp variant of the intracellular phosphate gene PTPN22 associated with the disease.

Elevated IL-6 contribute to anemia and fatigue associated with rheumatoid arthritis.

Twins studies reflect a genetic contribution to the disease and sibling of patients with seropositive disease have a 5-10 times increased risk of developing the disease than the general population.

An estimated 20%-25% of cases are seronegative, in that such patients do not express rheumatoid factor or anti-citrullinated peptide antibody ( ACPA).

Seronegative RA is a separate entity marked by polyarthritis, but with poorly defined pathogenic mechanisms and a course that is less destructive to joints.

ACPA and rheumatoid factor can be  detected before clinical disease onset.

An estimated 50% of patients are seronegative for early disease and become seropositive.

Seronegative patients experience delay in meeting diagnostic criteria to receive a clinical diagnosis of RA and the initiation of treatment compared with seropositive patients is delayed.

Seronegative patients are less likely to achieve remission in the first five years after meeting criteria.

Associated with an increased risk of death when severe, with advanced joint disease, functional limitations, disabilities, and extraarticular manifestations.

Extraarticular abnormalities include CNS lesions.

Extraarticular manifestations have become rare since introduction of biological disease modifying anti rheumatic drugs.

Increased risk of depression, stroke and dementia.

Rheumatoid vasculitis is an uncommon manifestation, with estimates of clinical apparent disease ranging from less than 1 to 5.4%.

Burden of comorbidity is higher than expected associated compared to people of the same age and sex.

Peak age of onset is between fourth and fifth decades but can begin at any time.

1987 American Rheumatism Association classification criteria:

- Morning stiffness lasting greater than 1 hour for more than 6 weeks
- Swelling in 3 or more joints for more than 6 weeks
- Swelling in hand joints for more than 6 weeks
- Symmetrical joint swelling for more than 6 weeks
- Erosions or decalcification seen on hand x-rays
- Rheumatoid nodules
- Presence of serum rheumatoid factor   

Interaction of T-cells and macrophages in joints plus their cytokines that drives the illness by stimulating the synovium to become hyperplastic and hypertrophic.

Disease-free dominant classified based on clinical phenotype.

The growing inflammatory synovium and degrading enzymes, such as collagenase erode bone and cartilage and connective tissues within the joint capsule.

Characterized by synovial inflammation and swelling, autoantibody production of rheumatoid factor and anti-citrullinated protein antibody, cartilage and bone destruction, and systemic involvement of the cardiovascular, pulmonary, skeletal systems, and psychological disorders.

The presence of anti-citrullinated protein antibody is associated with more rapid joint destruction and the presence of genotypes, encoding the shared epitope, smoking, and periodontitis.

The synovium lining layer has an increased number of cells and the sublining is infiltrated with inflammatory cells, including lymphocytes, mast cells and macrophages.

The prevalence of rheumatoid arthritis is about 0.8 percent worldwide.

Physical diagnosis of possible rheumatoid arthritis includes the metacarpophalangeal (MCP)/metatarsophalangeal (MTP) squeeze.

With RA swelling of joint is not always present.

To establish a diagnosis of rheumatoid arthritis, symptoms should be present for about at least 6 weeks to 3 months.

Morning stiffness that lasts usually an hour or longer usually reflects an inflammatory process.

Screening for rheumatoid arthritis, the rheumatoid factor and the anti-CCP tests should both be done, as many patients present with a positive result for one or the other.

When both the rheumatoid factor and the anti-CCP are both positive there are a lot fewer false-positives.

Rheumatoid factor (RF) is positive in about 80% of people with RA, but the test is not completely sensitive nor specific for RA.

Chronic hepatitis B or, more commonly, hepatitis C, are the main conditions associated with positive rheumatoid factor.

Endocarditis and chronic TB can cause a positive RF.

The anti-cyclic citrullinated peptide (anti-CCP) antibody is about as sensitive as RF, but much more specific for the diagnosis of RA.

RF and anti-cyclic citrullinated peptide are not necessarily positive in the same 80% of patients.

The higher the RF or anti-cyclic citrullinated peptide titers the poorer the prognosis.

A higher score calls for modifying treatment recommendations to a more aggressive approach.

