Despite the increasing success of transplantation, graft recipients experience a high burden of musculoskeletal symptoms that may hinder quality of life. Post-transplant musculoskeletal problems may result from sequelae of the organ dysfunction that indicated the transplant or from the subsequent anti-rejection therapy. Rheumatology consultants need to be familiar with the spectrum of musculoskeletal syndromes presenting in these unique patients and their appropriate treatment in the context of complex drug regimens and immunosuppression.
The aims of organ transplantation are not only patient and graft survival but also optimal quality of life. Yet up to 53% of renal, liver and cardiac transplant recipients report body pain that may be debilitating and affect daily function . Despite advances in the field of transplant medicine, evaluating and managing musculoskeletal pain remains a challenge and requires knowledge of the unique characteristics of transplant recipients. Many post-transplant musculoskeletal problems arise either as a direct consequence of the underlying disease that led to transplantation, as a result of metabolic shifts, drug toxicity or interactions, or because of immunosuppressive therapy following transplantation. The most common rheumatologic sequelae of organ transplantation not only include gout, osteoporosis and osteonecrosis but also include less well-defined myalgias and arthralgias. This article provides a comprehensive review of musculoskeletal complications of transplantation and outlines the unique differential diagnosis and treatment options in graft recipients.
Inflammatory arthritis
Gout
Prevalence of gout in transplant recipients
Gout, by far, the most common inflammatory arthritis seen in transplant recipients, can result in loss of productivity and diminished quality of life. Furthermore, the interactions between immunosuppressive drugs, gout medications and organ dysfunction pose a therapeutic challenge. The prevalence of gout varies according to the organ transplanted but is highest following renal and heart transplantation. Studies of renal transplant recipients have shown rates of asymptomatic hyperuricaemia ranging 50–80% with cyclosporine (CsA) and 11–25% with azathioprine therapy with the prevalence of gout with use of these agents ranging 4–28% and 0–8%, respectively . CsA-treated heart transplant recipients also have an increased risk of developing gout. Both pre-existing and new-onset gout may have an accelerated course following heart transplant, with rapid onset of chronic polyarticular disease and tophi formation . The presence of a pre-transplant gout diagnosis almost triples the chance of having active post-transplant gout and is associated with more severe disease than de novo gout .
By contrast, only 2–6% of liver transplant recipients develop gout . A study from a single transplant centre compared heart to liver recipients and found gout in 25% of heart versus 2.6% of liver transplants, despite a similarly high prevalence of hyperuricaemia . Heart transplant recipients were more likely to be older, male, with reduced glomerular filtration, a history of diabetes mellitus and pre-transplantation hyperuricaemia and to be on CsA, diuretics and aspirin, all known risk factors for gout. However, the transplantation of heart versus liver was the only risk factor that independently predicted the development of gout . The prevalence of gout in lung and bone marrow transplant (BMT) has not been reported.
Clinical features of gout in transplant recipients
As in non-transplant patients, post-transplant gout is more prevalent in men than in women . In renal recipients, it is associated with higher body mass index and older age . Similarly to classic gout, the first episode is typically monoarticular and involves the first metatarsophalangeal joint. However, polyarticular disease with tophi can develop rapidly, within 3–5 years of the first attack (compared with an average of 10 years in primary gout) due to greater degrees of hyperuricaemia . Atypical sites of involvement, including spinal gout, have been described and may create a diagnostic challenge .
Pathophysiology of gout in transplant recipients
Pre-transplant hyperuricaemia is associated with a greater incidence of post-transplant gout . Hyperuricaemia prior to kidney and heart transplants may be due to diuretic use, decreased renal perfusion and overall kidney dysfunction. CsA, a calcineurin inhibitor, further predisposes to hyperuricaemia and gout in the post-transplant phase by inhibiting fractional urate excretion within the first 3 months of therapy. Patients on CsA with higher serum urate levels and on diuretics are more likely to develop gout . Tacrolimus, with a similar mechanism of action, has also been associated with hyperuricaemia but with a significantly lower risk of new-onset gout compared with CsA . Furthermore, changing from CsA to tacrolimus has led to resolution of treatment-resistant gout . The mechanism accounting for the difference on gout risk between CsA and tacrolimus is unclear. Uric acid crystals have recently been shown to activate the innate immune system resulting in interleukin-1 (IL-1) release and the typical inflammatory response of gout . Hence, anti-rejection therapy typically targeting the adaptive immune system does little to prevent acute gout.
