“Joint Disease in Patients With Hemophilia: When Is a Rheumatology Consult Necessary?”

"Joint Disease in Patients with Hemophilia: When Is a Rheumatology Consult Necessary?"
Patrick F. Fogarty, MD, and Jeffrey R. Lisse, MD
December 24, 2012


CASE 1: BRIAN H.
Brian H. is a 40-year-old white male with severe hemophilia A and no inhibitor. He stands at 5'9", weighs 210 pounds, and has a BMI of 31. He has 3 target joints: right knee, left ankle, and left hip. Historically, Brian treated bleeding episodes on demand, but he has been on a prophylactic regimen for the past year with recombinant factor VIII (rFVIII) 40 U/kg twice weekly. Brian likes to eat out often rather than preparing meals for himself, and he routinely has a couple of beers with dinner. Until recently, he has led a sedentary life, believing that the pain he once experienced in his target joints would be worsened by physical exercise. However, on the recommendation of his treating physician, Brian has started to become more physically active. He power walks every other day and works with a physical therapist on an exercise program. Since initiating prophylaxis, he experiences fewer and less severe joint bleeds and a diminution of pain in target joints.

Recently, Brian experienced what seemed to be a hemarthrosis in his target knee joint. He can barely walk, and any sudden jarring causes a flare-up of pain in the affected joint. He treated this acute attack with rFVIII 40 U/kg, which offered some relief, but the pain returned 12 hours later. He repeated the factor dosage, but it proved ineffective, which was atypical, based on past acute bleeding events. When he arrives at the hemophilia treatment center (HTC) for an evaluation of the affected joint, a physical exam reveals it to be red, swollen, and hot to the touch. There is also pain with both active and passive range of motion, and the patient has a temperature of 100ºF.

As the treating physician, how would you proceed with this patient?

CASE 1: BRIAN H.
Expert Q&A with Patrick F. Fogarty, MD, and Jeffrey R. Lisse, MD



INTRODUCTION
The workup of an acute joint-related symptom in patients with hemophilia is complicated by any underlying hemophilic arthropathy, one of the most common and concerning effects of hemophilia.1 Although the pathogenesis of hemophilic arthropathy is unclear, research data suggest that it has similarities with the degenerative joint damage that occurs in osteoarthritis and the inflammatory processes associated with rheumatoid arthritis (RA) (see Appendix).1 Joint deterioration is regarded as an irreversible and progressive complication in all patients with hemophilic arthropathy.2 The knees, elbows, and ankles are the most frequently affected target joints.3

Due to improvements in hemophilia care, life expectancy has increased significantly in hemophilia patients, and clinicians are seeing the emergence of a middle-aged and elderly hemophilia population.4 ,5 However, there is little evidence-based data to guide the management of age-related comorbidities in these aging patients. As a result, integrating the expertise of specialists when devising treatment plans has become essential to optimal patient management.4,6

For clinicians who manage hemophilia patients, especially middle-aged and older patients, the musculoskeletal complications of hemophilia and other diseases with musculoskeletal presenting features, including degenerative joint diseases such as osteoarthritis (OA) and osteoporosis, can pose a challenge. 4, 5, 6, 7

Rheumatoid arthritis (RA), an autoimmune disorder, most often affects the smaller joints, such as those of the hands and/or feet, wrists, elbows, knees, and/or ankles, but any joint can be affected. RA is not a common comorbidity, but acquired hemophilia has been reported in patients with RA. 8, 9

In contrast, many individuals with hemophilia have significant problems with OA, usually due to the joint degeneration that results from hemophilic arthropathy. Today, however, many patients with preserved joints as a result of diligent use of prophylaxis are likely to experience OA as they age in a manner typical of the noncoagulopathic population.

The following discussions examine issues related to managing the more common joint disorders in patients with hemophilia.



The Case of Brian H.
Are his presenting symptoms hematologic in origin or indicative of a rheumatologic disorder, necessitating a consult between the treating physician and a rheumatologist?

