Musculoskeletal Flashcards
What is rheumatoid arthritis?
A chronic autoimmune condition, characterised by inflammation of the joint synovium
It is a symmetrical polyarthritis, typically affecting the small joints in a relapsing-remitting course, where disease flares can be sudden and unpredictable
Extra-articular manifestations may affect the lungs, skin, blood, eyes and other organs
The cause of RA remains unclear, however it is likely a mix of genetic, environmental and other factors
Joint structure?
The end of each bone is covered with cartilage that has a very smooth, slippery surface. The cartilage allows the ends of the bones to move against each other, almost without rubbing.
The joint is held in place by the synovium, which contains thick fluid to protect the bones and joint.
The synovium has a tough outer layer that holds the joint in place and stops the bones moving too far.
Strong cords called tendons anchor the muscles to the bones
Epidimiology of RA.
1. Prevalence
2. Gender
3. Age
- Affects around 1% of the UK population (400,000 adults aged 16 and over in the UK)
- More commion in women (female:male ratio of 2–4:1)
- Affects at any age but peak onset at 40 - 70 years
Symptoms of RA?
Main symptoms:
* Joint pain
* Joint swelling, warmth and redness
* Stiffness, especially first thing in the morning or after sitting still for a long time
Other symptoms can include:
* Fatigue
* A poor appetite
* Weight loss
* Fever
* Sweating
* Dry eyes – as a result of inflammation
* Chest pain – as a result of inflammation
* Fleshy lumps called rheumatoid nodules, which form under the skin around affected joints. They can sometimes be painful, but usually painless
Risk factors for RA?
- Age (more common in >40s)
- Being overweight
- Smoking
- Diet (some evidence that eating a lot of red meat and not consuming much vitamin C can increase risk)
- First degree relative with RA
What is the most important environmental trigger for RA?
Smoking
Increases disease susceptibility by 20- to 40-fold when associated with genetic factor
Smoking is more likely to cause the bones in the spine fuse together (for people with spondylarthritis)
Patients with RA should be counselled to reduce their risk of what other co-morbidity?
Cardiovascular disease
Advise on smoking cessation, weight loss and exercise
How is disease severity measured in people with RA?
With the 28-joint Disease Activity Score (DAS28)
A composite score calculated from the number of tender and swollen joints, erythrocyte sedimentation rate (an inflammation marker) or C-reactive protein levels, and a self-reported patient assessment of general health status according to a 100mm visual analogue scale
About half of all people with rheumatoid arthritis also have rheumatoid factor in their blood when the condition starts. However, around 1 in every 20 people without rheumatoid arthritis also test positive for rheumatoid factor
(Rheumatoid factors are proteins that the immune system produces when it attacks healthy tissue)
Patient’s with what symptoms should be referred for specialist opinion?
Suspected persistent synovitis (soft tissue joint swelling) of undetermined cause.
Refer urgently (even with a normal acute-phase response, negative anti-cyclic citrullinated peptide [CCP] antibodies or rheumatoid factor) if any of the following apply:
* the 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
What investigations should be undertaken following diagnosis of RA?
As soon as possible after establishing a diagnosis of RA:
* measure anti-CCP antibodies, unless already measured to inform diagnosis
* X-ray the hands and feet to establish whether erosions are present, unless X-rays were performed to inform diagnosis
* measure functional ability using, for example, the Health Assessment Questionnaire (HAQ), to provide a baseline for assessing the functional
response to treatment
If anti-CCP antibodies are present or there are erosions on X-ray:
* advise the person that they have an increased risk of radiological progression but not necessarily an increased risk of poor function, and
* emphasise the importance of monitoring their condition, and seeking rapid access to specialist care if disease worsens or they have a flare.
What is the aim of treatment for RA?
Remission or low disease activity if remission cannot be achieved
Consider making the target remission rather than low disease activity for people with an increased risk of radiological progression (presence of anti-CCP antibodies or erosions on X-ray at baseline assessment)
In adults with active RA, what markers should be measured until the target of remission or low disease activity is achieved?
C-reactive protein (CRP) and disease activity
(using a composite score such as DAS28) monthly in specialist care until the target of remission or low disease activity is achieved
First line pain relief medication for RA?
Regular Paracetamol +/- oral NSAID/Cox-2 inhibitor
NSAIDs are effective in reducing pain, swelling and stiffness associated with RA, but have no effect on long-term disease control
For NSAIDs, offer the lowest effective dose for the shortest possible time + PPI + review risk factors for adverse events regularly
If a patient has arthritis and is on low dose aspirin, how would their pain managment differ from a regular RA patient?
Paracetamol first, then consider opioid before starting an NSAID
First line management of patients with RA?
DMARD monotherapy e.g. MTX, leflunomide, sulfasalazine as soon as possible and ideally within 3 months of onset of persistent symptoms.
Hydroxychloroquine (weak DMARD) as alternative for for mild or palindromic disease (attacks of joint pain and inflammation that come and go)
Consider short-term bridging treatment with glucocorticoids (oral, intramuscular or intra-articular) when starting a new cDMARD
What is the ‘window of opportunity’ in RA management?
