Kuzmіna G.P.,LazarenkoO.M., Kniazieva O.V.
State
Establishment «Dnipropetrovsk Medical Academy»
Current issues
in the diagnosis and treatment of gout
Gout
is a heterogeneous disorder that results in the deposition of uric acid salts
and crystals in and around joints and soft tissues or crystallization of uric
acid in the urinary tract. Gout metabolic disorder characterized by hyperurecamia
(normal plasma urate 1-4mg/dl). Acute gout: sudden onset of severe
inflammation in the small joint due to precipitation of urate crystals in the
joint space. Chronic gout: pain and stiffness persist in the joint between
attacks [12].
Epidemiology. Gout
is the most common of microcrystalline arthropathy. Incidence has increased
significantly over the past few decades [1].Affects about 2.1 million worldwide
[12].Peak incidence occurs in the fifth decade, but can occur at any age [1].Gout
is 5 times more common in males than pre-menopausal females; incidence in women
increases after menopause. After age 60, the incidence in women approaches the
rate in men [12].People of South Pacific origin have an increased incidence
[1].
Predisposing Factors: heredity,
drug usage, renal failure, hematologic disease, trauma, alcohol use, psoriasis,
poisoning, obesity, hypertension, organ transplantation, surgery[2, 3].
Stages of Classic Gout
Asymptomatic hyperuricemia. Very common
biochemical abnormality. Defined as 2 SD above mean value. Majority of people
with hyperuricemia never develop symptoms of uric acid excess [5].
Acute Intermittent Gout (Gouty
Arthritis). Episodes of acute attacks. Symptoms may be confined to a single
joint or patient may have systemic symptoms [5].
Intercritical Gout. Symptom free period
interval between attacks. May have hyperuricemia and monosodium urate crystals
in synovial fluid [14].
Chronic Tophaceous Gout. Results from
established disease and refers to stage of deposition of urate, inflammatory
cells and foreign body giant cells in the tissues. Deposits may be in tendons
or ligaments. Usually develops after 10 or more years of acute intermittent
gout [12].
Pathogenesis. Urate
crystals stimulate the release of numerous inflammatory mediators in synovial
cells and phagocytes [4].The influx of neutrophils is an important event for
developing acute crystal induced synovitis [4].Chronic gouty inflammation
associated with cytokine driven synovial proliferation, cartilage loss and bone
erosion [3].
Criteria for the classification of
acute gouty arthritis[7, 12]
A.
Presence of characteristic urate crystals in the joint fluid or ...
B.
A torphus proven to contain gouty crystals or...
C.
Presence of 6 or more of 12 clinical/ lab:
1. >1 attack;
2. maximal inflammation developed within 1 day;
3. attack of monoarticular arthritis;
4. joint redness observed;
5.
1st MTP joint painful or swollen;
6. unilateral attack involving IяMTP
joint;
7. unilateral attack involving tarsal joint;
8. suspected tophus;
9. hyperuricaemia;
10. asymmetrical swelling within a joint (X-ray);
11. subcortical cysts without erosions (X-ray);
12. negative culture from joint fluid during
attack.
Clinical manifestations
Systemic:fever
rare but patients may have fever, chills and malaise [12].
Musculoskeletal:Acute onset of monoarticular joint pain. First MTP
most common. Usually affected in 90 % of
patients with gout. Other joints knees, footandankles.
Less common in upper extremities [6].
Skin:warmth, erythema and tenseness of
skin overlying joint. May have pruritusand
desquamation [5, 12].
Kidney:Renal colic with renal calculi
formation in patients with hyperuricemia is frequent [5, 8].
Investigations[8, 12]
-
Uric Acid. Limited value as majority
of hyperuricemic patients will never develop gout. Levels may be normal during
acute attack.
-
CBC. Mild leukocytosis in acute
attacks, but may be higher than 25 000/mm.
-
ESR. Mild elevation.
-
24hr urine uric acid. Only useful in
patients being considered for uricosuric therapy or if cause of
marked hyperuricemia needs investigation.
-
Trial of colchicines. Positive
response may occur in other types of arthritis to include pseudogout.
