Rheumatoid arthritis Flashcards
What are some of the symptoms a patient may initially experience before joint inflammation occurs?
Fever
Malaise
Weakness
Arthralgia
Which joints are most commonly affected by RA?
Joints of the hand, feet, knee and hip
How many people in the UK are affected by RA?
600,000 people and prevalence is said to be roughly 0.5-1%
At what age do people tend to develop RA?
Between 25-50 years
Define Rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease.
What is the key characterisation of RA?
Proliferative synovitis and inflammatory arthritis with erosions
What is the ratio of women to men that have RA?
2-3:1
Due to possible effect of the female hormones (oestrogen) as in addition use of the contraceptive pill shows higher proportion of RA sufferers.
Explain the role of genetics in RA predisposition?
It is believed that RA is multifactorial meaning that there is not one singular cause but is a combination of genetics, environmental and immunological factors but having said that there is a genetic predisposition.
What are some of the genes involved in RA?
70% of RA sufferers have HLA-DR4 present
STAT-4
TRAF1/C5
PTPN22
Describe some of the environmental factors that perhaps link to RA?
Tobacco smoke
Air pollution
Mineral oil
Silica
Infectious agents
Describe some of the immunological factors involved in the pathogenesis of RA?
RF
Anti-citrullinated cyclic peptide
Immune dysregulation
Antibody responses to modified peptides
Increased production of cytokines and chemokines
What is the concordance rate of twins with RA?
15-20% (15% in monozygotic twins)
Which allele is associated with an increased risk of RA?
MHC allele HLA-DRB1 increased risk of 4-12 times
What are some of the potential infections said to be associated with the onset of RA?
Mycobacterium
Mycoplasma
Streptococcus
Epstein Barr virus
Parvovirus
All suggested, nothing confirmed
What are the role of B cells in RA pathophysiology?
Produce auto-antibodies which cause complement activation
Bind to activated macrophages which they perpetuate inflammation
What are the roles of auto-antibodies in RA pathophysiology ?
Rheumatoid factor is directed against Fc factor fragment of IgG
Anti-citrullinated peptides are directed against antigens in the joint
What are the roles of T cells in RA pathophysiology?
They activate monocytes or macrophages and synovial fibroblasts by producing TNF-alpha, IL-1B or IL-6 which results in the production of MMPs which lead to the degradation of cartilage
Joint destruction might be caused by CD4 (+) T cell cytokines.
What is the function of the RANK ligand?
Promotes osteoclasts
Briefly outline the pathogenesis of RA.
There is normally an initiator event such as injury, infection and illness however then there is persistent inflammation where APCs are recruited and there is citrullination of proteins and it is perceived as a non-self immune response. Tis leads to a clonal expansion of B and T cells uncontrolled by T regulatory.
There is now inflammatory damage in the synovium, self antigens that were previously unseen now become exposed and the immune system attacks the cartilage, there is an infiltration of immune cells.
Fibroblasts and osteoclasts become activated by pro-inflammatory cytokines TNF and IL-6 resulting in the destruction of the bone.
State the co-morbidities of RA associated with systemic pro-inflammatory cytokines.
Iron redistribution in the liver
Free fatty acid deposition
Insulin resistance in the muscle
Lone bone mineral density - osteoporosis
Low stress tolerance, depression
Atherogenesis, MI, stroke
Which cytokines are associated with iron redistribution in the liver?
IL-6
Which cytokines are associated with free fatty acid deposition?
TNF-a and IL-6
Which cytokines are associated with insulin resistance in the muscle?
TNF-a and IL-1
Which cytokines are associated with low mineral bone density?
TNF-a, IL-6, IL-1
Which cytokines are associated with low stress tolerance and depression?
TNF-a, IL-6, IL-1
Which cytokines are associated with cardiac related complications MI, stroke etc?
Complement immune activation
IL-6 and TNF-a
When should an urgent referral be made from primary care with suspected synovitis?
Small joints of the hands or feet are affected
More than one joint is affected
There has been a delay of 3 months or longer between onset of symptoms and seeking medical advice
These symptoms should still be referred even if the patient is negative Rheumatoid Factor or Negative anti-cyclic citrullinated peptide [CCP] antibodies
Aside from the referral criteria which other symptoms would you expect from somebody with suspected Rheumatoid Arthritis?
