Systemic Lupus Erythematosus (SLE)

A multisystem, autoimmune conditions characterised by an autoantibody response to nuclear (ANA) and other cellular antigens, and by a broad spectrum of clinical presentations encompassing almost all organs.

Background/Epidemiology

  • Lupus erythematosus describes the typical rash seen in SLE, whilst many patients also have systemic features
  • Prevalence may be as high as 50/100,000 and the incidence is rising (currently 2-8/100,000)
  • Age of onset varies between 16-55 (most commonly early adulthood)
  • Female:Male ratio is 9:1
    • NB Males tend to present older, with less photosensitivity but more serositis (see below)
  • More common in Chinese, Southeast Asian and Afro-Caribbean compared to white European

Aetiology and Risk factors

  •  Genetics/Familial
    • Siblings of an individual with SLE are ~30× more likely to develop the disease and around 8% of individuals with SLE have an affected first degree relative
    • As with many other autoimmune diseases, an HLA allele (in SLE it is HLA-DRB1*3, DRB*2 and DRB*4) has been associated
    • Other genes, e.g. those encoding for complement C4 (C4A null allele), as well as a number of others involved in the inflammatory process
  • Environmental
    • Viruses
      • Epstein-Barr virus (EBV)
        • May reside in, or interact with, B cells and promote interferon α production by dendritic cells
    • Drugs
      • Drug induced lupus erythematosus can be caused by a number of drugs/drug types including antiarrhythmics, antibiotics (isoniazid), hydralazine, procainamide, anticonvulsants, antipsychotics (chlorpromazine), statins, biologics, chemotherapy agents, atenolol… etc
        • NB May be associated with HLA-DR4
        • Cutaneous and pulmonary features are usually more common than renal/CNS
        • Autoantibodies – homogeneous anti nuclear antibodies
        • Usually remits on stopping the drug

Pathogenesis

  • The exact event that triggers the pathogenesis is unknown.
  1. Increased amounts of apoptosis-related nucleic acids stimulate production of IFNα
  2. This promotes autoimmunity by breaking self-tolerance through activation of antigen-presenting cells (in particular HLA-DLRB)
  3. Immune complexes are formed and continue to drive the inflammatory response

see http://www.eular.org/myUploadData/files/sample%20chapter20_mod%2017.pdf for in detail.

Presentation

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  • SLE is a remitting/relapsing disease.  It is also often called the ‘immitator’, because many of its signs/symptoms are, alone, characteristic of other diseases.
  • Common presenting symptoms and signs
    • Rash/cutaneous symptoms
      • Malar rash– erythema over the cheeks and nasal bridge (sparing the nasolabial folds- cf dermatomyositis).  Can last days/weeks.  Usually painless/non-itchy but can be either.
      • Photosensitivity- Either acute or chronic.  Eruption/rash usually lasts 2 days and is commonly macular.
      • Discoid lupus- a plaque-like rash often characteristically oval and occuring on sun-exposed sites and are usually chronic.  It is thought that the presence of a discoid lupus suggests milder, less systemic disease
    • Constitutional symptoms
      • Fever is common
      • Malaise/fatigue (often severe)
    • Joint/Muscles
      • Non-erosive arthritis involving 2 or more peripheral joints- typically affecting the small joints of the hands
      • Arthralgia is the most common symptom at onset
      • Tenosynovitis- achilles tendonitis and tendon ruptures are not uncommon
  • Other features
    • Renal
      • Kidney is the most commonly affected visceral organ, with clinical manifestations occuring in around 40-70% of patients, caused by immune-complex deposition in the glomeruli
      • Glomerular nephritis is usually asymptomatic but can be detected on urinalysis (see below)
    • Other cutaneous features
      • Raynaud’s phenomenon (occurs in ~60%)
      • Erythema nodosum (panniculitis)
      • Oral Ulcers
      • Patchy, non-scarring alopecia
    • Neuropsychiatric
      • SLE can affect both the CNS and PNS
        • The American College of Rheumatology have classified 19 different neuropsychiatric syndromes of SLE, which include acute confusional state (similar to delirium); acute inflammatory demyelinating polyradiculopathy; anxiety disorder; aseptic meningitis; autonomic dysfunction; cerebrovascular disease; cognitive dysfunction, demyelinating syndrome; headache; mononeuropathy; mood disorders; choreal; MG; myelopathy; cranial neuropathy; plexopathy; polyneuropathy and…
        • Psychosis; Seizures- these are included in the diagnostic criteria for SLE
    • Pulmonary
      • Pleural serositis is a relatively common feature in SLE patients (pleuritic pain/rub)
      • More rarely, patients can be at higher risk of pulmonary embolism (particularly if associated with antiphospholipid syndrome), fibrosing alveolitis, alveolar haemorrhage (more common than with other connective tissue diseases), pulmonary infections; pleural effusion, lupus pneumonitis, shrinking lung syndrome
    • Cardiovascular
      • Chest pain may occur as a result of pericarditis
      • Patients are generally at increased risk of atherosclerosis and cardiovascular events (particularly coronary heart disease and hypertension)
    • GI
      • Abdominal pain occurs in around 30%
      • Hepato/Splenomegaly

Investigations

  • FBC and ESR
    • Mild normochromic normocytic anaemia is common
    • ESR is often raised (CRP can be normal)
    • Leukopenia/thrombocytopenia may be present but are often side effects of treatment rather than true features
  • U&Es and LFTs
    • Both liver and (especially) kidney function can be affected by SLE and should be monitored regularly (they are not particularly diagnostic- but are important to measure extent/severity of disease)
  • Serology
    • Antinuclear antibodies (ANA)
      • Good for screening (95% sensitivity)- i.e. if negative it is unlikely to be SLE but if positive, it is not specific for SLE
    • Anti-double-stranded-DNA (Anti-dsDNA)
      • More specific but sensitivity only 70%
      • Most commonly used to confirm SLE
    • Anti-Smith (anti-Sm) is the most specific test but only has a 30% sensitivity
  • Investigations of symptoms
    • ECG for chest pain
    • Urinalysis should be evaluated for haematuria, proteinuria
    • Serum creatinine may be useful in evaluating muscle pains (SLE can cause myositis)
    • Tissue biopsies can only really be useful in assessing severity and so should only be done if necessary- kidney biopsies are fairly common to help differentiate kidney injury due to lupus and that due to another cause

Management

No organ involvement (I.e. constitutional, dermatological and musculoskeletal symptoms)

  • For mild-moderate disease, musculo-skeletal symptoms may be treated with NSAIDs/simple analgesia.  UV protection should also be recommended where appropriate (SPF>50)
    • hydrochloroquine is used first line for mild disease and is particularly useful for rashes, joint/muscle symptoms and malaise, although it may take several weeks to work (also beware re ocular toxicity- retinopathy)
    • corticosteroid treatment is also commonly used and has a much quicker onset
      • use lowest dose possible (start 5mg daily)
    • Depending on control/severity, steroid-sparing (immunosuppressive) agents e.g. azathioprine may be used to reduce the steroid dose (NB before starting AZA- check for normal metabolism of AZA with TPMT assay)
  • Monitoring
    • ESR/PV (NOT CRP- can be normal with active disease)
    • Complement C3/4- classically low with active disease
    • Anti dsDNA titres

Major Organ Involvement/ Acute Flare

  • Lupus nephritis
    • An acute diagnosis of lupus nephritis usually requires a period of intense immunosuppressive treatment with IV Mycophenolate mofetil (MMF) or IV Cyclophosphamide (The former is considered more popular than the latter due to less side effects)
  • Neuropsychiatric lupus
    • Usually IV methyprednisolone +/- IV Cyclophosphamide

Co-morbidities

Lupus in pregnancy

  • Corticosteroids, HCQ and AZA are ‘safe’ to use in pregnancy- others are potentially teratogenic and could also effect fertility- so discussions should be made with any woman of child-bearing age
  • The contraceptive pill should be safe but (oestrogen hormones) can exacerbate SLE
  • Pregnant women with SLE are at increased risk of early loss of pregnancy, pre-eclampsia, IUGR, preterm delivery and DVT.
    • Women with SLE are also more likely to have anti-phospholipid syndrome and may require LMW-heparin/low-dose aspirin if there is a history of APS and miscarriage

Enteropathic arthritis

A group of inflammatory spondyloarthropathies associated with inflammatory bowel disease and to reactive arthritis following a infectious gastroenteritis/colitis.