GOUT AS A LIKELY DIAGNOSIS Epidemiology

The Third National Health and Nutrition Examination Survey (NHANES III) estimated the prevalence of gout in the US population to be 5.1 million between 1988 and 1994.10 During that period, gout affected more than 3 million men older than 40 and 1.7 million women older than 40, making this disease more common than RA and the most common form of inflammatory arthritis in adult men.10

The prevalence of gout in men increases with advancing age. Women have an increased risk of developing gout after menopause, and the incidence of gout becomes approximately equal between the genders after age 60 (Figure 1).10

Clinical Presentation

Acute gouty arthritis most commonly begins with involvement of a single joint or multiple joints in the lower extremities, most commonly the first metatarsophalangeal (ie, podagra), midtarsal, ankle, or knee joints. However, similar to hemophilic arthropathy, any joint in the feet, ankles, knees, hands, wrists, or elbows may be involved. Pain, erythema, and swelling often begin in the early morning and increase and peak within 24 to 48 hours. The pain is severe, and patients often cannot wear socks or touch bedsheets during flare-ups.11 Occasionally, a gout attack triggers a systemic inflammatory response manifesting with fevers, leukocytosis, elevated sedimentation rates, and elevated C-reactive protein (CRP) and may be difficult to distinguish from acute septic arthritis. 11, 12 Attacks typically subside within 5 to 7 days, even without treatment.11

Risk Factors

Hyperuricemia is considered the most important risk factor for the development of gout.13 Numerous other risk factors include genetics, dietary factors (eg, meat and seafood consumption), alcohol consumption (especially beer and spirits), metabolic syndrome, hypertension, obesity, diuretic use, and chronic renal disease.

Pathophysiology

Gout is an inflammatory crystal arthropathy caused by altered purine metabolism, often leading to hyperuricemia. 11, 12 Hyperuricemia is defined as the serum urate level, in body fluids, above which urate precipitates into monosodium urate (MSU) crystals. A urate level >6.8 mg/dL is considered hyperuricemia.12 When the local solubility limits of uric acid are exceeded, MSU crystals may be deposited in the joints, kidneys, and soft tissues. However, gout may also occur in the presence of normal serum uric acid levels. Pathogenic effects include arthritis, soft tissue masses (ie, tophi), nephrolithiasis, and urate nephropathy.11

Differential Diagnosis

Classification criteria to aid in the diagnosis of gout have been proposed by the American College of Rheumatology, and a consensus panel of experts from the European League Against Rheumatism (EULAR) has reviewed the evidence and made recommendations for diagnosing gout.14 Published clinical gout diagnostic (CGD) criteria: (1) >1 attack of acute arthritis, (2) mono/oligoarthritis attacks, (3) rapid progression of pain and swelling (<24 h), (4) podagra, (5) erythema, (6) unilateral tarsitis, (7) probable tophi, and (8) hyperuricemia.15

The main differential diagnosis of acute gout is pseudogout (calcium pyrophosphate deposition disease [CPPD]), other crystalline diseases, septic arthritis, atypical rheumatoid arthritis, trauma, OA, reactive arthritis, and fracture. The differential diagnosis should be considered based on the history and clinical presentation. 11, 12

Laboratory Evaluation

Synovial fluid analysis via aspiration of the affected joint is considered the gold standard for confirming a diagnosis of gout or other crystal-induced diseases and ruling out septic arthritis.11,12 Synovial fluid analysis offers a valuable diagnostic tool for evaluating any patient with acute monoarthritis. Once the fluid is aspirated, it can be examined grossly for color and turbidity. In general, transparent synovial fluid in the syringe is more suggestive of a noninflammatory condition, whereas fluid that appears turbid or purulent is more suggestive of inflammation or infection (eg, RA, septic arthritis). However, gross appearance alone is not diagnostic.12