Treatment of acute gout in transplant patients
A definitive diagnosis of gout must be established with aspiration of inflamed joints or tophi and demonstration of uric acid crystals. Septic arthritis must be excluded, particularly in acute monoarticular arthritis even in those with established gout due to the risk of unusual organisms. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective but should not be used with concomitant chronic kidney disease (CKD) or poorly compensated heart failure. NSAIDs should be avoided or used with extreme caution in patients receiving CsA so as to avoid exacerbation of intra-renal vasoconstriction . Colchicine is effective in non-transplant acute gout if started within 12 h of onset, but is associated with predictable gastrointestinal side effects . Colchicine is mainly eliminated by the liver, either unchanged or after metabolism by CYP3A4, and is dependent on the multidrug resistance (MDR) glycoprotein transport pump. CsA inhibits both CYP3A4 and MDR. Therefore, if colchicine is used with CsA a 60% dose reduction is necessary to avoid colchicine-induced myelosuppression and neuromyopathy (both of which have been described in renal and heart transplant recipients) . Most transplant patients receive a maintenance anti-rejection dose of oral corticosteroids. Increasing the basal dose of prednisone to 40 mg until gout symptoms improve and then tapering over 7–10 days is an effective option . The relative contraindications to systemic steroid therapy are well known and warrant consideration. Oral dexamethasone can be substituted for prednisone in patients with heart failure to minimise mineralocorticoid effects . Intra-articular steroid therapy is practical when one or two joints are inflamed and once infection has been excluded . Intramuscular corticotropin may also be effective . Recently, IL-1 receptor antagonists such as anakinra have been reported to be effective in non-transplant gout . Blocking IL-1 may be a viable treatment approach in transplant patients when contraindications to conventional therapy exist, but further research is needed.
Urate-lowering therapy in transplant recipients
Urate-lowering therapy may be initiated following the first attack of gouty arthritis. Allopurinol, a xanthine oxidase inhibitor, is the first line of urate-lowering therapy in transplant-associated gout starting at 50–100 mg, with dose titration to a target serum urate level of <6 mg dl −1 while monitoring blood counts, renal and hepatic functions as often as every 4 weeks in the initial stages. The inhibition of xanthine oxidase also interferes with azathioprine metabolism, and the combination may lead to severe myelosuppression . Mycophenolate mofetil does not interact with allopurinol and can safely be substituted for azathioprine . CsA dose reduction is also required when used with allopurinol as it increases CsA trough levels by 10–30% . Febuxostat, a non-purine xanthine oxidase inhibitor recently approved for the treatment of gout, has not yet been assessed in the transplant setting . Of note, febuxostat use in combination with azathioprine is contraindicated.
Uricosuric agents lower serum urate levels by inhibiting renal resorption of filtered urate . Probenecid is the only uricosuric drug available in the United States and is ineffective in CKD when creatinine clearance is less than 60 ml min −1 . By increasing uric acid excretion, probenecid may lead to nephrolithiasis, which in a denervated transplanted kidney may not present until after acute kidney injury has occurred . Furthermore, probenecid lowers CsA trough levels, requiring a CsA dose increase (see Table 1 ) . Benzbromarone is a potent uricosuric agent effective with creatinine clearance as low as 25 ml min −1 . Available in Japan and with limited access in Europe, it is used when patients fail or are allergic to allopurinol. In CsA-treated renal transplant patients, benzbromarone appears to be more effective in reducing serum urate levels than allopurinol and is well tolerated despite concerns of hepatotoxicity and nephrolithiasis . Finally, there are anecdotal reports of urate oxidase use in transplant patients to rapidly normalise serum urate levels and reduce tophi .
| Drug | Drug | Mechanism | Effect of interaction | Clinical Manifestation | Solution |
|---|---|---|---|---|---|
| Azathioprine (AZA) | Allopurinol | Inhibition of xanthine oxidase | Increased mercaptopurine levels | Severe leucopenia | Decrease AZA dose by 50–75%; start with allopurinol 50 mg; replace AZA with mycophenolate mofetil |
| Azathioprine | Febuxostat | Inhibition of xanthine oxidase | Increased mercaptopurine levels | Severe leucopenia | Contra-indicated by the manufacturer |
| Cyclosporine (CsA) | Probenecid, Sulphynpyrazone | Increased CsA clearance | Decreased CsA trough levels | Rejection | Increase CsA dose by 20–40%; follow levels |
| Cyclosporine | Colchicine | Decreased CsA clearance | Increased CsA trough levels | CsA toxicity | Decrease CsA dose by 10–30%; follow levels |
| Cyclosporine | NSAIDs | Increased intrarenal vascoconstriction | Reduced renal perfusion | Reduced kidney function | Limit NSAID use to 1–2 days or avoid use |
| Colchicine | Cyclosporine Tacrolimus | Inhibition of MDR and CYC P3A4 and reduced colchicine cellular clearance | Colchicine toxicity | Neuromyopathy, cytopenias | Decrease colchicine dose to 0.15–0.3 mg daily; monitor neurologic exam and CPK |
Suppressive anti-inflammatory therapy is necessary since low-dose prednisone used as part of the anti-rejection regimen is typically insufficient to prevent a gout flare. Colchicine may be used but at a reduced dose of 0.6 mg 2–3 times a week in the context of moderate CKD or calcineurin inhibitor therapy .
