Lecture 14 - pharmaceutical care of rheumatoid arthritis

Question 1

what is rheumatoid arthritis?

Answer 1

rheumatoid arthritis is a chronci systemica inflammatory autoimmune disease. it involves synovitis which is the inflammation and swelling of the synovium joint with subsequent destruction of the joint if left untreated. typically effects the joints of small hands and feet.

any synovial joint can be invovled .

Question 2

what is the pathophysiology of rheumatoid arthritis?

Answer 2

the autoimmune reaction primarily occurs in the synovial joints.
phagocytosis produces enzymes that breakdown collagen.

This leads to the oedema, proliferation of synovial memebrnae and ultiamtely pannus formation

pannus destroys cartilage and leads to bone erosion. The conseuqoences are loss of artiucalr surfaces and joint motion. msucle fibres undergo degenerative chnages, tendon and ligament eleasticity and contractiel power are lost

Question 2

what are clinical features of rheumatoid arthritis

Answer 2

RA most commonly presents with insidious joint pain,swellingandstiffnessover weeks to months

Some patients maypresent acutelywith severe joint pain and systemic features such as fever.

Typicalsymptomsof rheumatoid arthritis include:
- Symmetrical joint pain and swelling
- Multiple joints affected: usually small joints of hands and feet such as the proximal interphalangeal (PIP) joint, metacarpophalangeal (MCP) joint, wrist, knee, ankle, metatarsophalangeal (MTP) joint, and cervical spine

Associatedsystemic symptomsmay include:
- Fatigue or low-grade fever

Question 3

what does clinical examination of rheumatoid arthritis show

Answer 3

patients presenting with stiffness and severe joint pain should undergo a thorough mucoskeletal examination.

thematoidarhttitis is typically symemtrical polyarthropy joint but can beign as assymetrical.there is pormiennt hand and foor involvement

Thespineis generally unaffected, but patients can experience cervical spine instability

Question 4

what are extra articular manifestations rhemaotid arthritis can also present with

Answer 4

Eyes: dry eyes, scleritis, episcleritis, uveitis

Skin: leg ulcers, rashes (pyoderma gangrenosum and cutaneous vasculitis)

Heart: pericarditis

Lungs: pulmonary nodules, pulmonary fibrosis

Kidneys: amyloidosis (rare)

Rheumatoid nodules: commonly found on the extensor surface of the forearm and dorsum of the foot

Anaemia: usually normocytic or iron deficiency related due to NSAIDs

Liver: hepatomegaly
Muscle wasting and tendon rupture

Nerves: peripheral nerve entrapment, polyneuropathy

Raynaud’s phenomenon

Depression

Question 5

what are relevant lab investigations for Rheumatoid arthritis

Answer 5

Full blood count: normochromic, normocytic anaemia

Inflammatory markers (ESR/CRP): usually raised but may be normal

Liver function tests: raised ALP and GGT (acute phase reactants)

Rheumatoid factor (RF): usually positive in60-70%of patients but non-specific

Anti-cyclic citrullinated peptide(anti-CCP): morespecificthan rheumatoid factor and more sensitive in erosive disease

Antinuclear antibody (ANA): raised in up to 30% of cases (only check if other signs or symptoms could suggest lupus or another connective tissue disease)

Uric acid/synovial fluid analysis: excludes polyarticular gout

Urinalysis: microscopic haematuria/proteinuria may suggest connective tissue disease

Patients with either RF or anti-CCP antibodies are referred to as “seropositive”.

Question 6

what are relevant imaging investigations for arthritis

Answer 6

X-ray; affected joints should be imaged and may show RA-related damage such aserosionsand can help differentiate from signs of osteoarthritis

Musculoskeletal ultrasound: can demonstrate joint inflammation manifest as grey scale/Doppler positive synovitis or established erosive damage

MRI: can be useful if X-ray and ultrasound are inconclusive

Question 7

what is the diagnosis classification for rheumatoid arthritis?

