We read with interest the paper by Dixon et al, and the associated
paper published in 2011 on the risk of infection in glucocorticoid (GC)
use in RA.1,2 Whilst their analyses add somewhat to the evidence of the
risk of infection caused by GC in RA, because they are retrospective
observational studies of uncontrolled treatment decisions we have strong
reservations on the extent of their interpretations...
We read with interest the paper by Dixon et al, and the associated
paper published in 2011 on the risk of infection in glucocorticoid (GC)
use in RA.1,2 Whilst their analyses add somewhat to the evidence of the
risk of infection caused by GC in RA, because they are retrospective
observational studies of uncontrolled treatment decisions we have strong
reservations on the extent of their interpretations and conclusions. We
posit that:
(1.) The presence of strong confounding by indication severely limits
the usefulness of observational analyses on the risk of GC use in RA; and
this is especially so for analyses based on administrative datasets that
typically lack important detail on clinical variables;
(2.) The correction for such confounding (by number of rheumatologist
visits in the past 6 months and NSAID use) in this dataset is weak and
perhaps wrong, as many physicians will now adjust or even stop NSAID in
patients on GC;
(3.) The suggested explanations for their finding of an increased
risk of infection, say, 2 years after cessation of GC lacks biological
plausibility. Wouldn't the authors agree that it is much more likely is
that GC use is a strong (perhaps even the strongest) marker for disease
severity in RA, especially in countries such as Canada where GC use in RA
is traditionally low due to strong opinion leaders with large concern over
the safety of GC in RA?
Any observational analysis on the benefit-risk ratio of GC in RA
should start and end with a pointer to confounding by indication, an issue
which will always weaken any such analysis. Rather, it would be better to
collect data from all those randomized controlled trials that can be found
by an appropriate literature search and synthesize the findings, using
meta-analysis if appropriate. This is currently being undertaken (Jensen
et al, in preparation). If the question remains unanswered, then the best
way to find a definitive answer would be through a a large and and
sufficiently long pragmatic trial of GC in RA.Studies such as those by
Dixon et al should be interpreted with great caution.
References
1. Dixon WG, Kezouh A, Bernatsky S, et al. The influence of
systemic glucocorticoid therapy upon the risk of non-serious infection in
older patients with rheumatoid arthritis: a nested case-control study. Ann
Rheum Dis 2011;70:956-60.
2. Dixon WG, Abrahamowicz M, Beauchamp ME, et al. Immediate and
delayed impact of oral glucocorticoid therapy on risk of serious infection
in older patients with rheumatoid arthritis: a nested case-control
analysis. Ann Rheum Dis 2012.
Conflict of Interest:
both authors, consulting fees from Horizon and Mundipharma, Ltd
In October 2011, Beyer and colleagues published an interesting
article on the use of tocilizumab as rescue treatment for 3 patients with
giant cell arteritis(1). Their patients had a high systemic inflammatory
response and involvement of the aorta and its main branches, showing
Takayasu-like features. The authors noted that, perhaps, tocilizumab might
be less effective for 'classical' giant cell arteri...
In October 2011, Beyer and colleagues published an interesting
article on the use of tocilizumab as rescue treatment for 3 patients with
giant cell arteritis(1). Their patients had a high systemic inflammatory
response and involvement of the aorta and its main branches, showing
Takayasu-like features. The authors noted that, perhaps, tocilizumab might
be less effective for 'classical' giant cell arteritis (GCA) patients with
limited cranial involvement. In other case reports, tocilizumab has also
been used successfully in patients with giant-cell arteritis and elevated
acute phase reactants(2). In a series of cases recently published by Seitz
et al(3,4), interestingly, two of their patients had almost normal acute
phase reaction before starting treatment with tocilizumab and they did
respond quickly upon treatment. The results in these case reports may
indicate a good correlation between recent advances in the understanding
of the pathogenic mechanisms of GCA and the favorable response to
tocilizumab.
At least two distinct CD4+ T-cell subsets, namely Th17 and Th1 cells,
promote vascular inflammation in GCA. Th17 cells are explicitly
corticosteroid-sensitive. However, Th1 cells are corticosteroid-resistant
and abnormal Th1 responses continue, unaffected by corticosteroids,
identifying GCA as a long-term, chronic immune-mediated disease(5).
Interferon-gamma, the signature cytokine produced by the Th1 cell lineage,
is expressed in high amounts in patients who experiment ischaemic
complications. Thus, a major therapeutic challenge in controlling GCA
disease activity lies in persistent Th1 responses. A recent study(6) has
shown that in peripheral blood of active GCA patients Th1 and Th17 cells
are markedly expanded and regulatory T cells are decreased. In
experimental models, interleukin-6 (IL-6) is a potent inhibitor of
transforming growth factor beta (TGF-beta)-driven induction of Foxp3+
regulatory T cells(7). IL-6 not only suppresses the generation of these
regulatory T cells, but together with TGF-beta, it also induces naive T
cells to express interleukin-17 and to become pathogenic Th17 cells(7).
