Rheumatoid Arthritis

Question 1

What is the most common chronic inflammatory arthritis?

Answer 1

Rheumatoid arthritis

Question 2

What is the classic initial pattern of RA?

Answer 2

Synovitis of the small joints of the hands (MCPs and PIPs) and wrists.

Question 3

Are RA patients with extraarticular manifestations typically seropositive or seronegative?

Answer 3

Seropositive

Question 4

What is the pathophysiology of RA?

Answer 4

The primary site of pathology is the synovium of the joints. The synovial tissues become inflamed and proliferate, forming pannus that invades bone, cartilage and ligaments and leads to damage and deformities.

Question 5

What is the prevalence of RA in the general population?

Answer 5

1%

Question 6

What is the concordance rate for RA in monozygotic twins? In fraternal twins?

Answer 6

Twin studies show that the concordance rate for RA is 12-15% in monozygotic twins and 2-3% in fraternal twins.

Question 7

What percentage of RA is ‘sporadic’ (i.e. occurring in individuals with no family history of RA)?

Answer 7

80-90% of all RA is sporadic, that is, occurring in individuals with no family history of RA.

Question 8

What is the best characterised environmental risk factor for RA? Can you discuss about this in detail?

Answer 8

Smoking is the best characterised environmental risk factor for RA. It is more strongly associated with ACPA-positive (1.9-fold) compared with ACPA-negative (1.3-fold) RA. Cigarette exposure in the setting of two shared epitope alleles can increase the odds ratio for ACPA-positive RA by 21-fold. The smoking-associated risk of RA is dose-dependent (2-fold for >20 pack years) and persists for 10 to 20 years after a person quits smoking.

Question 9

In addition to smoking, what other inhaled factors have been associated with RA?

Answer 9

Silica dust and air pollution.

Question 10

Give some examples of the role of bacteria in the pathogenesis of RA.

Answer 10

While the exact role that they may play in the development of RA is uncertain, bacteria in the microbiomes of mucosal sites (e.g. mouth, lung, gut), may also contribute to RA development. For example, Porphyromonos gingivitis (an organism associated with peritonitis) can express peptidylarginine deaminase (PAD) enzymes athat can citrullinate resident proteins through the post translational modification of arginine to citrulline. Additionally, Prevotella copra is expanded in the stool of patients with RA and is thought to be associated with specific immune responses in these patients.

Question 11

Have viruses been associated with RA?

Answer 11

EBV and parvovirus B19 have been associated with RA.

Question 12

How does antibodies to citrullinated protein/peptide antigens (ACPA) contribute to RA pathogenesis?

Answer 12

ACPAs and anti-carbamylated antibodies can bind citrullinated and carbamylated proteins locally or form immune complexes that can deposit in the tissue, thereby directly playing a role in disease pathogenesis.

Question 13

What is the only modifiable risk factor demonstrated to reduce RA risk?

Answer 13

Smoking cessation

Question 14

Discuss the 2010 ACR/EULAR criteria for the classification of RA.

Answer 14

With the knowledge that early effective treatment in RA improves long-term outcomes, the 2010 ACR/EULAR classification criteria for RA were designed to identify individuals with RA at an earlier stage of disease compared with the 1987 ACR RA classification criteria. The criteria demonstrate 82% sensitivity and 61% specificity for RA when compared with control subjects with non-RA rheumatic disease. While these criteria can be a guide, the purpose of classification is to define a homogenous population for study purposes. Ultimately, the diagnosis of RA is established by the rheumatologist.

Question 15

What are the ACR/EULAR 2010 Classification Criteria for RA?

Answer 15

To apply these criteria, the patient must have at least one joint swollen with inflammatory arthritis on clinical examination that is not explained by another disease. MRI / US may be used to confirm clinical findings.

Question 16

Discuss the epidemiologic characteristics of RA.

Answer 16

Race - worldwide, all races. Native Americans (Algonquian and Pima Indians) have higher incidence.

Sex distribution - females > males 2-3:1

** Age** - the average age of onset of RA in women is 40-60 years, men are older.

Prevalence - Occurs in ~1% of adults in the United States. The prevalence increases with age.

Question 17

Describe the various ways RA can present.

