CRYSTAL-INDUCED ARTHRITIS

A variety of crystals can deposit in and around joints and cause an acute inflammatory
arthritis, as well as more chronic arthritis associated with progressive joint damage,
Crystals can be the primary pathogenic agent, as in gout, or an accessory factor, as in
calcium pyrophosphate deposition disease, in which crystals are deposited in joints that are
already abnormal. Examples of these crystals are

Gout
Gout is an inflammatory disease caused by deposition of monosodium urate monohydrate
crystals in and around synovial joints. The prevalence of gout varies between populations
but is approximately 1–2%, with a greater than 5 : 1 male preponderance. It is the most
common inflammatory arthritis in men and in older women. The risk of developing gout
increases with age and with serum uric acid (SUA) levels, which are normally distributed in

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the general population. Levels are higher in men, increase with age and are associated with
body weight.

Pathophysiology

About one-third of the body uric acid pool is derived from dietary sources and two-thirds
from endogenous purine metabolism.

The concentration of uric acid in body fluids depends on the balance between endogenous
synthesis, and elimination by the kidneys (two-thirds) and gut (one-third). Purine
nucleotide synthesis and degradation are regulated by a network of enzyme pathways.
Xanthine oxidase catalyses the end conversion of hypoxanthine to xanthine and then
xanthine to uric acid. The causes of hyperuricaemia are

Clinical features

The classical presentation is with an acute monoarthritis, which in over 50% of cases affects
the first MTP joint Other common sites are the ankle, midfoot, knee, small joints of hands,
wrist and elbow. The axial

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skeleton and large proximal joints are rarely involved.Typical features include:

• rapid onset, reaching maximum severity in 2–6 hours, and often waking the patient in the
early morning

• severe pain, often described as the ‘worst pain ever’

• extreme tenderness, such that the patient is unable to wear a sock or to let bedding rest
on the joint

• marked swelling with overlying red, shiny skin

• self-limiting over 5–14 days, with complete resolution.

During the attack, the joint shows signs of marked synovitis, swelling and erythema. There
may be accompanying fever, malaise and even confusion, especially if a large joint such as
the knee is involved. As the attack subsides, pruritus and desquamation of overlying skin

are common. The main differential diagnosis is septic arthritis, infective cellulitis or reactive
arthritis. Acute attacks may also manifest as bursitis, tenosynovitis or cellulitis, which have
the same clinical characteristics.

Many patients describe milder episodes lasting just a few days. Some have attacks in more
than one joint. Others have further attacks in other joints a few days later (cluster attacks),
the first possibly acting as a trigger. Simultaneous polyarticular attacks are unusual.

Some people never have a second episode after an acute attack. In others, several years
may elapse before the next attack. In many, however, a second attack occurs within 1 year
and may progress to chronic gout, with chronic pain and joint damage, and occasionally

severe deformity and functional impairment. Patientswith uncontrolled hyperuricaemia

who suffer multiple attacks of acute gout may also progress to chronic gout. Crystals may
be deposited in the joints and soft

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tissues to produce irregular firm nodules called tophi. These have a predilection for the
extensor surfaces of fingers, hands, forearm, elbows, Achilles tendons and sometimes the
helix of the ear. Tophi have a white

colour, differentiating them from rheumatoid nodules Tophi can ulcerate, discharging
white gritty material, become infected or induce a local inflammatory response, with
erythema and pus in the absence of secondary infection. They are usually a feature of long-
standing gout but can sometimes develop within 12 months in patients with chronic renal
failure. Occasionally, tophi may develop in the absence of previous

acute attacks, especially in patients on thiazide therapy who have coexisting OA. In addition
to causing musculoskeletal disease, chronic hyperuricaemia may be complicated by renal
stone formation and, if severe, renal impairment due to the development of interstitial
nephritis as the result of urate deposition in the kidney. This is particularly common in
patients with chronic tophaceous gout who are on diuretic therapy.

