RheumFocus: Allopurinol; Autoantibodies in RA
Published: Aug 20, 2014 | Updated: Aug 22, 2014
The rheumatology literature this week featured studies on allopurinol and severe cutaneous adverse reactions, the additive effects of autoantibodies on bone erosions in rheumatoid arthritis (RA), and predicting response to methotrexate in children with juvenile idiopathic arthritis (JIA).
Allopurinol and Skin Disasters
Compromised renal function correlated with the development of severe, life-threatening cutaneous adverse reactions (SCAR) in patients being treated with allopurinol, the xanthine oxidase inhibitor long used as a treatment for gout.
Severe baseline impairment of kidney function, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2, was present in 60% of patients with SCAR compared with only 15.9% of controls, according to Shuen-Iu Hung, PhD, of National Yang-Ming University in Taiwan, and colleagues.
This represented an eight times higher likelihood of developing SCAR in patients with severe renal impairment (OR 8, 95% CI 3.9-16.8, P<0.001), the researchers reported online in Annals of the Rheumatic Diseases.
About 2% of individuals develop mild hypersensitivity reactions when exposed to allopurinol, but 0.4% experience severe cutaneous reactions such as Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS).
One recognized risk factor for the occurrence of SCAR is carriage of the HLA-B*58:01 allele, but genetic predisposition doesn't account for all the increased risk.
Previous reports have suggested that adequate kidney function is required for patients to tolerate allopurinol, because the drug's primary metabolite, oxypurinol, is excreted renally.
To examine the role of renal function in allopurinol tolerance, Hung and colleagues prospectively enrolled 48 patients who were hospitalized with SCAR between 2007 and 2012, and 138 matched controls who tolerated allopurinol without skin hypersensitivity.
Women were almost seven times more likely to develop SCAR, as has been observed in other studies.
The mean of exposure to allopurinol was only 31 days among patients with SCAR, compared with 25 months in the tolerant patients (P<0.001). Maintenance dosage was a mean of 179 mg/day in the tolerant group, compared with 145 mg/day in the SCAR group (P=0.005).
Baseline eGFR was significantly lower in the SCAR patients, at a mean of 34 mL/min/1.73 m2, compared with 67.5 mL/min/1.73 m2 in the tolerant group (P<0.001).
In a multivariate analysis that adjusted for factors including age and sex, renal impairment remained an independent risk factor for SCAR (OR 5.64, 95% CI 2.46-12.9, P<0.001).
Renal impairment also correlated with mortality. Of the 26 patients with SJS/TEN, 10 of 15 whose eGFR was below 30 mL/min/1.73 m2 died, while the 11 whose eGFR was 30 mL/min/1.73 m2 or higher survived (P<0.001).
All patients with DRESS survived, but those with eGFR of 30 mL/min/1.73 m2 or above were in remission after a mean of 57.6 days compared with 113 days for those with lower eGFR (P=0.011).
Inadequate clearance of oxypurinol also correlated with poor outcomes. Among the SJS/TEN patients who died, plasma oxypurinol concentrations were 6.9 mg/L compared with 1.6 mg/L in those who survived (P=0.008).
Oxypurinol "has been considered to possess antigenic properties for the induction of SCAR as it can cause dose-dependent T-cell response in vitro," the researchers noted.
"Our analysis showed that renal impairment and the high concentrations of plasma oxypurinol correlated with the poor prognosis of allopurinol-SCAR, suggesting that delayed excretion of oxypurinol may cause the accumulated toxicity and generate irreversible deterioration," the researchers wrote.
The protein granulysin, released by those cytotoxic T cells, has been identified as a critical factor in the development of SJS/TEN through its effects on keratinocyte apoptosis.
Plasma levels of this protein also correlated with renal impairment, with a mean level of 342 ng/mL compared with levels below 40 ng/mL in patients with normal kidney function (P<0.05).
In addition, patients with SJS/TEN who died had elevated levels of granulysin for longer periods than survivors.
The observed increases in oxypurinol and granulysin may provoke a "vicious cycle" of kidney deterioration in patients with SCAR, with elevated oxypurinol levels persistently leading to the induction of cytotoxic T cells, the researchers suggested.
To interrupt this cycle and "attenuate the potentially continuous immune stimulation," clinicians might want to consider hemodialysis in patients with SCAR and renal insufficiency, according to Hung and colleagues.
"Whether such an intervention may improve the prognosis of allopurinol-SCAR needs further investigation," they concluded.
Antibodies and Erosions in RA
Patients with RA who are positive for both rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) had worse erosive disease than those without these autoantibodies, German researchers found.
The mean number of bone erosions in patients who were seropositive for RF and ACPA was 5.35 compared with 2.49 in those who were seronegative for both (t=3.45, P=0.001), according to Georg Schett, MD, and colleagues from the University of Erlangen-Nuremberg in Erlangen.