Answer 7

The 2020ACR-EULAR rheumatoid arthritis classification criteriaare commonly employed to aid diagnosis, with a score ofsix or morerequired for the diagnosis of rheumatoid arthritis.

Question 8

what features are associated with a worse prognosis or rheumatoid arthritis ?

Answer 8

High ESR/CRP
Early erosions on X-rays
High tender or swollen joint counts
Positive anti-CCP or rheumatoid factor

Question 9

descried the criteria for DAS20 monitoring

Answer 9

DAS28 score greater than 5.1 is considered to be indicative of high disease activity, between 5.1 and 3.2 of moderate disease activity and less than 3.2 of low disease activity

A patient scoring less than 2.6 is defined as being in remission

The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure
-> a decrease in DAS28 score of 0.6 or less is considered to show a poor response, while decreases greater than 1.2 points indicate a moderate or good response, dependent on whether an individual’s DAS28 score at the end point is above or below 3.2 respectively

Question 10

how is rhemaotif arthritis managed

Answer 10

Relief of Symptoms – Simple analgesics / NSAIDs
Long-term suppressive drug therapy with disease modifying anti-rheumatic drugs (DMARDs)
Progression onto biologic therapy
Encouraged to continue with a full, normal, busy life. Input from the Multidisciplinary team (MDT)

Question 11

describe the use of NSAIDs for ra

Answer 11

Use the lowest dose of NSAID for the shortest time period possible
Reduce and withdraw the NSAID when good response to DMARD achieved
NSAID examples – ibuprofen, naproxen, celecoxib, etoricoxib

Question 12

what DMARDs are used in RA

Answer 12

Methotrexate – dose titrated up to 15-25mg once weekly – oral or subcutaneous route
Sulfasalazine EC – dose usually titrated up to 40mg/kg split twice daily
Hydroxychloroquine - 200–400 mg daily, daily maximum dose to be based on IBW; ideally keep to 5mg/kg per day
Leflunomide – 10-20mg once daily

Used in COMBINATION – often triple therapy – MTX, SASP & HCQ

Question 13

what are pharmacological considerations fro methotrexate use in RA

Answer 13

First line DMARD, used in combination (SASP/HCQ)
Inhibition of dihydrofolate reductase involved in the metabolism of folic acid
In RA has anti-inflammatory action (not well understood)
Generally 7.5mg to 25mg once weekly – either ORAL or SUBCUTANEOUS route (Metoject brand / single use PEN)
The initial dose is inocreased by 2.5-5mg every 2-4 weeks until the disease is stabilised (generally up to 20mg weekly)
Onset of action - up to 12 weeks
Regular folic acid supplements are thought to reduce the toxicity of MTX. Typical dose 5mg once weekly usually 2-3 days after MTX therapy OR every day except MTX day (6/7)
Contraindicated in Pregnancy / Breastfeeding. Stop MTX in advance of planned conception
Contraindicated if any ongoing local or systemic infection, pre-existing bloods dyscrasias, significantly impaired hepatic / renal function or alcoholism
Use with caution in those with renal impairment – may lead to increased toxicity

Question 14

what are methotrexate monitoring requirements ?

Answer 14

Baseline Investigations
- FBC, creatinine / calculated GFR, LFTs (AST/ALT/albumin)

• Chest X-ray (unless done within the last 6 months)
• Pulmonary Function Tests

Blood Monitoring Schedule
- Check FBC, creatinine / calculated GFR, ALT and /or AST and albumin every 2 weeks until on a stable dose for 6 weeks.