To confirm or rule out infection, the fluid needs to be processed for Gram stain and culture. It is possible to have concomitant gout and septic arthritis. On microscopic examination, the number of white blood cells (WBCs) per high-power field can be estimated. The WBC count may be a useful adjunct in estimating the degree of inflammation present. With gout, synovial fluid analysis reveals leukocytosis, a nonspecific finding of inflammatory arthritis including infectious and crystalline causes.12 Synovial fluid WBC counts will usually be greater than 2000/mm3, and may be as high as
50,000/mm3.14 Crystal analysis is done with a microscope that is equipped to examine compensated polarized light. An accurate diagnosis can be made by a trained observer detecting and identifying MSU crystals (gout) or CPPD crystals (pseudogout). MSU crystals are strongly negatively birefringent and appear lancet-shaped when viewed under compensated polarized light.12 CPPD crystals are weakly birefringent and rhomboid or rod-shaped. CPPD crystals are more difficult to find and may be missed if the analysis is not done by a trained examiner. In addition to shape and birefringence, MSU and CPPD differ in color depending on the axis of orientation with respect to the polarizer. When the axis of the MSU crystal is parallel to the polarizer, it appears yellow; when perpendicular, it appears blue. The CPPD crystal is the reverse of that, so when the CPPD crystal is parallel, it appears blue, and when perpendicular, it appears yellow (Table 1).12

Recently, a method using dual-energy CT scanning of the affected joint has become available. This technology allows gouty crystals to appear as green pixelations when in and around the joint.17 In addition, ultrasound may be utilized in some circumstances to diagnose gouty arthritis and tophi, if any are present. There is a characteristic appearance, a so-called "double contour sign," that presents.18 These techniques allow for the diagnosis noninvasively, an obvious advantage in patients with coagulopathies.



TREATMENTS FOR GOUT
The goals of gout treatment are symptom control for acute attacks, risk factor modification, and pharmacotherapy to prevent recurrence and chronic sequelae.11 Table 2 provides an overview of treatments for acute gout. Nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids are first-line therapies for acute gout, depending on patient comorbidities. However, NSAIDs and aspirin have antiplatelet effects that are contraindicated in patients with hemophilia unless they are receiving continuous secondary prophylaxis with clotting factor concentrate. This is not feasible in most individuals for the duration of the usual treatment period with the antiplatelet agent.

Steroids may be considered in the absence of concomitant infection. In the case of systemic infections or septic arthritis, steroids should be avoided, if possible. Corticosteroids may be used locally as an injection or systemically (orally, intramuscularly, or intravenously). Corticosteroids are usually very effective, and response is noticed within 24 hours of beginning therapy.12 As a surrogate, injections of ACTH (adrenal cortical trophic hormone) have been used to stimulate the adrenal glands to make endogenous cortisol. 19, 20

Although colchicine is an effective second-line therapy, in higher doses the risks of adverse effects are currently thought to outweigh the benefits. These therapies may need to be supplemented by analgesics, including tramadol or short-acting opioids such as hydrocodone and oxycodone.11 All medications should be used cautiously in older persons, in whom the toxicity threshold is lower. Although not approved currently, inhibition of interleukin 1 (IL-1) with subcutaneous anakinra has been described.21 Anakinra has also been reported to be effective in refractory CPPD arthritis.22 Canakinumab, another IL-1 inhibitor, has also been shown to be effective in gout. It is currently not yet approved for this indication in the United States.23 These IL-1 inhibitors are, unfortunately, very expensive and have to be given as subcutaneous injections, so they should only be considered in refractory patients.21

Urate-Lowering Therapy for Chronic Gout

The primary treatment goal in chronic gout is to decrease urate levels to less than the level of crystal precipitation. The therapeutic target level should be <6 mg/dL. At this level, the risk of a gouty attack is decreased, as is the formation of tophi. The decision to start a hypouricemic agent needs to be considered on a patient-by-patient basis, taking into consideration factors such as the absence of definite other reversible causes of hyperuricemia, the number of attacks (2 or more acute gouty attacks), the degree of hyperuricemia, comorbidities, and the presence of tophi.12 Hypouricemic therapy should begin only after the acute attack has completely resolved, to avoid exacerbation of the attack. Table 2 provides an overview of treatments for chronic gout. Prophylactic agents (colchicine, NSAIDs, or systemic steroids) are initiated concurrently with hypouricemic drugs to decrease the risk of an acute attack, thought to be caused by fluctuations in the serum uric acid levels. This is usually continued for at least 6 months to 1 year.12 Hypouricemic drugs include xanthine oxidase inhibitors (eg, allopurinol and febuxostat), uricosuric agents (eg, probenecid, sulfinpyrazone, benzbromarone), and a polyethelynated PEG-uricase.12