Symmetrical in inflammation
Pain, tenderness, swelling, stiffness of the joint
Stiffness of the joint lasts from approximately 30 minutes after getting up in the morning
Joint redness and warmth
Symptoms tend to be in the small synovial lined joints of the hands, wrist or feet
The pain is becoming more persistent but were insidious in first presentation
What is important to consider about the symptoms regarding the duration of the inflammation of the joints?
Rheumatoid arthritis is a chronic, auto-immune condition therefore if somebody has waited for symptoms to resolve before getting them investigated, may present with symptoms indicating more severe joint deterioration (2 hours of morning joint stiffness).
Aside from symptoms directly relating to the joint inflammation, what other more generalised symptoms may a patient experience?
Weight loss
Fatigue
Changes in mental health
If Rheumatoid arthritis is left untreated what will eventually happen to the joint?
Results in progressive articular deterioration which means there will be a loss of function of the joint / bone / cartilage
Symptomatic presentation is deformity, limited motion and pain on motion and the fusion / dislocation of joints
What is also a characteristic appearance of Rheumatoid arthritis?
20% of patients who suffer with Rheumatoid arthritis will also have RA nodules. RA nodules are firm, noticeable lumps that form underneath the skin of some rheumatoid arthritis patients. They generally form on or near the base of the arthritic joints.
What symptoms could make a clear distinction between Osteoarthritis and Rheumatoid Arthritis?
Rheumatoid arthritis is an systemic auto-immune disease whereas Osteoarthritis can be seen as ‘wear and tear’ of the joint. Therefore the systemic symptoms associated with RA such as weight loss, fatigue and fever would not be associated with osteoarthritis.
What is some of the extra-articular manifestations that can occur with Rheumatoid Arthritis?
It can affect:
Lungs - patients are at risk of pulmonary fibrosis, interstitial lung disease
Heart - cardiovascular disease, increased risk of myocardial infarction, congestive cardiac failure, stroke
Eyes - Sjögren’s syndrome (very dry eyes)
Skin
Bone - increased risk of osteoporosis
How does the presentation of symptoms relate to the progression of the disease?
A patient with Rheumatoid Arthritis would experience fluctuations in their symptoms, known as flares and periods of apparent remission.
As the disease progresses the flares become more frequent and more severe, with each flare not recovering as well as the last
Describe what happens during chronic intermittence during the disease progression.
Chronic intermittence are periods of disease improvement.
What is responsible for a 1/3 of deaths in patients with RA?
Cardiovascular related illnesses
Outline how Rheumatoid arthritis links to Cardiovascular disease regarding the pathophysiology.
RA has widespread systemic inflammation so this can lead to vascularitis (inflammation of the blood vessels) resulting in changes to the vessel function.
RA also impacts cholesterol and blood clotting.
What is responsible for a 10% of deaths in patients with RA?
Respiratory disease and complications
Aside from the five previously mentioned which other more generalised extra-articular manifestations are there associate with RA?
Increased infection risk
Increased risk of depression
Increased risk of malignancies
Which malignancies are shown to be of an increased risk and which are shown to be associated with a decreased risk of RA?
Those with RA have be shown to have an increased risk of lung and lymphoma
But are shown to have a decreased risk of breast and bowel cancer
When is important to consider regarding extra-articular manifestations and drug therapy for RA?
-Use of DMARDs and biological therapies are good for reversing or at least halting disease progression, they themselves come with the potential of adverse events many of which can play into the extra-articular risks. For example biologics can increase risk of non-melanoma skin cancer
- Therefore there is a strong balance between controlling the disease, the co-morbidities associated with the disease and the risk of adverse effects
-Patient outcomes are compromised when treatment is delayed, progression of the disease, increased risk of extra-articular manifestations
-Supply of appropriate treatments can alter the duration of the disease
According to NICE what investigations should you to make for diagnosis if a patient has presented with symptoms that align with that of Rheumatoid Arthritis.
Found to have synovitis on clinical examination
Taking a blood test for:
Rheumatoid factor
Anti-cyclic citrullinated peptide (If RF negative)
X-ray the hands and feet in adults with suspected RA and persistent synovitis.
What is Rf and what is the significance of it?
Rf which stands for Rheumatoid Factor, is an auto-antibody found in around 70% of patients with RA.
It is a poor prognostic factors and usually indicates severe disease.
What is a limitation of using Rf?