Background/Epidemiology/Aetiology

  • Around 10-20% of patients with IBD (Particularly Crohn’s, but also in ulcerative colitis) will have some symptoms of peripheral arthritis
  • Typically, the age of onset is young adult (15-30 years) and it can precede the onset of bowel symptoms
  • Although the mechanism is not fully understood, as with UC and other spondyloarthropathies, there is a strong association with the HLA-B27 allele.  It is likely that the pathophysiology is similar to that of other seronegative arthropathies and IBD

Presentation

  • Axial disease- spondylitis and sacroiliitis (more common of IBD)
    • Insidious onset- lower back pain radiating to the buttocks (often alternating)
    • Often worse at rest, during periods of standing/sitting; better with exercise
      • may waken the patient from sleep
    • Usually independent of GI symptoms
  • Peripheral disease
    • Usually an asymmetrical, oligoarticular arthritis of the lower limbs (usually transient, episodic)
    • Can progress to involve more joints or even present as a more chronic polyarticular arthritis affecting hands also (type II)
    • Enthesitis/tenosinovitis is also common (e.g. achilles tendonitis and plantar fasciitis)
    • NB Symptom severity of peripheral arthritis tends to correlate with the severity of associated IBD i.e. during a flare of IBD, arthritis will worsen too
  • Extra-articular features
    • Symptoms of associated IBD
    • Skin manifestations- pyoderma gangrenosum (UC) and erythema nodosum (CD)
    • Anterior uveitis
  • Constitutional features e.g. mild fever, weight loss, malaise etc

Investigations

  • Aside from investigations for IBD/gastroenteritis etc
  • Inflammatory markers may be elevated
  • Joint aspiration (if indicated) usually show inflammatory cells but is negative for culture/crystals
  • Imaging of the joints (particularly the sacrum) may be useful in evaluating the severity of joint disease.

Management

  • NSAIDs should be given cautiously for symptomatic relief (may worsen GI symptoms- useful to ask patient if they have had problems in the past)
    • Intra-articular steroid injection may be useful 2nd line
  • Management of associated IBD may improve peripheral arthritis (not usually axial arthritis)
  • Sulfasalazine is generally the DMARD of choice as it will treat both symptoms of arthritis and IBD
    • Others may be used (e.g. methotrexate, azathioprine, ciclosporin)
    • Biologic agents (TNF-modulators- infliximab/adalimumab) can also be used in IBD patients who have not responded to conventional therapy

Respiration

Cellular respiration (Internal respiration)

This is a biochemical process that occurs in the mitochondria, using oxygen and carbon compounds (from sugars); and forming carbon dioxide and water.

  • The body requires ~250ml/min of oxygen
  • The body produces ~200ml/min of CO2

The respiratory quotient is the rate of CO2 production divided by the rate of O2 consumption.  I.e. normally 0.8

External Respiration

Mechanics of breathing

Pressures

  • Atmospheric pressure ~760mmHg (decreases with altitude)
  • Intra-alveolar pressure (also ~760mmHg) due to the open communication of the alveoli and the external air
  • Intrapleural pressure (~756mmHg) due to the closed pleural space

Forces

  • Because the lungs are elastic and have no muscles, it is important that they are attached to the wall of the chest (which can move to produce ventilation).  Two forces hold the thoracic walls and lungs together
    1. Intrapleural fluid cohesiveness– the strength of intrapleural fluids
    2. Transmural gradient
      1. =Alveolar pressure (760mmHg) – Intrapleural pressure (756mmHg) = 4mmHg

      2. Problems with transmural gradients: atelectasis; pneumothorax

Inspiration

  • Before inspiration, inspiratory muscles are relaxed
    • e.g. diaphragm (most powerful- responsible for 75% of thoracic enlargement); also external intercostals (pulls ribs up and forward)
      • (accessories include scalene muscles (elevates 1st &2nd ribs); sternocleidomastoid (elevates clavicle); pec major)
    • These then contract- enlarging the thoracic cavity (i.e. it is NOT air that is causing expansion)
  • As they contract, the intra-alveolar pressure falls to 759mmHg (due to Boyle’s law)
    • P1V1=P2V2

    • NB The intra-pleural pressure also falls to 754mmHg (due to thoracic expansion)- which ensures that the lung is filled to its full capacity

Expiration

  • Usually passive- i.e. inspiratory muscles relax and the thorax returns to normal volume- pressure increases (as at the peak of inspiration- alveolar pressure had once again normalised to atmospheric pressure) to force gas out of the lungs
    • During heavy breathing, active expiration uses abdominal wall muscles and internal intercostals

Air flow, Pulmonary elasticity and Compliance

  • Air flow (F) = difference of atmospheric and alveolar pressures divided by the resistance to air flow (ΔP/R)
    • Resistance to air flow is mainly determined by the radius (r) of the vessel
      • NB The total resistance of the entire respiratory system is primarily from the large airways and is normally minimal
    • Problems with air flow include COPD, Asthma
  • Pulmonary elasticity is composed of two inversely related factors
    • Elastic recoil: the ease at which the lung rebounds to preinspiratory volume at the end of inspiration
    • Compliance = the volume change per unit pressure change (ΔV/ΔP).
      • Measure of distendability- changes for different volumes of the lung (think of trying to blow up a full balloon and trying to squeeze out all of the air from a sponge- it gets harder)
      • A normal value at rest (static compliance) for both the lungs and the chest wall together is around 100ml/cmH20 (around 1l/kPa)
        • Separately they are 150-200ml/cmH20 and 200ml/cmH20, respectively
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        • This difference is due to surfactant-alveolar hysteresis (dependence of a property on past history)- or the air-water surface tension during initial inspiration provides resistance to a change in volume. Similarly, at maximal volumes, the lungs reach capacity.
  • Problems with elastic compliance include emphysema, pulmonary fibrosis, oedema, atelectasis
    • Note that the above graph changes in disease processes
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Surfactant and surface tension

  • Important factor contributing to compliance
  • LaPlace’s Law states that the inward-collapsing pressure (e.g. within alveoli) can be described as 2T/r where T is the surface tension and r is the radius
    • surfactant (produced by type II alveolar cells) reduces the surface tension.
    • it is more effective at doing so in smaller airways where it has a higher surface concentration

Work of breathing

=(Pressure × Volume) / time

  • Work of breathing is required to overcome elastic resistance (~65%) and non-elastic resistance (airflow and other)
    • expressed as joules of energy per unit time (or watts)
    • As respiratory rate increase- flow rate (F) increases- increasing turbulent flow and non-elastic resistance.  As tidal volume increases- the compliance of the lung decreases.
      • In obstructive disease, patients therefore try to reduce work of breathing by taking deep, slow breaths.  In restrictive disease, the opposite occurs.