Theoretically, given that IL-6 regulates the balance between Th17 and
regulatory T cells(8), it is possible that blocking IL-6-induced
intracellular signals by the anti-IL-6 receptor antibody tocilizumab
ameliorates the function of regulatory T cells, thereby helping to bring
the immune system into physiologic balance.
Thus, besides its possible use as a rescue treatment or steroid
sparing agent, perhaps, tocilizumab could have an additional role in
modifying the natural history of this disorder.
References
1.Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6
receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum
Dis 2011;70:1874-5.
2.Sciascia S, Rossi D, Roccatello. Interleukin 6 blockade as steroid-
sparing treatment for 2 patients with giant cell arteritis. J Rheumatol
2011;38:2080-1.
3.Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6
blockade. A case series. Swiss Med Wkly 2011;141:w13156.
4.Seitz M. Reply to the Letter to the Editor of Francisco Jose
Fernandez-Fernandez et al. Swiss Med Wkly 2012;142:w13504.
5.Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two
faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol
2011;23:43-9.
6.Terrier B, Geri G, Chaara W, et al. IL-21 modulates Th1 and Th17
responses in giant cell arteritis. Arthritis Rheum 2011 Dec 6. doi:
10.1002/art.34327.
7.Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental
pathways for the generation of pathogenic effector TH17 and regulatory T
cells. Nature 2006;441:235-8.
8.Korn T, Mitsdoerffer M, Croxford AL, et al. IL-6 controls Th17
immunity in vivo by inhibiting the conversion of conventional T cells into
Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2008;105:18460-5.
Recently Henes et al reported that serum levels of the proinflammatory
mediator high mobility group box-1 protein (HMGB1) were elevated and
showed a significant correlation with the burden of granulomatous
inflammation in patients with Granulomatosis with polyangiitis (GPA or
Wegener) (1). The same group has previously published data suggesting that
HMGB1 is a marker of GPA and that HMGB1 is not detec...
Recently Henes et al reported that serum levels of the proinflammatory
mediator high mobility group box-1 protein (HMGB1) were elevated and
showed a significant correlation with the burden of granulomatous
inflammation in patients with Granulomatosis with polyangiitis (GPA or
Wegener) (1). The same group has previously published data suggesting that
HMGB1 is a marker of GPA and that HMGB1 is not detected in patients with
Microscopic polyangiitis (MPA) (2).
We have recently studied AAV-patients with biopsy-proven renal
involvement. We found elevated serum HMGB1 levels in active disease
compared with remission in GPA, MPA and Churg-Strauss syndrome (CSS) and
have also demonstrated HMGB1 in active renal lesions in tissue stainings
irrespective of AAV subtype (3). This may reflect necrosis-induced
inflammation in the kidneys although systemic inflammation is also likely
to be important. Furthermore we have previously demonstrated elevated
levels of serum HMGB1 in other inflammatory diseases such as RA in which
granulomatosis is not a key finding (4). Our HMGB1 serum samples have been
analyzed with a Western Blot method whereas Henes et al utilized a
commercial ELISA. This methodological issue may be of importance as there
seems to be a discrepancy between Western Blot and ELISA results.
Urbonaviciute et al reported that serum/plasma components bind to HMGB1
and may interfere with its detection by ELISA systems and similar findings
were reported in a more recent cohort of patients with systemic lupus
erythematosus (5,6).
After reanalyzing our AAV-data (3) looking specifically at lung
involvement in addition to renal involvement we found that there was a
significant correlation between HMGB1 levels in 11 patients with lung
manifestations (Rho 0.37, p=0.02). However again we could not
differentiate between HMGB1 and ANCA subtypes as there were 7 GPA
patients, 3 MPA and 1 MPO-positive CSS patient.
The current study utilizes a new CT volumetry method to measure
granulomata in the lungs. As no follow-up remission data was presented it
is however not completely evident that HMGB1 levels correlate with
granuloma size in the individual patient.
Henes et al raise the question whether circulating HMGB1 reflects the
burden of granulomatous inflammation. Considering these and our results it
would be interesting to study HMGB1 as a marker of disease activity in a
wide range of disease manifestations and as a possible indicator of total
AAV disease burden. Moreover we interestingly found that even though HMGB1
was significantly lower in remission compared to active AAV renal disease
it still remained elevated compared to healthy controls. This may reflect
a persistent low-grade inflammatory activity or tissue damage despite an
appearance of clinical and histopathological remission. We would propose
investigating larger cohorts with serum and tissue staining with and
without a granulomatous phenotype in both active phase and in remission to
further elucidate the role of HMBG1 in vasculitidies. This may clarify
whether HMGB1 is a reliable predictor of disease activity and outcome in
AAV and a possible target for pharmacological modulation.
