Crystal-Induced Arthropathies

Learning Objectives

At the end of this session the participant will be able to:

Describe crystal deposition disorder.
Discuss the clinical presentation, causes, relevant diagnostic tests, and management of gout.
Discuss the clinical presentation, causes, relevant diagnostic tests, and management of Calcium Pyrophosphate Dihydrate (CPPD) Deposition Disease.
Discuss the clinical presentation, causes, relevant diagnostic tests, and management of Basic Calcium Phosphate (BCP) Deposition Disease.
Discuss the clinical presentation, causes, relevant diagnostic tests, and management of Oddball Crystals.
Discuss future directions for crystal-induced arthropathies.

Introduction

Crystal deposition can occur in articular and peri-articular tissues
Crystalline arthritis can be acute or chronic and involve multiple joints
Inflammation is due to the interaction between phagocytes and crystals
It is important to distinguish crystal deposition from infection, trauma, tumor, and degenerative arthritis

Overview

Type of Crystal and Related Disorder

Monosodium urate
- Gout
Calcium pyrophosphate
- Pseudogout
Basic calcium phosphate (hydroxyapatite)
- Calcific periarthritis Subacute arthritis “Milwaukee” shoulder

Gout

An inflammatory process in joints or peri-articular tissue

Results from tissue deposition of monosodium urate crystals (MSU)

Prevalence

Predominantly a disease of adult men
Rare in pre-menopausal women
Incidence is increasing
Prevalence is ̴9-14 per 1000

Reference

Arromdee et al. (2002)

Mikuls et al. (2005)

Definitions

Purines – bases derived from dietary and endogenous sources
Uric acid (urate) – the natural end product of purine metabolism
Stays soluble in plasma to 6.7 mg/dL
Largely excreted by the kidneys
Hyperuricemia – best defined as a serum uric acid level ≥ 6.8 mg/dL

Hyperuricemia

Humans lack uricase which oxidizes insoluble uric acid to the much more soluble allantoin.

Yet not all hyperuricemic patients develop gout. The 5 year cumulative incidence of gout in all patients with serum urate >7 mg/dL is 19%. The cumulative incidence with serum urate >9 mg/dL increases to 61%. (Lin et al., 2000)

A growing number of adults have serum urate values at or above the level of solubility.

Causes of Hyperuricemia

Underexcretion of uric acid by the kidney is the most common cause of hyperuricemia.

Seen often in:

renal insufficiency from diabetes, hypertension
lactic acidosis, ketoacidosis
diuretic use
dehydration
cyclosporine
lead poisoning

Mixed

alcohol overuse (mainly beer)

Pathogenesis of Gout

Once the limit of solubility is exceeded, urate crystallizes as a monosodium salt in synovial tissue, on the surface of cartilage, and ultimately in joint fluid.

Urate crystals activate inflammatory cells which initiates the acute gouty process.

Neutrophil migration into the joint appears to be the most important event in this process.

Pro-inflammatory cytokines in the joint enter the circulation and account for the systemic features experienced by gout sufferers.

Acute Gout: Clinical Presentation

An acute attack of intense pain – usually in lower extremity joints – following trauma, dietary indiscretion, dehydration, or acidosis.

Twinges of discomfort progress to severe pain over 8-10 hours with clinical evidence of synovitis.

Commonly affects the great toe (podagra), knee, mid-foot, wrist, and elbow. Rare reports in the spine.

Other Features of Acute Gout

Fever, chills accompany gout in a third of attacks.
Serum urate levels fall during acute gout, often resulting temporarily in a “falsely normal” value.
Weight bearing is often impossible with the acutely inflamed joint.
Attacks last for 4 to 8 days in the early phases and up to 2 weeks as time passes.

