Systemic Sclerosis / Scleroderma

Definition

  • Chronic, progressive, connective tissue disorder of unknown origin
  • Three main forms
    • Diffuse cutaneous form (dcSSc)
    • Limited cutaneous form (lcSSc)
    • Systemic sclerosis sine scleroderma (SScSD)

Pathogenesis

  • Three main features
    • Vasculopathy
    • Autoimmune activation of cellular and humoral systems
    • Progressive multiorgan vascular and tissue fibrosis
  • Vasculopathy
    • Altered ANS/ PNS > impaired neuropeptide sysnthesis + heightened alpha-2 receptor sensitivity > functional vasospasm
    • Immune response to multiple stimuli (eg viruses, ROS, cytokines, immune complexes) > endothelial cell injury > altered endothelial nitric oxide + prostacyclin synthesis + increased adhesion molecule expression > vasospasm
    • Endothelial cell injury > increased micorvessel permeability + leuckocyte diapedesis (facilitated by adhesion molecules) + coagulation and fibrolytic cascade activation with platelet activation + myointimal cell proliferation + thickened basement membrane > adventitial fibrosis > reduced luminal flow > increased profibrotic factors
    • Luminal obstruction + endothelial cell damage + adventitial fibrosis > self-propagating vasculopathy
    • Revascularisation mechanism defective despite high levels of VEGF > capillary malformation + obliterative vasculopathy of small-medium aa
  • Autoimmune activation
    • Activated T cells + macrophages accumulate in lesions
    • Circulating CD4+ cells bind to endothelium and fibroblasts
    • Leukocyte diapedesis facilitated by increased expression of adhesion molecules
    • TH2 response
      • T cell and macrophages show TH2 polarisation with IL-4 and IL-13 secretion (i.e. induction of TGF-beta, collagen sysnthesis, profibrotic signalling)
      • TGF-beta > auto/paracrine loop > sustained fibroblast activation
      • Deficiency in Tregs in SSc = lack of control over fibrotic process
    • Humoral activation
      • ANA occurs in almost all SSc patients
      • Antibodies to fibroblasys, endothelial cells, MMPs etc. have been described but the direct role is still inclear
  • Fibrosis
    • Follows autoimmunity and vascular damage
    • Tissue-resident fibrblasts, endothelial to fibroblast transformation and circulating mesenchymal progenitor cells from bone marrow contribute to process

Pathology

  • Classic
    • Widespread capillary loss
    • Obliterative vasculopathy of small arteries and arterioles
    • Skin and visceral fibrosis
  • Vasculature
    • Intimal proliferation in small to medium aa > luminal narrowing
  • Skin
    • Dermal expansion
    • Obliteration of hair follicles, sweat glands etc.
    • Invasion of adipose layer by fibrosis
    • Atropic epidermis with effaced rete pegs
  • Lungs
    • Alveolar wall inflitration with T cells, macrophages and eosinophils
    • Interstitial fibrosis + vascular damage
    • Progressive septal thickening > airspace obliteration + honeycombing + loss of pulmonary vasculature > impaired gas exchange + pulmonary hypertension
  • GIT
    • Most collonly lower esophageal involvement
    • Replacement of normal tract = reduced peristalsis + reflux +SBO + dysmotility
  • Renal
    • Commonly vascular lesions of interlobular and arcuate arteries
      • Elastic lamina duplication
      • Intimal proliferation
      • Thrombosis + microangiopathic haemolysis
    • Glomerulonephritis rare
    • Chronic ischaemia > shrunken glomeruli
  • Heart
    • Coronary arteriolar concentric intimal hypertrophy + luminal narrowin _ contraction band necrosis (=ischaemia-reperfusion injury)
    • Patchy mycocardial fibrosis > conduction defects
  • MSK
    • Fibrotic synovium and tendon sheaths