References
1. Henes FO, Chen Y, Bley TA, et al. Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis 2011;70(11):1926-9.
2. Wibisono D, Csernok E, Lamprecht P, et al. Serum
HMGB1 levels are increased in active Wegener's granulomatosis and differentiate between active forms of ANCA-associated vasculitis. Ann Rheum Dis 2010;69(10):1888-9.
3. Bruchfeld A, Wendt M, Bratt J, et al. High-mobility group box-1 protein (HMGB1) is increased in
antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med 2011;17(1-2):29-35.
4. Goldstein RS, Bruchfeld A, Yang L, et al. Cholinergic Anti-Inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis. Mol Med 2007;13:210-5.
5. Urbonaviciute V, Furnrohr BG, Weber C, et al. Factors masking HMGB1 in human serum and plasma. J Leukoc
Biol 2007;81:67-74.
6. Deena A Abdulahad, Johanna Westra, Johannes Bijzet, et al. High mobility group box 1 (HMGB1) and
anti-HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus. ART 2011;13:R71.
Rituximab (RTX) is an effective alternative for rheumatoid arthritis
patients that failed or are unable to tolerate treatment with anti-TNF
agents. The approved dose of RTX for rheumatoid arthritis is 1000 mg given
14 days apart. However, an analysis of the results of recent studies may
indicate that the 500 mg dose is equally effective and less expensive.
Rituximab (RTX) is an effective alternative for rheumatoid arthritis
patients that failed or are unable to tolerate treatment with anti-TNF
agents. The approved dose of RTX for rheumatoid arthritis is 1000 mg given
14 days apart. However, an analysis of the results of recent studies may
indicate that the 500 mg dose is equally effective and less expensive.
The 2 year results of the IMAGE trial have been recently published
(1). This large randomized controlled trial (RCT) compared RTX 500 mg
(n=249), RTX 1000 mg (N=250), and placebo (n=249) in rheumatoid arthritis
patients not previously treated with metrotrexate (all groups received
background methotrexate). Both doses of rituximab demonstrated equal
clinical efficacy and improvement in disability. The comparison of
radiological outcomes at 104 weeks did not show significant differences
between the 1000 mg and 500 mg groups, and both were significantly better
than
placebo. The authors commented, however, that all radiological outcomes
were numerically better with RTX 1000 mg. Of note, the initial 24 weeks
period is when the difference in the radiological progression between the
1000 mg and 500 mg doses was more pronounced, while after that the
rate of radiological progression was similar. Considering the numbers
presented, progression of the modified Sharp score (defined as any change
greater than zero) after 2 years occurred in 43% of the 1000 mg group and
51% of the 500 mg group (relative risk: 0.84, 95% CI [confidence
interval]: 0.69-1.03). If this difference is assumed to be real, 12 (95%
CI: 6 to infinite) patients would have to be treated with 1000 mg (instead
of 500 mg) in order to prevent one patient of having any progression in
the radiographic score after 2 years. The mean difference in the
radiological score between the RTX groups was 0.25 after 2 years (1), a
difference that is unlikely to be considered clinically relevant (2,3).
The radiological outcomes of the 500 mg dose of RTX have not been
tested in the population of rheumatoid arthritis with inadequate response
to anti-TNF therapy. These patients are actually the candidates to receive
RTX in a real clinical setting. The DANCER study (4) compared RTX 1000 mg,
RTX 500 mg and placebo (with background methotrexate in all groups) in
patients that failed treatment with DMARDS or biological agents.
Approximately 30% of the patients had previous treatment with anti-TNF
agents. At 24 weeks, there were no significant differences in parameters
of clinical efficacy between the 2 doses of RTX. The SERENE trial also
showed equal efficacy of the 500 and 1000 mg doses of RTX in patients that
failed to respond to methotrexate (5).
The definitive answer about the efficacy of the 500 mg dose of RTX in
preventing structural damage in patients that failed anti-TNF therapy can
only be given by an adequately powered RCT. However, considering the
evidence and the high costs of RTX therapy, we conclude that the burden of
proof of showing a better effectiveness in rheumatoid arthritis now
belongs to the 1000 mg
dose of RTX.