Reference

Urano et al. (2002)

Advanced Gout

With time and sustained hyperuricemia, gout can become polyarticular.
Renal stones occur in 25% of gouty patients.
Subcutaneous tophi can develop over extensor surfaces. These are firm nodules of urate crystals surrounded by a foreign body granuloma.
Chronic tophaceous gout can develop within the joints causing erosions and deformity.
Tophi, chronic pain, and deformities are the cardinal features of advanced gout.

Reference

Edwards (2007)

Making the Diagnosis

Presumed gout – a “soft” diagnosis based on a history of acute, intermittent, monoarthritis in the setting of hyperuricemia with or without a clinical response to colchicine

Definitive gout – microscopically proven MSU crystals in synovial fluid or tophi

In the acute attack, these are intracellular, needle shaped crystals with strong negative birefringence

Small, “chewed up” extracellular crystal fragments are seen late in attacks or between attacks

Lab Findings

Elevated synovial fluid WBC noted in most infectious and crystal induced arthritis
Crystals observed in synovial fluid do not rule out infection
Fluid culture and examination under a polarized light microscope is essential to confirm diagnosis
Elevated sedimentation rate (often impressive) is seen in acute gout but has no specificity
Synovial fluid analysis is the best way to make the diagnosis of gout or any other inflammatory arthritis
Cell count, culture, and crystal analysis (the 3 C’s) under a polarizing light microscope
Serum urate level (remember – this might be low during a flare)
Serum glucose, lipids, and creatinine to look for disease associations with gout

Radiographic Findings

Assess bone and joint damage using plain radiographs
Early inflammatory processes do not destroy joints
Classic mid to late stage findings: “overhanging edges” and asymmetric destruction

Treatment

Acute Therapy

Goal – rapid relief of pain and inflammation. Acute gout will respond to the following therapies if started within the first 24-36 hours of the attack.

Approaches

NSAIDs – most commonly used
Colchicine – poorest benefit to adverse event ratio
Corticosteroids – can be given orally, intramuscularly, intraarticularly
ACTH gel - subcutaneous

Examples of Therapeutic Approaches

Naproxen 500 mg immediately and every 6 hours for the first day. Then 500 mg BID for 7-10 days (continue at least 3 days after symptoms resolve).
Colchicine 0.6 mg orally hourly times 3 doses then every 8 hours for the next 48 hours. Maintain on BID until 3 days after resolution.
Prednisone orally starting at 30 mg per day and tapering by 5 mg every other day (order is based on .5 mg/kg of patient’s weight, with tapering individualized per clinical judgment)
Triamcinolone 60 mg IM immediately followed by naproxen 375 mg BID for 7-10 days
ACTH-gel 80 IU subcutaneously. May be repeated in 12 hours if any symptoms persist.

Chronic Therapy

Goal

Maintaining patient in a symptom-free state while reducing serum urate to less than 6.0 mg/dL

Maintenance anti-inflammatory therapy: low dose daily NSAID or colchicine 0.6 mg QD-BID until the goal is met for several months

Urate lowering therapy (ULT)

Life long commitment to therapy
Block uric acid production (allopurinol)
Enhance renal excretion of uric acid (probenecid)

Urate Lowering Drugs

Allopurinol

A xanthine oxidase inhibitor) is currently the best urate lowering therapy available to achieve serum uric acid levels below 6.0 mg/dL

Dosed once daily (100-800 mg per day)
Caution in renal and hepatic insufficiency

Probenecid

A uricosuric agent) requires BID or TID dosing and loses effect as renal function declines.

Dose range: 500 mg BID to 1000 mg TID

Best Urate Lowering Strategy

Begin with allopurinol at 100 mg a day

Hold the dose there for 3 weeks

Repeat a serum urate level and titrate dose up by 50-100 mg. Repeat this step until treatment goal is achieved.