Lung Volumes

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  • TLC- Total lung capacity- the volume in the lungs at maximal inflation (VC+RV) (~5.5-6l)
  • TV- Tidal volume- the volume of air moved into/out of the lungs during quiet breathing (~500ml)
  • RV- Residual volume- the volume of air remaining in the lungs after maximal exhalation (~1.2l)
  • ERV- Expiratory reserve volume- the maximal volume of air that can be exhaled (~1.2l)
  • IRV- Inspiratory reserve volume- the maximal volume of air that can be inhaled (~3l)
  • IC- Inspiratory capacity- the sum of IRV + TV
  • VC- Vital capacity- the volume of air breathed out after the deepest inhalation
  • FRC- Functional residual capacity- the volume in the lungs at the end-expiratory position i.e. at the start of breathing (~2.5l)

Ventilation

Total ventilation (MV- gas movement in one minute) = tidal volume × resp rate

NB Only two thirds of the tidal volume takes place in gas exchange- due to physiological dead space.

  • Physiological dead space is the sum of anatomical dead space and alveolar dead space
    • Anatomical dead space is the volume of the mouth, larynx, trachea and bronchi (i.e. the regions that don’t take part in gas exchange)
    • Alveolar dead space occurs when areas of the lung are being ventilated but not perfused (V/Q mismatch)
      • Problems causing an increase in alveolar dead space: pneumonia, pulmonary oedema, pulmonary embolism

Gas Exchange

The Oxygen cascade

  • Although the partial pressure of oxygen is around 21kPa or 160mmHg, the pressure of oxygen in the lungs, tissues and mitochondria decreases.
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  • The partial pressure of oxygen in the alveolar air can be calculated using the alveolar gas equation
    • PA(O2) = Fi(O2) (i.e. atmospheric pressure- usually 0.21kPa) – (Pa(CO2) / RQ)
      • where RQ is the respiratory quotient (see above- usually 0.8); Pa(CO2) is arterial pressure of CO2 (usually around 5kPa)
      • so PA(O2) is usually 14kPa (106mmHg)

Gas diffusion and dissolution

Fick’s law of diffusion: movement is proportional to the concentration gradient

Graham’s Law: movement is inversely proportional to the square root of the molecular weight of the molecules involved

  • Other factors affecting gas diffusion include surface area, membrane thickness and gas solubility
  • Total diffusion is proportional to A / T . D . ΔP
  • The amount of gas that dissolves in blood is directly proportional to the partial pressure and its solubility (Oxygen content = solubility x pressure) (variation of Henry’s law)
    • Under normal conditions that = 0.003 (/l/mmHg) x 100mmHg = 3mls/l
      • Considering we require 250ml/min of O2 and pump around 5l/min through the heart (i.e. 15ml/min of oxygen)- this is nowhere near enough

Oxygen transport

  • Haemoglobin is a molecule of red blood cells composed of a haem (Fe2+ containing) moiety and 4 globin chains (2 alpha and 2 beta)
    • Each molecule can carry 4 oxygen molecules.  It does this in a cooperative process i.e. binding of one O2 molecule facilitates a conformational change, increasing Hb’s affinity for further O2 binding

Oxyhaemoglobin_dissociation_curve

    • The result of this cooperative binding is a sigmoid curve
      • Can be altered by pH, temperature and amount of DPG (binds to deoxgenated Hb- it reduces affinity for oxygen)
      • A left shift is also seen in fetal haemoglobin (increased affinity for O2)
    • Fully saturated Hb can carry 1.36ml/g and normal Hb is around 150g/l. -> 200ml/l (more than enough).
  • Bohr effect
    • The effect of CO2 on the binding/release of O2:
    • At the tissues, an increase in CO2 concentrations causes the formation of bicarbonate and hydrogen ions- this decreases pH and pushes the dissociation curve to the right- encouraging the release of O2

Ventilation-Perfusion Relationships

The V/Q (ventilation/perfusion) ratio is an indicator of the efficiency of gas exchange as determined by ventilation and perfusion.  The ‘predicted normal’ value is 1 (i.e. ventilation is equal to perfusion.

  • In reality, the base of the lung is better ventilated and better perfused
    • Perfusion > ventilation (effect of gravity on blood)
    • V/Q is usually ~0.7 (V~0.8l/min and Q~1.1l/min)
  • The apex of the lung is less well ventilated and perfused but perfusion has dropped (
    • BUT Ventilation > perfusion
    • V/Q is usually ~3 (V~0.21l/min and Q~0.07l/min)

P(A-a) gradient

  • The difference between the concentration (partial pressure) of oxygen in the alveoli (P(A)- see equation above) and arteries (P(a)).
  • It is used to investigate V/Q mismatch and degree of shunt
    • Hypoxaemia with a normal gradient suggests hypoventilation or Low FiO2
    • Hypoxaemia with an increased gradient suggests V/Q mismatch or shunt
  • Normal values can vary from 0.5-1kPa or 5mmHg, but anything up to 2.5kPa or 20mmHg is accepted

Shunts

Passage of blood from the right heart to the left heart without being oxygenated, i.e. no ventilation occurs (V=0), i.e. V/Q = 0.  Therefore, they are causes of hypoxia.

  • causes of shunt include: Intracardiac (Tetralogy of fallot; Atrial/ventricular septal defects (+ a reason for high atrial pressures e.g. po valve stenosis); patent foramen ovale); Large vessels (Patent ductus arteriosus; Pulmonary AV malformations (occur in liver disease)); Pulmonary (pathological) shunts (Large pneumo- or haemo-thorax/ pleural effusion; CHF, po oedema; pneumonia; obstruction
  • NB In general, in V/Q mismatch there is some ventilation- therefore high-flow (100%, 15L) should improve hypoxia.  A shunt causes a hypoxia which can’t be reversed by high flow O2 (note that severe V/Q mismatch (relative shunt) may not respond either, but the potential is there).
  • The result is a venous admixture  (mixture of venous and arterial blood).

Reactive Arthritis (and Reiter’s syndrome)

Reactive arthritis is a relatively short-lived condition causing painful joint swelling.  It develops in response to and occurs shortly after an infection, usually of the bowel, genital tract or throat.

Background

Previously known as ‘Reiter’s syndrome’ (not commonly used now as Reiter was a Nazi war criminal), reactive arthritis classically presents with a triad of features.

It usually resolves within 3-12 months, but up to 15% of patients can develop chronic, and occasionally destructive/aggressive, arthritis, enthesitis or spondylitis.

ImageNB Although this is the classic description, only one third of patients will present with all three (sensitivity 50%; specificity 99%- i.e. not all patients with ReA have all three, but patients with all three usually have ReA).

Aetiology- which infections?