Other inflammatory conditions will increase the Rf value and hence is not diagnostic as a singular marker.
Aside from Rf which other antibody can be seen as a immunological parameter for somebody with RA?
Anti-nuclear antibody, however is only present in 40% of patients and usually indicates severe disease.
How does presence of Anti-cyclic citrullinated peptide presence occur?
They are auto-antibodies against citrullinated proteins and peptides. Citrullin is produced when there are changes to the amino acid arginine.
What is the specificity of Anti-cyclic citrullinated peptide to RA?
88-90%
To recap, what are the three immunological parameters associated with RA?
Rheumatoid factor
Anti-nuclear antibody
Anti-cyclic citrullinated peptide
What are the two inflammatory markers that may be assessed in the diagnostic process of RA?
Erthrocyte sedimentation rate
C-reactive protein
Describe how the erthroycyte sedimentation rate test works?
A blood sample is taken and then it is left to settle for 1 hour in a column. Due to the presence of inflammatory markers attached to our red blood cells causing their descent;
The more rapid the fall, the greater the inflammation
What are the disadvantages of using only the ESR and CRP test?
They are not specific to RA or inflammation in the joint alone.
CRP can be raised by any physical stress; surgery, infection, illness etc
When do ESR and CRP increase during inflammation?
ESR: 24-48 hours of inflammation
CRP: 4-6 hours after (acute phase protein) levels will peak 36-50 hours after
Any other investigations that will be carried out during diagnosis?
Haemogloblin test - as anaemia often occurs alongside RA
Radiology- showing erosion of joints, but it may not be apparent at the point of diagnosis and usually only indicates more severe disease
When does somebody with RA be deemed ‘zero-positive’ ?
If they test positive for RA or anti-cyclic citrullinated peptide, indicating they have more severe disease
Describe the two other tests you can make on examination which can indicate RA?
Inability of the patient to form a tight fist
Squeeze test:
Practioner either squeezes across the
Metacarpophalangeal (knuckles) or
Metatarsophalangeal (foot)
If RA positive gel feel and very painful for the patient
What is important to remember when trying to make a diagnosis for RA?
There is no specific one test that should be used as presentation can vary between patients.
Which aspects should be considered before reaching a diagnosis?
Take a full patient history:
Morning stiffness >30 minutes or after rest,
Family history
Lifestyle
Clinical presentation
Symmetrical effects on synovium joints
Symptoms
Investigations:
Inflammatory markers
Haematological markers
Immunological markers
Radiological investigations
If a patient is found to be Rheumatoid Factor positive, what additional procedure should be completed?
Measure functional ability using, for example, the Health Assessment Questionnaire (HAQ), to provide a baseline for assessing the functional response to treatment (disability, discomfort, pain, side effects, cost)
What other conditions could widespread pain be a symptom for?
Fibromyalgia
Polymyalgia
Osteoporosis
Gout
What is the importance of monitoring disease levels in RA?
To establish a baseline function
To assess a patient’s response to treatments - if interventions are working
To guide what should happen next
What monitoring parameter is used in RA?
DAS28 - number of joints out of 28
Number of swollen joints /28
Number of tender joints /28
Measurement of ESR or CRP
Global assessment of health score
Joints in the feet not included
What do the different DAS28 scores mean?
> 5.1 = active disease
<3.2 = low disease
<2.6 = remission
What can the DAS scores then be used for?
Eligibility for biological treatment
What are the disadvantages of using DAS?
If feet joints are affected they are not in the 28 joints so not included
Some patients don’t experience the characteristic increase in ESR, alters their DAS score
Why is appropriate early therapy crucial for RA?
Improves symptoms
Improves function
Reduces mortality
May reduce co-morbidities
What are the aims of treatment for RA?
Minimise pain and swelling
Prevent deterioration leading to deformity and radiological damage
Maintain quality of life
Control extra-articular manifestations
What is used for the symptomatic relief of RA?
NSAIDs or glucocorticoids used to reduce inflammation
Paracetamol and opioid based are not recommended
When would you expect Rheumatologists to prescribe a short course of steroids in the management of RA?
It is used to bridge when a new DMARD or drug treatment is used or in the treatment of a flare
(Remember after 3 weeks of steroid use, reducing dose must be used)
What route of administration can steroids be administered?
Oral, IV or Intra-artically
What is the goal of DMARD use?
Achieve remission, DAS score below 2.6
What type of DMARDs are patients with RA initiated on and give examples?