Investigations

The diagnosis of gout can be confirmed by the identification of urate crystals in the aspirate
from a joint, bursa or tophus In acute gout, synovial fluid shows increased turbidity due to
the greatly elevated cell count (> 90% neutrophils). In chronic gout, the appearance is more
variable but occasionally the fluid appears white due to the high crystal load. Between
attacks, aspiration of an asymptomatic first MTP joint or

knee may still reveal crystals. A biochemical screen, including renal function, uric acid,
glucose and lipid profile, should be performed

because of the association with metabolic syndrome. Although hyperuricaemia is usually

present, this does not confirm the diagnosis. Conversely, normal uric acid levels during an
attack do not exclude gout, as serum urate falls during the acute phase response. Elevated
ESR and CRP and a neutrophilia are typical of acute gout, and they return to normal as the

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attack subsides. Tophaceous gout may be accompanied by a modest but chronic elevation
in ESR and CRP. Radiographs are usually normal in acute gout but well-demarcated erosions
may be seen in patients with chronic or tophaceous gout Tophi may also be visible on X-
rays as soft tissue swellings. In late disease, destructive changes may occur similar to those
in other forms of advanced inflammatory arthritis.

Management

1-Oral NSAIDs

Oral NSAIDs are effective for pain relief in the acute attack and are the standard treatment,
but have to be prescribed with caution in old age.

. Patients with recurrent episodes can keep a supply of an NSAID and take it as soon as the
first symptoms occur, continuing until the attack resolves.

2-Oral colchicine,

Oral colchicine, which works by inhibiting microtubule assembly in neutrophils, is also very
effective. It is usually given in doses of 0.5 mg twice or 3 times daily. The most common
adverse effects are nausea, vomiting and diarrhoea.

3-Joint aspiration

Can give pain relief, and may be combined with an intraarticular

steroid injection if the diagnosis is clear and infection can be excluded.

4-corticosteroid

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A short course of oral or intramuscular corticosteroids can also be highly effective in
treating acute attacks.

5-urate-lowering therapy

Patients who have more than one acute attack within 12 months and those with
complications should be offered urate-lowering therapy

Indications are

• Recurrent attacks of acute gout

• Tophi

• Evidence of bone or joint damage

• Renal impairment

• Nephrolithiasis

• Very high levels of serum uric acid

The longterm therapeutic aim is to prevent attacks occurring by bringing uric acid levels
below the level at which monosodium urate monohydrate crystals form. A therapeutic
target of 360 μmol/L (6 mg/dL) . Agents used are

A-Allopurinol

Allopurinol is the drug of first choice. It is a xanthine oxidase inhibitor, which reduces the
conversion of hypoxanthine and xanthine to uric acid. The recommended starting dose is
100 mg daily, or 50 mg in older patients and in renal impairment. The dose of allopurinol
should be increased by 100 mg every 4 weeks (50 mg in the elderly and those with renal
impairment) until the target uric acid level is achieved, side-effects occur or the maximum

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recommended dose is reached (900 mg/day). Acute flares of gout often occur following
initiation of urate-lowering therapy. The patient should be warned about this and told to
continue therapy, even if an attack occurs. The risk of flares can be reduced by
administration of oral colchicine (0.5 mg twice daily) or NSAID therapy for the first few
months. In the longer term, annual monitoring of uric acid levels is recommended. In most
patients, urate-lowering therapy needs to be continued indefinitely.

B-Febuxostat is a xanthine oxidase inhibitor that is useful in patients who fail to respond
adequately to allopurinol, and those in whom it is contraindicated or has been poorly
tolerated. It undergoes hepatic metabolism and so no dose adjustment is required for renal
impairment. It is more effective than allopurinol at reducing uric acid levels and, as a result,
commonly provokes attacks at the recommended starting dose (80 mg daily). In view of
this, treatment with colchicine or NSAID should be considered for the initial 6 months.

C-Uricosuric drugs, such as probenecid or sulfinpyrazone,

can be effective but require several doses each day and maintenance of a high urine flow to
avoid uricacid crystallisation in renal tubules. Salicylates antagonize the uricosuric action of
these drugs and should be avoided. Uricosurics are contraindicated in overproducers, those
with renal impairment and in urolithiasis (they increase stone formation). The uricosuric
benzbromarone can be very effective and safe in mild to

moderate renal impairment, but can cause hepatotoxicity.