• ONCE on a stable dose, check monthly FBC, creatinine / calculated GFR, ALT and /or AST and albumin for 3 months.
• THEREAFTER check FBC, creatinine / calculated GFR, ALT and /or AST and albumin at least every 12 weeks.
  … some patients may still need monthly monitoring

Question 15

what is sulphalazine

Answer 15

Used in combination with other DMARDs

Mode of action not well understood

Start at 500mg daily up to 40mg/kg/day – titrate up by 500mg every week

Nausea, vomiting & headaches common side effects – may be less troublesome if dose titrated up gradually

For rheumatology patients EN preparation used

Onset of action – up to 12 weeks

Yellow – orange discolouration of urine

Question 16

what are suphalazien mintirogn requirements

Answer 16

Baseline Investigations
FBC, creatinine / calculated GFR, LFTs (AST/ALT/albumin)

Blood Monitoring Schedule
Check FBC, creatinine / calculated GFR, ALT and /or AST and albumin every 2 weeks until on a stable dose for 6 weeks.
ONCE on a stable dose, check monthly FBC, creatinine / calculated GFR, ALT and /or AST and albumin for 3 months.
THEREAFTER check FBC, creatinine / calculated GFR, ALT and /or AST and albumin at least every 12 weeks.
Standard DMARD blood monitoring schedule for 12 months then no routine monitoring needed

Question 17

Describe hydroxychloroquine use

Answer 17

Commonly used as add-on therapy

Mode of action not understood

Dose 200–400 mg daily, daily maximum dose to be based on IBW; maximum 6.5 mg/kg per day

Little side-effects but very rarely ocular toxicity

Pre-treatment assessment - FBC, U&E, LFT. Ask about visual impairment which is not corrected by glasses. Record near visual acuity of each eye

Ocular complications with hydroxychloroquine are rare, but potentially serious.
Complications include both corneal & retinal disease.

Requires baseline ophthalmological exanimation & ongoing yearly screening via their optician

Royal College of Ophthalmologists Guidance – HCQ Retinopathy: Recommendations on Monitoring (Dec 2020) – 5x5 rule – keep dosage < 5mg/kg/day & monitor after 5 years of drug use

Question 18

describe leflunomide

Answer 18

Licensed in RA

Inhibits pyrimidine synthesis & also has effects on stimulated T-cells

Leflunomide inhibits the reproduction of rapidly dividing cells

Good evidence that it slows erosion progression

Used in combination with other DMARDs – often if MTX not tolerated

Dose 10-20mg per day – loading doses not well tolerated

Side effects include – diarrhoea, GI upset, hair loss, liver dysfunction, blood dyscrasias

Long half life so difficult to manage if side effects develop

Question 19

what are monitoring requirements for leflunomide

Answer 19

Baseline Investigations
FBC, creatinine / calculated GFR, LFTs (AST/ALT/albumin)
Check weight & blood pressure

Blood Monitoring Schedule
Check FBC, creatinine / calculated GFR, ALT and /or AST and albumin every 2 weeks until on a stable dose for 6 weeks.
ONCE on a stable dose, check monthly FBC, creatinine / calculated GFR, ALT and /or AST and albumin for 3 months.
THEREAFTER check FBC, creatinine / calculated GFR, ALT and /or AST and albumin at least every 12 weeks

Weight & blood pressure should be checked each time the patient attends for monitoring

Question 20

why do we monitor DMARDs?

Answer 20

Ensure that no signs of DMARD-related toxicities developing
Important to identify toxicities early to reduce risk of long term organ damage or even fatality
Regular review affords opportunity to assess tolerability and adherence
Bone Marrow – monitor FBC, report signs of infection
Liver – monitor LFTs and report signs of liver impairment
Renal – monitor U&Es and exclude proteinuria
Gastro-intestinal – monitor for GI upset and ulceration
Respiratory – monitor for cough or SOB  CXR and PFTs as necessary
Skin – rashes
Eye – changes in vision, dry eye symptoms

Question 21

what is the guidance for pregnancy

Answer 21

There is usually an improvement in rheumatoid arthritis during pregnancy. This may be due to the increase in pregnancy related globulin that has anti-inflammatory properties.
Regarding DMARD treatments used in rheumatoid arthritis:
Prednisolone is compatible with pregnancy – preferred steroid
Methotrexate use during pregnancy is contraindicated (teratogenic); manufacturers advise the use of effective contraception during and for at least 6 months after administration for women and at least 3 months for men
Suphasalazine may be used if there is folate supplementation (folic acid 5mg/day)
Leflunomide – insufficient evidence to support its use

Question 22

what are biologics used?