Classification

  • dcSSc
    • Prominent and early visceral involvement
    • Development of internal organ injury often weeks to months after first episode of Raynaud’s phenomenon
    • Soft tissue swelling + pruritus = early inflammatory ‘oedematous’ stage
      • Distal limbs and face
      • Diffuse hyperpigmentation
      • Carpal tunnel syndrome
      • Arthralgias and reduced mobility
    • Oedematous stage evolves into fibrotic stage
      • Skin induration
        • Loss of body hair
        • Loss of skin oils
        • Loss of sweating
      • Joints
        • Flexion contratures of fingers
        • Stiff joints due to supporting structure fibrosis
      • Evolving internal organ injury
  • lcSSc
    • Long-standing Raynaud’s, indolent skin changes and limited organ involvement
    • Subsets
      • CREST syndrome – calcinosis cutis, Raynaud’s, esophageal dysmotility, slcerodactyly and telangiectasia
      • 15% develop severe pulmonary arterial hypertension without interstitial lung disease
  • SScSS
    • Systemic features of systemic sclerosis without scleroderma

Presentaiton

  • Raynaud’s phenomenon
    • Episodic vasocontriction of fingers/toes
    • Triggers include
      • Cold
      • Emotional stress
      • Vibration
    • Pallor (vasoconstriction) followed by cyanosis (ischaemia) resolving with erythema (reperfusion)
    • Distorted nailfold capillaries under oil-immersion microscopy
  • Skin
    • Skin thickening
      • Symmetrical and bilateral
      • Starts int he fingers, advancing distal to proximal
      • Loss of dorsal creases of the fingers
    • Colour changes
      • diffuse tanning or vitiligo-type hypopigmentation
      • pigment loss spares perifolliuclar areas > salt and pepper appearance
    • Obliteration of appendages = dry skin, hair loss, no sweating
    • Reduced mobility
      • Flexion contractures of fingers
      • Contractures
      • Masukopf facies
        • Taut, shiny skin
        • Loss of wrinkles
        • Expersionless facies
        • Thinning of lips with accentuation of incisors and radial furrowing around the mouth
        • Beak-like nose
    • Micostomia
    • Telangiectasia
    • Chronic ulceration
      • Extensior surfaces of the PIPJ, volar pads of fingers and bony prominences (elbows, malleoli)
      • Healing leaves pits
      • Loss of fingertip soft tissue may result in acro-osteolysis
    • Calcium deposition
      • Calcium hydroxyapatite crystals
      • Finger pads, palms, extensor surface of forarm, olecranon bursa, prepatellar bursa
      • Persistent firm, non-tender subcut lumps
  • Lungs
    • ILD
      • HRCT
        • Ground-glass opacification seen in 50%
        • Mediastinal lymphadenopathy, traction bronchiectasis, honeycombing etc.
      • BAL
        • Elevated neutrophils (2%) / eosinophils (3%) = worse disease
    • PAH
      • Exertional dyspnoea
      • Reduced exercise capacity
      • Angina
      • Right-sided ehart failure
      • Echo for screen, confirm with right heart catheterisation
      • BNP correlates to prognosis
    • Aspiration penominitis complicating reflux
    • Endobronchial telangiectasia leading to pulmonary haemorrhage
    • Obliterative bronchiolitis
    • Cheast wall fibrosis
  • GIT
    • Oral Cavity
      • Xerostomia, microstomia
      • Periodontal diase
      • Mandibular condylar resoption
    • Upper GI
      • GORD
        • Reduced lower esophaageal sphincter
        • Dysmotility in distal 2/3 leading to reduced clearance
        • Reduced gastric clearance
        • CT – dilated esophagus with intraluminal air
      • Gastroparesis
        • Early satiety
        • Distension
        • Aggravated reflux
        • Gastric antral vascular ectasia may lead to recurrent bleeding
      • Rarely, primary biliary sclerosis
    • Lower GI
      • Impaired motility
      • Malabsorption
      • Diarrhoea from bacterial overgrowth syndrome
      • Pseudoobstruction
      • Wide mouth sacculations / diverticula > perforation
      • Pneumatosis cystoides intestinalis (air trapping in bowel wall > risk of rupture)
  • Renal
    • Sclerodermal renal crisis occurs in 15%, usually within 4 years
    • Obliterative vasculopathy + luminal obstruction > reduction in renal flow > juxtaglomerular hyperplasia > increased renin > AT activation > vicious cycle of renal vasoconstriction
    • Presents with accelerated HTN + fulminant renal insufficiency
    • Mild proteinuria, granular casts, microscopic haematuria
    • MAHA + thrombocytopaenia
  • Cardiac involvement
    • Generally silent, clinically evident disease = poor prognosis
    • Pericardial effusions
    • Dysrythymia
    • Valvular regurgitation
    • Hyerptrophy
    • Heart failure
    • BNP is prognostic
  • MSK
    • Carpal tunnel
    • Arthralgia and stiffness
    • Contractures
    • Rendon rubs
    • Inflammatory myositis
  • Others
    • Sicca complex (dry eyes, dry mouth)
    • Hypothyroidism
    • Sensory trigeminal neuropathy
    • Pregnancy adverse outcomes
    • Erectile dysfunction