  • GU
    • Chlamydia trachomatis is generally thought to be the most common aetiological infection.  Particular the L2b serotype.
      • NB Chlamydia may be detectable in the synovial fluid (this is not the case of enteric bacteria)
      • This may be an asymptomatic infection
    • Other possible pathogens include HIV and ureaplasma urealyticum
  • GI
    • Most commonly Campylobacter jejuni, but can also be seen after Salmonella, Shigella and Yersinia infections
    • NB Many patients won’t have a ‘diagnosis’ of which bacteria- but may have a history suggestive of a recent gastroenteritis

Epidemiology

  • Around 5/100,000 patients per year get ReA.
  • Around 1-4% of patients get ReA after enteric infection
  • Around 0.5-1% of patients with urethritis develop ReA

Pathophysiology

  • As with other seronegative arthropathies, there is an association with HLA-B27 allele of the MHC-class I protein.
  • The exact mechanism of how initial infection causes the arthropathy is largely unknown, although it is possible that a systemic infection (or indeed, infiltration of bacteria into the joint space), causes an inflammatory response in the joint which is perpetuated by the presentation of antigens (either auto-antigens or pathological antigens) to an HLA-B27.
  • The inflammation itself is mediated by CD4+ T cells and their inflammatory cytokines e.g. TNF, IL-6, IL-1/1B, IL10

Presentation

  • Symptoms tend to present 2-4 weeks post-infection (note that up to 10% of patients may have been asymptomatic) and onset is generally acute (symptoms develop within several days)
  • For presentation of conjunctivitis and urethritis, see posts
  • Constitutional symptoms are very common- e.g. fatigue, mild fever, muscle aches
  • Musculoskeletal symptoms
    • Typically lower limb, asymmetrical oligoarthritis with a relatively acute onset (swollen, hot, painful, tender, red joints- with associated joint effusions)
    • Tendonitis/enthesitis of the lower limbs (achilles’ tendonitis/ plantar fasciitis) is also relatively common.  The patient may also have dactylitis (sausage digits)
    • Back pain is reported in around 50% of patients with ReA
      • Note that physical examination evidence of active spondylitis/sacroiliitis (e.g. loss of ROM) is not commonly seen.  Examination of the back may even be normal.
  • Extra-articular features
    • Skin/mucosal changes are quite common
      • Keratoderma blennorrhagicum (hyperkeratotic skin presenting as vesicles on erythematous skin of the soles/palms/trunk/scalp, eventually converging- covering a larger plaque of skin.  Usually yellow/brown in colour)
      • rarely erythema nodosum
      • mouth ulcers

Investigations

  • There are no specific investigations for ReA, but inflammatory markers will usually be high in active disease and can be used as an indicator of disease progression.
  • A stool sample or urethral swab may reveal the underlying causal organism (if there is still evidence of underlying infection, this should be treated.  However, the result itself is unlikely to influence the management of ReA).
  • X-rays may be done but can be normal, particularly in early disease.
    • there may be evidence of bony erosion and bony reaction in severe or late disease
  • HLA-B27 may be checked if patients have long-standing symptoms (again, unlikely to affect management)

Management

  • NSAIDs and intra-articular corticosteroid injections are used to manage joint symptoms
    • In patients who do not respond, systemic steroids may also be tried
  • Physiotherapy may also be useful
  • DMARDs may be started in patients who have had symptoms for >3 months (?sulfasalazine (normally used for arthritis associated with IBD) but others e.g. azathioprine, methotrexate may also be used)
    • NB there is a distinct lack of evidence regarding DMARD use in ReA, likely due to its self-limiting nature.
  • Treatment of underlying infection should be started but will not affect prognosis of ReA.

Psoriatic Arthritis

An inflammatory arthritis associated with psoriasis, usually seronegative for rheumatoid factor, sharing many clinical aspects with the other seronegative arthropathies.

Although generally not thought to be as severe as rheumatoid arthritis, patients with PsA are at risk of deformity and significant loss of function.

Epidemiology

  • Prevalence of psoriasis in the general population is around 2-3%
    • Prevalence amongst those with arthritis is around 7%
    • Prevalence or arthritis amongst those with psoriasis is reported between 6-42% (wide due to lack of definition); 30% is the estimated value
  • The exact prevalence of psoriatic arthritis is not known but reports vary from 0.04%-0.1%. (incidence around 3.4-8 per 100,000)
  • Age of onset is between 30-55 years; equal sex distribution
  • Majority (70%) of patients will present with psoriasis before arthritis; Around 15% will present with arthritis before psoriasis and 15% will develop the conditions together.

Pathophysiology/Aetiology

  • Genetic factors
    • Strong hereditary component
    • Linked the HLA-B38/B39 (peripheral PsA) and HLA-B27 (spondylitis PsA)
  • Viral/infective role is possible but no specific viruses have been identified
  • Immune factors
    • PsA is associated with lymphocytic infiltration of the skin, joints and entheses.  This is mainly involves T-cells (CD4+ T cells) and their inflammatory cytokines e.g. TNF, IL-1, IL-6, IL-1B, IL-10 etc).

Presentation

Musculoskeletal

  • Inflammatory arthritis- i.e. painful, hot, swollen, erythematous joints
    • NB joints are usually less painful/tender than in rheumatoid
    • Joints are also more likely to present in a ‘ray’ distribution i.e. all the joints of one digits affected rather than the same joints of both hands (more typical of RA)
    • However, like RA, symptoms do worsen at rest/night and improve with movement
  • Can be classified as
    • Asymmetrical oligoarticular arthritis
      • Most common presentation, affecting the hands and feet first
        • Asymmetrical knee involvement is also seen
      • Inflammation may involve the tendons, tendon sheaths and entheses, causing a dactylitis appearance (sausage-fingers)
    • Symmetrical Polyarthritis
      • Rheumatoid like in presentation but
        • more commonly DIP>PIP joint involvement; relatively asymmetrical; no nodules
    • DIP arthritis
      • Isolated DIP involvement is less common but can occur
      • Often associated with dactylitis and nail dystrophy (paronychia)
    • Spondylitis +/- sacroiliitis (+/- peripheral arthritis)
      • Occurs in 5-36% of patients with PsA
      • Unlike ankylosing spondylitis, spinal involvement can be asymmetrical and features of sacroiliitis may be minimal or absent
      • Radiological features, too, are less obvious in PsA and are more likely to show discrete foci of affected spine rather than the caudo-cranial progression seen in Ank Spon
    • Arthritis mutilans
      • Rare, rapidly deforming form of arthritis (1-5% of patients)
      • Caused by resorption of the bone- giving a ‘pencil in cup’ appearance on x-ray and a telescopic movement of the digit
  • Enthesitis is a major feature of PsA
    • Achilles tendonitis and plantar fasciitis are common manifestations

Extra-articular features

  • By definition- PsA should be associated with psoriasis (a diagnosis, however, can still be made based on family history and presentation of symptoms)
  • Anterior uveitis
  • SAPHO syndrome
    • synovitis
    • acne
    • pustulosis
    • hyperostosis
    • osteitis

Investigations

  • There are no specific investigations for PsA- diagnosis is primarily clinical
  • Inflammatory markers can be elevated
  • X-ray changes
    • bony erosions at the edge of cartilage, often asymmetrical
    • bony ankylosis/joint subluxation may also be seen
  • MRI may be useful in evaluating the soft tissue changes

Management

  • NSAIDs are recommended for symptomatic treatment
  • Intra-articular steroids may be used second line.  NB Oral corticosteroids should be avoided as psoriasis rash may rebound upon treatment withdrawal.
  • DMARDS
    • Early treatment with DMARDS should be considered for peripheral arthritis and enthesitis, +/- skin/nail disease.
    • Ideally treat both the skin and musculoskeletal symptoms (if both are present)
      • Methotrexate is often the best treatment for this reason
    • Antimalarial DMARDs e.g. hydrochloroquine should be avoided as these can cause skin reactions (exfoliative dermatitis) that may worsen psoriasis
    • If just arthritis symptoms are present- leflunomide may be a better option for active peripheral arthritis
  • Physiotherapy plays a role in axial disease
  • Biologic agents (only anti-TNF agents for psoriatic arthritis) may be offered to patients
    • with active arthritis (>=3 tender/swollen joints) which has not responded to at least 2 DMARDs (alone or in combination), one usually being methotrexate
      • OR after 1 DMARD if there is one of:
        • >=5 joints; elevated CRP >3 months; or structural bone damage due to disease
    • with active enthesitis and/or dactylitis which has not responded to NSAIDs or local steroid injection
    • with predominantly axial disease that is active and has not responded to NSAIDs
      • NB treatment should be stopped if there is an inadequate response

Osteoarthritis

A degenerative disorder of synovial joints, characterised by

  1. Focal areas of damage to the articular cartilage
  2. Remodelling of underlying bone and the formation of osteophytes (new bone at joint margins)
  3. Mild synovitis

Any joint can be affected but most commonly the larger weight-bearing joints (hip, knee) are affected.  Hands can also be affected, as can the spine.