Newer Agents: Febuxostat and Pegloticase

Febuxostat and pegloticase (formerly PEG-uricase) may offer an advantage in patients who are allergic or refractory to treatment with allopurinol. Febuxostat is a nonpurine selective inhibitor of xanthine oxidase for treating hyperuricemia in patients with gout. It was approved by the US Food and Drug Administration (FDA) in February 2009. Current data indicate that it is a potent inhibitor of the enzyme that leads to urate reduction and is comparable in efficacy with allopurinol.12 It needs no adjustment for mild to moderate renal impairment.24

Pegloticase is the pegylated form of uricase, the enzyme that catalyzes conversion of urate to allantoin, a more soluble metabolite.12 Uricase is not produced by humans. In clinical trials, it has been shown to be effective25 and was recently approved for intravenous use. It has a relatively high rate of allergic reactions, some life-threatening, and has to be given as an intravenous infusion on a regular basis, usually at an infusion center. 12, 26

Pain Management

Table 3 provides a pain control schedule for patients with hemophilia, based on sequential steps of increasingly aggressive treatment.6

Although widely used, acetaminophen may have adverse effects (eg, liver dysfunction) that may become enhanced in older patients, particularly those with liver disease.6 As noted earlier, NSAIDs and aspirin use in patients with hemophilia require continuous secondary prophylaxis with clotting factor concentrate. Selective cyclooxygenase 2 (COX-2) inhibitors are better tolerated in the gastrointestinal tract than are nonselective NSAIDs, but the risk of cardiovascular disease is comparable.6 For optimal management, the involvement of pain control teams in comprehensive HTCs may become necessary.6

Joint Aspiration in Hemophilia

Joint aspiration (arthrocentesis) is one of the most controversial issues in hemophilia management. According to one author, arthrocentesis should always be performed in major hemarthrosis (voluminous, very tense, and painful joint). Aspiration of the elbow, knee, and ankle can be performed in an outpatient setting, not necessarily by an orthopedic surgeon. Arthrocentesis of the hip and shoulder should be done under radiographic control in an operating room by an orthopedic surgeon. Joint aspiration should always be done under factor coverage and in aseptic conditions.28 The overriding concern is always to rule out an acute infection if one is suspected. Unfortunately, joint aspiration (or arthroscopic examination and aspiration), Gram stain, and culture may in some cases be the only method available to do this.

Supplemental Information
TABLE 2
Pharmacotherapy for Acute and Chronic Gout6,11,12,26,27

TABLE 3
Steps for the Use of Analgesics in Patients With Hemophilic Arthropathy6

RELATED ACTIVITY
Hemophilia Experts Video Summit: How We Manage Musculoskeletal Complications of Hemophilia in Adult Patients is a moderated panel discussion featuring hemophilia experts Patrick Fogarty, MD; Angela Forsyth, PT, DPT; Susan Karp, RN, MS; Samir Mehta, MD; and Tammuella Chrisentery Singleton, MD. To view and earn CE credit,
click here.

POLL QUESTION
How often have you referred patients with hemophilia to a rheumatologist based on presenting symptoms that seemed indicative of an inflammatory disorder such as gout?




OSTEOARTHRITIS
Osteoarthritis (OA) is the most common form of arthritis, comprising about 80% of all cases and affecting some 27 million individuals in the United States.29,30 The condition can occur as a result of abnormal loads on normal joints (as in the case of obesity) or normal loads on abnormal joints.31 Modifiable and nonmodifiable risk factors for OA include excess body mass; joint injury from trauma or sports; occupations involving excessive mechanical stress, heavy lifting, or repetitive motion; gender; advanced age; race; and genetic predisposition. 30,31

