Crystalline Diseases

1. Be able to identify the salient features of an acute arthritis and come up with a differential diagnosis based on features in the history and physical examination.
2. Recognize the importance of ruling out septic arthritis in the process of evaluating an acute monoarthritis.
3. Recognize the importance of a joint aspiration and synovial fluid analysis in making the diagnosis.
4. Describe the importance of pain relief in the setting of an acute monoarthritis.
5. Be able to ascertain the epidemiology and trigger factors in gout and CPPD in a given patient and counsel them regarding the same.
6. Describe the laboratory and radiographic investigations that may be helpful in supporting the diagnosis of gout and CPPD and also understand their shortfalls.
7. Know the medications used in the acute and chronic management of gout (see references: 1, 2) and CPPD and be able to explain the potential side effects.
8. Describe the course of these conditions and their co-morbid disease associations (see references: 1, 2).
9. Describe two types of calcium crystals that can lead to arthropathy.

1. Know the purine metabolism pathway and the steps affected by urate lowering therapy and logically explain potential drug interaction and toxicities.
2. Know the clinical presentation of gout and Pseudogout and be able to recognize the pattern of classic joint involvement and distinguishing clinical features of an inflammatory arthritis.
3. Describe the role of inflammation in gout.
4. Know the classic locations for a gouty tophus (see images: 1, 2, 3).
5. Know the crystals involved and be able to recognize them under polarized microscopy (see images: 1, 2, 3, 4).
6. Know the similarities and differences in synovial fluid analysis in acute crystal arthropathy and septic arthritis.
7. Know the role of the kidney in urate transport.
8. Know the radiological features of gout and Pseudogout (see images: 1, 2, 3, 4, 5, 6).
9. Know the mechanism of action of the various pharmacological interventions and their side effects and drug- drug interactions.
10. Describe when to initiate therapy with urate lowering therapy and the risks of potentially inducing a flare upon such initiation. Describe how to prevent flares associated with urate lowering therapy.
11. Know the real and important distinction between gouty arthropathy and asymptomatic hyperuricemia especially in the setting of concurrent hydrochlorothiazide therapy.
12. Know also that gouty arthropathy is but one aspect of the gouty diathesis.
13. Understand the importance of appropriate corticosteroid use.
14. Know the recent advances in pharmacotherapy of gout.

1. Be able to clearly anatomical and accepted medical terms describe the patients presentation assuming that the attending physician can see neither you nor the patient and is on the other end of the phone.
2. Be able to clearly and in lay terms explain the diagnosis and plan of care to the patient.
3. Counsel patient clearly on lifestyle issues as they impact on the disease.
4. Explain the need for compliance in the setting of a chronic condition.
5. Educate patient regarding the co-morbid conditions associated with gout and help screen as appropriate.
6. Explain the potential side effects of planned treatments and plan for monitoring for the same.
7. Recognize the need to include the patient's perspectives in the treatment of this life-long disease.

1. Be an educated patient advocate.
2. Respect patient privacy and discuss all patient related issues with honesty and integrity.
3. Respect the patients' right to refuse treatment.
4. As a corollary respect your right as the physician to lay out a clear plan and expect an attempt at compliance.
5. Show empathy.

1. Have a mechanism to seek and incorporate feedback from patients and attending physicians into your practice.
2. Learn from your mistakes and incorporate changes into your practice to prevent errors in the future.
3. Have resource/resources you go to for refreshing knowledge base- textbook, web resources or journal articles.

1. Recognize barriers to the institution of your plan of care for the individual patient- medical, psycho-social, economic or cultural.
2. Be able to deliver the care needed in a multi-disciplinary setting.
3. Understand the impact of the interventions both in medical terms and in economic terms.

• Jordan, K. Up-to-date management of gout. Curr Opin Rheumatol. 2012; 23(2): 145-51.
• Richett P, Bardin T. Gout. Lancet 2010;23:318-28.
• Pascual E, et. al, Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011; 23: 161-9.
• Zhang W, et. al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65: 1301-11.
• Zhang W, et.al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65: 1312-24.
• Zhang W, et. al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011; 70: 563-70.
• Zhang W. et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis 2011; 70:571-5.
• Tuhina Neogi, Gout. N Engl J Med 2011; 364:443-452
• Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-1068
• 2012 American College of Rheumatology Guidelines for Management of Gout Part I: Systematic Non-pharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia
  Dinesh Khanna,1,* John D. FitzGerald,2,* Puja P. Khanna,1,* Sangmee Bae,2 Manjit Singh,3 Tuhina Neogi,4 Michael H. Pillinger,5 Joan Merill,6 Susan Lee,7 Shraddha Prakash,2 Marian Kaldas,2 Maneesh Gogia,2 Fernando Perez-Ruiz,8 Will Taylor,9 Frédéric Lioté,10 Hyon Choi,4 Jasvinder A. Singh,22 Nicola Dalbeth,11 Sanford Kaplan,12 Vandana Niyyar,13 Danielle Jones,13 Steven A. Yarows,14 Blake Roessler,1 Gail Kerr,15 Charles King,16 Gerald Levy,17 Daniel E. Furst,2 N. Lawrence Edwards,18 Brian Mandell,19 H. Ralph Schumacher,20 Mark Robbins,21 Neil Wenger,2 and Robert Terkeltaub7
• 2012 American College of Rheumatology Guidelines for Management of Gout Part II: Therapy and Anti-inflammatory Prophylaxis of Acute Gouty Arthritis Dinesh Khanna,1,* Puja P. Khanna,1,* John D. FitzGerald,2,* Manjit K. Singh,3 Sangmee Bae,2 Tuhina Neogi,4 Michael H. Pillinger,5 Joan Merill,6 Susan Lee,7 Shraddha Prakash,2 Marian Kaldas,2 Maneesh Gogia,2 Fernando Perez-Ruiz,8 Will Taylor,9 Frédéric Lioté,10 Hyon Choi,4 Jasvinder A. Singh,11 Nicola Dalbeth,12 Sanford Kaplan,13 Vandana Niyyar,14 Danielle Jones,14 Steven A. Yarows,15 Blake Roessler,1 Gail Kerr,16 Charles King,17 Gerald Levy,18 Daniel E. Furst,2 N. Lawrence Edwards,19 Brian Mandell,20 H. Ralph Schumacher,21 Mark Robbins,22 Neil Wenger,2 and Robert Terkeltaub