The effects of estrogen on immune function, probably play a role in the predominance of females of the disease.

The most prominent risk factor for rheumatoid arthritis is genetic: first-degree relatives have a risk increased by a factor of 2 to 5.

Several infectious agents have been proposed proposed as etiologic or contributing agents, including: EB virus, retroviruses, bacterial super antigens, mycoplasma, species, as well as organisms, such as oral Porphyromonas gingivalis, and Prevotella species.

The most prominent behavior risk factor for the development of RA is cigarette smoking.

Additional factors increase the risk of rheumatoid arthritis include: obesity, low, vitamin D levels, use of oral contraceptives.

Factors that decrease the risk of rheumatoid arthritis include: a Mediterranean diet, omeg three fatty acids intake, fish oil supplementation, and alcohol consumption.

A positive MCP hand squeeze in the presence of a positive RF factor or anti-cyclic citrullinated peptide titer is strong evidence for presence of RA.

Cells in the synovium produce cytokines that, with locally produced autoantibodies drive the chronic inflammatory process.

A3 adenosine receptor (A3AR) overexpressed in synovial tissue and peripheral blood mononuclear cells of patients and stimulation of the receptor decrease production of TNF-alpha.

Mortality in severe end-stage disease is comparable to three-vessel coronary artery disease or stage IV Hodgkin’s disease.

Most cases are sporadic but concordance rates in monozygotic twins range from 15-30%, and 5% among dizygotic twins (MacGregor AJ et al).

Monozygotic twins have an increased concordance rate of rheumatoid arthritis compared to dizygotic twins.

Estimated that hereditability accounts for 60% of the role in etiology.

Patients with rheumatoid arthritis are more likely to be related to each other than are patients without rheumatoid arthritis, with the familial component extending beyond the primary family.

The greatest rheumatoid arthritis genetic susceptibility effect is conferred by the HLA locus.

HLA-DRB1 gene encoding similar amino acids position 70-74 provide a shared epitope hypothesis.

The shared epitope is associated with anticitrullinated protein antibody development is consistently associated with markers of severe disease and mortality in RA.

HLA-DR4 associated with aggressive disease, extraarticular processes and Felty’s syndrome.

HLA-DRB1 associated with rheumatoid factor or anti-citrullinated antibodies

HLA-DRB1 locus alleles that contain a common amino acid motif (QKRAA), the shared epitope, confirm particular susceptibility to rheumatoid arthritis (Gregersen et al).

Amino acid positions 11, 71, and 74 within HLA-DRB1 are the major determinants of RA susceptibility.

The HLA -DRB1 focus, is associated with disease susceptibility , radiological severity, mortality, and treatment response.

Interaction with IL-6 and other cytokines, immune cells, synovial fibroblasts and osteoclasts associated with signs and symptoms of rheumatoid arthritis including, cartilage destruction, bone degradation and pannus formation.

Interleukin-6 (IL-6) found in abundance in rheumatoid synovium and markedly elevated in the serum of patients rheumatoid arthritis.

IL-6 levels correlate with rheumatoid disease stage, severity of joint destruction and many systemic manifestations of RA.

Extraarticular manifestations include: rheumatoid nodules, skin ulcers, episcleritis, pleuropericarditis, vasculitis, lymphadenopathy, peripheral neuropathy, and Sjogren syndrome.

Rheumatoid arthritis not associated with uveitis.

Patients with rheumatoid arthritis are at increased risk of venous thromboembolism, and that the risk increases shortly after the diagnosis of rheumatoid arthritis and remains elevated during the first decade (Holmqvist ME et al).

Increases the risk of diabetes by increasing insulin resistance.

Rheumatoid nodules in the lungs are most common in patients with rheumatoid factor and also have subcutaneous nodules.

Pulmonary manifestations include pulmonary nodules, interstitial fibrosis, pleural effusions, bronchiectasis, bronchiolitis, pulmonary hypertension and rarely vasculitis.

Rheumatoid arthritis is a systemic disease associated with the higher risk of lymphoma and lung cancer and a lower risk of breast, colorectal and prostate cancers.

Significant joint destruction can occur within 2 years of the onset of disease.