References
1. Tak PP, Rigby W, Rubbert-Roth A, et al. Sustained inhibition of
progressive joint damage with rituximab plus methotrexate in early active
rheumatoid arthritis: 2-year results from the randomised controlled trial
IMAGE. Ann Rheum Dis 2011 [Epub ahead of print].
2. Welsing PM, Borm GF, van Riel P. Minimal clinically important
difference in radiological progression of joint damage. A definition based
on patient perspective. J Rheumatol 2006;33:501-7.
3. Vastesaeger N, Xu S, Aletaha D, et al. A pilot risk model for the
prediction of rapid radiographic progression in rheumatoid arthritis.
Rheumatology (Oxford) 2009;48:1114-21.
4. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The
efficacy and safety of rituximab in patients with active rheumatoid
arthritis despite methotrexate treatment: results of a phase IIB
randomized, double-blind, placebo-controlled, dose-ranging trial.
Arthritis Rheum 2006;54:1390-400.
5. Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of
different doses and retreatment of rituximab: a randomised, placebo-
controlled trial in patients who are biological naive with active
rheumatoid arthritis and an inadequate response to methotrexate (Study
Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)).
Ann Rheum Dis 2010;69:1629-35.
We read with interest the article by Houssiau, et al [1], which
provided evidence that mycophenolate mofetil (MMF) was not significantly
superior to azathioprine (AZA) in preventing renal flares in European
patients with lupus nephritis (LN), with a renal relapse rate of 19%, 25%
in the MMF, AZA group, respectively. However, inconsistency exists
compared with other studies up to now [2-5]. Recently...
We read with interest the article by Houssiau, et al [1], which
provided evidence that mycophenolate mofetil (MMF) was not significantly
superior to azathioprine (AZA) in preventing renal flares in European
patients with lupus nephritis (LN), with a renal relapse rate of 19%, 25%
in the MMF, AZA group, respectively. However, inconsistency exists
compared with other studies up to now [2-5]. Recently, Dooley, et al [2]
indicated that MMF was superior to AZA in maintaining a renal response to
treatment and in preventing relapse in patients with LN, in which patients
were mainly from Asia, Latin/North America, Europe. Furthermore,
Contreras, et al [3] substantiated African-Americans with LN had the worst
outcome when compared to Hispanics/Caucasians, but the study was not
powered to detect small differences in comparison. Moreover, Sahin, et al
[4] showed that both therapeutic approaches with MMF and AZA were
effective as a maintenance therapy for LN, without significant differences
in Turkey patients. Nevertheless, Tse, et al [5] found MMF treatment for
LN significantly reduce incidence of complications in Asian patients.
Therefore, which one is better for treatment of LN is still needed to
clarify based on large sample size and different ethnicity in the future.
References
1. Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus
mycophenolate mofetil for long-term immunosuppression in lupus nephritis:
results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083-9.
2. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus
azathioprine as maintenance therapy for lupus nephritis. N Engl J Med.
2011;365:1886-95.
3. Contreras G, Tozman E, Nahar N, et al. Maintenance therapies for
proliferative lupus nephritis: mycophenolate mofetil, azathioprine and
intravenous cyclophosphamide. Lupus. 2005;Suppl1:s33-8.
4. Sahin GM, Sahin S, Kiziltas S, et al. Mycophenolate mofetil versus
azathioprine in the maintenance therapy of lupus nephritis. Ren Fail.
2008;30:865-9.
5. Tse KC, Tang CS, Lam MF, et al. Cost Comparison between
mycophenolate mofetil and cyclophosphamide-azathioprine in the treatment
of lupus nephritis. J Rheumatol. 2009;36:76-81.
We are writing in response to 'Kinetics of viral loads and risk of
hepatitis B virus reactivation in hepatitis B core antibody-positive
rheumatoid arthritis patients undergoing anti-tumor necrosis factor alpha
therapy' by Lan, et al[1]. We performed a similar retrospective study in
the rheumatoid arthritis and the spondyloarthritis patients comorbid with
chronic hepatitis B treated by anti-tumor ne...
We are writing in response to 'Kinetics of viral loads and risk of
hepatitis B virus reactivation in hepatitis B core antibody-positive
rheumatoid arthritis patients undergoing anti-tumor necrosis factor alpha
therapy' by Lan, et al[1]. We performed a similar retrospective study in
the rheumatoid arthritis and the spondyloarthritis patients comorbid with
chronic hepatitis B treated by anti-tumor necrosis factor alpha (anti-TNF-
alpha). Our study was slightly different from Lan's in that none of our
patients receive preemptive antiviral therapy. We reviewed a total 220
patients who had been treated with etanercept or adalimumab from January
2002 to November 2010 in Chung Shan Medical University Hospital, Taiwan.