Joints in OA patients are traditionally swollen, but the swelling is likely to be bony, with minor soft tissue components. Osteophytosis is one of the hallmarks of OA.29,32,33 It is thought that hyaline cartilage, once damaged, will not heal.33 It is devoid of blood vessels and nerves, and the few chondrocytes that are present in the matrix are incapable of correcting injuries. Deterioration may take decades to become symptomatic, as the cartilage is slowly eroded. Buttressing and overgrowth by bone then occurs, leading to osteophyte, or "bone spur," formation.32 This also may lead to deformities, because the damage and remodeling often occur asymmetrically.29

Joint fluid in OA patients is usually "noninflammatory," meaning that the WBC count is less than 2000/mm3.34 Radiographs will show narrowing of the joint spaces, representing cartilage loss, and osteophytes.29 Pathology visible on MRI includes joint narrowing, subchondral osseous changes, and osteophytes.31

Unfortunately, treatment is mainly symptomatic.31 Pain relief, local corticosteroid or hyaluronic acid injections, and topical therapies are the mainstay; however, none prevents disease progression.

The differential diagnosis can be dependent on the clinical presentation. The most common joints affected are the knees, hips, first carpometacarpal (CMC) and first metatarsophalangeal (MTP) joints, as well as the distal interphalangeal (DIP) joints. 29,35,36 Often this is asymmetric. Joints that were damaged from hemophilia also may be involved.



RHEUMATOID ARTHRITIS
Rheumatoid arthritis classically presents as symmetric polyarthritis affecting the small joints of the hands and feet. In this form, it should not be difficult to differentiate from the arthritis of hemophilia. However, some patients present with monoarthritis, and this may take time to evolve into the characteristic polyarthritis of RA.37

Serologic testing for rheumatoid factor (RF) and anti—cyclic citrullinated proteins (anti-CCP) may be positive in about 50% to 85% of patients, but sensitivity may vary with early cases.38 Synovial fluid is usually inflammatory (WBC >2000 cells/mm3, predominantly polymorphonuclear leukocytes), and radiographs may show the characteristic juxta-articular osteopenia and erosions; however, the latter findings may lag. Although radiography is the first choice in imaging RA, some physicians advocate use of other imaging techniques, such as ultrasound and MRI, for earlier diagnosis.39 However, these are not always available, nor are their use standardized.

Joint infection is a rheumatologic complication of paramount concern for treating clinicians Organisms favor damaged joints, so the possibility that recurrent swelling in a target joint represents infection must always be entertained. Synovial fluid analysis is important in diagnosing and managing septic arthritis and should comprise Gram stain, culture, leukocyte count with differential, and crystal examination under a polarized microscope.40 In the case of indolent organisms such as Mycobacterium tuberculosis, synovial biopsy may be necessary.41



OSTEOPOROSIS AND HEMOPHILIA
Case 2: Joseph P.

Joseph P. is a 60-year-old white male who stands at 5'8" and weighs 145 pounds. He has severe factor VIII deficiency and an inhibitor. He is also seropositive for hepatitis C virus. He has never received prophylaxis and treats his bleeding episodes on demand with recombinant factor VIIa 90 µg/kg q2h. His factor level is <1%, and his inhibitor titer has held steady at 50 BU/mL for the past several years. Both ankles are target joints, and in 2005 and 2006, he had the right and left ankle fused, respectively, due to the numerous bleeds and constant pain he was experiencing, as well as a loss of mobility. Although the surgeries have alleviated much of Joseph's pain and restored a good deal of his mobility, arthritis in his hip and shoulders has limited his physical activity. On a recent visit to his HTC, he expresses concern about his bone health, as a result of discussions he has had with his wife, who takes calcium and vitamin D supplements for osteopenia in her wrists and spine. He asks whether he should be on a similar course of treatment.

What is your recommendation for Joseph P? Is he at risk for osteopenia or osteoporosis, given his medical history? Do you refer him for a DEXA scan?