Differential
diagnosis: bursitis,
calcium pyrophosphate dihydrate crystal deposition disease (CPPD, pseudogout),
osteoarthritis, osteomyelitis, psoriatic arthritis, rheumatoid arthritis, septic
arthritis, synovitis, tendinitis, traumatic arthritis [9].
Treatment and management
EULAR evidence based recommendations
for gout
1. Every
person with gout should be fully informed about the pathophysiology of the
disease, the existence of effective treatments, associated comorbidities and
the principles of managing acute attacks and eliminating urate crystals through
lifelong lowering of serum uric acid(SUA) level below a target level
[10].
2. Optimal
treatment of gout requires both non-pharmacological and pharmacological
modalities and should be tailored according to:
a. specific
risk factors (levels of serum urate, previous attacks, radiographic signs) [11];
b. clinical
phase (acute/recurrent gout, intercritical gout, and chronic tophaceous gout)
[12];
c. general
risk factors (age, sex, obesity, alcohol consumption, urate raising drugs,drug
interactions, and comorbidity) [11, 12].
3. Patient
education and appropriate lifestyle advice regarding weight loss if obese,
diet, and reduced alcohol
(especially beer) are core aspects of management [11,
12].
4. Associated
comorbidity and risk factors such as hyperlipidaemia, hypertension,
hyperglycaemia, obesity, and smoking should be addressed as an important part
of the management of gout [11, 12].
5. The choice
of drug (s) should be based on the presence of contraindications, the patient’s
previous experience with treatments, time of initiation after flare onset and
the number and type of joint(s) involved [10].
6. Recommended
first-line options for acute flares are colchicine (within 12 hours of flare
onset) at a loading dose of 1 mg followed 1 hour later by 0.5 mg on day 1
and/or an non-steroidal
anti-inflammatory drugs(NSAID), oral corticosteroid (30–35
mg/day of equivalent prednisolone for 3–5 days) or articular aspiration and
injection of corticosteroids. Colchicine and NSAIDs should be avoided
in patients with severe renal impairment. Colchicine should not be given to
patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors such as
cyclosporin or clarithromycin [10].
In Ukraine,
as an alternative to colchicine, homvio-revman used for long-term treatment.
7. In
patients with frequent flares and contraindications to colchicine, NSAIDs and
corticosteroid (oral and injectable), IL-1 blockers should be considered for treating
flares [10].
8. Recommended
prophylactic treatment is colchicine, 0.5–1 mg/day, a dose that should be
reduced in patients with renal impairment [10].
9. Intra-articular
aspiration and injection of long acting steroid is an effective and safe
treatment for an acute attack [12].
10. The
therapeutic goal of urate lowering therapy is to promote crystal dissolution
and prevent crystal formation; this is achieved by maintaining the serum uric
acid below the saturation point for monosodium urate (<360 µmol/1) [10].
11. In
patients with normal kidney function, allopurinol is recommended for first-line
urate-lowering
therapy (ULT), starting at a low dose (100 mg/day) and
increasing by 100 mg increments every 2–4 weeks if required, to reach the
uricaemia target. If the SUA target cannot be reached by an appropriate dose of
allopurinol, allopurinol should be switched to febuxostat or a uricosuric or
combined with a uricosuric. Febuxostat or a uricosuric are also indicated if allopurinol
cannot be tolerated [10].
12. When gout
associates with diuretic therapy, stop the diuretic if possible: for
hypertension and hyperlipidaemia consider use of losartan and fenofibrate,
respectively [12].
Classification of drugs for the
treatment of Acute Gout (Figure 1)
•
NSAIDs. Dose of NSAIDs for acute
attack of gout: NSAIDs in high doses taken with food are: Naproxen – 750 mg
immediately, then 500 mg every 8-12 hours. Diclofenac: 75-100 mg immediately,
then 50 mg every 6-8 hours. Indomethacin: 75 mg immediately, then 50 mg every
6-8 hours. After 24-48 hours, reduced doses are given for a further week.
Contraindications: active peptic ulcer disease/impaired renal function/allergy
to NSAIDs [11].