Epidemiology

  • It is the most common cause of joint pain- affecting around 8.5 million people in the UK
    • 20% of adults aged 45-64 have osteoarthritic pain in the knee and around 12% of people >65 have osteoarthritic hip pain
  • Prevalence increases with age; and affects females slightly moreso than males (1.7:1)

Aetiology/Risk factors

  • Age
  • Obesity/overweight
  • Previous trauma
  • Genes
    • Osteoarthritis carries significant hereditability, often moreso than rheumatoid arthritis
    • Bone morphogenic protein (BMP) and wingless type (WNT) genes have been implicated, as well as MTPs
  • Reduced muscle strength / joint laxity or malalignment
  • Bone density
    • High bone density increases the likelihood of development
    • Low bone density increases the likelihood of progression
  • Occupation
    • Athletic, labour i.e. over-using joints

Pathophysiology

oa

  • Biomechanical factors e.g. trauma, ligament laxity, joint instability are drivers for the development in OA.  It is thought that microtrauma around the joint activates an immune response, causing inflammation.  It is this that degenerates the cartilage and initiates new bone formation (and possibly pain too- although this is more likely to be mechanical).
  • It can be described as the far end of the spectrum of normal healing.

Presentation

  • Joint pain develops over years.  As a result, some patients will present at a stage where the pain is severe enough to warrant management
    • Pain is often better in the mornings/at rest and worse on exertion
      • If affecting the lower limb- ask about walking distance and stairs
      • Note that pain in the knee may be referred from the hip
  • Reduced range of joint movement (usually due to pain but can be due to stiffness/progression of the disease)
    • In joints like the knee and shoulder, there may be a ‘catch’ on movement (pseudo-locking)
      • the knee may also ‘give-way’ (important to ask)
      • advanced disease of the knee may produce a varus deformity
    • In the hip- painful restriction of internal rotation is usually the first sign
      • A fixed flexion deformity (Thomas’s test positive) is also commonly seen
  • This may result in an abnormal gait (usually antalgic)
  • There may also be swelling of the joint- not usually grossly erythematous, but more fluid in the joint space (check for effusion of the knee).  The joint can be tender (less common cf rheumatoid).  Bony swelling is more commonly seen later on (these are often asymptomatic)
    • e.g. DIP joints- Heberden’s nodes); PIP (Bouchard’s nodes)
  • There may be joint crepitus
  • Muscle wasting of the effected area may also be seen.  This can be due to the patient not wanting to use the joint due to pain but can also worsen the progress of OA.

Investigations

  • Management is largely determined by the history (pain is a greater indicator for management than investigation findings)
  • X-ray
    • Osteophytes
    • Loss of joint space/ cartilage loss
    • Bone cysts
    • Subarticular sclerosis
  • Other tests e.g. FBC/LFTs/bone biochemistry are usually normal
  • MRI may be useful if another cause of pain is suspected e.g. ligament injury
  • Aspiration of effusion should only be done if there is suspicion of infection/septic arthritis

Management

  • Varies with the severity of symptoms, x-ray findings, patient preference etc
  • Drugs for pain are commonly NSAIDs and paracetamol (take before pain starts if possible)
    • Paracetamol and topical NSAIDs are recommended first line
    • use the analgesic ladder for pain control
    • If pain is not controlled and there are reasons not to go for surgery, intraarticular steroids are often very useful
  • Physiotherapy/exercises may be useful if the patient has problems with muscle wasting
  • Weight loss
  • Surgery
    • Indicated if there is OA evidence on x-ray and if the disease is significantly affecting the patient’s daily lifestyle
    • Joint arthroplasties tend to last around 10-15 years

Crystal Arthropathies

Gout

Crystal deposition disease characterised by the presence of monosodium urate (MSU) crystals in tissues resulting in inflammation.

Hyperuricaemia (urate >0.36 in females and >0.42 in males) is the underlying metabolic abnormality seen in gout.  Note that hyperuricaemia doesn’t necessarily cause gout BUT instead, a sudden change in urate levels is thought to precipitate gout pathology.

There are 2 main classifications:

  • Primary i.e. ‘idiopathic’ (or caused by environmental factors)
  • Secondary i.e. iatrogenic (usually due to thiazide diuretic use)

 Epidemiology

  • Peak age of onset is 40-60 years old
    • NB Hyperuricaemia is thought to be asymptomatic for a decade or longer prior to onset of symptoms
    • Prevalence increases with age
  • More common in men (3.6:1)
  • Occurs in around 1.4% of the general population

Causes/Risk factors

  • Male
  • Diet (increased purines) e.g. high red meat, seafood; (impaired degradation of purine) e.g. alcohol (also dehydration due to alcohol can raise serum urate)
  • Diuretics
  • Obesity
  • Hypertension; coronary heart disease
  • Diabetes
  • Chronic renal failure (impaired urate excretion)
  • Hypertriglyceridaemia

Pathophysiology

  • Gout usually affects the peripheral joints where the temperature is low enough for crystals to precipitate
    • Gouty tophi are typically found in the finger tips, olecranon bursae, helix of the ear etc
  • Whilst hyperuricaemia increases the risk of developing gout, most hyperuricaemic patients won’t develop gout.  Also, patients with gout may not necessarily be hyperuricaemic
  • Hyperuricaemia can either be due to underexcretion (90%) or over-production (10%) or both.
  • It is thought that when crystals precipitate, they invoke an innate immune response.
    • IL-1-beta is thought to be one of the main mediators of the inflammatory cascade occuring in gout.

Presentation

  • Acutely painful joint (over 6-12 hours to peak)
    • Inflamed- swollen, tender, erythematous
    • Commonly affected joints include
      • 1st (Large) Meta-TP joint (50% of all and 70% of first attacks)
      • Mid-TP joints
      • Heel
      • Ankle
      • Knee
      • Fingers
      • Wrist
      • Elbows
    • NB although gout is typically monoarticular, polyarticular gout is not uncommon (first presentation in about 10%)
    • Symptoms may resolve spontaneously after around a fortnight, but may flare again later on in a similar fashion (a typical episodic/intermittent history)
  • Gouty tophi are firm, white, translucent nodules that usually are found with long-standing hyperuricaemia/gout (most likely after first presentation)
    • Commonly in fingers, toes, medial forearm (ulnar), elbow, knee, achilles tendon, ear helix etc
    • Usually asymmetrical presentation
  • Constitutional symptoms (fever, malaise etc) are less common in gout, but can be present so are not to be used to distinguish from inflammatory arthropathies e.g. rheumatoid

