Sjogrens + Crystal Flashcards
HLA association in primary sjogrens?
HLADR52
Causes of secondary sjogrens?
- Autoimmune connective tissue disease: RA, SLE, systemic sclerosis, polymyositis
- Primary biliary cirrhosis
- Association with viral infections: Hep C, HIV, EBV, human T cell lymphotropic virus (HTLV)
Clinical features of Sjogren’s
Glandular Symptoms
- inflammation of the salivary glands - decreased production of saliva = xerostomia (dry mouth)
- xerophthalmia (dry eyes)
- Sicca syndrome: dry mouth + dry eyes
- Nasal dryness
- Vaginal dryness: dyspareunia
- Pharyngeal/tracheal/bronchial dryness
Extraglandular Symptoms
- General: fatigue + arthralgia
- Skin: Raynaud
- Vasculitis (10% of cases) - palpable purpura of the legs, GN
- Neuropsych: depression
- pulmonary: ILD
- Gastro: dyspepsia, reflux
- sensory polyneuropathy
Classical presentation: middle aged woman with dry eyes, dry mouth accompanied by RA or SLE
Investigations for sjogrens
- ESR elevated (non specific)
- Anti Ro60/SSA (most common) and anti La/SSB
- ANA and RF also positive
- dsDNA not typically present
- also: polyclonal hypergammaglobulinaemia (high IgG), low C4
- Can have cytopenia
- Cryoglobulinemia
Eye exam
- Schirmer test: shows decreased tear production
- Slit lamp: rose bengal stain showing damaged epithelium of cornea and conjunctiva
Biopsy: labial salivary glands - destruction, dense focal lymphocytic infiltrations
US of parotid: honeycomb or cloud like structure of the glandular parenchyma, alternating hypoechoic areas and band-like hyperechoic septa and cysts
Treatment for sjogrens
- Secondary: treat the underlying cause
GLANDULAR
Dry Mouth
- Regular dental care (can cause dental caries)
- Adequate hydration and food that stimulate salivary flow
- Fluoride
- If moderate/severe: artificial saliva, muscarinic agonists (pilocarpine), immunosuppression (hydroxychloroquine)
Dry Eyes
- Artificial tears
- Moderate disease: topical immunosuppression, eg: topical cyclosporine
Avoid anticholinergic agents to reduce sicca.
EXTRAGLANDULAR disease
Non lifethreatening:
- Arthralgia with NSAIDs or hydroxychloroquine
- Consider immunosuppression: leflunomide, SSZ, AZA, ciclosporin, cyclphosphamide
- Life Threatening: pulse methylpred +/- plasma exchange +/- rituximab if cryoglobulinemia
Complications of sjogrens
- Risk of associated conditions - SLE, RA
- Corneal scarring, visual impairment
- Increased risk of developing NON HODGKINS LYMPHOMA, MALT lymphoma (parotid swelling) - MALT lymphoma are most common
- RTA type 1
- Pregnancy: fetal loss, infant with neonatal lupus syndrome and associated complete heart block
Pathophysiology of sjogrens
Biopsy have shown inflammatory infiltrates composed of CD4 positive T lymphocytes.
What malignancy has an increased risk in Sjogrens?
Diffuse large B cell (NHL) and MALT lymphomas
Hypocomplementemia and lymphopenia at the same time as Sjogren diagnosis may predict lymphoma development. New and persistent adenopathy or other symptoms suggestive of lymphoma should prompt further evaluation with LN biopsy
RF
- recurrent swelling of partoid gland
- Splenomegaly
- RF
- Cryoglobulinemia
- Low C4
What factors in sjogrens leads to worse prognosis
- Low complement level, lymphocytopenia and cryoglobulinemia at diagnosis are predictive of unfavourable outcome due to lymphoma, severe disease manifestations (such as vasculitis) and premature death
What autoimmune disease are normally associated with Sjogren?