(Answer questions 1 – 5 on a piece a paper. The Answer Key is at the bottom of the page.)

1. An 80 year old man presents with an acutely swollen R ankle and with erythema and pain. He has a known history of gout with previous attacks in both the first MTP of the R foot and the L ankle. He has Chronic kidney disease, atrial fibrillation and hyper- cholesterolemia and is on Furosemide, Lisinopril , Metoprolol, coumadin and a statin. He continues to drink alcohol liberally. His laboratory tests reveal WBC 3200/µL, platelets 100,000/µL, Hb 9.8g/dL, creatinine 3.6mg/dL, uric acid 9.0mg/dL and INR 4.0. The most appropriate management step in this patient is:

1. Aspiration of the R ankle with administration of intra-articular steroids
2. Initiation of allopurinol guided by EGFR
3. Initiation of colchicine 0.6 mg 2 tabs now followed by 1 tab an hour later and then I tab twice a day
4. Start prednisone 40mg a day and titer down based on response

2. A previously healthy 70 year old lady is admitted with pneumonia and on the 2nd day of hospitalization develops a painful swollen R knee with tenderness and warmth. She is afebrile. The rest of her articular exam is normal except for nodular osteoarthritis of her hands and crepitus in the L knee. The most appropriate first step in her management is:

1. Start prednisone 40mg a day and titer down based on response
2. Aspiration of the R knee with administration of intra-articular steroids
3. Initiation of colchicine 0.6 mg 2 tabs now followed by 1 tab an hour later and then I tab twice a day
4. Initiation of allopurinol guided by EGFR

3. You are asked to evaluate a currently asymptomatic 67 year-old man who has a long history of gout. During the past six months, he has had multiple acute gouty flares involving the left wrist, the right knee, and the first metatarsophalangeal joints. A year ago, he underwent heart transplantation because of viral cardiomyopathy. At that time, his regimen of allopurinol, 300 mg daily, and colchicine, as needed for acute flares, was discontinued. He has taken no regular medication for gout since then, except for indomethacin during the recent flares.

Current medications are cyclosporine, 400 mg; azathioprine, 100 mg daily, and prednisone, 10 mg daily. Physical examination reveals a tophus in the left olecranon bursa. No joint tenderness or swelling is present. Leukocyte count is 7500/cu mm with a normal differential. Serum creatinine level is 1.8 mg/dL. Serum uric acid level is 10.6 mg/dL. The best treatment plan for this patient is:

1. Begin allopurinol, 100 mg daily, and continue other medications unchanged
2. Begin allopurinol, 300 mg daily, and reduce the dose of azathioprine
3. Begin allopurinol, 100 mg daily, and reduce the dose of azathioprine
4. Begin allopurinol, 100 mg daily, and reduce the dose of cyclosporine
5. Begin allopurinol, 300 mg daily, and reduce the dose of cyclosporine

4. A 46-year-old man is evaluated because of a three-month history of progressive generalized weakness without pain and the recent onset of numbness in the hands and toes. For the past three weeks, the patient has required support while walking and assistance in rising from a chair. Medical history includes hypertension and two attacks of gout. He has taken colchicine, 0.6 mg twice daily, for the past four years, and he currently takes hydrochlorothiazide, 50 mg daily. He drinks 2 to 3 cans of beer daily. At the time of physical examination, the patient cannot stand or walk without assistance. Blood pressure is 160/100 mm Hg. There is marked symmetric proximal muscle weakness which is more severe in the legs. Sensation to pinprick and vibration is decreased in the toes. Deep tendon reflexes are absent.

Laboratory studies:
Hemoglobin 12.5 g/dL
Mean corpuscular volume 99 fL
Erythrocyte sedimentation rate 32 mm/hr
Serum aspartate aminotransferase 125 U/L (AST)
Serum creatinine 1.9 mg/dl
Serum creatine kinase 2010 U/L
Serum uric acid 8.0 mg/dL

Which of the following is the most likely diagnosis?