12 weeks from initial symptom onset
DMARDs should ideally be started within this timeframe
What is the ‘treat to target’ in RA management?
Core principle for RA management
The clinician and patient agree on a treatment goal, and the patient is monitored monthly, with timely treatment escalation, until the treatment target is achieved
Proven to result in improved functional and radiographic outcomes
Second line management of patients with RA?
If remission or low disease activity has not been achieved despite dose escalation:
Offer additional cDMARDs (oral methotrexate, leflunomide, sulfasalazine or hydroxychloroquine) in combination in a step-up strategy
What are DMARDs?
Disease-modifying antirheumatic drugs
Inhibit structural damage to cartilage and bone
What are the 3 types of DMARDs?
- Conventional synthetic (csDMARDs)
- Biologic (bDMARDs)
- Targeted synthetic (tsDMARDs)
What are the conventional DMARDs?
Methotrexate, leflunomide or sulfasalazine (Hydroxychloroquine can be used as an alternative for patients with mild or palindromic disease)
First line treatment for RA.
Each csDMARD has a unique mechanism of action within the inflammatory cascade
Conventional DMARDs: Methotrexate.
Generally used as a first-line csDMARD in RA
Regime
* Starting doses of 10–15mg/week, titrated up to 15–25mg/week
* Onset of action of around 4–12 weeks
* Co-administration of a minimum dose of 5mg folic acid once weekly to help reduce the risk of side effects and improve tolerability
Contraindications
* Significantly impaired hepatic function
* Alcoholism
* Pregnancy
* Known active peptic ulceration
* Immunodeficiency,
* eGFR <10 mL/min
Can be given by subcutaneous injection when patients are unable to tolerate oral doses because of gastric side effects, or to increase bioavailability and efficacy
Conventional DMARDs: Leflunomide.
Alternative in patients where methotrexate is contraindicated or there is early intolerance
Has both immunomodulatory and immunosuppressive characteristics
Regime
* Loading dose of 100mg daily for three days then maintenance dosage of 10–20mg daily
* However, many clinicians do not use this loading dose regimen because patients are unable to tolerate the associated gastrointestinal side effects
* Therapeutic effect starts after 4–6 weeks, and further improvement may be seen for up to 4–6 months.
Side effects
* Haematological ADRs
* Hepatotoxicity
* Hypertension; a patient’s blood pressure should be checked before commencing treatment and periodically thereafter
Conventional DMARDs: Sulfasalazine
Alternative to methotrexate however, methotrexate has lower rates of erosions and higher levels of drug persistence over time
Regime
* To reduce the side effect of nausea, the dose is usually titrated upwards from 500mg daily, increasing by 500mg each week to a maintenance dose of 2–3g daily, usually taken in two divided doses
* If a patient struggles with tolerance, a more gradual dose titration can be used
* Onset of action of 6–12 weeks
Side effects
* Haematological abnormalities (report unexplained bleeding, bruising, purpura, sore throat, fever or malaise)
* Can colour urine, tears and stain contact lenses yellow-orange
Conventional DMARDs: Hydroxychloroquine
May be used in milder disease, disease with palindromic onset or as an additive therapy to other csDMARDs
Although its efficacy as a DMARD or additional benefit in triple therapy regimes has been questioned in some systematic reviews
Regime
* SPC recommends a maximum dose of 6.5mg/kg/day based on ideal body weight, but the Royal College of Ophthalmologists recommends keeping the dose <5mg/kg/day based on actual body weight
* Usually given as an oral tablet, typically in one to two divided doses per day
Side effects
* Retinopathy
Refer patients to a secondary care ophthalmologist after five years of treatment for ongoing annual retinopathy screening, or after a year if risk factors for retinopathy are present, such as
* Concomitant tamoxifen use
* Impaired renal function (eGFR <60mL/min/1.73m2)
* Hydroxychloroquine dose >5mg/kg/day
How long can conventional DMARDS take to be effective?
2-3 months
How are csDMARDs monitored?
All subject to standard tests:
* FBC
* creatinine/calculated GFR
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
* Albumin
With some requiring additional monitoring (see table)
CRP or ESR is also typically monitored for DAS-28 calculation to assess efficacy
Tests are completed at initiation, then every 2 weeks for 6 weeks
Once the patient is stable
* Test monthly for 3 months, then at least every 12 weeks thereafter (more frequent monitoring is appropriate in patients at higher risk of toxicity)
Following a dose increase
* Monitoring is required every 2 weeks for 6 weeks, and then reverts to the previous schedule
What can DMARDS be bridged with to give a more rapid effect of symptomatic control?
Glucocorticoids
Act by inhibiting cytokine release and are effective at reducing inflammation and suppressing the immune system to give rapid relief of symptoms
Depending on the number of affected joints, they may be administered as an intra-articular injection for local action or as an intramuscular depot injection, intravenous infusion or short-term oral therapy for systemic effects
In patients with severe or moderate disease activity (measured by DAS28) despite having tried at least two csDMARDs (including methotrexate), what else can be offered?