Answer 22

TNF α inhibitors- Etanercept, infliximab, adalimumab, golimumab, certolizumab
Anti-CD20 - Rituximab
IL6 inhibitors - Tocilizumab, Sarilumab
JAK inhibitors - Tofacitinib, Baricitinib, Upadacitinib, Filgotinib

Question 23

what is the eligibility criteria for rhemaotid arthritis?

Answer 23

DAS28 > 5.1 (at two points one month apart)

NICE guidance – DAS28 > 3.2 (moderate disease)

At least 2 previous DMARDs (one of which is MTX)

Adequate response at 3 months is defined as an improvement in the DAS28 score by > 1.2 or the achievement of a DAS28 score of ≤ 3.2

Question 24

pre biologic screening

Answer 24

Standard screening encompasses:
Routine blood checks for baseline; FBC, U&Es, LFTs, CRP, ESR, Lipids (for JAK and IL-6 inhibitors), Immunoglobulins (for Rituximab)
Virology: Hep B, Hep C, HIV, Varicella and TB screens
Chest X-ray to exclude any respiratory pathology/latent TB
Patient review to check for all contra-indications
Patient education on risks and benefits of biologic therapy.
Patients provided with appropriate written information on the medicine

Question 25

what are caution or contraindications of biologics

Answer 25

Active infection

Conditions which may increase the risk of infections eg leg ulcers, previous joint infection

history of hep B or C

Active or latent tuberculosis

Active of history of cancer

Chronic cardiovascular or pulmonary disease

Question 26

describe TNFa inhibitors

Answer 26

Examples of TNFa inhibitors are infliximab, etanercept, adalimumab, certolizumab and golimumab.

Cautions or contraindication are TB, infection risk, MS, CHF, and previous cancers

Potential side effects are hypertension, injection site reactions, skin problems, including rash and dry skin, headaches, dizziness, nerve problems, GI affects, infections, muscle pain, allergic reactions, and blood disorders

Different modes of delivery IV or SC and frequency allow to tailor to patient’s lifestyle. there are biosimilar products available for infliximab, etanercept and adalimumab

Question 27

descried rituximba

Answer 27

Rituximab ais a an anti-cd20 mab which binds specifically to the transmembrane antigen CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. It is licensed for RA.

It is administered as an IV infusion – set dose :2x 1000mg at Day 1 & Day 15, usually repeated every 6 months.

Cautions are infections, PML, Hypogammaglobulinemia

Side effects are infusion reactions - pre-treatment with antihistamine, steroid and paracetamol. Infection and changes in blood pressure

Question 28

describe IL-6 inhibitors

Answer 28

IL-6 inhibitors are Tocilizumab & Sarilumab. They are Licensed for RA
Tocilizumab IV dose is 8mg/kg, 4 weekly or SC 162mg, 2 weekly and Sarilumab SC 200mg every 2 weeks
Cautions are Infection, Previous history of intestinal ulceration or diverticulitis, Hepatic Impairment and Haematological abnormalities

Side-effects are CRP response is muted due to IL6 inhibition – should be noted when assessing for infection/sepsis, Upper respiratory tract infections, Elevated lipids, Neutropenia, Hepatic dysfunction and Injection site reactions

Question 29

describe janus kinase inhibitors

Answer 29

JAK are mall molecule inhibitors – all ORAL - Tofacitinib, Baricitinib, Upadacitinib, Filgotinib

Cautions are Severe hepatic impairment, History or risk of VTE
ILD, History of Diverticulitis and Haematological Abnormalities

Side-effects are Herpes Zoster Infection, Diverticulitis, Headache, Increased CK, Increased Lipids, Increased liver enzymes, Cough, VTE