We monitored the serum aminotransferase (ALT) levels, hepatitis serologic
status including HBV surface antigen (HBsAg), HBV surface antibody
(HBsAb), HBV core IgG antibody (HBcAb), and HBV DNA. The endpoints were
the biochemical flare defined by persistent twofold elevation of ALT from
normal upper limit in >/=2 consecutive tests and the virological flare
defined by HBV DNA viral load increased by one log10IU/mL compared with
the baseline.
Among those 220 patients, 23 (10.45%) patients had chronic hepatitis
B (HBsAg+) without preemptive antiviral therapy. Twelve were excluded due
to missing data. Of these remaining 11 patients, 7 (63.6%) had virological
flares but none of them had biochemical flare. Six of 7 (85.7%) HBV flares
occurred within 6 months after initiating TNF blockers.
On contrary to Lan, et al[1], our patients experienced no biological flare
and had lower viral load at baseline (HBV DNA 475.36+/-777 IU/mL). Three
similarities were observed in both studies. Firstly, in the study of Lan,
62.5% (5 of 8) HBsAg (+) patients without preemptive antiviral therapy
developed reactivations of hepatitis B while our data showed 63.6% (7 of
11) of patients had virological reactivations. Secondly, those with HBV
reactivation in both studies had good clinical outcome after antiviral
treatment. Thirdly, most of the patients developed reactivations (85.7% vs
100% in Lan, et al) within the first 6 months after initiating anti-TNF-
alpha.
All patients with rheumatic diseases who plan to receive biological
treatment should undergo the baseline screening tests for HBV including
HBsAg, anti-HBs, anti-HBc and HBV DNA. Antiviral treatment should be
initiated before the biological treatment in patients with active
hepatitis[2]. According to the clinical practice guideline of the European
Association for the Study of the Liver (EASL), immunotolerant patients
with persistently normal ALT levels and a high HBV DNA level do not
require immediate liver biopsy or therapy[2]. However, there is no
guideline for patients treated with anti-TNF agents. The cost of
preemptive antiviral therapy was high[3] and the time of discontinuation
of antiviral therapy was still unclear. Moreover, long-term antiviral
treatment increases the risk of drug resistance through viral
mutations[2,4]. Careful and close follow-up of ALT and HBV DNA is
essential, especially in the first 6 months of anti-TNF-alpha. Immediate
initiation of antiviral therapy when reactivation once detected is a good
strategy for management.
References
1 Lan JL, Chen YM, et al. Kinetics of viral loads and risk of hepatitis B
virus reactivation in hepatitis B core antibody-positive rheumatoid
arthritis patients undergoing anti-tumour necrosis factor alpha therapy.
Ann Rheum Dis 2011;70:1719-1725.
2 European Association For The Study Of The Liver. EASL Clinical Practice
Guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227-242.
3 Colombo GL, Gaeta GB, et al. A cost-effectiveness analysis of different
therapies in patients with chronic hepatitis B in Italy. Clinicoecon
Outcomes Res 2011;3:37-46.
4 Kim SS, Cheong JY, et al. Current Nucleos(t)ide Analogue Therapy for
Chronic Hepatitis B. Gut Liver 2011;5(3):278-87
We read with interest the meta-analysis of registries and prospective
observational studies conducted by Mariette and colleagues on the risk of
malignancies in patients with rheumatoid arthritis (RA) treated with tumor
necrosis factor (TNF) antagonists. (1) Their meta-analysis highlights the
complexity surrounding this important clinical issue, when TNF antagonists
are considered for patients with RA with...
We read with interest the meta-analysis of registries and prospective
observational studies conducted by Mariette and colleagues on the risk of
malignancies in patients with rheumatoid arthritis (RA) treated with tumor
necrosis factor (TNF) antagonists. (1) Their meta-analysis highlights the
complexity surrounding this important clinical issue, when TNF antagonists
are considered for patients with RA with a malignancy or a prior history
of malignancy. Their meta-analysis revealed that although TNF antagonists
did not increase the risk of all-site malignancies, including lymphomas,
they did increase the risk of skin cancer, particularly non-melanoma skin
cancer (NMSC) with a pooled odds ratio (OR) of 1.45 (95% confidence
intervals [CI] 1.17-1.76) based on four prior studies which showed ORs
ranging from 1.20 to 1.83. Another recent meta-analysis of randomized
controlled trials (RCTs) on the same topic showed similar results with a
relative risk (RR) for NMSC of 2.02 (95% CI 1.11-3.95). (2)
We would like to point out that our own retrospective cohort study of
20,648 patients with RA assembled from the Department of Veterans Affairs
(VA) national administrative databases in the United States demonstrated
remarkably similar results to those of Mariette et al with a hazards ratio
(HR) of 1.42 (95% CI 1.24-1.63) for an increased risk of NMSC, despite the
inherent limitations associated with a retrospective cohort study. (3)
Thus based on evidence available to date, use of TNF antagonists in
patients with RA appears to increase the risk of NMSC. This may be
especially true for older patients, males, those on chronic steroids and
non-steroidal anti-inflammatory drugs (NSAIDs), and those with a history
of prior malignancies, as shown in our study. (3) Rheumatologists should
be vigilant about such a risk when using these biologic agents in RA.