•
Colchicine.Colchicine is alkaloid
from Colchicum autumnale. Suppresses gouty inflammation neither analgesic nor
anti-inflammatory. No effect on blood uric acid level [13].
Treatment
of Acute attack: effective within first 24h of attack. A small dose (0.5-1.5
mg) taken at first symptom of attack abort it. Dose: lmg PO followed by 0.25 mg
1-3 hourly till the acute attack is over or total dose of 6 mg is given or diarrhea
starts. Maintenance dose 0.5-1 mg/day for 4-8 weeks. Prophylaxis of gout: 0.5-1
mg/day (prevents further attack). Doses should be decreased in renal and
hepatic dysfunction [12].
•
Corticosteroid. Corticosteroid gives
dramatic symptomatic relief. Used if NSAIDs are contraindicated, if Gout is
monoarticular: intra-articular administration (e.g., triamcinolone, 10-40 mgdepending
of size of joint). For Polyarticular gout: IV or Orally Methylprednisolone 40
mg/day IV tapered over 7 days. Prednisolone 40-60 mg/day orally tapered over 7
days [12].
Figure
1. Algorithm for the medical treatment
of acute gout. PPI: proton pump inhibitor [12].
NSAID
or COX-2(consider PPI)orColchicineorCorticosteroid (oral, i.m. and IA)
Aspriate joint if diagnosis is unclear or
suspicion of infection
Drugs for Chronic gout(Figure
2)
•
Probenecid. Probenecid Uses: Chronic
gout and hyperuricaemia: (2ndline/ adjuvant drug) 0.5 g/dayinitially,
with gradual increase to 1-2 g daily. It gradually lowers blood urate level. Ineffective
in the presence of renal insufficiency (serum creatinine >2 mg/dl). Adverse
effects: rashes, allergic dermatitis, upper GIT irritation, and drowsiness.
Inhibits excretion of penicillin, dapsone indomethacin, and acetazolamide [11].
•
Sulfinpyrazone. Sulfinpyrazone Uses:
In chronic gout: start with 100-200 mg BD, gradually increatseaccording to
response (max. dose 800 mg/d). Uricosuric action is additive with probenecid
but antagonized by Salicylates. It inhibits platelet aggregation. Adverse
effects: gastric irritation/rashes/ hypersensitivity reaction [12].
•
Uric acid synthesis inhibitor
Allopurinol. Competitive inhibitor of uric
acid synthesis by inhibiting xanthine oxidase.
Xanthine oxidase is involved in the metabolism of hypoxanthine and
xanthine to uric acid. Promptly lowers plasma urate and urinary uric acid
concentration and facilitates tophus mobilization. Allopurinol is very
effective in uric acid overproducers. Dose: initially 100 mg/d of allopurinol
is given for 1 week, the dose is increased to 200-300 mg/d, if serum uric acid
is still high. ADRs: precipitation of acute gouty arthritis in the initial
month of therapy/Gl upset/skin rash/alopecia. Probenecid increases the
excretion of allopurinol. If patient taking both Probenecid and Allopurinol,
than increase dose of allopurinol and decrease dose of Probenecid [13].
At
this time, the question remains to optimize treatment methods and prevention of
not onlygout exacerbations but also аsymptomatic hyperuricemia, which increases the risk of
cardiovascular diseases. Perhaps the solution to this
problem will, in the future, identification of genes that affect the propensity
to develop gout in patients with аsymptomatic hyperuricemia, search for new drugs, which
become the target genetic loci.
Figure 2. Algorithm for the medical treatment of
chronic gout [12].
Chronic treatment If comorbidities
are present use losartan and fenofibrate Prophylactic cover of colchicines (0.5 mg b.d. for
6 months) or NSAID (low dose for 6 weeks) Titration of allopurinol up to 900 mg/day against
SUA and renal function Aiming SUA 0.30 mmol/l Contraindication (CI) or AEs and normal renal
function CI or AEs and abnormal renal function Failure to reach target SUA and no CI/AEs Febuxostat Sulphinpyrazone Probenecid Febuxostat Benzbromarone Benzbromarone Renal impairment No renal impairment Benzbromarone Benzbromarone Sulphinpyrazone Probenecid Lifestyle advice about diet and alcohol intake
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