Goal is a serum uric acid of < 6.0 mg/dL

Reference

Hahn & Edwards (2005)

Many Medications Have Mild but Real Effects on Lowering Serum Uric Acid

Carefully prescribing medications not generally used to specifically lower serum uric acid but which do lower those levels can provide an alternative approach

The list is long but, losartan, the anti-hypertensive agent, and fenofibrate, the lipid lowering agent, are most notable

For a rather impressive list of these agents, please consult: Daskalopoulou, S. S., Tzovaras, V., Mikhailidis, D. P., & Elisaf, M. (2005). Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Current Pharmaceutical Design, 11(32), 4161-4175.

Non-Pharmacologic Approaches to Urate Lowering

Lifestyle modifications

Weight loss
Low purine diet
Abstinence from alcohol
Management of co-morbidities is essential

High Purine Foods

To reduce dietary purine burden, high purine foods should be avoided:
Shellfish (clams, lobster, mussels, oysters, scallops, shrimp)
Small fish (anchovies, herring, sardines)
Organ meats (brains, heart, kidney, liver, sweetbreads)
Beer

Reference

Choi et al. (2004a)

Choi et al. (2004b)

Calcium Pyrophosphate Dihydrate (CPPD) Deposition Disease

This form of crystalline arthropathy is manifested by CPPD deposition in cartilage and synovial tissues and marked heterogeneity of clinical presentations.

Chondrocalcinosis occurs in 10-27% of the population and increases with age. Symptomatic CPPD Deposition Disease occurs in 1-5 per 1000 population.

Factors/conditions strongly associated with CPPD

Aging
Osteoarthritis
Gout
Hemochromatosis
Hyperparathyroidism
Hypermagnesimia
Hypophosphatasia

Reference

Rosenthal (2006)

Clinical Presentation of CPDD Deposition Disease

Acute mono-arthritis (pseudogout)
Polyarticular noninflammatory arthritis (pseudo OA)
Polyarticular inflammatory arthritis (pseudoRA)
Neuropathic-like joint destruction (pseudo-Charcot)
Asymptomatic

Reference

Rosenthal (2006)

CPDD Deposition Disease: Diagnosis

Synovial Fluid Analysis

Rhomboid or rectangular shaped crystals with weak positive birefringence
Dominant cell type – neutrophils

Classic X-ray finding

Punctate linear deposits of CPPD crystals in the menisci and cartilage called chondrocalcinosis

CPDD Deposition Disease: Treatment

No therapy is available to deplete the crystal burden.
Non-steroidal anti-inflammatory agents moderate symptoms.
Oral colchicine is effective as well.
Intra-articular corticosteroids often help in acute setting.

Basic Calcium Phosphate (BCP) Deposition Disease

Caused by deposition of calcium phosphate crystals (hydroxyapatite) in cartilage and peri-articular structures such as tendons.
Seen more commonly in older women.
Marked variability of clinical presentations.

Clinical Manifestations of BCP Deposition Disease

Non-inflammatory destructive arthropathy
- “Milwaukee” shoulder
Acute inflammatory arthritis
- gout or pseudogout
Acute calcific periarthritis
- hips and shoulders in middle-aged and older women
Osteoarthritis with BCP crystals
- accelerated joint destruction in OA
Diffuse Idiopathic Skeletal Hyperostosis (DISH)
- elderly or middle-age men
- may be asymptomatic

Reference

Jaovisidha & Ryan (2006)

Lab Features

No helpful serum biomarkers.
Synovial fluid is generally non-inflammatory.
BCP crystals are not birefringent and can not be seen by regular microscopy unless in clumps (“shiny coins”). These clumps will stain with alizarin red S stain.
Can co-exist with CPPD Deposition Disease.