CASE 2: JOSEPH P.
Expert Q&A with Patrick F. Fogarty, MD, and Jeffrey R. Lisse, MD



ASSOCIATION BETWEEN OSTEOPOROSIS AND HEMOPHILIA BORNE OUT BY CLINICAL TRIALS
Nearly 20 years ago, Gallacher and investigators examined the association between osteoporosis and hemophilia based on an unexpected femoral neck fracture and vertebral compression fractures in 2 patients with severe hemophilia.42 The study involved 19 patients with severe hemophilia and 19 age-matched controls. Bone density at the lumbar spine (L2-4), as measured by dual-energy x-ray absorptiometry (DEXA), was significantly lower in the hemophilia patients (HPs) at (mean + SEM) 1.109 + 0.042 g/cm2 versus 1.234 + 0.027 in controls; P = 0.018. Femoral neck density was also lower at 0.877 + 0.034 g/cm2 versus 1.067 + 0.032; P <0.0005. Serum total alkaline phosphatase was elevated in HPs at 200 ± 10 U/I versus 158 ± 8; P = 0.004. Similarly, ϒ-glutamyl transferase was elevated at 42 ± 7 U/I (HPs) versus 20 ± 2; P = 0.007. Serum total testosterone and sex-hormone binding globulin (SHBG) were higher in HPs at 26 ± 2.5 nmol/L versus 17.4 ± 1.6 (P = 0.009) and 56 ± 6 nmol/L versus 27 ± 3 (P = 0.0005), respectively. Free androgen index, however, was lower in HPs at 44 ± 5 versus 69 ± 7; P = 0.008.

These results suggest significant osteopenia associated with hemophilia and that the degree of osteopenia was associated with significantly increased risk of fracture.42 Although the cause of the association between severe hemophilia and osteopenia noted in this study was not immediately apparent to investigators, they suggest that it may be partly due to liver dysfunction in HPs as well as to recurrent joint and muscle bleeds that lead to less mobility. Routine bone density measurements and, if necessary, antiosteoporotic treatment were recommended by the researchers.42

More recently, Wallny and investigators (2007) measured bone mineral density (BMD) by DEXA in 62 male individuals with severe hemophilia.7 Based on World Health Organization (WHO) criteria for osteoporosis and osteopenia, 43.5% of patients had osteopenia and 25.8% had osteoporosis; 88.7% had arthropathy; 11.3% had clinically healthy joints; and 50% of patients had 5 to 7 affected joints.7

The study results indicate that BMD significantly decreases in this patient population, with increasing severity and number of joints affected by arthropathy. Researchers suggest that arthropathy, which leads to inactivity, is the primary cause of reduced bone mass.7



LINK BETWEEN HEMOPHILIA AND LOW BONE MASS
Physiology of Bone Development

Bone mass increases during childhood and adolescence and reaches a peak in the mid-20s. After that point, bone mass remains relatively constant in women until menopausal-related bone loss begins. In men, a more gradual age-related loss of bone mass occurs.43

Under conditions that accelerate bone loss, such as inactivity, osteoclast activity increases and outpaces osteoblast activity, resulting in a net loss of bone mass. If this occurs prior to the mid-20s, then the peak bone mass will be less than expected. If such conditions are present after the mid-20s, then progressive bone loss may occur that can eventually lead to skeletal fragility (osteoporosis).43 A diagnosis of osteoporosis means bone that has both reduced mass and impaired quality or structural integrity, resulting in decreased bone strength and the tendency to fracture during circumstances when fractures normally should not occur.43

Hemophilia could lead to a lower peak bone mass and lower BMD scores based on the fact that avoidance of weight-bearing physical activity during childhood or adolescence can reduce the peak bone mass achieved. Historically, hemophilia patients have been instructed to avoid physical activity except for such things as walking and swimming. In addition, acute hemarthrosis and chronic hemophilic arthropathy will lead to local disuse, muscular atrophy, and a generalized decrease in physical activity. This, in turn, will affect the achievement of peak bone mass if it occurs before the mid-20s and may cause loss of bone mass in those older than 20.43

Treatment to Prevent Bone Loss in Hemophilia

A range of treatment options are available to prevent bone loss in hemophilia patients (Table 4). Nonpharmacologic treatments such as encouraging weight-bearing physical activity, treating the diseased joints to maintain mobility, and consuming adequate amounts of calcium and vitamin D are appropriate options for all patients with the bleeding disorder.43

