Lecture 14 - pharmaceutical care of rheumatoid arthritis Flashcards
what is rheumatoid arthritis?
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 .
what is the pathophysiology of rheumatoid arthritis?
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
what are clinical features of rheumatoid arthritis
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
what does clinical examination of rheumatoid arthritis show
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
what are extra articular manifestations rhemaotid arthritis can also present with
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
what are relevant lab investigations for Rheumatoid arthritis
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”.
what are relevant imaging investigations for arthritis
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
what is the diagnosis classification for rheumatoid arthritis?
The 2020ACR-EULAR rheumatoid arthritis classification criteriaare commonly employed to aid diagnosis, with a score ofsix or morerequired for the diagnosis of rheumatoid arthritis.
what features are associated with a worse prognosis or rheumatoid arthritis ?
High ESR/CRP
Early erosions on X-rays
High tender or swollen joint counts
Positive anti-CCP or rheumatoid factor
descried the criteria for DAS20 monitoring
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
how is rhemaotif arthritis managed
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)
describe the use of NSAIDs for ra
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
what DMARDs are used in RA
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
what are pharmacological considerations fro methotrexate use in RA
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
what are methotrexate monitoring requirements ?
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
what is sulphalazine
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
what are suphalazien mintirogn requirements
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
Describe hydroxychloroquine use
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
describe leflunomide
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
what are monitoring requirements for leflunomide
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
why do we monitor DMARDs?
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
what is the guidance for pregnancy
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
what are biologics used?
TNF α inhibitors- Etanercept, infliximab, adalimumab, golimumab, certolizumab
Anti-CD20 - Rituximab
IL6 inhibitors - Tocilizumab, Sarilumab
JAK inhibitors - Tofacitinib, Baricitinib, Upadacitinib, Filgotinib
what is the eligibility criteria for rhemaotid arthritis?
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
pre biologic screening
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
what are caution or contraindications of biologics
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
describe TNFa inhibitors
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
descried rituximba
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
describe IL-6 inhibitors
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
describe janus kinase inhibitors
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
