Rheumatology: RA

Question 1

RA Dx Criteria

Answer 1

Need at least four of seven criteria:

1. Morning stiffness lasting at least 1 hr
2. Soft- tissue swelling or fluid in at least 3 joint areas simultaneously
3. At least one area swollen in a wrist, MCP, or PIP joint*
4. Symmetric arthritis*
5. Rheumatoid nodules
6. Abnormal amounts of serum rheumatoid factor
7. Erosions or bony decalcification on radiographs of the hand and wrist

Question 2

Stage I

Answer 2

Early

1. No destructive changes on radiographs
2. May have radiographic evidence of osteoporosis

Question 3

Stage II

Answer 3

Moderate

1. Radiographic evidence of osteoporosis; may have slight subchondral bone or cartilage destruction
2. No joint deformities; limitation of joint mobility may be present
3. Adjacent muscle atrophy
4. Nodules and tenosynovitis may be present

Question 4

Stage III

Answer 4

Severe

1. Radiographic evidence of osteoporosis as well as cartilage and bone destruction
2. Joint deformity without ankylosis
3. Extensive muscle atrophy
4. Nodules and tenosynovitis may be present

Question 5

Stage IV

Answer 5

Terminal

1. Fibrous or bony ankylosis
2. Criteria of stage III

Question 6

Onset of RA

Answer 6

RA can present as:
Abrupt and acute
Gradual and insidious
Subacute between these extremes
A gradual onset is most common (at least 50% of cases)
An abrupt and acute onset is much less common (10–25%).

Question 7

Presentation of RA

Answer 7

RA usually starts as an articular disease with one or many joints affected.
It can start with an extra-articular or non-articular presentation, such as a local bursitis, tenosynovitis, or carpal tunnel syndrome.
A systemic presentation with diffuse polyarthralgia (joint pain) or polymyalgia (muscle pain) can also happen.
Onset also frequently has a variety of non-specific symptoms such as, generalized weakness, fatigue, anorexia, weight loss or fever
5-10% of people have some episodes then never have it again
Most common: polycyclic progressive where levels of disease activity fluctuate

Question 8

Areas of Cartilage Destruction

Answer 8

RA does not like the spine aka does not affect usually
End up having cartilage destruction
Hypertrophy because endothelial GF, other GFs which creates chronically swollen inflamed tissue; don’t always see redness

Question 9

OA vs. RA

Answer 9

Systemic inflammation in RA – C reactive protein go up, ESR goes up; these are usually in range or only slightly elevated in OA
More bony swelling and destruction in RA than OA

Question 10

Genetic Factors

Answer 10

RA has a multifactorial etiology. With research showing genetic factors account for 60% the risk to develop RA.
Associated with HLA-DR4 and the DR– associated alleles, DRB10401 and DRB10404 and contribute 30–50% of the genetic risk.
The HLA susceptability genes are a called the “shared epitope” theory located on the third hypervariable region of the HLA-DRB1 zone

Question 11

Possible Trigger of RA

Answer 11

Hormonal and reproductive factors may play a role in the predominance of RA in women.
Parity, breast feeding and the use of exogenous hormones have been implicated in susceptibility to the disease.
Environmental and lifestyle factors include: obesity, dietary exposure to antioxidants, smoking, coffee consumption and certain specific occupational exposures.
There is no conclusive epidemiological evidence for a single infectious trigger

Question 12

Cellular Processes in RA

Answer 12

Something becomes an Ag and stimulates something to release IFN, IL-6, etc. that go to T helper cells; stimulate T cells and differentiate into different cell lines; RANK L on surface of osteoblasts an osteoclasts
Osteoblasts are stimulated by T cell and lead to erosions in RA, and stimulation from macrophages from autoAb that cause hyperplasia of chondrocytes, VEGF cause vasculature growth and become leaky and macrophage also stimulate adipocytes and increase risk for heart attack and stroke because can cause metabolic syndrome
Adaptive response is stimulated and causes all these things

Question 13

Hx and Dx of RA

Answer 13

Morning stiffness and symmetrical swelling in the wrists, PIPs and MCPs is the typical history for rheumatoid arthritis.
▪Early diagnosis of RA is critical but many cases of ‘early arthritis’ are not RA.
▪Antibodies to cyclic citrullinated peptide (anti-CCP) occur earlier than rheumatoid factor (RF) and are more specific for RA.
▪Aggressive early administration of disease-modifying antirheumatic drugs (DMARD’s) is critical to a good outcome

Question 14

Rheumatoid Factor

Answer 14

RF is a series of antibodies that recognize the Fc portion of an Ig molecule as their antigen.
Most measured RFs are IgM RFs.
There are many conditions associated with a +RF therefore a positive test does not make the diagnosis.
However…..having a +RF especially at a significant titer does indicate increased risk for more aggressive disease and extra-articular problems.
Disease activity cannot be monitored by RF levels

Question 15

False Positive RF

Answer 15

RF occurs in normal healthy people 2-4% until the age of 60 and then goes to 5% until 70 years old then increases to 10-25% after 70.

