Wegener Granulomatosis

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Wegener Granulomatosis Powered By Docstoc
					 STARRING: April Buazon, Daniel Fegredo,
 Christina Parkinson, Tabish Shah, Ezman
Shariff, Rebecca Waterworth, Emma Woolley
                                  History
2000:
79 year old Caucasian male
Presented with a sore throat which did not clear with antibiotics.
Developed profuse epistaxis w/ nasal pain and fatigue.

PMH:
Hypothyroidism
High cholesterol
Angina

FH:
None relevant
                                                         DH:
SH:                                                      Levothyroxine
Lives at home with wife                                  Omeprazole
Professor of Economic History                            Clopidogrel
No alcohol history.                                      Bisoprolol
No smoking history.
                                                         Simvastatin
          Differentials of Epistaxis
•Trauma                  •Syphilis

•Infection               •Congenital

•Metabolic               •Autoimmune

•Blood                   •Neoplastic

•Endocrine               •Sarcoid

•Neurological

•Drugs
            Differentials of Epistaxis
Trauma -Fractures               Bloods -Haemophlia
       -Facial Surgery                 -Purpura
       -Dental extraction              -Apalastic Anaemia
       -Foreign Body                   -Thrombocytopenia
                                       -HTN
Infection-Influenza                    -Myeloproliferative disorders
         - Common cold
         -Sinusitis             Drugs   -Anticoagulants
         -Rhinitis                      -Cocaine
         -Hepatitis                     -Alcohol
         -HIV/AIDS
         -Malaria               Autoimmune -SLE
         -Yellow fever                     -Vasculitis

Metabolic- Vit C+K deficiency   Neoplastic -Leukaemia
                                           -Nasal tumours
Other   -Hepatic failure
        -Renal failure          Sarcoidosis
        -DIC
           History - Continued
2000:
Diagnosed with nasal polyps.

Treatment
5 polyps were surgically removed however symptoms persisted.
Investigations???
         Investigations for epistaxis
Full history               -Including family, drug, alcohol and
                  travel

Blood Tests                -FBC, ESR, CRP, LFTs U&Es
                           -Clotting screen
                           -Auto-antibodies
                           -Blood Typing

Radiological Studies       -X-Ray
                           -CT Scan

Nasopharyngoscopy          -Bronchial Wash
                           -Cultures
                          Blood Results
Auto-antibody investigations revealed presence of C –ANCA

What does this suggest?
            cANCA Positive

•Wegener’s Granulomatosis
•Microscopic polyangiitis
•Polyarteritis nodosa
•Churg-Strauss Syndrome
                History - Continued
Treated with 80mg/day Prednisolone
Patient went into remission.

2003
Patient was experiencing side effects from the high dose steroids
-Osteoporosis
-Secondary DM
-Purpura


Doctors decided to stop steroid therapy all together
2/52 after removal of steroid therapy:

Patient kidney function rapidly declined from an eGFR of 60 to 10, entering end
stage renal failure.

Patient put on CAPD and placed back on Prednisolone 1g/day


2004

Patient develops peritonitis, therefore CAPD was replaced with Hemodialysis.

2008-Present

Patient was involved in a minor RTA, suffered minor trauma to both feet

Feet trauma led to ulcers that wouldn’t heal due to steroid-induced DM and PVD
He was referred to MRI Diabetes Centre.
Has had multiple amputations of the left foot and eventual left BKA.
               On Examination

General Observation         Abdominal
• Purpuric hands and arms   • Appendectomy scar
• AV fistula on right arm   • No organomegaly
• Hyperpigmented face
• Left below knee
  amputation

Cardiorespiratory           Diabetic Foot
• Normal                    • Glove and stocking
                               neuropathy
                            • Neuropathic ulcers
             Current Medications
Levothyroxine           Dialysis 3 times weekly
Omeprazole              Glucosamine
Clopidogrel             Alandronic acid
Bisoprolol              Lanthanum
Simvastatin             Calcichew
                        Aspirin
                        Paracetamol
                        Pregabalin
                        Prednisolone
          Wegener’s Granulomatosis
A form of small vessel vasculitis (inflammation of blood vessels)
characterised by necrosing inflammation of small arteries, arterioles,
capillaries and venules in conjunction with the presence of ANCAs.