Labs

  • FBC
    • Normocytic/microcytic anaemia of chronic inflammation
    • Iron deficiency may occurs from GAVE / chronic esophagitis bleeding
    • Macrocytic anaemia from malabsorption / bacterial overgrowth / therapy
    • MAHA from traumatic passage of vessles through fibrin/platelet thrombi coated vessles implies scleroderma renal crisis
    • Thrombocytopaenia / leukopaenia usually therapy effect
  • ESR generally normal
  • Antibodies
    • ANA sensitive but not specific
    • Anti-topoisomerase-1 (anti-Scl-70) and centromere are mutually exclusive specific anitbodies for SSc
      • Anti-topoisomerase
        • 31% of dcSSc and 13% of lcSSc
        • Negative prognostic marker
      • Anti-centromere
        • 40% of lcSSc and 2% dcSSc
        • Associated with PAH but rare with ILD, cardiac or renal disease
        • Positive prognostic marker
      • Nuceloar immunofluorescence pattern implies anti-U3-RNP (fibrillarin), Th/To or PM/Scl
      • Speckled IF pattern impliies anti-RNA polmerase III
      • Anti-Beta2GPI associated with increased ischaemic risk

Treatment

  • No treatment alters the course but treatments slow progression and provide symptomatic relief
  • Immunosupressives
    • Glucocorticoids of limited benefit for stiffness but do not affect skin or visceral involvement and may contribute to scleroderma renal crisis – use should be avoided
    • Cyclophosphamide of beenfit in ILD
    • Methotrexate and mycophenolate mofetil of modest benefit for skin disease
  • Anti-fibrotics
    • No strong prospective evidence for D-penicillamine, minocycline, relaxine, IFN-gamma or TNF inhibitors
    • Some retrospective evidence for D-penicillamine use
  • Vascular
    • Dress warm / move to somewhere warm with coconuts and beaches
    • Moderate benefit with calcium channel blockers
    • alpha1-blockersm 5-PDE inhibitors, SSRI, topical nitroglycerine, IV PGs may help Raynaud’s
    • Low dose aspirin may be of benefit
    • Bosentan, an endothelin-1 receptor antagonist reduces new ulcers
  • GIT
    • Treat reflux – PPI at high doses
    • Photocoagulation for GAVE
    • Short courses of metronidazole / erythromycin / tetracyclin for bacterial overgrowth
    • Octreotide may be trialled for small bowel hypermotility
  • PAH
    • Bosentan of PDE inhibitor
    • Diruesism anticoagulation and digoxin as needed
    • Suplemental oxygen if documented hypoxemia
    • Prostacyclin analogues may be of benefit
  • Renal crisis
    • Aggresive treatment with ACE-I
    • Early use of dialysis
  • Skin
    • Skin disease stabilises with time
    • Hydrophilic ointments
    • Bath oils
    • Regular massage
    • No effective therapy for calcinosis

Related Diseases

  • Mixed Connective Tissue Disease
    • lcSSc coexisting with symptoms of SLE, polymyositis, RA is suggestive of MCTD
    • Associated with high titres of anti-U1-RNP
    • SSc-specific antibodies not found
    • Elevated ESR and hypergammaglobulinemia
    • Good response to glucocorticoids
  • Eosinophilic fasciitis
    • Coarse peau d’orange skin
    • Rare visceral involvement
    • Raynaud’s absent
    • SSc-specific antibodies absent
    • Peripheral eosinophilia may be present acutely
    • Biopsy of skin generally neded for diagnosis
    • Responsive to glucocorticoids
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The Pharmacology of the Antipsychotics #1 – Basic Principles