1. Colchicine-induced neuromyopathy
2. Alcohol-induced neuromyopathy
3. Inclusion body myositis
4. Polymyositis
5. Amyotrophic lateral sclerosis

Which of the following findings on synovial fluid analysis is consistent with an asymptomatic lady with a minimal knee effusion that was aspirated after obtaining the X- ray below?

1. Turbid and watery fluid with a cell count of 10,000/µL with needle shaped strongly negatively birefringent crystals
2. Turbid watery fluid with a cell count of 5,000/µL with rhomboid weakly positively birefringent crystals
3. Turbid watery fluid with a cell count of 8,000/µL with no crystals
4. Clear, viscous fluid with a cell count of 400/µL and weakly positively birefringent crystals

(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom on the page.)

1. The correct answer is D.

   Acute gout can be treated with colchicine, NSAID’s such as indomethacin, intra-articular injections of corticosteroids or oral or parenteral corticosteroids. In this patient on Coumadin with a supra-therapeutic INR injecting the ankle poses the risk of intra-articular bleeding. The impaired renal function precludes the use of NSAID’s and colchicine. Colchicine is also relatively contraindicated in the setting of the patient’s impaired marrow function (likely the result of ETOH). Initiating allopurinol in the setting of an acute attack of gout will only exacerbate the patient’s symptoms. Systemic corticosteroid therapy affords the best risk-benefit profile for this patient.

2. The correct answer is B.

   This lady has no comorbid conditions. Both acute gout and acute pseudo-gout can happen in the setting of an inter-current illness/hospitalization. Given the mono articular presentation it would be best to attempt a synovial aspiration and treat with intra-articular steroids. There is nothing in the history or examination to suggest a septic joint. While systemic corticosteroids and colchicine may help they are not indicated as first-line treatments given the mono articular presentation. Furthermore obtaining the synovial fluid will help clarify the exact cause of the crystalline arthropathy.

3. The correct answer is C.

   This question is designed to highlight the interaction between allopurinol and azathioprine. Allopurinol and azathioprine should not be co-prescribed unless the combination cannot be avoided. Allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine which may result in potentially fatal blood dyscrasias. Concomitant use requires special precautions: the dose of azathioprine should be reduced to 25% of the recommended dose and the patient’s blood count should be monitored carefully and frequently. After oral administration and absorption, approximately 90% of azathioprine is converted to 6-mercaptopurine (6-MP). At this point, 6-MP can undergo metabolism by 1 of 3 different pathways; 2 of these pathways serve to inactivate 6-MP and produce metabolites that are largely inactive, while the third pathway results in the production of active metabolites. The 2 inactivating pathways are carried out separately by the enzymes thiopurine methyltransferase (TPMT) and XO. The inactivation pathway catalyzed by TMPT is straight forward, but unfortunately, is subject to the influence of genetic polymorphism. The inactivating XO pathway is also straight forward in terms of converting 6-MP to the inactive metabolite 6-thiouracil. However, anything that inhibits XO will shunt 6-MP down the pathway that results in the formation of the active 6-thioguanine (TGN) and 6-methyl-MP (MMP) metabolites. This is where allopurinol, and likely febuxostat, interact with azathioprine. There have been rare case reports of allopurinol increasing the serum levels of cyclosporine and cyclosporine itself can cause/worsen hyperuricemia.

4. The correct answer is A.

   Certain drugs produce painless, largely proximal; myopathy .These drugs include the amiodarone, chloroquine, hydroxychloroquine and the antimicrotubular drug colchicine. Muscle biopsy can be useful in the identification of toxicity since autophagic vacuoles are prominent pathologic features of these toxins. Colchicine can also cause a neuropathy in the setting of impaired renal function. Myotoxicity is a potential consequence of addiction to alcohol. Toxicity usually occurs in the setting of poor nutrition and possible contributing factors such as hypokalemia and hypophosphatemia. Acute muscle weakness with myoglobinuria may occur with prolonged severe hypokalemia, hypophosphatemia, or hypomagnesaemia that is seen in chronic alcoholics. Low vitamin D levels are related to muscle atrophy while changes in muscle antioxidant enzymes may play a role in alcoholic myopathy. Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking or present with a painless, acute hypokalemic myopathy that is completely reversible with replacement therapy.

5. The correct answer is D.

   Synovial fluid analysis includes initial inspection at bedside. Normal synovial fluid is clear and viscous. In inflammatory conditions the fluid becomes turbid due to the presence of cells and it loses its viscosity since the inflammatory process breaks down the hyaluronate content of the synovial fluid. Pseudogout is an acute inflammatory arthropathy triggered by calcium pyrophosphate crystals. These may be seen on radiographs as chondrocalcinosis. However both osteoarthritis and chondrocalcinosis can coexist without necessarily presenting as pseudogout. The patient in this question was asymptomatic. Hence the correct answer is D with the non-inflammatory synovial fluid and incidental finding of calcium pyrophosphate crystals.