Septic arthritis
Despite the inherent risk of infection from immunosuppression, the prevalence of post-transplant septic arthritis is less than 1% . Bacteria are most commonly implicated and include the usual Gram-positive as well as Gram-negative organisms such as Nocardia , Pseudomonas , Serratia and Salmonella . Fungal articular infections with Aspergillus , Cryptococcus , Coccidioides and Candida have been reported, especially in the BMT population . Septic arthritis caused by M. tuberculosis and atypical mycobacteriae have been well described . Cytomegalovirus arthritis with demonstration of viral particles in the synovium has been reported as well. Infectious arthritis in the transplant recipient is typical, with monoarticular involvement of large, weight-bearing joints (knee and ankle), but the wrist, elbow and hip are not exempt. Synovial fluid leucocyte counts may, however, not be markedly elevated nor show the usual neutrophil predominance; peripheral white blood cell counts may also be normal . Therefore, a high index of suspicion for infectious arthritis is needed, and cultures for bacterial, mycobacterial and fungal organisms should be sent routinely.
Other inflammatory arthritis
Immunosuppressive drugs have been linked to cases of aseptic inflammatory arthritis. Tacrolimus may induce acute calcium pyrophosphate arthritis in liver transplant recipients, possibly via its effect on renal magnesium loss . Mycophenolate mofetil has been reported to cause an acute inflammatory syndrome in patients with Wegener’s granulomatosis and was implicated in a case of acute inflammatory oligoarthritis in a renal transplant recipient .
Osteoporosis
Predisposing factors for osteoporosis in the pre-transplant phase
Transplant candidates, particularly those awaiting kidney grafting, are at risk for osteoporosis. Bone biopsies may reveal osteitis fibrosa (high turnover resulting from sustained hyperparthayroidism), adynamic bone or a mixed picture. Gonadal dysfunction in addition to metabolic acidosis and medications (particularly loop diuretics and anticoagulants) can further lower bone mineral density (BMD) . Vitamin D deficiency, reduced calcium absorption, hypogonadism, alcohol excess, decreased synthesis of insulin-like growth factor-1 (IGF-1), hyperbilirubinaemia and corticosteroids use in the case of autoimmune hepatitis, all contribute to the high prevalence of osteoporosis in chronic liver disease . Decreased BMD is particularly common in primary biliary cirrhosis, a disease primarily affecting post-menopausal women . Vitamin D deficiency from intestinal congestion, in addition to loop diuretics and renal insufficiency, may be important contributors in end-stage cardiac disease . Risks in patients with pulmonary diseases include hypoxaemia, corticosteroid therapy and tobacco use . Pancreatic insufficiency leading to vitamin D and calcium malabsorption as well as hypogonadism are significant risk factors for osteoporosis in cystic fibrosis . Glucocorticoids, hypogonadism due to high-dose chemotherapy and total body irradiation add to the risk in BMT recipients. Immobility, ageing and low body mass index (BMI) are also common issues in chronically ill patients awaiting transplantation .
Because of the significant risk factor burden for osteoporosis, transplant candidates should be evaluated with dual-energy X-ray absorptiometry (DXA), and secondary causes of osteoporosis treated. Vitamin D deficiency should be corrected to a 25(OH) D level of ≥30 ng ml −1 , and all patients should ingest the recommended daily allowance of calcium. The exception to anti-osteoporosis treatment is severe CKD patients in whom bisphosphonates are contraindicated and in whom hyperparathyroidism and hyperphosphataemia should be addressed .
Osteoporosis after transplantation
As many as half of transplant patients develop osteoporosis. The most rapid rates of bone loss and the highest fracture rates are seen during the first year following transplant and are strongly related to glucocorticoid therapy. Glucocorticoids increase bone resorption via renal calcium wasting, inhibition of intestinal absorption of calcium and hypogonadism. They also inhibit osteoblast function and proliferation and act directly to stimulate osteoclastogenesis. Steroid myopathy may compromise balance and further contribute to fracture risk .