Conventional DMARDs
Methotrexate , Sulfasalazine, Leflunomide
Azathiopurine, Penicillamine, Gold, Ciclosporin are not used frequently anymore
Give some examples of Anti-TNF biologics used in the treatment of RA?
Adalimumab
Etanercept
Certolizumab
Golimumab
Infliximab
Aside from Anti-TNF biological drugs which other biologics are used and give their drug targets?
Tocliziumab - IL-6 inhibitor
Rituximab - anti CD-20 antibody
Abatacept - antibody blocking T cell activation, prevents co-stimulatory molecules
Anakinra - IL-1 receptor
What is an example of a JAK inhibitor used in RA?
Tofacitanib
What is the main strategy according to NICE for treating RA?
Treat to target
Patients with RA should have frequent reviews of their tretment and disease and the response should be escalated until it is controlled, ideally for most patients this would be a DAS28 <2.6
How often should a patient have a blood test for ESR and CRP?
Monthly
What is the first line drug treatment for RA?
Monotherapy of a conventional DMARD
Aim to start within 3 months of symptoms onset to prevent deterioration
Either Methotrexate, Sulfasalazine, Leflunomide
Choice will depend on patient and drug characteristics
What is an alternative to oral methotrexate?
s/c methotrexate, appears to have no adverse effects and can be more effective
When is hydroxychloroquine used in the treatment of RA?
For mild or palindromic disease
Once a patient is initiated on cDMARD monotherapy what other considerations should be made?
Bridging this therapy with a short course of steroids (glucocorticoid), this should be removed by 3 months with a reducing dose
Escalate dose as tolerated and according to response (adverse effects) by blood tests every couple of weeks and DAS scores and CRP every month until target is reached
Which corticosteroid usually used as bridging therapy?
Prednisolone 7.5mg to 10mg a day up to 30mg a day
Methylprednisolone 120mg weekly IV, IM, Intra-artically
Are steroids always used for bridging therapy?
No they are prescribed on a base by base treatment and often depends how active the disease is in the patient.
Once optimisation of the DMARD monotherapy has taken place, but the patient DAS28 score remains above 2.6, what is the step up strategy?
Additional DMARD should be added on to the monotherapy
Another therapy from Methotrexate, Sulfasalazine or Leflunomide
Reminder monitoring for adverse effects should now be back to roughly every other week
What is the third line treatment for RA if DAS28 targets are still not reached?
Introduction of biological DMARDs
Which factors must be considered before deciding which biological therapy to initiate?
Cost
Patient and drug characteristics
Is methotrexate contra-indicated in the individual as many biologics rely on use of co-therapy
Adverse effects
Dosing frequency
Co-morbidities - one drug to treat two conditions reducing risk of adverse effects
Golimumab - Ulcerative colitis and RA
or co-morbidities may contra-indicate a drug
Allergy - some contain latex, biosimilar of Etanercept is latex free
Which factors must be considered before deciding which route of administration of biologics to use?
Are they available in a s/c form, which saves hospital time for IV
Poor adherence , Manual dexterity may prefer the IV form
Which biological drugs are licensed for use in moderate RA?
Anti-TNF:
Adalimumab
Etanercept
Infliximab
JAK inhibitors:
Filgotinib
Upadacitinib
Antibody blocking T cell activation:
Abatacept
+/- with methotrexate
Which biological drugs are licensed for use in severe RA?
Anti-TNF:
Adalimumab
Etanercept
Infliximab
Certolizumab
Golimumab
JAK inhibitors:
Filgotinib
Upadacitinib
Baricitinib
Tofacitinib
Anti-IL-6:
Sarilumab
Tocilizumab
Antibody blocking T cell activation:
Abatacept
Anti B cell
Rituximab
+/- with methotrexate
What is used to differentiate between moderate and severe disease?
Moderate disease is a DAS28 score of between 3.2 and 5.1
Severe disease is a DAS28 score of above 5.1
When may biological therapies be initiated earlier in the treatment of a patient with RA?
If a patient has had reactions to cDMARDs or they are contra-indicated etc.
If there is no specific guidance of what biologic should be used, what one is recommended?
Most cost effective
What is the formulation of targeted DMARDs and how can this be beneficial?
Oral
Beneficial for those with manual dexterity issues and needle phobic
Don’t require storage in the fridge
No injection site reaction
What is a key risk associated with Tocilizumab and Sanrilumab?
