Rheumatology Week 6 Summary

Question 26

There are five tumor necrosis factor-a (TNF-a) inhibitors currently used in Canada in the treatment of rheumatic diseases. These are:

• infliximab (Remicade)
• etanercept (Enbrel)
• adalimumab (Humira)
• golimumab (Simponi)
• certolizumab pegol (Cimzia)

List 4 potential side effects of these drugs.

Infection
Tuberculosis is of particular concern. All patients starting anti-TNF therapy should be screened for latent TB with a chest x-ray and PPD. Patients on these medications are also at increased risk of certain other unusual infections, including histoplasmosis. These drugs should be held in the event of any febrile illness or unusual infection.

Malignancy
TNF-a is known to have anti-tumor effects in laboratory settings, leading to concern that TNF blockade may increase cancer risk. To date, it is not clear whether TNF blockers increase the risk of lymphoma or solid tumors in patients on TNF inhibitors and the relationship between TNF-inhibitor use and malignancy is still being investigated. These medications are contraindicated in patients with a history of malignancy.

Congestive heart failure
Anti-TNF therapy should be avoided in patients with Class III or IV heart failure due to a trend toward increased hospitalizations and greater mortality.

Demyelinating disorders
These have been described in post-marketing surveillance. These agents should be avoided in patients with any history of prior demyelinating conditions.

Infusion reactions
Approximately 10% of patients receiving infliximab infusions will have mild infusion reactions necessitating a decreased rate of infusion or pretreatment with an H1 receptor antagonist and/or corticosteroids. Less than 2% of patients have severe reactions including bronchspasm, hypotension and anaphylaxis.

Injection site reactions occur in many patients receiving these medications subcutaneously, but they are generally minor.

Question 27

Cyclophosphamide is an alkylating agent that crosslinks DNA so that it cannot replicate, resulting in double stranded DNA breaks. It is cytotoxic to resting and dividing lymphocytes, and acts to suppress primary cellular and humoral immune responses. It is considered to be one of the most potent immunosuppressive drugs available.

List four side effects associated with cyclophosphamide use. Are there ways to minimize cyclophosphamide toxicity?

The toxicity profile of cyclophosphamide includes:

• Infections, including unusual or opportunistic infections such as PCP, nocardia and TB.
• Malignancies, including leukemia, skin and bladder cancer
• Gonadal toxicity in men and women
• Myelosuppression (mostly leucopenia and neutropenia)
• Hemorrhagic cystitis
• Nausea
• Alopecia

Methods of minimizing toxicity include:

• Minimizing the duration of therapy
• Avoiding night time doses (This reduces duration of bladder exposure to the toxic metabolite acrolein and thus reduces risk of hemorrhagic cystitis.)
• Forced diuresis (Drinking 8 glasses of water/day)
• Intermittent IV pulse therapy rather than daily oral therapy
• Using MESNA (sodium 2-mercaptoethane sulfonate). This inactivates the toxic metabolite acrolein in the urine, thereby protecting the bladder from its effects. Acrolein is responsible for causing hemorrhagic cystitis and bladder cancer.

Question 28

List the major and minor risk factors that identify patients who should be assessed for osteoporosis. What examination manoeuvers increase the likelihood that a person has osteoporosis or a vertebral compression fracture?

Major Risk Factors:

1. Age over 65 years
2. Vertebral compression fracture
3. Fragility fracture after age 40 (A fragility fracture is one that occurs with minimal trauma, such as a fall from standing height or less.)
4. Family history of osteoporotic fracture
5. Systemic glucocorticoid therapy for more than 3 months
6. Malabsorption syndrome
7. Primary hyperparathyroidism
8. Propensity to fall
9. Osteopenia apparent on x-ray film
10. Hypogonadism
11. Early menopause (before age 45)

Minor Risk Factors

1. Rheumatoid arthritis
2. Past history of clinical hyperthyroidism
3. Chronic anticonvulsant therapy
4. Smoker
5. Excessive alcohol intake
6. Excessive caffeine intake
7. Weight less than 57 kg
8. Weight loss greater than 10% of weight at age 25
9. Chronic heparin therapy

No single physical examination manoeuver is sufficient to diagnose osteoporosis or vertebral fracture without additional testing. However, the following features increase the likelihood of OP and help identify individuals who would benefit from earlier screening.

1. Height loss >3cm from patient’s maximal adult height (+ LR 1.1-3.2)
2. Body weight <51kg (+LR 7.3)
3. Wall-to-occiput distance >0 cm (as a measure of kyphosis) (+LR 4.6)
   (Distance >7cm rules in a thoracic fracture with high degree of accuracy)
4. A rib-to-pelvic distance ≤2 fingerbreadths predicts occult lumbar vertebral fractures. This is measured by placing your fingers between the inferior margin of the ribs and the iliac crest at the mid-axillary line (+LR 3.8). When the rib-to-pelvic distance is 0 fingerbreadths, the +LR is 11.5.
5. A tooth count of <20 teeth (+LR 3.4).

Green AD, Colón-Emeric CS, Bastian L. Does this woman have osteoporosis?. JAMA 2004 Dec. 15; 292: 2890-2900.

Question 29

Name 8 musculoskeletal conditions that are associated with diabetes.

1. Limited joint mobility
   (Diabetic cheiroarthropathy or stiff hand syndrome. This is characterized by tight, waxy skin on the hands and flexion deformities at the MCPs and IP joints. Associated with pain and stiffness.)
2. Diabetic amyotrophy
   (A polyneuropathy of L2, 3 and 4 characterized by proximal lower extremity pain and weakness.)
3. Neuropathic arthropathy (Charcot joint)
4. Adhesive capsulitis
5. Dupuytren’s contracture
6. Carpal tunnel syndrome
7. Diffuse idiopathic skeletal hyperostosis
8. Flexor tenosynovitis
9. Reflex sympathetic dystrophy

Question 30

List 5 extra-articular features that are associated with ankylosing spondylitis.

1. Uveitis
2. Inflammatory bowel disease
3. Constitutional symptoms
4. Enthesitis
5. Restrictive lung defects due to decreased chest expansion
6. Apical fibrosis
7. Aortic insufficiency
8. Conduction disturbances
9. Aortitis