Answer 17

a) Typical patterns of onset (90% of patients)
* **Insidious (55-65%) **- onset with arthritic sympomts of pain, swelling and stiffness, with the number of joints increasing over weeks to months.
* Subacute (15-20%) - similar to insidious onset but more systemic symptoms.
* **Acute (10%) **- severe onset, some have fever.

b) Variant patterns of onset (10% of patients)
* Palindromic (episodic) pattern - Usually involves less than five joints and resolves withing several days. After an asymptomatic period, a flare in the same or another joint(s) occurs. Over time, 33 to 50% evolve into RA involivng more joints persistently. Seropositive patients and those with elevated actue-phase reactants are more likely to progress to RA. The optimal treatment for individuals with “palindromic/episodic” RA is not known; however, antimalarial therapy may decrease the frequency of attacks and progression to RA.
* Insidious onset of elderly (>65years) - Present with severe pain and stiffness of limb girdle joints often with diffuse swelling of hands, wrists and forearms. May be difficult to differentiate from PMR and RS3PE.
* Arthritis Robustus - Typically seen in men. Patients have bulky, proliferative synovitis causing joint erosions and deformities, but the patient experiences little pain or disability.
* Rheumatoid nodulosis - Patients with recurrent pain/swelling in different joints, subcutaneous nodules and subchondral bone cysts on radiographs.

Question 18

What are the most common joints involved during the course of RA?

Answer 18

Question 19

What is the difference in joint involvement pattern between RA and OA?

Answer 19

Question 20

Which joints tend to become symptomatic first in RA - small or large joints?

Answer 20

Small joints generally become symptomatic before large joints in RA.

Question 21

What joints is it uncommon to get RA involvement in?

Answer 21

Involvement of the thoracolumbar, sacroiliac or hand DIP joints is very rare in RA nad should suggest another diagnosis, such as seronegative spondyloarthritsi (sacroiliac joints), psoriatic arthritis (DIP joints) or OA (lumbar spine, DIP joints).

Question 22

Using the 2010 RA Classification Criteria, what percentage of patients with undifferentiated arthritis (UA) will progress to RA? What percentage will have persistent UA? What percentage will be diagnosed with another type of inflammatory arthritis? What percentage will undergo spontaneous remission?

Answer 22

When using the newer 2010 RA classification criteria:
* **6% to 22% **of patients with UA will progress to RA,
* **53% **will have persistent UA
* *** 3% **will be diagnosed with **another type of inflammatory arthritis, **and 22% will undergo **spontaneous remission. **

(NB: Comparatively, among patients with UA who do not meet the 1987 RA classification criteria, 33% will progress to RA [by 1987 criteria] over the following year, 33% will be diagnosed with another type of inflammatory arthritis, and 33% will undergo spontaneous spontaneous remission.)
–> These differences likely reflect the improved sensitivity of the 2010 criteria (with a significant proportion of UA patients now classificed as RA at the time of initial evaluation) as well as the mandate within the new classification criteria to rule out competing diagnoses as the cause of inflammatory arthritis before applying the criteria to a specific patient (improved specificity).

Question 23

What are predictors of progression to RA by 2010 classification criteria?

Answer 23

Predictors of progression to RA by 2010 classification criteria include:
1) Higher score on 2010 classification criteria at baseline (42% with a score of 5 will develop RA; therefore, number of involved joints, duration of symptoms and presence of autoantibodies and elevated inflammatory markers are all important factors); and
2) Grey scale synovitis on ultrasound.

Question 24

What inflammatory cells are found in the synovium of RA patients?

Answer 24

The synovium is the primary site for the inflammatory process in RA. The inflammatory infiltrate consists of mononuclear cells, primarily CD4+ T lymphocytes (30-50% of cells) as well as activated macrophages, B cells (5% of cells) plasma cells (some making RF and ACPA) and dendritic cells that can lead to an organisational structure that resemples a lymph node.

Notably, unlike the synovial fluid, few, if any, polymorphonuclear leukocytes (PMNs) are found in the synovium.

The inflammatory cytokine milieu causes the synovial lining cells (macrophage-like and fibroblast-like synoviocytes) to proliferate. The inflammaed synovium becomes thickened, boggy and oedematous and develops villous projections.

The proliferative synovium is called pannus and it is capable of invading bone and cartilage, causing destruction of the joints. One of the most important cells in the pannus contributing to cartilage destruction is the fibroblast-like synoviocyte, which has tumour-like characteristics capable of tissue invasion.