The Dopamine Hypothesis

  • Theory derived from three points
    • Decrease of dopaminergic transmission by reserpine causes psychosis
    • Serendipitous discovery that chlorpromazine was effective for schizophrenia
    • Psychosis induced by drugs that increase dopamine (cocaine, amphetamines, L-dopa)
  • Does not explain
    • Cognitive affects of schizophrenia that appear to be due to decreased dopamine in the prefrontal cortex
    • Pyschotomimetic effects of drugs acting at other pathways (eg.  LSD)

Pathophysiology of Psychosis –   the Best Guesses

  • Common pathway of psychosis
    • Excessive dopamine in the the mesolimbic pathway
    • Drug effects on this pathway include:
      • Amphetamines – increased presynaptic DA release
      • Cocaine / amphetamine / methyphenidate – inhibition of presynaptic DA reuptake
      • L-dopa – increased DA availability
      • Ketamine / phencyclidine – antagonism of glutamate-mediated tonic inhibiton of DA release in the mesolimbic pathway
  • Positive and negative symptoms of schizophrenia
    • Glutamate NMDA-R stimulation results in
      • Tonic inhibition of mesolimbic DA release (presumed reason for positive symptoms)
      • Facilitation of mesocortical DA release (presumed reason for negative symptoms)
    • Schizophrenia simulated by infusion of NMDA antagonists
  • Psychosis related to delirium and dementia
    • Deficiency in cholinergic transmission
    • Neuronal loss

Dopamine Receptor Subtypes 

  • D1 receptor subfamily – D1 and D5
  • D2 receptor subfamily – D2, D3, D4

Central Dopamine Receptors

Subfamily Location Action
D1 & D2 substantia nigra

striatum

motor control
D1 & D2 limbic cortex information processing
D2 anterior pituitary inhibition of prolactin release

Peripheral Dopamine Receptors

Subfamily Location Action
D1 substantia nigra

striatum

motor control
D1 & D2 limbic cortex information processing
D2 anterior pituitary inhibition of prolactin release

 

Dopamine Pathways

  • Mesolimbic pathway
    • Positive symptoms of schizophrenia
    • Ventral tegmental area > nucleus accumbens
  • Mesocortical pathway
    • Negative symptoms of schizophrenia
    • Ventral tegmental area > prefrontal cortex
      • Dorsolateral prefrontal cortex – cognition / executive function
      • Ventromedial prefrontal cortex – emotions / affect
  • Nigrostriatal pathway
    • EPSE and tardive dyskinesia
    • Pars compacta of the substantia nigra > striatum
      • Motor planning pathway
  • Tuberoinfundibular pathway
    • Hyperprolactinemia
    • Arcuate + periventrucular nuclei of hypothalamus > infudibular region

Autonomic Pharmacology I – Introduction

Starting a comprehensive revision of the basic clinical sciences because why not. Part 1 of many.

Anatomy

  • Crucial to remember that SNS/PSNS are anatomical divisions, NOT pharmacological or physiological
  • SNS
    • Preganglionic fibres > thoracolumbar spinal nerves > paravertebral chains / prevertebral ganglia > postganglionic fibres > innervated tissues
  • PSNS
    • Preganglionic fibres > cranial nerves + 3rd/4th sacral spinal roots > parasympathetic ganglia outside target organs (ciliary, ptrygopalatine, submandibular, otic, pelvic etc) + ganglion cells diffusely located on target organs

Distribution

  • Cholinergic
    • All preganglionic efferent autonomic fibres
    • Motor fibres to somatic muscle
    • Most PSNS postganglionic fibres
    • Few SNS postganglionic fibres
  • Noradrenergic
    • Most postganglionic SNS fibres

Cholinergic Transmission 

  • Action potential arrives at synpase and trigger calcium influx
  • Calcium interacts with vesicle-associated membrane proteins (VAMPs) on ACgh vesicles
  • Vesices fuse into membrane and ACh spills out into cleft
  • ACh crosses cleft and binds to receptor
  • Acetylcholinesterase eventually breaks up ACh in cleft