References
1. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies
associated with tumour necrosis factor inhibitors in registries and
prospective observational studies: a systematic review and meta-analysis.
Ann Rheum Dis 2011 Nov;70(11):1895-904. Epub 2011 Sep 1
2. Askling J, Fahrbach K, Nordstrom B, et al.
Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-
analysis of randomized controlled trials of adalimumab, etanercept, and
infliximab using patient level data. Pharmacoepidemiol Drug Saf 2011;20(2):119-30. doi: 10.1002/pds.2046. Epub 2010 Dec 7.
3. Amari W, Zeringue AL, McDonald JR, et al.
Risk of non-melanoma skin cancer in a national cohort of veterans with
rheumatoid arthritis. Rheumatology (Oxford) 2011;50(8):1431-9. Epub
2011 Mar 16.
Conflict of Interest: none
Department of Epidemiology and Biostatistics, School of Public
Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032,
PR China;
*Correspondence: Dong-Qing Ye, M.D, Department of Epidemiology and
Biostatistics, School of Public Health, Anhui Medical University, 81
Meishan Road, Hefei, Anhui, 230032, PR China,
Department of Epidemiology and Biostatistics, School of Public
Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032,
PR China;
*Correspondence: Dong-Qing Ye, M.D, Department of Epidemiology and
Biostatistics, School of Public Health, Anhui Medical University, 81
Meishan Road, Hefei, Anhui, 230032, PR China,
McMahon, et al1 have reported that high plasma leptin levels confer
increased risk of atherosclerosis in systemic lupus erythematosus (SLE)
patients, and are associated with inflammatory oxidised lipids. In the
study, leptin levels are significantly higher in patients than in
controls, which are also higher in the 43 SLE patients with plaque than
without plaque and associate with inflammatory biomarkers of
atherosclerosis such as piHDL (proinflammatory high-density lipoprotein),
Lp(a) and OxPL/apoB100, furthermore, age and hypertension, and so on.
In fact, relationship between leptin and SLE have been studied
increasingly both in humans and animal models, but different results
exist2-10. Hahn, et al4 developed a mouse model of multigenic lupus
exposed to environmental factors known to accelerate atherosclerosis in
humans--high-fat diet with or without injections of the leptin, where the
lupus-prone strain (BWF1 mice), addition of leptin increased
proinflammatory high-density lipoprotein scores, indicating the presence
of piHDL as well as atherosclerosis, accelerated proteinuria. Moreover,
several investigations have confirmed the higher leptin levles are
significantly associated with SLE compared to controls6,8,10, especially
the serum leptin levels with age, hypertension3,5,8,9, but Chung, et al5
found no significant relationship between leptin or adiponection levels
and coronary calcification in SLE pantients and controls. On contrary,
lower leptin levels in SLE patients4 or no statistically significant
differences between leptin levels in SLE patients and the controls7 are
discovered as well.
As is known, leptin belongs to the type I cytokine superfamily and
has an important role in regulating immune functions. Leptin protects T
lymphocytes from apoptosis and regulates T-cell proliferation and
activation, and influences cytokine production from T lymphocytes,
generally switching the phenotype toward a Th1 response 11-13.
Consequently, in order to better understand the link between SLE,
atherosclerosis and leptin, further to clarify the associaiton of leptin
and SLE based on large samples not only in humans, but in animals are
still needed.
References
1. McMahon M, Skaggs BJ, Sahakian L, et al. High plasma leptin levels
confer increased risk of atherosclerosis in women with systemic lupus
erythematosus, and are associated with inflammatory oxidised lipids. Ann
Rheum Dis 2011;70:1619-24.
2. Hahn BH, Lourenco EV, McMahon M, et al. Pro-inflammatory high-
density lipoproteins and atherosclerosis are induced in lupus-prone mice
by a high-fat diet and leptin. Lupus 2010;19:913-7.
3. Kim HA, Choi GS, Jeon JY, et al. Leptin and ghrelin in Korean
systemic lupus erythematosus. Lupus 2010;19:170-4.
4. De Sanctis JB, Zabaleta M, Bianco NE, et al. Serum adipokine
levels in patients with systemic lupus erythematosus. Autoimmunity 2009;42:272-4.