SLE
RA
Autoimmune thyroiditis
Normal process of purine catabolism
- Purine catabolism –> hypoxanthine –> xanthine oxidase converts hypoxanthine to xanthine and then uric acid
- Humans lack urate oxidase to convert allantoic acid
What does serum urate concentration depend on?
Intrinsic purine production
Purine intake through diet
Excretion - renal and GIT
Difference between allopurinol and rasburicase.
- Allopurinol is a xanthine oxidase inhibitor, therefore inhibiting the formation of uric acid
- Rasburicase is a recombinant form of urate oxidase, an enzyme that converts uric acid to allantoin which is more water soluble and therefore more readily excreted renally. It causes an reaction with an enzyme that turns uric acid into an inactive substance, allantoin, thereby reducing uric acid levels
○ Able to lower pre-existing elevated uric acid
○ Used for TLS
○ Rasburicase and allopurinol should not be given together as allopurinol will reduce the effect of rasburicase due to its inhibition of xanthine oxidase and consequently reduced uric acid concentration.
○ Rasburicase is contraindicated in patients who are glucose-6-phosphate dehydrogenase deficient because these patients cannot break down hydrogen peroxide, a byproduct of rasburicase, which can lead to hemolysis
Primary causes of urate overproduction
Primary urate overproduction due to inborn errors of metabolism
- Accelerated purine synthesis (PRPP synthase enzyme hyperactivity)
Impaired purine salvage (HGPRT1 deficiency):
- Complete HGPRT 1 deficiency - Lesch Nyhan syndrome, X linked recessive, severe hyperuricaemia, gout, nephrolithiasis, mental retardation, movement and behavioural disorders
- Partial HGPRT1 deficiency: Kelley Seegmiller Syndrome - gout, limited or no neurological symptoms
Hereditary defects of energy metabolism (accelerated ATP consumption); G6PD, fructose 1 phosphate aldolase deficiency.
Secondary causes of urate overproduction
Occurs secondary to increased cell turnover
- Autoimmune and haemolytic anaemia
- Sickle cell disease
- Polycythemia vera
- Ineffective erythropoiesis (megaloblastic anaemia, thalassemia)
- Myeloproliferative and lymphoproliferative disorders
- TLS
Dietary causes of urate overproduction
- Food high in purines: seafood (especially shellfish), red meat (particularly organ meat)
- Fructose: sucrose in soft drinks metabolised to fructose + glucose - alters hepatic metabolism to increase purines
- Alcohol
Increase ATP degradation and purine turnover
Increase lactate reduces renal urate excretion
Beer - high in urines
Food associated with lower urate: low fat dairy products, milk proteins, cherries (uricosuric effect), heavy caffeine consumption
Primary causes of urate underexcretion
Renal urate transporter mutations
- ABCG2 loss of function: decreased renal and gastrointestinal excretion
- URAT1 gain of function: increased reabsorption in kidney
Secondary causes of urate underexcretion
CKD
Medications: thiazide, loop diuretics, aspirin, pyrazinamide, ciclosporin, niacin (vitamin B3)
Cytokine involved in gout
IL1
- Once crystals form, resident tissue macrophages phagocytose them to initiate an inflammatory cascade, Interleukin IL-1 production fuels the process and promotes synthesis of additional cytokines (for example, tumor necrosis factor a, IL-6),
- Additionally, complement activation on the crystal surface generates split products that stimulate and attract neutrophils
- Collectively, these signals promote neutrophil infiltration, the hallmark of an established gout attack.