Biological DMARDs or Targeted synthetic DMARDs
NICE stipulates that should be used in combination with methotrexate but local agreements may vary
Combination therapy using a b/tsDMARD and methotrexate (‘anchor therapy’) is advocated because of superior efficacy and reduced risk of b/tsDMARD immunogenicity
Example of TNF alpha inhibitors
Infliximab, adalimumab, golimumab, etanercept, certolizumab pegol
Mechanism of action of bDMARDs?
TNF-alpha inhibitors
* Adalimumab, certolizumab, etanercept, golimumab and infliximab
* Block TNF-α, resulting in dampening of the inflammatory cascade and blocking IL-1 activity
Monoclonal antibody
* Rituximab, tocilizumab, sarilumab
* Rituximab - binds specifically to the transmembrane antigen CD20, depleting B-cells, affecting B- and T-cell interaction, antigen presentation and cytokine production
* Tocilizumab and sarilumab — block the actions of interleukin-6 (IL-6), a multifunction cytokine which regulates immune responses. IL-6 blockade is associated with reduced production of acute-phase proteins and auto-immune antibodies
CTLA-4 inhibitor
* Abatacept
* Cytotoxic T-lymphocyte associated antigen-4 inhibitor
* Causes attenuation of T-cell activity by blocking a co-stimulatory signal, thereby reducing expression of activation markers, secretion of cytokines and stimulation of macrophages to reduce inflammation
IL-17 inhibitor
* Secukinumab
If someone with severe active rheumatoid arthritis has had an inadequate response to or is intolerant of other DMARDs (including at least one TNF alpha inhibitor) What can be tried?
RTX in combination with MTX
What are targeted synthetic (tsDMARDs)?
Janus kinase inhibitors (JAKis)
* Inhibit the activity of one or more of the janus kinase family of enzymes
* Tofacitinib and baricitinib (active on the majority of the four JAK family members (JAK1, JAK2, JAK3 and TYK2))
* Filgotinib and upadacitinib (JAK-1 selectivity)
Subject of a Pharmacovigilance Risk Assessment Committee (PRAC) investigation owing to safety concerns (CVD, VTE, malignancy, infection)
Treatment with a b/tsDMARD therapy should only be continued if what response is achieved?
Only if there is a moderate response measured using EULAR criteria at six months after starting therapy
Monitoring requirements for b/tsDMARDs?
(Pre-screening, frequency etc.)
Standard tests:
* FBC
* Creatinine/calculated GFR
* ALT and/or AST
* Albumin blood
* Chest radiograph
* Tuberculin skin test (TST) or IFN-γ release assay (IGRA) or both as appropriate
* Serology for hepatitis B and C
* HIV serology if risk factors for HIV infection
First 4 tested every 3–6 months (in practice this could be 3-monthly for the first 12 months and then 6-monthly)
The following should also be considered:
* Varicella zoster virus antibody test if no positive history of previous varicella infection and, if negative, consider varicella zoster vaccination if no contraindications
* Herpes zoster (Shingles) vaccination if patient >50 years and no contraindications
* Hepatitis B vaccination for at-risk patients
Factors that influence b/tsDMARD selection?
On the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled,
long-term clinical study.
True or False?
True
If already taking anakinra, patients should continue therapy with anakinra until they and their consultant consider it is appropriate to stop
Short-term treatment with glucocorticoids is used for managing RA flares.
When can they be used for long-term treatment?
When the long-term complications of glucocorticoid therapy have been fully discussed and all other treatment options (including biological and targeted synthetic DMARDs) have been offered
What needs to be monitored with patients on hydroxychloroquine / chloroquine?
Ocular function - risk of retinopathy
Non-pharmacological treatment of RA?
Physiotherapy
* Access to specialist PT
* Learn about the short-term pain relief provided by methods such as transcutaneous electrical nerve stimulators (TENS) and wax baths
Occupational therapy
Access to specialist OT
Hand exercise programmes
Consider a tailored strengthening and stretching hand exercise programme for adults with RA with pain and dysfunction of the hands or wrists if:
* they are not on a drug regimen for RA, or
* they have been on a stable drug regimen for RA for at least 3 months.
Podiatry
* All adults with RA and foot problems should have access to a podiatrist
* Functional insoles and therapeutic footwear should be available for all adults with RA if indicated
Psychological therapy
Offer psychological interventions (for example, relaxation, stress management and cognitive coping skills [such as managing negative thinking])
What is Spondyloarthritis?
A group of inflammatory conditions that have a range of manifestations. Can be:
Axial
* radiographic axial spondyloarthritis (ankylosing spondylitis)
* non-radiographic axial spondyloarthritis (same as radiographic but physical changes to the back cannot be seen on an x-ray)
Peripheral
* psoriatic arthritis
* reactive arthritis
* enteropathic spondyloarthritis (spondyloarthritis associated with inflammatory bowel disease)
People with predominantly axial spondyloarthritis may have additional peripheral symptoms, and vice versa