Typically affects the lungs and kidneys


Epidemiology and Aetiology
•The annual incidence in the UK 5.8/million
•Male to female ratio is1:1-2.1
•Peak age of 35-55
•Familial association with rheumatoid arthritis, SLE, irritable bowel disease
or multiple sclerosis.
     The Wegener’s Granulomatosis (WG) pathology is due to the action of
     the Antineutrophil Cytoplasmic Autoantibody (ANCA)



     In WG, ANCAs are bind with proteinase 3 (PR3) which is expressed in
     neutrophils that have been primed by inflammatory cytokines.




PR3-ANCA Neutrophils bind to vascular epithelium and release
reactive oxygen species (ROS) and proteolytic enzymes which
causes granuloma formation and necrosing vasculitis in the epithelial
cells.


 Churg Strauss Syndrome, Microscopic Polyangitis and Wegener’s
 Granulomatosis are known as an ANCA-associated vasculitides
 (AAV)
                                        Neutrophil extracellular traps (NET)
                                        Release PR3
                                        Stimulate ANCA release
  Adhesion molecule up-regulation
  membrane expression of PR3




                       PR3




(In WG)                             (In WG)
                 Signs and Symptoms
•Epistaxis, Rhinorrhea, Rhinitis, Nasal septum perforation
•Ulcers, sores and crusting in and around the nasal area
•Sinusitis, malaise, weakness, unexplained fever, night sweats,
myalgia, arthralgia
•Conjunctivitis, Scleritis, Peri-orbital swellings
•Chronic ear infections
•Purpura / rashes
•Cough, Haemoptysis, wheeze, SOB
•Proteinuria, Haematuria
                         Complications

Almost any part of the body can be affected, but the major late stage complications
associated with untreated Wegener’s are:


•Renal failure due to rapidly progressive glomerulonephritis
•Respiratory failure from upper airway obstruction, tracheal stenosis and pulmonary
involvement
•Myocardial infarction due to inflammation of coronary vessels
•Nasal septum perforation
•Hearing loss after formation of inflammatory granulated tissue in the middle ear
                             Investigations
•Blood Tests -cANCA (can be false +ve)
             - ESR/CRP (non specific markers for inflammation)
             - U&Es (creatinine and BUN)
•Urinalysis - proteinuria / haematuria
•Biopsy - relevant area (renal, lung, nasal)
•CXR - exclude cavities and nodules
•CT chest - exclude lung parenchyma involvement
•Sinus CT - exclude sinus disease
•Nasal endoscopy
•Lung Function Tests
                     Treatment
Fauci's scheme:
• cyclophosphamide 2mg/kg/day - 3-6 months
• prednisolone 1-2mg/kg/day - 3 months

Reported induced remission in 80 – 100 % of cases but doesn’t
prevent relapse – 50% of patients will relapse within two years

                Side-effects:
                • Infection                • Infertility
                • Cytopenias               • Myelodysplasia
                • Cystitis                 • Bladder Cancer



Langford et al. – 42% morbidity based on treatment
                         Treatment
  EUVAS (European Vasculitis Study Group) have conducted several
  studies to either reduce exposure or find an alternative.

                   Alternatives:
                   •azathrioprine – no difference in relapse rates but less
                   side-effects
                   •methotrexate – similar findings, current studies as a
                   remission drug, replacing cyclophosphamide
                   •rituximab – as a remmision drug, further studies
                   needed
Exposure:
Compared differing administration and amount of cyclophosphamide given
• 2mg/kg/day p.o.
• 15mg/kg i.v. every 2 weeks for 6 then every 3 weeks there after

- no difference in duration of remission
- higher rates of relapse with i.v. – 10%
- comparable rates of leucopenia and infection
                                 Prognosis
WG is considered fatal and if left untreated the complications causes death of
patients within 6-12 months from renal or pulmonary failure.