Location of first gout flare
Usually monoarticular
1st MTP involvement most common (podagra)
Chronic gouty arthritis
Chronic synovitis can occur secondary to MSU crystal mediated inflammation, can be polyarticular and mimic arthritis
Diagnosis of gout
(A) Diagnostic: synovial fluid aspirate showing needle shaped, negative birefringent monosodium urate crystals
(B) Urate: may be reducd during gout flars
Elevated inflammatory markers
(C) Xray: bone erosions, cortical break in bone, overhanging edge with sclerotic margin
(D) US
- Tophi
- Double contour sign
(E) Dual Energy CT
- high accuracy for tophaceous and well established gout
- Poor sensitivity in early gout
- Green (gout), purple (pseudogout)
NOTE:
- Urate crystals are almost always visible in acute gout
- Can be found in asymptomatic joints (previously involved and uninvolved in gouty patients)
Management of gout flare
- NSAID, COX2 inhibitor (eg: celecoxib)
- Prednisone
- Colchicine
- Intraarticular corticosteroid injection
Urate lowering therapy
(A) Xanthine oxidase inhibitors: reduce urate production
Allopurinol, febuxostat
(B) Uricosuric agents: promote the urinary excretion of uric acid: probenecid, benzbromarone
Losartan, fenofibrate, SGLT2 inhibitor
(C) Uricase
Rasburicase, pegloticase
What urate levels are aimed for in gout?
<0.36mmol/L in all patients
<0.3mmol/L in severe gout - frequent gout flares, subcutaneous tophi, gouty bone erosions
Tophi, erosions, chronic persistent symptoms, multiple joint involvement
MOA, adverse effects and drug interactions of allopurinol
MOA: non-competitive xanthine oxidase inhibitor
SE:
- Allopurinol hypersensitivity syndrome: rare, desquamating rash, fever, eosinophilia, end organ damage
HLAB5801 in high risk patients
Prevention - adjust initial dose for renal fx
- Increase in gout flares on initiation or titration of ULT
Drug interactions
- Other medications metabolised by XO: azathioprine, mercaptopurine, theophylline
- Thiazide diuretics can decrease renal excretion - increase allopurinol hypersensitivity syndrome
- Thiazide and probenecid decrease the efficacy of allopurinol
MOA, Contraindications, SE, drug interactions of febuxostat
- MOA: Non-purine analogue, selective xanthine oxidase inhibitor that is metabolised in the liver
- HEPATIC metabolism
- CI: history of CVD - has higher CV mortality but recent studies don’t really show this is true
- SE: nausea, diarrhoea, transminitis, rash (rare)
Effect:
Main benefit over allopurinol is that it lowers serum uric acid more and can be used in patients who are allopurinol allergic/intolerant
MOA, SE and drug interactions of probenecid and benzbromarone
URICOSURIC THERAPY
- Inhibit URAT1 and GLUT9 in proximal tubules, reducing reabsorption and promote elimination of urate.
Probenecid:
- Increases renal urate clearance
- Good hydration, urinary alkalinisation
- Requires GFR >30-40ml/min
- Useful addition to allopurinol or febuxostat
Benzbromarone
- Most potent uricosuric
- Requires GFR >20ml/min
- Close monitoring of LFTs
- Contraindicated with history nephrolithiasis, moderate to severe CKD
SE: urolithiasis, git symptoms, rash, lft derangement
Interactions: penicillin, inhibits secretion and increase serum concentration
Drug interactions of febuxostat and allopurinol
Purine analogues (azathioprine and mercaptopurine) combined with xanthine oxidase inhibitors can cause bone marrow toxicity.
MOA + SE of colchicine
Binds and stabilises tubulin subunits –> inhibition of microtubule polymerisation –> inhibition of urate crystal phagocytosis, neutrophil activation, migration and degranulation
SE: GIT symptoms
Rhabdomyolysis
Polyneuropathy
CNS symptoms
What metabolic disease are associated with pseudogout (calcium pyrophosphate deposition disease)/pathogenesis.