Adrenergic Transmission 

  • Tyrosine > (rate-limiting step) DOPA > Dopamine > Noradrenaline > Adrenaline
  • Action potential > calcium influx > VAMPs > release of NA
  • Termination by:
    • reuptake by NET (norepinephrin transporter)
    • simple diffusion away from receptor site (eventual plasma or liver metabolism)
    • breakdown by monoamine oxidase (minor effect)

Analgesia in Cancer

Stepwise provision of analgesia

  1. Baseline paracetamol 1g qid
  2. Adjunct NSAID if no-contraindications for 1 week periods with breaks inbetween.
    1. Consider co-administration of PPI
  3. Add regular oral opiod
    1. Morphine 15mg SR BD or 5mg IR qid
    2. Halves starting doses in elderly or frail patients
    3. Consider switching to transdermal opiods if stable pain (slow onset, long duration)
      1. Buprenorphine patch 20mcg/hr
      2. Fentanyl patch (lowest dose = 12mcg/hour = 45mg morphine/day)
  4. Short-acting opiods for breakthrough pain
    1. 1/6th of regular daily dose PRN q1hour (eg. 5mg morphine IR)
    2. Represent if 3X consecutive doses used
    3. If incipient (predictable) pain (eg. anticipated pain with dressing due to MSK involvement); take analgesia 30 minutes before activity at 1/6th the daily dose.
  5. Retitrate regular opiods if breakthrough pain occurs
    1. Calculate 24-hour opiod requirement incoporating rescue doses and make that the new dose
    2. This does not apply to incipient pain
  6. Consider use of adjunct analgesia
    1. Neuropathic pain
      1. Anticonvulsants (including pregabalin and gabapentin)
        1. NOT crabamazepine due to haematological ADR and drug metabolism effects
      2. Antidepressants
    2. Bone pain
      1. Bisphosphonates
      2. Denosumab for breast and prostate metastases to bone (may require atypical PBS authorisation techniques)
    3. Palliative radiochemotherapy
    4. Refractory pain
      1. Nerve blocks
      2. Indwelling catheters

Considerations with opiod therapy and adjunct treatments

  1. Constipation –  hydration + aperients
  2. Emesis – ondansetron/metoclopramide/domperidone
  3. Sleep disturbances and nightmares
  4. Respiratory depression – monitor for initial doses

Asthma & Asthma Attacks

Asthma

  1.  Definition
    1. reversible airway obstruction
    2. airway inflmmation
    3. increased broncho- hyperresponsiveness (hypersensitive)
  2. Epi
    1. prevalence of 1 in 10 (> 2 million australians)
    2. > 300 million worldwide
  3. Types
    1. Extrinsic (allergic trigger e.g. inside – dust mites, outside – spores; IgE mediated)
    2. Intrinsic (irritant trigger e.g. pollution or infection; non IgE mediated)
    3. Mixed
    4. Exercise-induced
    5. Occupational
    6. Aspirin or NSAID induced
  4. Risk Factors
    1. Family History
    2. Parental smoking
    3. Past medical history, allergic march.
    4. Medications eg aspirin or NSAIDs
    5. RSV infections
  5. Workup
    1. History (Diagnostic)
      1. Symptoms – Wheeze, dysponea, cough, chest tightness, provocative factors.
      2. Always confirm history with spirometry.
      3. Early life – bronchopulmonary dysplasia, neonatal incubation, parental smoking
      4. Allergen screening of home and work environment.
      5. At risk groups – elderly, pregnant.
    2. History (Control)
      1. How often did Asthma interfere with activities?
      2. How often are you short of breath?
      3. How often are you awakened by your Asthma?
      4. How often do you use your rescue inhaler?
    3. Examination (General)
      1. expiratory wheeze
      2. prolonged inspiration to expiration ratio.
      3. hyper-expanded chest
      4. systemic signs of atopy e.g. eczema.
    4. Examination (Resp distress)
      1. Tachypnea, dyspnea, accessory muscle use, anxiety, cyanosis (if severe)
      2. Tachycardia, pulsus paradoxus.
  6. Investigations
    1. Spirometry – obstructive pattern
      1. Reduced FEV1, reduced or normal FVC, reduced FEV1/FVC.
      2. > 12% improvement with bronchodilator in FEV1.
    2.  X ray (not diagnostic)
      1. hyper-expansion
      2. flattened diaphragm
      3. increased wall markings (due to inflamed airways)
  7. Management, by severity (NIH recommendations)
    1. Asthma education
    2. Write action plan
    3. Intermittent asthma: aSx, normal PFT, <2 exacerbation/wk
      1. Long term: no regular medications
      2. Rescue: inhaled SABA
      3. step up Mx if > 2 exacerbations per wk.
    4. Mild persistent: > 2+ episodes/wk affecting activity, occasional nocturnal sx
      1. Long term: inhaled low dose ICS for long term inflammatory control
      2. Rescue: inhaled SABA
    5. Moderate persistent: daily Sx with SABA effecting activity, 2+ episodes possibly lasting days, nocturnal sx >1/wk
      1. Long term: ICS + LABA
        1. Consider lowering dose of each over time.
      2. Rescue: inhaled SABA
    6. Severe persistent: freq episodes interfering with sleep and activity
      1. Long term: high dose ICS + LABA. Monteleukasts. Consider IV steroids,  Anti-IgE Therapy (Omalizumab).
      2. Rescue: high dose inhaled SABA

