A patient with known steroid-dependent rheumatoid arthritis (RA) developed an acute symmetrical polyarthropathy of small and medium-sized joints associated with markedly elevated inflammatory markers suggestive of RA flare, on day 4 after deceased-donor renal transplantation. The patient received standard induction immunosuppression with methylprednisolone and basiliximab, and had commenced prednisolone, tacrolimus and mycophenolate mofetil. Serological investigations and joint aspirate to exclude infective causes and crystal arthropathy were unremarkable. High-dose prednisolone (50 mg daily) resulted in partial but unsustained symptomatic improvement. On suspicion of a medication-related adverse event, tacrolimus and mycophenolate mofetil were changed to cyclosporine A and azathioprine on day 16. This was followed by rapid improvement in symptoms and normalization of inflammatory markers. Unexpected sequelae in the early post-transplantation period create diagnostic and management challenges. Medication-related adverse events are not uncommon, and we speculate in this case on the potential for medication-induced immune system dysregulation stimulating disease activity in a chronic autoimmune condition after introduction of new immunosuppressants.
A 63-year-old male underwent deceased donor renal transplantation in May 2012. His past medical history included end stage kidney disease and haemodialysis since 2009 from post-infectious glomerulonephritis in the setting of polyarticular septic arthritis (Staphylococcus aureus) and a solitary kidney. Other relevant history included stable ischaemic heart disease, atrial fibrillation, type 2 diabetes, nephrectomy (renal cell cancer) in 1988, osteoporosis and rheumatoid arthritis (RA). The RA was diagnosed at age 28, and managed with methotrexate and prednisolone until the patient commenced haemodialysis. Methotrexate was then ceased and prednisolone continued at a minimum of 15 mg daily. Despite relatively quiescent disease he had significant joint deformity, joint destruction and bony erosions. The patient either did not tolerate or declined other disease-modifying agents such as hydroxychloroquine and had not received biologics.
Deceased-donor renal transplantation was uncomplicated. There was a 5/6 human leukocyte antigen mismatch, with no known donor-specific antibodies, and both donor and recipient were cytomegalovirus IgG negative. Standard induction immunosuppression with intravenous methylprednisolone 1 g and basiliximab 20 mg was administered pre-operatively and basiliximab again on day 4. Oral prednisolone 30 mg daily, mycophenolate mofetil 1 g twice daily and tacrolimus 0.075 mg/kg twice daily were commenced post-operatively. Trimethoprim–sulphamethoxazole as pneumocystis jirovecii pneumonia prophylaxis was also commenced. In the evening of day 4, the patient complained of bilateral hand, wrist, elbow and knee arthralgia that he felt was consistent with an RA flare. There was no evidence of joint erythema or effusions, and no fever or skin rash on examination. The symptoms were relatively mild, so he was observed and discharged on day 7. By day 8 he required admission for worsening arthralgia, reduced mobility and unstable angina. The angina was thought related to anaemia (Hb 90 g/L), and managed effectively with blood transfusion and anti-anginal medication.
Extensive investigation of the arthralgia followed. The patient remained systemically well and denied any new rash or fevers. Examination revealed symmetrical polyarthritis affecting the wrists, metacarpophalageal joints, elbows, shoulders and knees, with joint-line tenderness and joint effusions. Initial investigations were: creatinine of 115 μmol/L showing stable graft function, C-reactive protein (CRP) of 232 mg/L (previously 14.4 mg/L on day 2), ESR of 105 mm/h, and trough tacrolimus level of 12.5 ng/mL (slightly above target range). Further investigations included: rheumatoid factor (RF) of 62 IU/mL, anti-cyclic citrullinated peptide antibody (anti-CCP) of >250 U/mL, uric acid of 0.39 mmol/L, and three negative blood cultures. Hand X-rays supported bilateral and symmetrical chronic deforming and erosive inflammatory arthropathy, consistent with RA. The patient had not undergone anti-CCP testing previously, nor had RF testing for over 10 years. A joint aspirate of the right knee revealed an elevated polymorph count, without evidence of crystal arthropathy or septic arthritis.