In addition, the highest volume of erosions was seen in patients with both autoantibodies, at 7.66 mm3compared with 3.32 mm3 in seronegative patients (t=5.418, P<0.001), the researchers reported online inAnnals of the Rheumatic Diseases.
The presence of these autoantibodies in RA is associated with a more severe disease course and a greater risk for structural joint damage.
A mechanistic explanation for the association between damage and the presence of ACPA was recently reported, with the demonstration that antibodies against the citrullinated protein vimentin led to the induction of osteoclasts and subsequent bone loss.
While RF as an autoantibody has been recognized much longer than ACPA in RA, the influence of RF on bone and joint damage and the potential mechanisms involved have been less clear.
To explore the effects of these autoantibodies and the interplay between them, Schett's group enrolled 238 patients with RA between 2011 and 2013, obtaining high resolution peripheral quantitative CT scans of the metacarpophalangeal (MCP) joints from all participants.
In a total of 714 joint CT scans, there were 897 erosions, most often in the second MCP joint.
In multivariate analyses adjusting for age, sex, disease activity, and duration of disease, significant associations were seen among the double seropositive group compared with the double seronegative group for the number of erosions (t=2.441, P=0.017) and for erosion volume (t=2.582, P=0.014).
Duration of disease also contributed in the seropositive group for number of erosions (t=3.713, P=0.005) and volume (t=3.335, P=0.013).
The researchers then compared erosions according to antibody titers, and found that patients who were positive for ACPA had higher erosion scores when RF titers also were high.
"These observations suggest that RF may act as an enhancer of bone loss in patients with RA, and acts as an additive to ACPAs," Schett and colleagues wrote.
Likely mechanisms for the effects of RF on bone include this immune complex's ability to activate monocytes and macrophages, which in turn release cytokines such as tumor necrosis factor-alpha that can induce osteoclasts.
"The combination of both antibodies additively increases the burden of bone erosion in RA, which is most likely based on the ACPA-specific mechanism, as previously described, and immune-complex mediated mechanisms related to RF."
Predicting Response in JIA
Several clinical factors such as the number of affected joints predicted which children with JIA would respond to treatment with methotrexate, researchers from Germany found.
Although methotrexate is commonly used in the treatment of JIA worldwide, adverse events are common and have been reported in up to 42% of recipients, according to Gerd Horneff, MD, of Asklepios Klinik in Sankt Augustin, and colleagues.
"Prediction of response can prevent further exposing of patients to the side effects of methotrexate and also save time by progressing to treatment with an alternative therapy (e.g., biologic drugs) as soon as possible to prevent irreversible complications," the researchers wrote online in Pediatric Rheumatology.
On a multivariate analysis, the following were associated with achieving a 30% improvement on the American College of Rheumatology Pediatric criteria (PedACR 30) at month three of treatment with methotrexate:
- Tender joint count: OR 0.92 (95% CI 0.88-0.97, P=0.002)
- Number of active joints: OR 1.26 (95% CI 1.16-1.36, P<0.001)
- Parent assessment of overall well-being: OR 1.02 (95% CI 1.01-1.03, P<0.001)
- Use of nonsteroidal anti-inflammatory drugs: OR 1.89 (95% CI 1.08-3.34, P=0.027)
Previous efforts to identify predictors of response to methotrexate have focused mainly on disease subtypes, and have had conflicting results.
To see if clinical or laboratory factors could be predictive, Horneff and colleagues analyzed data from a German longitudinal registry that included 731 patients enrolled between 2005 and 2010.
Two-thirds were female, and mean age of onset was 7.4 years. Mean number of swollen joints was 4.9, mean number of tender joints was 5.8, and mean number of active joints was 5.9.
By 3 months, 77.4% were PedACR 30 responders, as were 83.1% at 12 months.
More pronounced 70% responses (PedACR 70) were seen in 43.1% at month three and in 65.9% at 12 months.
A PedACR 70 response at 1 year was associated with number of tender and active joints and parent's global assessment, as for the PedACR 30 at 3 months, but also inversely with disease duration more than a year (OR 0.54, 95% CI 0.39-0.77, P=0.001) and the presence of morning stiffness (OR 1.58, 95% CI 1.10-2.28,P=0.014).
The area under the receiver operating curve at 12 months for these factors was 67.2%, with a sensitivity of 90.7% and a specificity of 27%.
The researchers also determined that a PedACR 30 at 3 months was "a highly significant positive predictor" for achieving a PedACR 70 by 1 year (OR 4.03, 95% CI 2.64-6.14).
These findings could help clinicians in treatment decision-making for children with JIA, the authors concluded.
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