Calcineurin inhibitors contribute to bone loss via T-lymphocyte effects and a cytokine-mediated increase in bone turnover, as well as by reducing testosterone production . They may also increase risk for renal bone disease as they are a major cause of chronic renal insufficiency in non-renal solid-organ transplant recipients . Little clinical data are available on the skeletal effects of other immunosuppressive agents .
Additional factors contributing to bone loss after BMT may include slowed proliferation and differentiation of bone marrow stromal cells to the osteoblastic lineage, and the residual presence of stromal cells damaged by myeloablative therapy. The direct effects of graft-versus-host disease (GVHD) on bone cells and the need for immunosuppressive therapy may increase osteoporosis risk in allograft recipients .
Persistent secondary hyperparathyroidism after renal transplant is a major challenge and might progress to tertiary hyperparathyroidism. An elevated parathyroid hormone (PTH) level is found in as many as half of these patients up to 2 years after transplantation , and is further complicated by the lack of guidelines defining appropriate PTH levels in this population .
Prevention and treatment of post-transplant osteoporosis
Bisphosphonates induce osteoclast apoptosis and thereby reduce bone resorption . Several studies have addressed their role in prevention and treatment of early rapid bone loss following transplantation. Bisphosphonates appear to be efficacious and are recommended in preventing lumbar spine and hip bone loss in BMT, cardiac, liver and lung transplant recipients . Unfortunately, fractures remain a significant issue even after initiation of bisphosphonate therapy . Intravenous rather than oral route may be preferred when proper oral administration is difficult, poor absorption due to intestinal congestion a concern or oesophageal disease a contraindication. Appropriate duration and long-term effects of treatment are not known; there are data that suggest BMD stability even after discontinuation of anti-resorptive therapy .
Use of bisphosphonate therapy immediately after renal transplant is controversial owing to concerns that anti-resorptive therapy could worsen adynamic bone disease . Although safe and effective at attenuating lumbar bone loss , bisphosphonates are generally reserved for high-risk renal transplant patients with a T score of < −2 SD and with good graft function .
Active vitamin D metabolites might be helpful in bone protection as well. Calcitriol may be as effective as alendronate in preventing bone loss after cardiac transplantation, particularly at the hip, but the requirement for serum and urinary calcium monitoring may decrease its appeal . A systematic review of controlled trials of kidney transplant recipients found that vitamin D sterol along with bisphosphonates (via any route) and calcitonin all provided lumbar spine benefit and the former two agents also had beneficial effects at the femoral neck. However, in head-to-head comparison, bisphosphonates were superior to vitamin D sterols . Gonadal hormone replacement and exercise training also appear to be protective. Calcitonin may provide some benefit in the later post-transplantation period but is not effective in early bone loss . Teriparatide, a recombinant human parathyroid hormone 1–34, although effective in the treatment of glucocorticoid-induced osteoporosis , did not improve BMD in the early period after kidney transplantation . Further investigation of PTH agonists, antibodies to receptor activator for nuclear κB ligand (RANKL) and other novel therapies targeting the Wnt signalling pathway are ongoing .
Osteoporosis
Predisposing factors for osteoporosis in the pre-transplant phase
Transplant candidates, particularly those awaiting kidney grafting, are at risk for osteoporosis. Bone biopsies may reveal osteitis fibrosa (high turnover resulting from sustained hyperparthayroidism), adynamic bone or a mixed picture. Gonadal dysfunction in addition to metabolic acidosis and medications (particularly loop diuretics and anticoagulants) can further lower bone mineral density (BMD) . Vitamin D deficiency, reduced calcium absorption, hypogonadism, alcohol excess, decreased synthesis of insulin-like growth factor-1 (IGF-1), hyperbilirubinaemia and corticosteroids use in the case of autoimmune hepatitis, all contribute to the high prevalence of osteoporosis in chronic liver disease . Decreased BMD is particularly common in primary biliary cirrhosis, a disease primarily affecting post-menopausal women . Vitamin D deficiency from intestinal congestion, in addition to loop diuretics and renal insufficiency, may be important contributors in end-stage cardiac disease . Risks in patients with pulmonary diseases include hypoxaemia, corticosteroid therapy and tobacco use . Pancreatic insufficiency leading to vitamin D and calcium malabsorption as well as hypogonadism are significant risk factors for osteoporosis in cystic fibrosis . Glucocorticoids, hypogonadism due to high-dose chemotherapy and total body irradiation add to the risk in BMT recipients. Immobility, ageing and low body mass index (BMI) are also common issues in chronically ill patients awaiting transplantation .