5. Chung CP, Long AG, Solus JF, et al. Adipocytokines in systemic
lupus erythematosus: relationship to inflammation, insulin resistance and
coronary atherosclerosis. Lupus 2009;18:799-806.
6. Vadacca M, Margiotta D, Rigon A, et al. Adipokines and systemic
lupus erythematosus: relationship with metabolic syndrome and
cardiovascular disease risk factors. J Rheumatol 2009;36:295-7.
7. Wisowska M, Rok M, StepieK, et al. Serum leptin in systemic lupus
erythematosus. Rheumatol Int 2008;28:467-73.
8. Ryan MJ, McLemore GR Jr, Hendrix ST. Insulin resistance and
obesity in a mouse model of systemic lupus erythematosus. Hypertension
2006;48:988-93.
9. Sada KE, Yamasaki Y, Maruyama M, et al. Altered levels of
adipocytokines in association with insulin resistance in patients with
systemic lupus erythematosus. J Rheumatol 2006;33:1545-52.
10. Garcia-Gonzalez A, Gonzalez-Lopez L, Valera-Gonzalez IC, et al.
Serum leptin levels in women with systemic lupus erythematosus. Rheumatol
Int 2002;22:138-41.
11. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J
Allergy Clin Immunol 2005;115:911-9.
12. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the
mouse obese gene and its human homologue. Nature 1994;372:425-32.
13. Busso N, So A, Chobaz-Peclat V, et al. Leptin signaling
deficiency impairs humoral and cellular immune responses and attenuates
experimental arthritis. J Immunol 2002;168:875-82.
We read with interest the retrospective case-control study by de Jong et al.(1) The authors found an intriguing association between statin use and development of rheumatoid arthritis (RA). Some comments regarding the
methodology and authors statements, may be appropriate.
Evaluating treatment effects in observational studies can be problematic as prognostic factors influencing treatment decisions...
We read with interest the retrospective case-control study by de Jong et al.(1) The authors found an intriguing association between statin use and development of rheumatoid arthritis (RA). Some comments regarding the
methodology and authors statements, may be appropriate.
Evaluating treatment effects in observational studies can be problematic as prognostic factors influencing treatment decisions can cause so-called "confounding by indication". The baseline characteristics show that the prevalence of cardiovascular co-morbidity is considerably higher in cases versus controls. Since statin therapy is standard care in people with a high cardiovascular risk, this could explain more statin use in the RA group. Moreover, one study showed that the lipid profile of subjects who later developed RA is more atherogenic than of subjects who did not develop RA.(2) As the authors have correctly mentioned in the
discussion, data on hyperlipidemia is limited. We therefore disagree with the statement that statins may promote the development of RA. To our opinion, this association could be based on the underlying predisposition to develop hyperlipidemia and cardiovascular disease, which is already present long before individuals develop RA.
Another point of concern is the selection of the study population. The investigators selected all patients with the ICPC code L88 (arthritis) if they were referred to a rheumatologist or had had a prescription of at least one DMARD or two or more prescriptions of corticosteroids. In the Netherlands many patients are referred to the rheumatologist and only 10-20% has indeed RA. Furthermore, corticosteroids and DMARDs are prescribed for many (rheumatic) diseases other than RA. This could mean that patients with polymyalgia rheumatica, psoriatic arthritis or even systemic lupus erythematosis (SLE) are included in the cases group. In part, this problem could have been solved by verification of the diagnosis in the medical
record. Furthermore, the controls do not seem to be matched for general practitioner (GP). Some GP's are more keen on cardiovascular risk management and prescribe statins more frequently. Would multilevel logistic regression analyses not have been more appropriate to correct for this sampling bias?
As to the underlying mechanisms behind the association, the authors suggest that statins increase the production of autoantibodies by promoting a shift in the TH1/TH2 balance. However, Kanda et al. demonstrated a reduction of the Th1/Th2 and CD4/CD8 ratios, rheumatoid
factor, erythrocyte sedimentation rate and C-reactive protein levels after statin use, implying an anti-inflammatory effect and down-regulation of T-cell mediated immune responses(3). To date there are more studies showing an anti-inflammatory (4) and beneficial effect on onset and activity of Th1 mediated diseases like RA(5) and multiple sclerosis(6) than case reports showing a possible triggering effect of statins on auto-immune diseases like autoimmune hepatitis(7) and SLE(8).
Despite the possibility of confounding by indication, this study raises important questions regarding the role of statins in the development of RA. We definitely concur more evidence is needed to confirm
this association before statins are withheld, since cardiovascular disease is a prominent health problem especially among individuals with prodromal RA.