2 years is a reasonable time in which to divide erosive from nonerosive rheumatoid arthritis, i.e. patients who have nonerosive disease by 2 years are unlikely to show subsequent erosive damage.

Up the 70% of patients have radiographic damage within the first 3 years after the onset of symptoms.

Treatment strategy is to provide an initial aggressive therapy soon after diagnosis, and to progress to more aggressive therapy in pursuit of clinical remission guided by assessment of disease activity.

The goal of treatment is to aggressively treat patients to get a rapid remission.

Therapeutic goals for treating rheumatoid arthritis or eliminating signs and symptoms such as joint pain, swelling and stiffness, and preventing joint damage or its progression, and maximizing physical function and quality-of-life.

The goal of therapy is to achieve disease remission, as state in which no or minimal residual inflammation is a discernible.

Remission does not occur in most patients, and sustained remission lasting  at least six months occurs in very few patients.

Multiple DMARD responses are lost overtime in many patients.

Structural joint damage develops in approximately 20-30% of patients fulfilling remission criteria, indicating current clinician criteria are not optimal.

A disease remission is attainable in 50% of patients with rheumatoid arthritis.

Disease activity score of 28 joints-C-reactive proteins is a composit disease activity score based on swelling and tenderness of 28 joints, the patient’s assessment of disease activity and C-reactive proteins and is commonly used to monitor RA disease activity.

The likelihood of getting a remission is higher with earlier and more aggressive treatment.

Treating to clinical remission alone may not prevent progression of joint damage and disability, therefore remission of subclinical disease activity is also needed.

There is an early window of opportunity to treat and put people into remission.

Early diagnosis and therapy correlates with better outcomes, higher rates of remission, and reduced joint damage, reduced disability for patients with either sepositive or seronegative RA.

The Vectra DA test integrates 12 biomarkers into a single blood test that is a specific measure of disease activity as it fluctuates over time.

The Vectra DA test is scored on a range of 0 to 100.

Drug of choice since the 1990’s is methotrexate but combination therapy is better.

General consensus is that the presence of rheumatoid arthritis requires treatment.

With very mild disease hydroxychloroquine, sulfasalazine, or minocycline may suffice.

In the presence of erosive disease or high risk for erosive disease, the gold standard is to start with methotrexate therapy.

If methotrexate is insufficient or only partially helpful, tumor necrosis factor (TNF) inhibitors are the next course.

Methotrexate alone can place about 10% of patients into remission.

TNF inhibitors place about 30% of people into remission.

Majority of people treated with a combination of methotrexate and a TNF inhibitor do well.

Early use of disease modifying antirheumatic drug (DMARD) therapy has

become the standard of care.

Methotrexate remains the DMARD of choice in patients without contraindications to its use.

Biologic response modifiers (BRMs) provide clinically important improvement in patients not responding to traditional disease modifying antirheumatic drugs (DMARDS).

Biologic response modifiers target specific immune pathways, reduce inflammation, and can lead to better control of symptoms and structural damage.

Biologic response modifiers include tumor necrosis factor inhibitors, and interleukin 1 receptor antagonist, B cell depleting anti-CD 20 antibodies, a selective co-stimulation modulator inhibiting T cell activation by binding to CD 80 and CD86 and an interleukin 6 inhibitor.

JAKs are a family of intracellular tyrosine kinases that functions as mediators of signaling down stream of multiple cytokines and growth factors involved in the pathogenesis have several inflammatory and autoimmune diseases.

JAK1 inhibitors are a potential therapeutic option: filgotinib.

Addition of a tumor necrosis factor-α antagonist to methotrexate increases clinical remission likelihood.

In patients with active disease in the presence of methotrexate and anti-TNF agenst the use of

rituximab, abatacept, or tocilizum ab provides additional options.

Upwards of 11% of RA patients may be MTX intolerant.

Sustained remission is rare and treatment requires ongoing fight pharmacologic therapy.

All anti-TNF (tumor necrosis factor) agents have clinical and radiologic benefits in early arthritis.

Infliximab initiated for rheumatoid arthritis was significantly associated with an increased risk of serious infections compared with other TNF-alpha antagonist regimens and non-biologic comparator medications (Grijalva CG et al).