Asthma Attacks 

  1. Be calm, assure patient. Anxiety worsens.
  2. Sx: tachypnea, tachy/bradycardia, silent chest.
  3. Management
    1. Treat before assessment, consider ICU referral.
    2. Upright posture, high flow 100% oxygen
    3. salbutamol 5mg & ipratropium bromide 0.5mg nebs.
    4. Consider hydrocortisone 100mg IV

 

 

 

 

 

 

GP OSCE Preventative Help

  • Take a family history
  • SNAPR (smokes, nutrition, alcohol, recreational drugs)
  • General medical health
    • Diabetes
    • Renal impairment
    • Cardiovascular risk
  • Cancer screening
    • Pap >18yrs q2yrs
    • Mammogram >50 yrs q2yrs (PCM prior if painful)
    • FOBT >50yrs q2yrs
  • Emotional health
  • Falls risk
    • Ask:
      1. Have you had two or more falls in the past 12 months?
      2. Are you presenting following a fall?
      3. Are you having difficulty with walking or balance?
    • If positive, do full geriatric assessment 
  • Vaccinations
  • Systems review if time for other common general medical problems
  • Sexual history if indicated
  • Young / Adolescent : HEADSS
    • Home
    • Employment / Education
    • Activities
    • Drugs
    • Sexuality
    • Suicidality
  • NOT recommended by RACGP
    • PSA
    • TFT
    • Vitamin D
    • Visual acuity
    • Spirometry

By specific group (RACGP guidelines)

All groups get SNAP motivational interviewing + thorough physical exam

  • 45-50
    • Weight,BMI, BP
    • Lipids + BSL
    • Pap 
  • 50-65
    • Weight, BMI, BP
    • Lipids + BSL + urine protein
    • Pap, CRC, mammography
    • Vaccinate for diphtheria-tetanus-acellular pertussis, influenza, pneumococcal, (herpes zoster if >60)
  • >65
    • Vaccinate: pneumococcal + herpes zoster
    • Falls assessment
    • Vision + hearing
    • Dementia screen (screen by asking about memory)
    • Lipids + BSL + urine protein
    • Pap, CRC, mammography
  • Aboriginal >15
    • Vaccinate with
      • Influenza
      • 23vPP (>50yrs only if no risk factors)
    • Mental health screen
    • STI
  • Aboriginal > 35
    • BMI + BP 
    • Urine protein + UEC
    • Lipids + BSL

Hepatitis B Salient Points

Presentation

  • History depends on stage
    • Replication – asymptomatic but lab finding come up
    • Prodromal – anorexia, N+V, pruitus, malaise and fatigue
    • Icteric – dark urine, pale stools, jaundice, RUQ pain
    • Convalescent – resolution
  • Tender hepatomegaly with firm, sharp and smooth edge

Natural history

  • 95–99% of previously healthy adults have a favorable course and recover completely
  • A small percent develop fulminant hepatitis

Diagnosis

Capture

Treatment

  • Directed by liver biopsy showing fibrosis
  • Monotherapy options: entecavir, tenofovir, peginterferon
  • Combination therapy options: tenofovir + emtricitabine