Investigations

NB Usually a clinical diagnosis but

  • Joint fluid microscopy and culture may be used if there is concern about septic arthritis or if the diagnosis is otherwise uncertain
    • Urate crystals may be seen and confirms gout
  • Serum urate
    • not usually useful at presentation as many people with hyperuricaemia do not have gout (also serum levels tend to fall during an acute attack)
    • usually measure 4-6 weeks after and treated as hyperuricaemia if necessary
  • Joint x-ray
    • May be useful.  Features that might be seen in gout include chondrocalcinosis (calcification of cartilage).
    • More useful to late/recurrent gout where punched out lesions (subcortical cysts), sclerosis and tophi may be seen also

Management

  • An acute attack
    • NSAIDs
  • Prevention
    • Allopurinol 1st line (Febuxostat 2nd line)
      • may be used – start slow and increase
        • after two or more attacks of gout within a year OR
        • after the first attack in people at higher risk with tophi, x-ray features of gouty arthritis, renal impairment, known urate stones or on long-term diuretic medication
      • Start 1-2 weeks after acute episode and adjust dose such that serum urate is under 300umol/l (measured first at 4-6 weeks after attack)
      • Co-prescribe NSAIDs for at least a month or colchicine for 6 months
      • Note that these drugs may precipitate an attack of gout initially.
      • Urate should be monitored annually (every 3 months in first year)
    • Lifestyle advice

Pseudogout (CPPD)

Crystal arthropathy characterised by the deposition of calcium pyrophosphate crystals.  CPPD disease is calcium pyrophosphate deposition disease and can be classified as

    • asymptomatic
    • OA with CPPD
    • Acute CPP crystal arthritis
    • Chronic CPP crystal inflammatory arthritis

Background and Epidemiology

  • Pseudogout is the acute arthritis associated with CPPD.
  • Frequency increases with age (about 10-20% of people >60 some CPPD)
  • Unlike gout, pseudogout is distributed equally between males and females

Aetiology/Risk factors

  • Dehydration- particularly patients on loop diuretics (NB NOT thiazides as with gout)
  • Also PPIs have been shown to be associated (possibly due to hypomagnesaemia
  • Patients with osteoarthritis may be slightly more at risk
  • Other conditions e.g. Haemochromatosis, hypothyroidism

Presentation

  • Similar to gout (above) BUT
    • milder severity of pain and symptoms of inflammation
    • more insidious onset e.g. over several days rather than hours
    • More commonly occurs in larger joints e.g. knee rather than MTPs

Investigations

  • Joint aspiration with microscopy/culture may reveal crystals
    • cf gout- intracellular crystals are classical of pseudogout
  • X-rays may show linear opacifications or cartilage (Calcium deposit)

Management

  • NSAIDs are the mainstay of treatment (there are no treatments for prevention)
  • Intra-articular corticosteroid injections may be helpful
  • Colchicine may also be used if either of the above are ineffective/contraindicated

Rheumatoid Arthritis

A chronic, inflammatory, autoimmune disease characterised by an inflammation of the synovial joints.

Background/Epidemiology

  • Common: Around 1% of the population in the UK
  • More commonly presents later on in life (onset in 40s/50s; average age of patients 70)
  • More common in women than men (2-4:1)
  • Associated with significant morbidity
    • Pain/disability
    • About 1/3 stop working within 2 years

Pathophysiology

  • Genetic Susceptibility
    • HLA-DR4 and HLA-DRB1
    • Hereditability
      • Monozygotic vs Dizygotic vs Gen Pop (15-35% vs 5% vs 1%)
  • Triggers
    • Smoking (increasing evidence that this could be a trigger as well as an exacerbating factor)
    • Viral infection
    • Bacterial infection
      • Periodontal infection (Porphyromonas gingivalis can cause citrullination of proteins)
  • Citrullination
    • A normal post-translational modification required for normal function of many proteins (including filaggrin in the skin) and as part of inflammatory change in other proteins (e.g. fibrin)
    • In RA- an immune response is mounted to citrullinated proteins
  • Immune Reaction
    • The triggering event causes T cells to migrate to the synovium/joint where they are activated
    • B-cell activation and the production of autoantibodies (anti-cyclic-citrullinated peptide antibodies)
    • Formation of immune complexes and subsequent activation of the complement system and further recruitment of macrophages and other inflammatory cells
    • Further inflammation is proposed to cause further citrullation and further reaction

tileshop.jpg

Presentation

  • Joint features
    • Arthritis is usually insidious onset, symmetrical polyarthritis, typically the small joints of the hands and feet (particularly PIP/MCP cf OA and DIP)
      • Pain is often worse at rest (may waken sleep) or just after rest; improves with activity
    • Other features of inflammation e.g. red, hot, swollen, joints
      • Swelling is around the joint (not bony- described often as boggy)
    • Stiffness
      • Often in the morning/after rest and will usually last >30mins
    • On examination
      • As well as the above, there may be reduced range of movement
      • Hand deformities
        • Ulnar deviation
        • Swan neck (hyperextension of PIP and flexion of DIP caused by flexor synovitis that increases the flexor pull on the MCP joint)
        • Boutonniere’s (flexion of PIP and hyperextension of DIP caused by chronic synovitis in which the PIP is forced into flexion, raising tension in the extensors of the DIP)
        • Z-deformities of thumb (hyperextension of the IP joint and fixed flexion and subluxation of the MCP)
        • Piano-key deformity of the wrist (the ulnar head can be depressed (like a piano key))
      • Rheumatoid nodules
        • hard, firm swellings over the extensor surfaces
  • Constitutional symptoms are common
    • profound fatigue
    • mild fever
    • sweats
    • weight loss
  • Extra-articular features
    • Eyes
    • Skin
      • vasculitic rash (palpable purpura)
    • Nervous system
    • Lung
      • Pleural involvement (pleural effusion); pulmonary fibrosis (interstitial disease)
    • Cardiac
      • Increased risk of atherosclerosis (atherosclerotic events); pericarditis
    • (NB Renal involvement is rare)
  • Constitutional symptoms are common
    • Fatigue, malaise, mild fever, weight loss

Investigations

  • Blood tests
    • FBC may be normal or may show normocytic anaemia and/or reactive thrombocytosis.  LFTs: Alk Phos is commonly mildly raised; U&Es (not often helpful in diagnosis but raised urate may suggest polyarticular gout rather than RA)
    • Serology
      • Rheumatoid factor is still occasionally used (positive in 70% of patients) but is going out of practice
      • Anti-CCP antibody is more sensitive and specific for rheumatoid arthritis
  • Imaging
    • X-rays of the hands/feet
      • May show soft tissue swelling, periarticular osteopenia, loss of joint space, erosions and deformity
    • Chest x-ray may help in identifying any lung involvement

Management

  • In a new patient
    • First line (SIGN- thus in Tayside) recommended treatment is DMARD treatment (methotrexate usually first line) within 3 months
      • Combination therapy can be tried in patients who do not have an adequate response (NOTE: many are now treating RA initially with combination (e.g. Methotrexate and sulfasalazine) treatment as there is growing evidence that if the disease can be controlled/suppressed quickly, there is a better prognosis)
      • aim is to get a DAS28 score of <2.6 (remission); if this isn’t possible then at least <3.2 (low DAS28)
      • *Varies by case, depending on patient.
    • NSAIDs should be co-prescribed, where necessary, for symptomatic relief.  Lowest dose possible.  Gastroprotection (PPI) is also recommended for those at risk of gastroduodenal ulcer
    • Low-dose oral corticosteroids can be used in combination with DMARD tx for short term relief of symptoms
      • If long-term use is required, ensure bone protection
  • Biological agents
    • Considered only
      • after a trial of at least 2 DMARDs (6 months each, with 2 months at a standard dose)
      • persistently severe disease (DAS28 >5.1 on at least 2 occasions, 1 month apart)
    • At 6 months, if there is an inadequate response (DAS28 reduction <1.2), the agent should be discontinued