BCP Deposition Disease: Treatment

“Milwaukee” shoulder

Treatment is generally unsatisfactory because of the degree of destruction at diagnosis
NSAIDs and intra-articular steroids may be helpful
Repeat aspiration and physical therapy are often necessary

Acute inflammatory arthritis and periarthritis

NSAIDs and oral colchicine are standard approach
Ice may also be helpful

Diffuse Idiopathic Skeletal Hyperostosis (DISH)

NSAIDs and other simple analgesics for symptomatic patients
Occasionally requires osteophytectomy

Oddball Crystals

Cholesterol Crystals

Not phagocytized nor associated with inflammation
Found in chronic effusions, especially bursal

Calcium Oxalate Crystals

Appear as envelopes or double-pyramids and stain with alizarin red S stain
Found in renal failure associated arthropathy

Future Directions for Crystal-Induced Arthropathies

On the Horizon

Clinical trials are ongoing as new urate-lowering medications continue to be tested.
New data supporting a direct role of uric acid in various non-articular diseases including renal disease, hypertension, obesity, and coronary artery disease.
New educational efforts to improve patient understanding and compliance.

References

Arromdee, E., Michet, C. J., Crowson, C. S., O’Fallon, W. M., & Gabriel, S. E. (2002). Epidemiology of gout: Is the incidence rising? Journal of Rheumatology, 29(11), 2403-2406.
Choi, H. K., Atkinson, K., Karlson, E. W., Willett, W., & Curhan, G. (2004a) Purine-rich foods, daily and protein intake, and the risk of gout in men. New England Journal of Medicine, 350(11), 1093-1103. doi: 10.1056/NEJMoa035700
Choi, H. K., Atkinson, K., Karlson, E. W., Willett, W., & Curhan, G. (2004b). Alcohol intake and risk of incident gout in men: A prospective study. Lancet, 363(9417), 1277-1281. doi:10.1016/S0140-6736(04)16000-5
Daskalopoulou, S. S., Tzovaras, V., Mikhailidis, D. P., & Elisaf, M. (2005). Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Current Pharmaceutical Design, 11(32), 4161-4175.
Edwards, N. L. (2007). Gout. In J. H. Klippel, J. H. Stone, L. J. Crofford, & P. H. White (Eds.). Primer on the rheumatic diseases (13th ed.). New York: Springer-Verlag.
Edwards, N. L. (2007). Gout. In J. H. Klippel, J. H. Stone, L. J. Crofford, & P. H. White (Eds.). Primer on the rheumatic diseases (13th ed.). New York: Springer-Verlag.
Hahn, P. C., & Edwards, N. L. (2005) Management of hyperuricemia. In W. J.
Koopman & L. W. Moreland (Eds.), Arthritis and allied conditions
(pp. 2341–2355). Philadelphia, PA: Lippincott Williams & Wilkins.
Jaovisidha, K., & Ryan, L. (2006). Chapter 7. Clinical manifestations of basic calcium phosphate (apatite) deposition disease. In R. L. Wortmann, H. R. Schumacher, Jr., M. A. Becker, & L. M. Ryan (Eds.), Crystal-induced arthropathies: Gout, pseudogout, and apatite-associated syndromes. New York: Taylor and Francis Group.
Lin, K. C., Lin, H. Y., & Chou, P. (2000). The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. Journal of Rheumatology, 27(6), 1501-1505.
Mikuls, T. R., Farrar, J. T., Bilker, W. B., Fernandes, S., Schumacher, Jr., H. R., & Saag, K. G. (2005). Gout epidemiology: Results from the UK General Practice Research Database, 1990–1999. Annals of Rheumatic Diseases, 64(2), 267-272.
Rosenthal, A. K. (2006). Chapter 6. Pseudogout: Presentation, natural history, and associated conditions. In R. L. Wortmann, H. R. Schumacher, Jr., M. A. Becker, & L. M. Ryan (Eds.), Crystal-induced arthropathies: Gout, pseudogout, and apatite-associated syndromes. New York, NY: Taylor and Francis Group.
Urano, W., Yamanaka, H., Tsutani, H., Nakajima, H., Matsuda, Y., Taniguchi, A., et al. (2002). The inflammatory process in the mechanism of decreased serum uric acid concentration during gouty arthritis. The Journal of Rheumatology, 29(9), 1950-1953.

Acknowledgements

Arthur Bankhurst, M.D.

Professor, Internal Medicine

Chair, Department of Rheumatology