Combination therapy of anti-TNF agents and methotrexate have better response rates than either agent alone.

In combination with methotrexate, Infliximab is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.

Infliximab has efficacy in both early (>3 months and ≤3 years) and established moderately to severely active RA.

In early RA, results were noted in some patients within 2 weeks after the first Infliximab infusion, and the majority of patients demonstrated clinical response at 54 weeks.

The recommended dose of Infliximab is 3 mg/kg given as an intravenous induction regimen at 0, 2, and 6 weeks, followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active RA.

Infliximab should be given in combination with methotrexate.

Patients with disease present less than 1 year have a significant likelihood of responding to treatment than individuals who have the disease duration of greater than 10 years.

One year ACR 20 response rate 35-57% for methotrexate.

One year ACR 20 response rate for leflunomide (Arava) about 45%.

One year ACR 20 response rate for etanercept (Enbrel) of 72% and ACR 50 of 49% at two years.

70% have no erosions of joints at two years with etanercept.

In a monotherapy study of tofacitinib in RA patients that did not respond to DMARD therapy the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone.

Predisposes to infections and increased risk of lymphoma.

Patients are a greater risk for cardiovascular morbidity and mortality.

The use of TNF inhibitors in other traditional and biologic disease modifying anti-rheumatic drugs to treat RA is associated with a reduced risk of major adverse cardiovascular events, presumably through a reduction in inflammation.

There is an increase in hospitalizations for acute myocardial infarction and rheumatoid arthritis, but among such patients there is a lower in hospital mortality, particularly in cases of STEMI.

Goal of therapy is to maximize control of the disorder within 2 years of diagnosis to prevent irreversible damage.

Hands are affected in virtually all patients.

The wrists, metacarpophalangeal joints, and proximal interphalangeal joints are most commonly involved.

Extra-articular manifestations predicted by severe joint disease, a positive antinuclear antibody, assay, IgA rheumatoid factor, rheumatoid nodules, and some HLA_DR haplotypes.

 5% of people with rheumatoid arthritis have rheumatoid nodules within two years of disease onset, and the cumulative prevalence is about 20–30%

Therapeutic intervention early in the disease can lead to decreased joint damage and this particularly true if treated aggressively with combinations of medications.

Intensive weight bearing exercises improve aerobic conditioning and muscle strength in patients with RA without increase in disease activity.

People with early rheumatoid arthritis who are overweight or obese are less likely than those of normal weight to achieve sustained remission over time.

The presence of antibodies to cyclic citrullinated peptides (CCP) is highly predictive of developing rheumatoid arthritis.

Patients with early polyarthritis positive for anti-CCP antibodies have a 93% chance of developing classic rheumatoid arthritis in 3 years.

One third of rheumatoid factor negative patients have a positive anti-cyclic citrullinated peptide antibody test.

Some patients present with sudden onset of episodic and transient monoarthritis or oligoarthitis without residual joint disease referred to as palindromic arthritis.

May present with glomerulonephritis and rheumatoid vasculitis both of which have active urinary sediment.

In a review of 63 randomized control studies with 29,243 patients with rheumatoid arthritis treated with biological response modifiers, no significant association with increased risk of malignancy was noted compared to other disease- modifying anti rheumatic drugs or placebo (Lopez- Olivo, MA et al).

In naive treated RA patients tofacitinib is superior to methotrexate in reducing signs and symptoms of RA and inhibiting the progression of structural joint damage (ORAL Start Investigators).

Upadactinib, A second generation JAK inhibitor that selectively blocks the signaling molecule of JAK1, is superior to abatacept in the achievement of remission in patients refractory to biologic DMRDS.
The use of Janus kinase inhibitors (Tofacitinib in RA is associated with increased risk of major adverse cardiac events and cancers.
Peresolimab, humanized IgG1  monoclonal antibody binds  and activates PD-1 has potential efficacy in the treatment of rheumatoid arthritis.

One reply on “Rheumatoid arthritis”

I like that you pointed out how the risk of rheumatoid arthritis would increase over time as autoantibody levels increase. I was listening to a podcast of a doctor earlier and I learned a few things about RA. It seems like a pretty inconvenient condition, but thankfully, there are rheumatologists now.

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