Notes about treatments

Methotrexate

  • Prior to treatment
    • FBC, LFTs, U&Es
      • Contraindicated (or at least caution should be taken) in patients with liver impairment, renal impairment, active infection, immunodeficiency syndromes
    • (Usually) CXR
      • see side effects below)
    • NB Do not use if pregnant/planning pregnancy (clear for 3 months)
  • Initiation of treatment
    • Start at sub-maximal dose (10-15mg/week) and increase dose by 5mg every 2-4 weeks up to 20-25mg/week (depends on response/tolerability)
    • Folic acid 5mg daily (except day of methotrexate) should be co-prescribed
    • FBC, ESR, LFTs and U&Es every 2 weeks until the dose and disease have been stable for 6 weeks.
      • Thereafter, monthly until stable for a year.  After that, 3 monthly.
  • Stopping treatment
    • Development of rash/ulcerations
    • Development of dry cough, dyspnoea and fever (see below)
    • Low WBC/neutrophil/platelet count
    • Raised (>x2-fold) AST/ALT
    • Renal impairment
    • Moderate/Severe infection
  • Side effects
    • Common
      • GI
        • Anorexia; nausea (may be treated pharmacologically if troublesome); vomiting; diarrhoea; oral ulcers (ask about)
      • Alopecia
    • Less common
      • Myelosuppression
    • Rare
      • Hepatotoxicity (cirrhosis)- Avoid alcohol where possible
      • Pulmonary toxicity (interstitial pneumonitis, rarely fibrosis)
        • be wary of dry cough, dyspnoea, fever

Biological Agents

  • Prior to treatment, the main thing to evaluate is risk of TB exposure.  If, from the history, there is a risk, testing for TB should be done
    • Skin test (mantoux) may be considered but may be false negative if patients are on DMARD treatment
    • Elispot test may be a better alternative (specialist)
    • Chest x-ray should also be considered
  • Treatment should be stopped/not started if there is evidence of infection.
  • If there is a significant history of cancer (family or personal), there may be a risk of cancer – risk/benefit should be considered.

Sjogren’s Syndrome

Background

  • One of the three most common systemic autoimmune diseases; characterised by dry mucous membranes (dry eyes/mouth)
  • Classified as either primary or secondary
    • Primary Sjogren’s is a solitary disease
    • Secondary Sjogren’s is associated with another autoimmune condition
      • Commonly rheumatoid arthritis.
      • Connective tissue diseases e.g. SLE, scleroderma are also common
  • Prevalence between 0.4% and 0.8%.  Prevalence rises with age (average age of onset 30-50.  Much more common in females (9:1)
  • Can be difficult to diagnose- several classification criteria have been published to aid diagnosis (see below)

Pathophysiology

  • The exact cause and pathogenesis of SS is poorly understood, though it is likely to be multifactorial
  • It has been proposed that an initial insult triggers a number of immune reactions eventually leading to the symptoms of SS

gregfd

  1. The initial insult
    1. Environmental factors
      1. Viral infection has been proposed but no single virus implicated (EBV, HCV, CMV, HIV, HTLV-1)
      2. The cell damage/death caused by viral infection (or other cause) can cause ER remodelling and interaction with Ro (SS-A) proteins to increase their antigenicity and expression on glandular surfaces/
        1. La (SS-B) can also interact with viruses to increase antigenicity
          1. see http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2010.02342.x/full
  2. Innate immune response
    1. Production of cytokines by the injured gland that upregulate chemokines and cell adhesive molecules into the vasculature (endothelial venules) to promote lymphocyte/dendrocyte migration to the gland
  3. Humoral immune response
    1. production of antibodies to SS-A antigen by HLA-DR-positive antigen-presenting cells by B lymphocytes under the influence of T-helper lymphocytes
      1. formation of immune complexes containing anti-SS-A that bind to the dendritic cells in the gland by their Toll receptor and Fc-gamma
        1. production of interferons, which further activates the innate immune response, activates metalloproteinases and apoptosis
  • This is thought to occur in genetically predisposed individuals e.g. HLA-DR3
  • Results in lymphocytic infiltration of exocrine glands

Presentation

  • The predominant symptoms of SS are dry eyes (xerophthalmia) and dry mouth (xerostomia) that usually presents in women aged 40-60
    • may present as
      • difficulty eating/swallowing (particularly dry foods), tongue sticking to the roof of mouth
      • difficulty talking
      • dental/periodontal disease
      • altered taste
      • oral candidiasis
      • painful/red eye (gritty)
    • However these are relatively non-specific for SS
      • Age-related change
      • Drugs (antihistamines, anticholinergics, antidepressants (TCAs and SSRIs), diuretics, beta blockers etc)
      • Dehydration
      • Vitamin A deficiency
      • Radiotherapy
      • Rosacea
      • Amyloidosis, Sarcoidosis, Lymphoma
    • This may be hard to diagnose and overlooked in many patients
  • Other features of dysfunctional exocrine glands
    • dry cough (trachea/bronchi)
    • vaginal dryness and dyspareunia
    • nasal dryness and nosebleeds
    • dry skin (xerosis)
    • signs of malabsorption (pancreas- can even result in pancreatitis (acute or chronic)
      • NB raised serum amylase in patients with SS is more likely to be caused by parotitis
  • Bilateral parotitis (or inflammation of other salivary glands e.g. submandibular)
    • Often recurrent/chronic swollen glands (often described as having no apparent cause)
    • Discomfort is usually mild-moderate (rarely severe)
  • Arthralgia/arthritis can be a feature of primary SS
    • Usually asymmetrical and can affect both large and small joints
    • Pain/stiffness is usually milder than Rheumatoid disease
  • Fatigue is common
  • Extraglandular features
    • Periepithelial infiltration (relatively common)
      • Interstitial nephritis
        • renal stones
        • tubular acidosis
        • osteomalacia
        • nephrogenic diabetes insipidus
        • hypokalaemia
      • bronchiolitis
    • Extraepithelial extraglandular (related to B-cell hyperactivity, hypergammaglobulinaemia and immune complex formation) – all relatively uncommon
      • Purpuric rash
      • Glomerulonephritis
      • Peripheral neuropathy
      • Reynaud’s phenomenon

On examination

  • Eyes
    • May be dilatation of conjunctival vessels
    • Look for corneal lesions
    • May be blepharitis
    • Look at tear film (may be reduced/absent)
  • Dry mouth
  • Enlarged salivary glands
  • May be features of other inflammatory diseases

Investigations

  • Blood tests
    • FBC is usually normal
      • possible anaemia of chronic disease
      • Abnormal WCC may suggest lymphoma, coexistant SLE or may in fact be a feature of SS
      • ESR/PV may be elevated or normal
    • Rheumatoid factor
      • Often high (higher than patients with RA)
    • Anti-Ro/Anti-La
      • Present in 60-70% of patient with primary SS (not secondary)
      • Usually associated with worse disease pathology/symptoms
      • Rarely ever present in non-SS sicca syndrome
    • Other antibodies e.g. Anti-CCP, ANA, antiphospholipid antibodies etc may also be positive (particularly in secondary disease- but even without other disease)
    • U&Es and LFTs may indicate some extraglandular involvement e.g. raised creatinine (can occur in up to 50%)
  • Imaging (not particular diagnostic but may gauge severity of disease- not usually routine)
    • Parotid ultrasound
    • Sialography and Salivary Scintigraphy may show gland dysfunction but is not specific for SS
    • MRI may identify features of chronic salivary gland inflammation
    • CT may identify associated lymphoma (rare)
  • Rarely is a biopsy performed, although biopsy/histology are the most definitive test