Chronic hepatic or pulmonary disease; Other rheumatic diseases (SLE, PSS, MCTD, Sjogren’s, Polymyositis or Sarcoid); Malignancy; Infections; Cyroglobulinemia

Question 16

Anti-CCP

Answer 16

The Anti-CCP assay looks for antibodies against serum anti-cyclic citrullinated peptide antibodies (anti-CCP).
These antibodies if detected have a high specificity and sensitivity for RA.
They can be seen in serum up to 10 years before the onset of RA.
Anti-CCP antibodies have been reported to be an independent and important predictor of joint damage and disease progression.
The current assay has a sensitivity of 78%, specificity 98%.
Anti-CCP – specific for synovial fluid itself and direction T and B cells to the fluid; acts like an antigen but is not an antigen, which then stimulates the whole cascade

Question 17

Anti-Mutated Citrullinated Vimentin (anti-MCV)

Answer 17

A new antibody screening test for RA developed over the last 2-3 years and available on the market for patient screening now.
It is a highly RA specific antibody 93.2% with sensitivity of 76.9%.
Measures IgG antibodies to mutated citrullinated vimentin (MCV) which are found in inflamed synovium in RA patients.
Also is a predictor of severe outcome in RA patients

Question 18

Prognosis

Answer 18

70 percent of joint erosions detectable by x-ray of hands and feet occur in the first two years of disease.

At 20 years, over 60 percent of RA patients belong to functional class III (significantly impaired, self-caring, using aids, requiring joint replacements) or class IV (loss of independence, requiring daily care).

Increased evidence of: Infections, Cardiovascular disease and Malignancies.

Life-expectancy of RA less than age-sex matched control populations up to 15 years, especially in patients with: Polyarticular disease, Systemic extra-articular disease, Persistent disease activity (high ESR, CRP), RF and anti-CCP positivity, HLA-DR & chain ‘shared epitope’.

Question 19

Other Manifestations of RA

Answer 19

General: fever, LAD, weight loss, fatigue.
Dermatologic: palmar erythema, subcutaneous nodules, vasculitis.
Ocular: episcleritis, scleritis, choroid and retinal nodules.
Pulmonary: pleuritis, nodules, interstitial lung disease, bronchiolitis obliterans
Cardiac: pericarditis, myocarditis, coronary vasculitis, nodules on valves.
Neuromuscular: entrapment neuropathy, peripheral neuropathy, mononeuritis multiplex.
Hematologic: Felty’s syndrome, Large granular lymphocytic syndrome, lymphomas.
Other: Sjogren’s syndrome and amyloidosis

Question 20

Boutonniere and Swan Neck Deformity

Answer 20

PIP flexion and DIP hyperextension for boutonniere deformity

Swan neck deformity- DIP flexion and PIP hyerextension

Question 21

Cervical Spine Involvement

Answer 21

Occurs in 30-50% of patients and is found at the C1-C2 level.
C1-2 anterior subluxation is atlantoaxial subluxation that can lead to spinal cord compression.
C1-2 vertical subluxation (occurs in 5% of RA patients) can cause herniation and death

Happens in 30-50% of patients with untreated RA
For RA patient intubation: NEVER tilt their head back because can kill them; C spine x-ray with flexion and extension to make sure they do not have this issue

Question 22

Management of RA

Answer 22

Early RA—Patients with early disease that meet ACR criteria for the diagnosis and classification of RA and have had evidence of active disease for a period of not more than three months.

Established or persistent RA—Established RA is characterized by active, well-defined disease for at least six to twelve months. Significant and irreversible damage may be observed at this stage, leading to functional disability

Question 23

Plaquenil

Answer 23

Least toxic of all DMARD’s and can be safely combined with others.
Works best in combination or in mild cases as monotherapy.
Dose: 200mg bid and adjusted if needed for lower weight.
Side-effects: N/V, diarrhea, HA, dizziness, myopathy, hemolysis, rash, hyperpigmentation, retinal toxicity.
Monitor: eye exam once 6mo after starting then q1yr
Is safe in pregnancy

Question 24

Azulfdine

Answer 24

Sulfasalazine – in early disease as monotherapy usually in combinations.
Low potential toxicity.
Dose: 1-3g/day in divided doses.
Side-effects: N/V, rash, HA, dizziness, azoospermia, neutropenia, pulmonary infiltrates with eosinophilia, elevated LFT’s.
Monitor: LFT, CBC, BMP
Safe in pregnancy