Differential diagnosis included infection-related arthralgia, polyarticular gout, RA flare, or a medication-related adverse reaction. Gout was thought unlikely as no crystals were present on joint aspirate and the patient had no history of gout. Initial management included prednisolone increase from 30 to 50 mg daily, and further investigations were undertaken. Following prompt symptomatic improvement, prednisolone dose was lowered to 40 mg daily in lieu of significant hyperglycaemia. He was discharged home on day 14, but unfortunately represented 2 days later unable to walk, with worsening severe polyarthritis requiring readmission. Graft function and tacrolimus level remained stable.
Investigations and further questioning specific for infection followed. The patient had not travelled recently and had limited animal exposure (domestic pets only). He had been well without infective symptoms in the weeks preceding transplantation. The donor had undergone a cardiovascular-related death with no symptoms of recent infection, and the recipient of the other donor kidney remained well. Limited investigations were carried out (Table 1), and an infectious diseases opinion was sought. It was considered that the temporal course of the arthropathy, reassuring history relating to the potential for donor-transmitted infection, and normal culture and serology results, made an infective cause of the polyarthritis whilst still possible, highly unlikely.
Table 1. Investigations undertaken to exclude infective causes of an acute inflammatory polyarthropathy with results
Acute inflammatory arthritis from a flare of RA or other acute autoimmune process was considered. Lupus serology including ANA, ENA and complements were within normal parameters. In the setting of high-dose immunosuppression, a rheumatological opinion considered RA flare unlikely, though unable to be excluded. Continuation and subsequent wean of high-dose steroids was recommended. Administration of disease-modifying agents including biologics was not advised due to diagnostic uncertainty and excessive risk with immunosuppression escalation, particularly when considering the potential for undiagnosed donor-transmitted infection.
Given the ongoing severity of the patient's symptoms, only partial response to high-dose steroids, and suspicion of a medication-related adverse event, a change in management was instituted on day 16. Following a single pulse of intravenous methylprednisolone (250 mg), the tacrolimus was changed to cyclosporine A and the mycophenolate mofetil to azathioprine 1.5 mg/kg daily; the severity of symptoms at the time dictating a change in both medications simultaneously. Rapid improvement in the patient's inflammatory markers and arthritis occurred by 48 h, with normalization of CRP within a week (Fig. 1).
The patient remained well and arthritis-free with a normal CRP for the next three months. Prednisolone was weaned slowly, with the patient still on 30 mg by 4 weeks post-transplantation and 20 mg at 8 weeks. Ten weeks after transplantation the creatinine rose to 158 μmol/L and a renal transplant biopsy showed borderline acute cellular rejection (Banff '97 score: i1, ti2, t1, ci1, ct1, cg1). He was treated with intravenous methylprednisolone 250 mg daily for three days followed by 20 mg of prednisolone daily, and changed from azathioprine to mycophenolate mofetil 1 g BD. He did not experience any recurrence of joint symptoms.
The patient is now 18 months post transplantation. He is maintained on prednisolone 10 mg daily, mycophenolate mofetil 500 mg BD and cyclosporine A. He has had no further rejection or recurrence of acute inflammatory arthritis. Attempted further reduction of prednisolone has aggravated the patient's chronic joint symptoms.
This case highlights the difficulties managing unexpected adverse events in the early post-transplantation period, particularly unusual presentations such as an inflammatory arthropathy. Musculoskeletal pain is a common problem after renal transplantation, however an acute inflammatory arthropathy is rare. The differential diagnosis is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatological disorders, and medication-related adverse events. In our case, many of these differential diagnoses were excluded through supportive investigations and the temporal course of events.
Infection-related arthritis is commonly due to viral infections. After recent transplantation, high-dose immunosuppression increases the risk of reactivation of quiescent viral infection and de novo viral infection in the recipient, as well as donor-transmitted infection. In our patient, missing a donor-transmitted infection was a significant concern, however reassuring clinical improvement with supportive investigations (negative polymerase chain reaction and serology for particular viral infections known to present with arthralgia in this population), made an infection-related arthritis highly unlikely.
A medication-related adverse event proved the most likely cause of the patient's symptoms. After transplantation, new medications including potent immunosuppressants are commenced simultaneously and adverse events are not uncommon. Medication-related adverse events are inevitably a diagnosis of exclusion, and as these immunosuppressants are vital for graft survival, isolation and subsequent cessation/alteration of the presumed causative agent can be challenging and fraught with risk.
