Calcineurin-inhibitor induced pain syndrome

Calcineurin-inhibitor-induced pain syndrome (CIPS) describes a reversible acute pain syndrome that occurs in patients with transplants taking calcineurin inhibitors as immunosuppressive therapy to prevent transplant rejection ¹. The most common calcineurin inhibitors prescribed following organ transplant are tacrolimus and cyclosporin ^1,4.

Epidemiology

CIPS has been reported to occur in approximately 5% of all patients with transplants, including those who have undergone kidney, heart, liver, pancreas and bone marrow transplants ².

Clinical presentation

CIPS presents as an acute onset of pain within the peripheral lower limbs and joints ³. Involvement is usually symmetrical and the pain usually progresses sequentially from distal to more proximal joints ³.

Symptoms may commence from as soon as weeks post-transplant surgery to as long as 14 months after ¹. Duration of symptoms varies but can persist for up to 18 months ³.

Pain is exacerbated by weight-bearing activities such as standing or walking ³.

Pathology

There are several proposed theories for the pathophysiology of CIPS. The most popular theory suggests that the cause of pain is related to calcineurin inhibitors inducing alterations in vascular permeability leading to altered bone perfusion and permeability causing interosseous vasoconstriction and bone marrow edema ^{2, 3}. This theory is supported by both the distribution of pain within the distal lower limbs and imaging findings indicative of bone marrow edema ¹.

Some animal studies have found calcineurin causes increased bone turnover due to action on osteoblasts and osteoclasts ³.

This theory is supported by some studies finding symptomatic patients using calcineurin inhibitors to have elevated ALP levels when compared with asymptomatic patients ¹.

Radiographic features

Plain radiograph

Radiographs are generally normal ².

MRI

MRI is very sensitive for identifying affected joints. The main key feature of MR imaging is bone marrow edema ^3,4. The joints/ bones affected have a low T1 signal and high T2 signal in keeping with subchondral and periarticular bone edema ³.

Nuclear medicine

Bone Scintigraphy

Symmetrical intense tracer uptake in bones and joints affected ³. This is indicative of increased perfusion, vascularity and metabolism ².

Treatment and prognosis

It is important to remember that symptoms of CIPS will generally resolve with appropriate treatment. Therefore, early recognition and treatment can prevent prolonged periods of pain ³.

Treatment focuses on regulating bone marrow vascularity and bone turnover. There are several different approaches to establishing this including; reducing calcineurin inhibitor dose, changing immunosuppressants and adding a calcium channel blocker ^3,4. Some studies also suggest bisphosphonates and calcitonin can be used to inhibit osteolysis ^3,4.

Resting with legs elevated ².

Imaging features resolve as symptoms improve and the syndrome is completely reversible over a few months ².

History and etymology

A pain syndrome in patients with transplants treated with cyclosporin was first described by the French rheumatologist G Bouteiller and colleagues in 1989 ^1,5. The term calcineurin-inhibitor-induced pain syndrome (CIPS) was then later coined by the German nephrologist Wolfgang H. Grotz and colleagues in 2001 ⁴.

Differential diagnosis

• chronic regional pain syndrome (CRPS) ^1,4: marrow edema on MRI can make differentiation difficult based on imaging alone ¹ and differentiation is made based on:

  • clinical history: CRPS occurs after recent trauma or surgery ¹

  • pattern of disease: CRPS affects the lower and upper limbs and is not typically symmetrical ¹

  • commonly associated symptoms of CRPS include erythema and swelling within the skin and soft tissue ¹

• osteonecrosis (the most common cause of post-transplant limb pain) due to immunosuppression with steroids ^1,4

• insufficiency fracture ³

• osteoporosis ³

• gout (secondary to hyperuricemia caused secondary to calcineurin inhibitor medications) ¹

• polyneuropathy ^2,4

• peripheral atherosclerosis ⁴

• post-renal transplant patients can develop pain secondary to hyperparathyroidism ³