Question 25

Methotrexate

Answer 25

Considered the most effective non-biologic DMARD.
Acts quickly and comes oral or injectable.
Doses: 7.5-25mg weekly
Needs 1mg folate at least daily.
Side-effects: oral ulcers, N/V/diarrhea, rash, Hematologic abnl, LFT abnl, pneumonitis, lymphoma.
Monitor: CBC, BMP, LFT
Never give bactrim with this drug, avoid etoh and must be off of 3 months before pregnancy

Question 26

Etanercept (Enbrel)

Answer 26

Is a soluble p75 TNF receptor fusion protein that consists of two p75 TNF receptors bound to the Fc portion of IgG. It is administered once or twice weekly via subq injection.

Question 27

Infliximab (Remicade)

Answer 27

Is a chimeric monoclonal Ab directed against TNF

It is administered via IV every 6-8 weeks and the dose can be adjusted as needed.

Question 28

Adalimumab (Humira)

Answer 28

Is a humanized monoclonal Ab that is administered subq every two weeks and in some rare cases weekly.

Question 29

Golimumab (Simponi)

Answer 29

Is a humanized monoclonal antibody directed against TNF given subq every 4 weeks. Can also be given IV as Simponi Aria every 8 weeks.

Question 30

Certolizumab (Cimzia)

Answer 30

Pegylated Fab fragment of a monoclonal antibody against TNF

Given subq 200mg every other week or 400mg q4 weeks

Question 31

Anti-TNF drugs

Answer 31

etanercept, infliximab, adalimumab, golimumab, certrulizumab; very active in adults

Risks: Infections some of which can be serious, reactivation of Hep B and/or Hep C (less risky with Hep C), can be risky in patients with CHF, can reactivate TB, may increase risk for malignancy.
Monitor: PPD, CXR, CBC, LFT, BMP, Hepatitis status. Can lead to soluble antibodies that can cause lower efficacy

Question 32

T cell costimulatory blocker

Answer 32

abatacept

soluble fusion protein comprising CTLA-4 and the Fc portion of IgG1
It prevents CD28 from binding to its counter-receptor, CD80/CD86, due to its higher affinity for CD28.
Given IV every 4 weeks
Risks: Similar to the Anti-TNF but has a warning about COPD patients increasing exacerbations.
Monitor: PPD, CXR, CBC, LFT, BMP, Hepatitis status

Question 33

CD 20 monoclonal antibody

Answer 33

B Cell Therapy
rituximab

Rituximab (Rituxan) - is a B cell depleting monoclonal anti-CD20 antibody
Causes B cell depletion of immature B cells (only the ones still with CD20 on their cell surface) but leaves Stem cells and plasma cells alone
Given IV 1g day 1 and day 15 and not redosed for a minimum of 16 weeks.
Less risk for infection or possible malignancy.
Can reactivate Hep B

Question 34

IL I receptor blocker

Answer 34

anakinra; works in children, but not much in adults for fever and inflammation

a recombinant human IL-1Ra, is approved for the treatment of RA.
Is significantly less potent than TNF inhibitors in most patients.
More effective in the treatment of autoinflammatory conditions such as the TNF receptor-1 associated periodic syndrome (TRAPS), Systemic JIA and if needed Adult onset Still’s Disease

Question 35

IL 6 receptor blocker

Answer 35

tocilimumab; very active in adults

Humanized monoclonal antibody against IL6 receptor.
Given IV q4weeks or subq either weekly or every other week based on weight.
Risks: infection, elevated LFTs, elevated cholesterol, could lower ANC.
Monitor: PPD, CXR, CBC, LFT, BMP, Hepatitis status, cholesterol

Question 36

Jak Inhibitor

Answer 36

tofacitinib/Xeljanz; small molecule

Inhibits Janus Kinas 3 (Jak3) enzyme which interferes with the Jak-Stat signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.
Given orally BID
Risks: infection, elevated LFTs, elevated cholesterol, could lower ANC.
Monitor: PPD, CXR, CBC, LFT, BMP, Hepatitis status, cholesterol

Question 37

Methotrexate Mechanism of Action

Answer 37

Methotrexate inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and proteins by binding to dihydrofolate reductase

Inhibition of adenosine deaminase results in increased adenosine concentrations, which inhibits inflammation

At low doses, methotrexate may selectively inhibit replication and function of T and B lymphocytes. In addition, methotrexate can suppress the secretion of IL-1, IF-gamma, and TNF, increase the secretion of IL-4, impair the release of histamine from basophils, and decrease chemotaxis of neutrophils. The efficacy of methotrexate for rheumatoid arthritis is likely multifactorial; however, inhibition of AICAR transformylase appears to be a main mechanism