GI perfuration, wouldn’t give to people with gastric ulcerations
Disadvantage of targeted DMARDs?
Risk of VTE
How are biological drugs monitored for effectiveness?
European League against Rheumatism - must have a moderate response
For those with moderate disease – they must have a moderate response (DAS 28 improvement of > 0.6 and < 1.2) at 6 months to continue.
For those with severe disease – they must have a moderate response (DAS28 improvement of > 1.2) at 6 months to continue
When would you consider stepping down treatment in a patient with RA?
If the patient has been stable (DAS28 score below 2.6) for over a year and without requiring corticosteroids (for example flares).
What would treatment step down for RA involve?
Cautiously reducing drug doses or stopping drugs, depending how many therapies patients are on
When should use of NSAIDs be considered in patients?
For symptomatic relief when the control of pain and stiffness is inadequate, under the supervision of the prescriber.
What are some symptoms of an arthritis flare?
Increase of swelling and / or stiffness in the joints
Worsening pain in the joints
Increased tiredness
General ‘unwell’ feeling
Night sweats / fever / weight loss
Think PeaNUTS - all of which is getting increasingly worse
Pain
Night sweats
Unwell
Tiredness
Swelling
What can trigger a flare?
It is important to remember flares can be completely unpredictable and sometimes have no known cause.
However some triggers can include infections such as chest or urinary infection or physical or mental stress
What considerations should be made before a patient with RA is started on NSAID therapy?
Consideration of the drug toxicities and patient risk factors
NSAID should be the lowest effective dose and for the shortest duration
-Co-administration of a PPI to reduce GI side effects
-Review risk factors regularly
-Should only be short-term (flares or during dose escalation of DMARD therapy)
What specific factors should be taken into consideration before starting NSAIDs?
Age
Pregnancy
Hepato-toxicity
Cardio-renal toxicity
Gastrointestinal associated side effects
Which NSAIDs should be used for symptomatic relief?
Standard NSAIDs such as Diclofenac, Ibuprofen, Naproxen or selective COX-2 inhibitors such as Celecoxib
Except in the management of flares to rapidly decrease inflammation, when else can glucocorticoid therapy be used?
Only when:
The long-term risk associated with steroid therapy have been discussed and
All other treatment options including biologics and targeted synthetic DMARDs have been offered
Once stabilised on RA therapy how often should monitoring occur?
Every 6 months
Under which circumstances may monitoring frequency increase?
Recent flares
Changes to therapy
Patient experiences an adverse effect
If risk factors change
Development of co-morbidities
What would be assessed in the annual review of a patient with RA?
Assess disease activity , damage and functional ability (according to the Health Assessment Questionnaire)
Check for developed drug morbidities
Cross referrals
Effects on the personal life
When may a patient need to access specialist Rheumatology care team?
Management during a flare
Reporting of side effects
Ongoing drug monitoring
What are the key differences between the EULAR guidelines and the NICE guidelines regarding management of RA?
Initial therapy:
EULAR - Methotrexate unless contra-indicated and then Sulfasalazine or Leflunomide
NICE - Methotrexate, Leflunomide, Sulfasalazine
Step up therapy:
EULAR - if poor prognostic factors are present add a bDMARD or JAK inhibitor. If they are absent change the DMARD or add
NICE - second cDMARD
What are examples of the poor prognostic factors included the in EULAR guidelines?
Presence of Rheumatoid factor r anti-citrullinated cyclic peptide especially at high levels
High disease activity
Early joint damage
Failure of 2 or more cDMARDs
Which indicates the disease is more severe
When is the efficiency of DMARDs measured according to EULAR?
Improvement at 3 months
Target achieved at 6 months
What are some of the factors drug choice is made upon?
Patient preference
Patient characteristics (co-morbidities and risk factors, contraception)
Treatment characteristics (Cautions, contra-indications, Side effects, dosing, interactions, monitoring requirements)
Describe the involvement of the broader multi-disciplinary team involved in the management of a patient with RA?
Physiotherapist referral - regular exercise including activities to enhance joint flexibility, muscle strength
TENs and wax baths
Occupational therapy referral if they are having difficulty with everyday activities or problems with hand function
Podiatrist referral- functional insoles and therapeutic footwear
Hand exercise programmes - stable RA or not on drug therapy