Because of the significant risk factor burden for osteoporosis, transplant candidates should be evaluated with dual-energy X-ray absorptiometry (DXA), and secondary causes of osteoporosis treated. Vitamin D deficiency should be corrected to a 25(OH) D level of ≥30 ng ml −1 , and all patients should ingest the recommended daily allowance of calcium. The exception to anti-osteoporosis treatment is severe CKD patients in whom bisphosphonates are contraindicated and in whom hyperparathyroidism and hyperphosphataemia should be addressed .
Osteoporosis after transplantation
As many as half of transplant patients develop osteoporosis. The most rapid rates of bone loss and the highest fracture rates are seen during the first year following transplant and are strongly related to glucocorticoid therapy. Glucocorticoids increase bone resorption via renal calcium wasting, inhibition of intestinal absorption of calcium and hypogonadism. They also inhibit osteoblast function and proliferation and act directly to stimulate osteoclastogenesis. Steroid myopathy may compromise balance and further contribute to fracture risk .
Calcineurin inhibitors contribute to bone loss via T-lymphocyte effects and a cytokine-mediated increase in bone turnover, as well as by reducing testosterone production . They may also increase risk for renal bone disease as they are a major cause of chronic renal insufficiency in non-renal solid-organ transplant recipients . Little clinical data are available on the skeletal effects of other immunosuppressive agents .
Additional factors contributing to bone loss after BMT may include slowed proliferation and differentiation of bone marrow stromal cells to the osteoblastic lineage, and the residual presence of stromal cells damaged by myeloablative therapy. The direct effects of graft-versus-host disease (GVHD) on bone cells and the need for immunosuppressive therapy may increase osteoporosis risk in allograft recipients .
Persistent secondary hyperparathyroidism after renal transplant is a major challenge and might progress to tertiary hyperparathyroidism. An elevated parathyroid hormone (PTH) level is found in as many as half of these patients up to 2 years after transplantation , and is further complicated by the lack of guidelines defining appropriate PTH levels in this population .
Prevention and treatment of post-transplant osteoporosis
Bisphosphonates induce osteoclast apoptosis and thereby reduce bone resorption . Several studies have addressed their role in prevention and treatment of early rapid bone loss following transplantation. Bisphosphonates appear to be efficacious and are recommended in preventing lumbar spine and hip bone loss in BMT, cardiac, liver and lung transplant recipients . Unfortunately, fractures remain a significant issue even after initiation of bisphosphonate therapy . Intravenous rather than oral route may be preferred when proper oral administration is difficult, poor absorption due to intestinal congestion a concern or oesophageal disease a contraindication. Appropriate duration and long-term effects of treatment are not known; there are data that suggest BMD stability even after discontinuation of anti-resorptive therapy .
Use of bisphosphonate therapy immediately after renal transplant is controversial owing to concerns that anti-resorptive therapy could worsen adynamic bone disease . Although safe and effective at attenuating lumbar bone loss , bisphosphonates are generally reserved for high-risk renal transplant patients with a T score of < −2 SD and with good graft function .
Active vitamin D metabolites might be helpful in bone protection as well. Calcitriol may be as effective as alendronate in preventing bone loss after cardiac transplantation, particularly at the hip, but the requirement for serum and urinary calcium monitoring may decrease its appeal . A systematic review of controlled trials of kidney transplant recipients found that vitamin D sterol along with bisphosphonates (via any route) and calcitonin all provided lumbar spine benefit and the former two agents also had beneficial effects at the femoral neck. However, in head-to-head comparison, bisphosphonates were superior to vitamin D sterols . Gonadal hormone replacement and exercise training also appear to be protective. Calcitonin may provide some benefit in the later post-transplantation period but is not effective in early bone loss . Teriparatide, a recombinant human parathyroid hormone 1–34, although effective in the treatment of glucocorticoid-induced osteoporosis , did not improve BMD in the early period after kidney transplantation . Further investigation of PTH agonists, antibodies to receptor activator for nuclear κB ligand (RANKL) and other novel therapies targeting the Wnt signalling pathway are ongoing .
Related posts:
Inflammatory osteoarthritis of the hand
Management of osteoporosis in a pre-menopausal woman
Prevention and cure of rheumatoid arthritis: Is it possible?
Evidence-based management of rapidly progressing systemic sclerosis
Treatment-resistant inflammatory myopathy
Primary angiitis of the central nervous system: differential diagnosis and treatment
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