Calcineurin inhibitors (CNI) including tacrolimus have been associated with a musculoskeletal pain syndrome affecting the lower limbs. Calcineurin-induced pain syndrome (CIPS) was first named in 2001 by Grotz et al. with a series of nine renal transplant recipients, and more extensive reporting has occurred since. Onset is typically 3 to 12 months after transplantation. The disorder is characterized by debilitating symmetrical osteoarticular pain of the knees and feet, which persists for a number of months and is usually self-limiting. Inflammatory markers are rarely elevated. Symptoms often improve with CNI dose-reduction or cessation, and pathogenesis is hypothesized to be related to intraosseous vasoconstriction. Whilst CIPS has some features consistent with our patient's presentation, the early onset after transplantation and the systemic and inflammatory aspects argue against it.
Several case reports have found mycophenolate mofetil to be associated with an acute inflammatory syndrome characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers soon after initiation of therapy in renal transplantation or treatment for ANCA-associated vasculitis. Symptoms begin 3–5 days after initiation or dose-increase of mycophenolate, and rapidly resolve with mycophenolate cessation. The pathogenesis has been attributed to a paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils. Our patient was able to tolerate reintroduction of mycophenolate mofetil after the episode of rejection, thus it is unlikely to be the cause of symptoms.
Whilst a coincidental flare of the patient's underlying RA seems implausible in the setting of high-dose immunosuppression, an alternative hypothesis is that immune system dysregulation induced by use of immunosuppressant medication caused a paradoxical response and subsequent flare of the patient's RA. The pathogenesis of different autoimmune diseases is heterogeneous – as demonstrated by the variation in response to different immunosuppressants and recurrence rates of autoimmune primary diseases after transplantation. Disruption of immune system homeostasis with potentially undesirable or paradoxical responses has also been demonstrated by administration of different immunosuppressants and immunomodulators. A specific example includes medications from the interferon family being associated with promotion of renal allograft rejection, exacerbation of pre-existing autoimmune disease and development of de novo autoimmune disease in certain populations.
The pathogenesis of RA is complex, and recent studies suggest disease activity in RA is mediated by an imbalance between Th17 and T-regulatory (T-reg) cells. T-regs are thought to suppress pathologic immune responses in autoimmune disease. In RA, reduced number of T-regs and dysfunctional T-regs have been observed, and depletion of T-regs in a mouse model of RA increases disease activity which can then be reversed with adoptive transfer of T-regs.
Medications used in renal transplantation which specifically target IL-2 may be implicated in disrupting this Th17/T-reg balance. Li et al. reported that tacrolimus (blocker of IL-2 transcription) at serum concentrations above 6 ng/mL, compared with lower tacrolimus level, cyclosporine A and sirolimus in renal transplant recipients, was associated with greater imbalance between Th17/T-reg cell numbers in peripheral blood, specifically higher Th17 levels and lower T-reg levels.
Basiliximab, a monoclonal antibody directed against IL-2 receptors, may therefore also be implicated in this hypothesis. Bluestone et al. compared the effect of basiliximab in addition to standard immunosuppression (cyclosporine A, mycophenolate mofetil and steroid taper) with belatacept (a CTLA-4Ig) and standard immunosuppression on T-regs in peripheral blood after renal transplantation. A profound but transient reduction in CD4+CD25+FOXP3 T-regs was observed in the basiliximab but not the belatacept arm within 7 days of treatment.
Our case describes acute onset polyarthritis immediately after transplantation. Whilst a discrete cause was not proven, the sequence of events, supportive investigations excluding other differentials, temporal relationship with basiliximab and persistent resolution of symptoms with cessation of tacrolimus and change to cyclosporine A, suggest that dysregulation of T-reg/Th17 function through IL-2 blockade may have had a causative role. Such a hypothesis has limited theoretical immunological support. Transplant immunology is complex, and as our arsenal of highly specific immunosuppressant and immunomodulating medications integrated into clinical practice increase, the occurrence of unusual and seemingly paradoxical reactions, although uncommon, will likely continue to present management challenges. We emphasize the importance of careful clinical assessment, vigilance with exclusion of infection, and wide consultation with specialist services and medical literatures when faced with unexpected and unexplained adverse events after transplantation.