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Rheumatology > Sjogrens + Crystal > Flashcards

Sjogrens + Crystal Flashcards

1
Q

HLA association in primary sjogrens?

A

HLADR52

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2
Q

Causes of secondary sjogrens?

A
  • 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)
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3
Q

Clinical features of Sjogren’s

A

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

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4
Q

Investigations for sjogrens

A
  • 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

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5
Q

Treatment for sjogrens

A
  • 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

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6
Q

Complications of sjogrens

A
  • 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
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7
Q

Pathophysiology of sjogrens

A

Biopsy have shown inflammatory infiltrates composed of CD4 positive T lymphocytes.

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8
Q

What malignancy has an increased risk in Sjogrens?

A

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
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9
Q

What factors in sjogrens leads to worse prognosis

A
  • 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
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10
Q

What autoimmune disease are normally associated with Sjogren?

A

SLE
RA
Autoimmune thyroiditis

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11
Q

Normal process of purine catabolism

A
  • Purine catabolism –> hypoxanthine –> xanthine oxidase converts hypoxanthine to xanthine and then uric acid
  • Humans lack urate oxidase to convert allantoic acid
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12
Q

What does serum urate concentration depend on?

A

Intrinsic purine production
Purine intake through diet
Excretion - renal and GIT

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13
Q

Difference between allopurinol and rasburicase.

A
  • 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
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14
Q

Primary causes of urate overproduction

A

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.

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15
Q

Secondary causes of urate overproduction

A

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
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16
Q

Dietary causes of urate overproduction

A
  • 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

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17
Q

Primary causes of urate underexcretion

A

Renal urate transporter mutations

  • ABCG2 loss of function: decreased renal and gastrointestinal excretion
  • URAT1 gain of function: increased reabsorption in kidney
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18
Q

Secondary causes of urate underexcretion

A

CKD

Medications: thiazide, loop diuretics, aspirin, pyrazinamide, ciclosporin, niacin (vitamin B3)

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19
Q

Cytokine involved in gout

A

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.
20
Q

Location of first gout flare

A

Usually monoarticular

1st MTP involvement most common (podagra)

21
Q

Chronic gouty arthritis

A

Chronic synovitis can occur secondary to MSU crystal mediated inflammation, can be polyarticular and mimic arthritis

22
Q

Diagnosis of gout

A

(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)
23
Q

Management of gout flare

A
  • NSAID, COX2 inhibitor (eg: celecoxib)
  • Prednisone
  • Colchicine
  • Intraarticular corticosteroid injection
24
Q

Urate lowering therapy

A

(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

25
Q

What urate levels are aimed for in gout?

A

<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

26
Q

MOA, adverse effects and drug interactions of allopurinol

A

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
27
Q

MOA, Contraindications, SE, drug interactions of febuxostat

A
  • 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

28
Q

MOA, SE and drug interactions of probenecid and benzbromarone

A

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

29
Q

Drug interactions of febuxostat and allopurinol

A

Purine analogues (azathioprine and mercaptopurine) combined with xanthine oxidase inhibitors can cause bone marrow toxicity.

30
Q

MOA + SE of colchicine

A

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

31
Q

What metabolic disease are associated with pseudogout (calcium pyrophosphate deposition disease)/pathogenesis.

A

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
32
Q

Investigations of CPPD

A
  • 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

33
Q

Calcium phosphate deposition disease

A
  • 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

34
Q

When is anti Ro elevated?

A
  • sjogrens
  • primary biliary cirrhosis
  • SLE
35
Q

Causes of gout (PM)

A

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
36
Q

Cryo and sjogrens

A

Normally type 2

37
Q

What is the renal handing of urate

A

-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

38
Q

Causes of impaired renal clearance of urate

A
  • 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
39
Q

Urate and cardiovascular disease

A
  • 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
40
Q

Gout and CKD

A
  • Gout and hyperuricemia associated with CKD

- Gout is associated with progression with CKD

41
Q

Interaction between urate crystals and the inflammatory stem

A

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
42
Q

What can also cause negatively birefringent crystals?

A

Betamethasone crystals mimic monosodium urate crystals

43
Q

MOA of colchicine

SE

A

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

44
Q

Biological therapy for gout

A

Agents will inhibit IL-1b

  • Anakinra
  • Canakinumab
45
Q

Treatment for pseudogout

A

Acute: same as gout

Chronic/Recurrent

  • Colchicine
  • Anakinra
  • Methotrexate

Rheumatology (9 decks)

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