With regard to pharmacologic treatments (Table 4), several questions need to be addressed before prescribing therapy. First, is the low BMD value actually the patient's peak bone mass that is going to be maintained into middle age? If yes, neither antiresorptive nor anabolic medication is indicated while bone mass is stable. This is impossible to ascertain with a single BMD measurement. However, a recent post hoc analysis of osteoporotic fractures in older women suggests that osteoporosis will develop in approximately 15 years for less than 10% of older postmenopausal women.44

Second, is the patient actually losing a significant amount of BMD, as judged by 2 different BMD measurements spaced 18 to 24 months apart? If yes, the decision to treat with an antiresorptive medication should be based on an estimate of that individual's fracture risk, such as by FRAX®, the WHO fracture risk assessment tool (http://www.shef.ac.uk/FRAX/tool.jsp) that incorporates age and BMD. For patients younger than 45 years, treatment may not be indicated until the apparent BMD is far below 2.5 SD from peak mass, unless the patient has already demonstrated fragility through prevalent fractures.43

Finally, is the patient hypogonadal, as measured by testosterone levels in males? If so, replacement should be considered.43

Risks of Therapy

No treatment is entirely benign, and any perceived benefits must be weighed against potential harm induced by treatment. Some of the available osteoporosis treatments, such as estrogen and raloxifene, are not indicated for use in males. Bisphosphonates, the primary class of drugs for osteoporosis, are potent medications that reside in the skeleton, with a half-life estimated to be 10 to 20 years for alendronate. It is known that the cumulative dose of bisphosphonate is associated with increased risk of the rare but serious condition known as osteonecrosis of the jaw.43 Atypical femoral fractures have also been reported.45 Recombinant parathyroid hormone, the only anabolic agent available in the United States, is a daily injection and can only be used for 2 years, due to an increased cancer occurrence in animal studies.46 Denosumab (anti-RANK ligand antibody) has been associated with an increase in infections and some skin rashes. 47, 48


Supplemental Information



PHYSICAL ACTIVITY FOR PREVENTION OF OSTEOPOROSIS IN SEVERE HEMOPHILIA
Khawaji and colleagues (2010) examined the relationship between different aspects of physical activity and BMD in patients with severe hemophilia on long-term prophylaxis.49 The study group consisted of 38 patients with severe hemophilia (mean age 30.5 years). All patients received long-term prophylaxis to prevent bleeding. The BMD of the total body, lumbar spine, total hip, femoral neck, and trochanter was measured by DEXA. Physical activity was assessed using the self-reported Modifiable Activity Questionnaire, an instrument that collects information about leisure and occupational activities for the prior 12 months. There was only significant correlation between duration and intensity of vigorous physical activity and bone density at lumber spine L1-L4 for duration (r = 0.429 and P = 0.020) and for intensity (r = 0.430 and P = 0.019), whereas there was no significant correlation between all aspects of physical activity and bone density at any other measured sites.49

These results suggest that with adequate long-term prophylaxis, adult patients with hemophilia are maintaining bone mass, whereas the level of physical activity in terms of intensity and duration play a less important role. These results may underscore the importance of early-onset prophylaxis.49 Additional studies support these
findings. 49, 50


Supplemental Information
RELATED ACTIVITY
For additional information on the management of osteoporosis and other comorbidities in aging hemophilia patients, click here. You will be directed to a vodcast on the subject featuring esteemed Blood CME Center faculty member Louis Aledort, MD.



CONCLUSIONS
Clinicians who manage hemophilia patients face many challenges when dealing with musculoskeletal complaints, especially in their aging patients. They must be able to distinguish between, and know when to refer for, the musculoskeletal complications of hemophilia and other age-related diseases with musculoskeletal presenting features, including gout, OA, RA, and osteoporosis. A rheumatologist's expertise can supplement that of the hematologist in any patient who appears atypical. The above mentioned conditions are common, so their appearance in a patient with hemophilia would not be unexpected. Familiarity with diagnostic and treatment strategies, as well as knowing when to refer their patients for specialty care, are keys to successful patient management.






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