Diagnostic criteria 

Set up to try and aid diagnosing SS:

  • Ocular symptoms (at least one of):
    • Dry eyes >3 months
    • Foreign body sensation in the eyes
    • Use of artificial tears >3x per day
  • Oral symptoms (at least one of)
    • Dry mouth >3 months
    • Recurrent or persistently swollen salivary glands
    • Need liquids to swallow dry foods
  • Ocular signs (at least one of)
    • Schirmer’s test =<5mm/5 mins (without analgesia)
      • Blotting paper in the lower eyelid
    • Positive vital dye staining (van Bijsterveld >=4)
      • Involves putting a dye onto the eye and examining for surface damage (score severity 0-3; in conjunctiva left, right and over the cornea (max 9))
  • Histopathology
    • Lip biopsy showing focal lymphocytic sialoadenitis (focus score >=1 per 4 square mm)
  • Oral signs (at least one of)
    • Unstimulated whole salivary flow (=<1.5ml in 15mins)
    • Abnormal parotid sialography
    • Abnormal salivary scintigraphy
  • Autoantibodies
    • Either Anti-SSA (Ro) or Anti-SSB (La)

For Primary Sjogren’s- EITHER Any 4 of 6 criteria, one of which must be histopathology or autoantibodies OR Any 3 of the 4 objective criteria (last 4- signs and investigations)

For secondary Sjogren’s- In patients with another well-defined major connective tissue disease, the presence of one symptom plus 2/3 objective criteria is indicative of secondary SS

Management

Management is essentially symptom control

  • Eyes
    • Artificial tears
    • If more severe, blockage of the puncta by electrocautery can be used
      • Prior to surgery, puncta blockers may be trialed to check efficacy
    • Pilocarpine may also be used
    • Hydration glasses
  • Oral
    • Artificial saliva
    • Pilocarpine
    • Dental hygiene
  • Joint pain and myalgia is best managed with hydrochloroquine

Ankylosing Spondylitis

Chronic seronegative spondyloarthropathy which primarily involves the axial skeleton.

Background/Epidemiology

  • AS results in inflammation of the joints of the spine and is one of a group of spondyloarthropathies which includes Reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease and undifferentiated spondyloarthropathy
  • Prevalence of 0.1-2.0% of the population
  • Peak onset is in late adolescence/early adulthood (15-25)
  • More common in males (3:1)

Aetiology/Pathophysiology

  • HLA-B27
    • HLA-B27 allele confers around a 5-fold increase in risk- 2% of people with HLA-B27 have AS, but 92% of patients with AS have HLA-B27)
  • It is proposed that HLA-B27 heavy chains could undergo transformation such that residues of the HLA chain is occupying its own binding site
  • Another explanation is that incorrect folding of HLA-B27 molecules causes abnormal trimerisation and dimerisation.  Surface expression of these grouped molecules can initiate an immune response
  • Unlike other autoimmune conditions, inflammation in AS is partially mediated by CD8+ (cytotoxic) T cells as well as CD4+ (helper) T cells
  • The classic pathological features include subchondral granulation tissue that erodes the joint and is slowly replaced by fibrocartilage and then ossification.  This occurs at sites of attachment of ligaments/capsules to bone (enthesitis)
    • When this occurs between the discs (at the annular fibrosus insertion), you get fusion of the vertebrae via syndesmophytes and classic ‘bamboo’ spine appearance

Presentation

  • Insidious onset
  • Constitutional symptoms are fairly common, particularly during flares e.g. fever, weight loss, fatigue

Back symptoms

  • Morning stiffness which will characteristically last >30 mins (not always)
  • Back pain
    • Improves with physical activity
    • Can often waken sleep/ worse at night
    • May be felt as non-specific buttock pain, particularly in early disease
      • Alternating buttock pain is classical of sacroiliitis
  • Tenderness of the spine (sacroiliac) and reduced range of movement (lumber flexion)
    • In advanced disease, there may be loss of lumbar lordosis, buttock atrophy and an exaggerated thoracic kyphosis (question mark posture)
    • Reduced Schober test (<5cm)

Other joint symptoms

  • Enthesitis of the heel (Achilles’ tendonitis and plantar fasciitis) and the tibial tuberosity
    • Can be swollen, painful- particularly in morning
  • Peripheral arthritis
    • Commonly asymmetrical and in hips, shoulder girdle, joints of the chest wall, pelvis and TMJ (cf rheumatoid)
    • Common presentation in children; also symptoms are usually milder than those of the back or than those seen in RA.

Extra-articular symptoms

  • Anterior uveitis– occurs in 20-30% of patients with ank spon.
    • NB Around a third-half of patients who develop anterior uveitis will go on the develop AS

Investigations

  • There are no routine blood tests that will aid a diagnosis
    • FBC may show anaemia of chronic disease
    • Inflammatory markers may be raised and may correlate with disease activity but are non-specific
    • Rheumatoid factor may exclude rheumatoid disease (if negative), as may other antibodies
    • Genetic testing for HLA-B27 may be used (not routine)
  • Spinal imaging
    • MRI is most useful for early disease as osteophytic change may be a late feature- enthesitis/sacroiliitis will not usually be seen on an X-ray in early disease
    • X-rays may show features of sacroiliitis (blurring/fusion of the joint line)- more common in established disease
      • Can be normal early on
      • Later features include
        • Sacroiliitis (subchondral erosions/sclerosis)
        • squaring of the lumbar vertebrae
        • rarely, late/severe AS causes ‘bamboo spine’
        • syndesmophytes
  • CXR may show apical fibrosis (fibrotic lung disease is not uncommon in AS)

Diagnostic criteria (New York criteria)

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Management

  • NSAIDs or COX2 inhibitorys are the first-line drug offered to patients
    • Past evidence has suggested DMARDs (e.g. MTX/sulfasalazine) are not effective in relieving back symptoms, however, they may be helpful in patients with peripheral arthropathy.  More recent evidence is suggesting they might be beneficial in AS.
    • Other pain killers may be required
    • Corticosteroids (either oral or intraarticular injection) may be beneficial in a patient with recurrently painful arthritis affecting minimal joints
  • Biological agents (adalimumab; etanercept; infliximab- all TNF)
    • Can be used in patients with
      • confirmed (New York) Diagnosis
      • a score of >=4 on the Bath AS disease activity index
      • at least 4cm on the 0-10cm spinal pain visual analogue scale
  • Physiotherapy is VERY important as it can often prevent the fusion of the spinal joints and greatly limit morbidity
  • Surgery is a last resort to correct deformities and manage associated arthropathy
  • Lifestyle advice is important due to the complications of AS

Complications

  • Progression can lead to fixed and flexed posture (bamboo spine)
  • Cricoarytenoid arthritis may also occur, as can pleural disease, necrobiotic nodules, Caplan’s syndrome (usually associated with pneumoconiosis), fibrosing alveolitis and other idiopathic interstitial lung disease
  • Cardiovascular
    • Atherosclerosis
      • Treat cardiovascular risk factors e.g. hyperlipidaemia, hypertension etc
    • Aortic regurgitation, mitral regurgitation, AV block, fibrosis
  • Apical lung fibrosis
  • Secondary osteoarthritis/osteoporosis
  • Eye problems (recurrent/severe uveitis)
  • Amyloidosis (may cause renal dysfunction)
  • Cauda equina syndrome