Associated with
- Hypomagnesemia (renal or GIT loss)
- Hyperparathyroidism
- Haemochromatosis
- Hypophosphatasia
- Acromegaly
- Wilson disease
Association with OA and joint injury
Nucleation of CPP crystals in cartilage enhanced by:
- Increased calcium (hyperparathyroidism) and iron (Haemochromatosis)
- Decreased magnesium (Mg inhibits nucleation)
- Hypothyroidism
- Cartilage damage due to OA
Investigations of CPPD
- Joint aspirate for calcium pyrophosphate crystals: rhomboid positive birefringent crystals
- Xray: chondrocalcinosis present
knee, wrist and shoulders most commonly affected
in the knee this can be seen as linear calcifications of the meniscus and articular cartilage - Ca, PTH, phosphate, ALP, Mg, iron studies
CT spine for axial involvement
- Cervical stenosis from CPPD in ligamentum falvum and transvere ligament of atlas
Crowned dens syndrome: CPPD surrounding the odontoid (C2) process
IVD calcifications and sacroiliac joint involvement
Calcium phosphate deposition disease
- Common cause of cartilage calcification and can be radiographically indistinguishable from CPPD
- Deposit primarily in periarticular tendons, burase and other soft tissues
- Can cause Milwaukee shoulder syndrome - painful swollen often destructive process of the genohumeral joint and rotator cuff
- Not seen on polarized microscopy
- Seen on electron microscopy or under light microscopy as nonbirefringent clumps that stain alizarin red
Tx: NSAIDs, joint aspiration and tidal lavage, intra-articular glucocorticoid injection
When is anti Ro elevated?
- sjogrens
- primary biliary cirrhosis
- SLE
Causes of gout (PM)
Gout is a form of microcrystal synovitis caused by the deposition of monosodium urate monohydrate in the synovium. It is caused by chronic hyperuricaemia (uric acid > 0.45 mmol/l)
Decreased excretion of uric acid
- drugs*: diuretics
- chronic kidney disease
- lead toxicity
Increased production of uric acid
- myeloproliferative/lymphoproliferative disorder
- cytotoxic drugs
- severe psoriasis
Lesch-Nyhan syndrome
- hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) deficiency
- x-linked recessive therefore only seen in boys
features: gout, renal failure, neurological deficits, learning difficulties, self-mutilation
Cryo and sjogrens
Normally type 2
What is the renal handing of urate
-95-100% urate is filtered at the glomerulus
- 99% is reabsorbed in proximal tubule
URAT1 and OAT4
URAT1: inhibited by probenecid, benzbromarone, losartan, fenofibrate
- Influenced by genetic polymorphisms including ABCG2, SLC2A9
- Excretion; 5-10% filtered load
Causes of impaired renal clearance of urate
- Genetic: accounts for 60% of S urate variability
- Renal disease: especially tubular dysfunction - lead, polycystic disease, cystinuria, analgesic nephorpathy
- Alcohol
- Drugs: thiazides, calcineurin inhibitors
- Low urine volume
- Obesity
- HTN
Urate and cardiovascular disease
- Hyperuricemia is an independent risk factor for CVD
Increase serum urate/gout associated with:
- HTN
- Hyperlipidemia
- Obesity
- Impaired glucose tolerance
- Mortality
- Coronary disease
- Heart failure
- AF
- Cerebrovascular accident
Gout and CKD
- Gout and hyperuricemia associated with CKD
- Gout is associated with progression with CKD
Interaction between urate crystals and the inflammatory stem
Involves many components including:
- Toll like receptors, FC receptors, integrins
- PHAGOCYTOSIS by monocytes/macrophages
- NLRP3 inflammsone assembly
- Production of IL1B
- Macrophage/osteoclast activation in bone lesions
What can also cause negatively birefringent crystals?
Betamethasone crystals mimic monosodium urate crystals
MOA of colchicine
SE
MOA:
Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis
SE
- Nausea, vomiting, diarrhoea
- Acute myopathy
- Multisystem failure
Beware:
- Renal failure
- Inhibitors of cytochrome P450 3A4
Cyclosporin, clarithromycin, ketoconazole, verapamil
Biological therapy for gout
Agents will inhibit IL-1b
- Anakinra
- Canakinumab
Treatment for pseudogout
Acute: same as gout
Chronic/Recurrent
- Colchicine
- Anakinra
- Methotrexate