Relapse-remitting disease in 50% of all patients (long duration and troublesome),
returning within 2 years of stopping treatment.


Management:
• 1-2 weeks FBC if on oral – detect leucopenia
•urine cytology every 6 months
•fertility counselling should be offered
•minimise chronic morbidity with steroid therapy
•follow up ANCA serology every 6 months - prevent impending complications
•check renal function every 6-12 months
               Glucocorticoid Therapy
GC therapy introduced by Dr. Philip Hench in the 1950s – revolutionised
treatment of rheumatic and inflammatory diseases.

Prednisolone-equivalent dose of < 7.5 – 10 mg/day = low dose



Glucocorticoid Use:
Worldwide
- long-term use in adults 1-3%

United Kingdom
- 1/3 of patients on a 2 year therapy was on > 7.5 mg/day
- 20% take it for > 6 months – considered long-term
- 5% on daily GC for > 5 years
Doses (Equivalent to 20mg Hydrocortisone)
Steroid              Dose

Cortisone acetate    25 mg

Prednisolone         5 mg

Methylprednisolone   4 mg

Betamethasone        750 mcg

Dexamethasone        750 mcg

Deflazacort          6 mg
                         Clinical Uses
 Anti-inflammatory/immunosuppressive therapy:
• Asthma – by inhalation or            • Other inflammatory conditions of
  systemically                           skin, eye, ear or nose
• Hypersensitivity state – e.g. severe • Prevent graft-versus-host disease
  allergic reactions                     after organ or BM transplantation
• Autoimmune diseases – e.g.           • Neoplastic diseases in combination
  rheumatoid athritis                    with cytotoxic drugs
• Inflammatory diseases – e.g.
  Crohn’s disease


 Replacement therapy in adrenal failures e.g. Addison’s disease – a
 mineralocorticoid is also necessary
                  Side Effects
System                  Adverse Reaction
GI                      Pancreatitis
                        Candidiasis
                        Oesophageal Ulceration
                        Peptic Ulceration
Musculoskeletal         Myopathy
                        Osteoporosis
                        Fractures
                        Growth Retardation
Endocrine               Adrenal Suppresion
                        Cushing’s
CNS                     Aggravated Epilepsy
                        Depression; Psychosis
Eye                     Cataracts; Glaucoma
                        Papilloedma
Immune                  Increases infection risks
                  Study on Side Effects
Looked at 6517 long-term GC users for 2 and a half years of varying doses.
Data was collected from completed mailed surveys and pharmacy data.

Findings:
•Weight gain – 80%
•Skin bruising/thinning – 68%
•Sleeping disturbance – 65%
•Cataracts – 15%
•Fractures – 12%

-Longer duration on low doses associated more with acne, skin bruising,
weight gain and cataracts
-Higher doses (> 7.5 mg/day) associated more with sleep disturbance and
fractures
                   Study on Side Effects




Curtis et. al. (2006) looked at women on long-term use.
                          Conclusion
GC therapy – undeniable success but not without a lot of side effects.


Patients:
- educated about prevalence of side effects
- monitored constantly
- warned about stopping suddenly
- possibly receive calcium and vitamin D
- considered for bisphosphanates
- given a steroid card
                            Bibliography
McDonough AK, Curtis JR, Saag KG The epidemiology of glucocortoid-associated adverse
events. Current Opinion in Rheumatology 2008, 20:131-137

Kallenberg CGM Pathophysiology of ANCA-Associated Small Vessel Vasculitis. Curr
Rheumatol Rep 2010, 12:399-405

Seo Philip Wegener’s granulomatosis: managing more than inflammation. Current
Opinion in Rheumatology 2008, 20:10-16

Langford CA Cyclophoaphamide as induction therapy for Wegener’s granulomatosis and
microscopic polyangiitis. Clinical and Exp Immuno 2011, 31-34

Lamprecht P, Gross WL Wegener’s Granulomatosis . Herz 2009, 47-53

www.webmentorlibrary.com

www.vasculitis.org
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