D-Pegloticase

is a biological treatment in which the enzyme uricase has been conjugated to

monomethoxypolyethylene glycol. It is indicated for the treatment of tophaceous gout
resistant to standard therapy.

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In addition to drug treatmentLocal ice packs can also be used for symptomatic
relief,predisposing factors should be corrected if possible. Patients should be advised to
lose weight where appropriate and to reduce excessive alcohol intake, especially beer.
Thiazide diuretics should be stopped if possible and substituted with

angiotensin-converting enzyme (ACE) inhibitors, as these have a uricosuric effect. Patients

should be advised to avoid large amounts of seafood and offal, which have a high purine
content, but a highly restrictive diet is notnecessary.

Calcium pyrophosphate dihydrate

crystal deposition disease

This condition is associated with deposition of calciumpyrophosphate dihydrate (CPPD)
crystals within articular and hyaline cartilage and is sometimes known as‘pseudogout’. It is
rare under the age of 55, but occurs in 10–15% of people between the ages of 65 and 75
years and in 30–60% of those over 85. The knee (hyaline cartilage and menisci) is by far the
most common site, followed by the wrist (triangula fibrocartilage) and pelvis (symphysis
pubis). Risk factors are

Common

• Age

• Osteoarthritis

• Primary hyperparathyroidism

Rare

• Familial

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• Haemochromatosis

• Hypophosphatasia

• Hypomagnesaemia

In many patients, chondrocalcinosis is asymptomatic and an incidental finding on X-ray

examination, but others present with an acute inflammatory arthritis (pseudogout) or a
chronic inflammatory arthropathy superimposed on a background of OA, especially at the

knee associated with joint damage and functional limitation.

Clinical features

A common presentation is with an acute inflammatory arthritis that resembles acute gout,
sometimes termed ‘pseudogout’. Examination reveals a warm, tender erythematous joint
with signs of a large effusion. Fever is common and the patient may appear confused and
ill. The knee is most commonly affected, followed by the wrist, shoulder, ankle and elbow.
Trigger factors include trauma, intercurrent illness and surgery. Sepsis and gout are the
main differential diagnoses. Chronic arthropathy may also occur in association with CPPD
crystal deposition disease, affecting the same joints that are involved in acute pseudogout.
The presentation is with chronic pain, early morning stiffness, inactivity gelling and
functional impairment. Acute attacks of pseudogout may be superimposed. Affected joints
usually show features of OA, with varying degrees of synovitis. Effusion and synovial
thickening are usually most apparent at knees and wrists; wrist involvement may result in
carpal tunnel syndrome. Inflammatory features may be sufficiently pronounced to suggest
RA, but tenosynovitis and extra-articular involvement are absent, and large and medium

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rather than small joints are targeted. Severe damage and instability of knees or shoulders
may occasionally lead to consideration of a neuropathic joint, but no neurological
abnormalities will be found.

Investigations

Examination of synovial fluid using compensated polarized microscopy will demonstrate

CPPD crystals and permit distinction from gout. The

aspirated fluid is often turbid and may be uniformly blood-stained, reflecting the severity of
inflammation. Since sepsis and pseudogout can coexist, Gram stain and culture of the fluid
should be performed to

exclude sepsis, even if CPPD crystals are identified in synovial fluid.

X-rays of the affected joint may show evidence of calcification in hyaline cartilage and/or
fibrocartilage, although absence of calcification does not exclude the diagnosis. Signs of OA
are frequently present. Screening

for secondary causes should be undertaken, especially in patients who present under the
age of 25 and those with polyarticular disease.

Management

Joint aspiration can often provide symptomatic relief in pseudogout and sometimes no
further treatment is required. Patients with persistent symptoms can be treated with intra-
articular corticosteroids, colchicine

or NSAID. Since most patients with pseudogout areelderly, NSAID must be used with
caution. Early active mobilisation is also important. Chronic pyrophosphateinduced
arthropathy should be managed as for OA

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