References
1. de Jong HJI, Klungel OH, van Dijk L, et al. Use of statins is associated with an increased risk of rheumatoid arthritis. Ann Rheum Dis 2011 Oct 6. epub ahead of print.
2. van Halm VP, Nielen MM, Nurmohamed MT, et al. Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis. Ann Rheum Dis 2007;66:184-8.
3. Kanda H, Yokota K, Kohno C, et al. Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol 2007;17:364-8.
4. McCarey DW, Sattar N, McInnes IB. Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases? Art Res Ther 2005;7:55-61.
5. Jick SS, Choi H, Li L et al. Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann Rheum Dis 2008;68:546-551.
6. Willey JZ, Elkind MSV. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases.
Arch Neurol 2010;67(9):1062-1067.
7. Alla V, Abraham J, Siddiqui J, et al. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol 2006;40(80):757-61.
8. Noel B. Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review. J Eur Acad Dermatol Venereol 2007;21:17-24.
The study by Feydy and colleagues1 clearly evidences the importance of controls for assessment of the significance of clinical/radiologic observations/signs. Their eloquent study appropriately challenges the preconceived notion that enthesitis or enthesial reaction is an identifier for spondyloarthropathy2-5 and confirms the perceptions derived from studies of human skeletal collections.6,7 Those studies...
The study by Feydy and colleagues1 clearly evidences the importance of controls for assessment of the significance of clinical/radiologic observations/signs. Their eloquent study appropriately challenges the preconceived notion that enthesitis or enthesial reaction is an identifier for spondyloarthropathy2-5 and confirms the perceptions derived from studies of human skeletal collections.6,7 Those studies revealed no statistically significant correlation of enthesitis with presence of inflammatory arthritis.7
Enthesial discontinuities ("divots"), originally thought to be erosive in nature, were rare on examination of defleshed skeletons and their presence did not correlate with presence of underlying disease.7 Examination of skeletons also did not reveal any difference in the character of enthesopathy occurring in spondyloarthropathy and that occurring in the general population (healthy individuals) and led us to speculate that MRI might provide insights. We suggested that these lesions might actually be analogous to those found in the distal femur, attributed to tendon avulsion injuries.7
Feydy's study1 is precisely on point. They demonstrated no significant difference in character of lesions, with one exception: bone edema. Perhaps bone edema may well be the response to an acute or subacute avulsion, which resolves with chronicity? Sedimentation rates appear inconsistent in patients with spondyloarthropathy. It will be interesting if Feydy's group can correlate MRI findings of bone edema with laboratory measures of injury, rather than invoke inflammation.
References
1. Feydy A, Lavie-Brion M-C, Gossec L, et al. Comparative study of MRI and power Doppler ultrasonography of the heel in patients with spondyloarthritis with and without heel pain and in controls. Ann Rheum Dis 10.1136/annrheumdis-2011-200336
2. Mander M, Simpson JM, McLellan A, et al. Studies with an enthesitis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis 1987;46:197-202.
3. Hueft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis 1003;62:127-32.
4. de Miguel E, Cobo T, Mu?oz-Fern?ndez S, et al. Validity of enthesis ultrasound assessment in spondyloarthropathy. Ann Rheum Dis 2009;68:169-74.
5. D'Agostino MA, Said-Nahal R, HaCQUARD-Bouder C, et al. Assessment of peripheral enthesitis I the spondyloarthropathyies by ultrasonography combined with power Doppler: A cross-sectional study. Arthritis Rheum 2003;48:523-33.
6. Dutour O. Enthesopathies (Lesions of muscular insertions) as indicators of the activities of Neolithic Saharan populations. Amer J Phys Anthropol 1986;71:221-224.
7. Shaibani A, Workman R, Rothschild B. The Significance of enthesophyte/enthesopathy as a skeletal Phenomenon. Clin Exp Rheumatol 1993;11:399-403.
Dear Editor,
We read with interest the paper by Dixon et al, and the associated paper published in 2011 on the risk of infection in glucocorticoid (GC) use in RA.1,2 Whilst their analyses add somewhat to the evidence of the risk of infection caused by GC in RA, because they are retrospective observational studies of uncontrolled treatment decisions we have strong reservations on the extent of their interpretations...
Dear Editor,
In October 2011, Beyer and colleagues published an interesting article on the use of tocilizumab as rescue treatment for 3 patients with giant cell arteritis(1). Their patients had a high systemic inflammatory response and involvement of the aorta and its main branches, showing Takayasu-like features. The authors noted that, perhaps, tocilizumab might be less effective for 'classical' giant cell arteri...
Dear editor,
Recently Henes et al reported that serum levels of the proinflammatory mediator high mobility group box-1 protein (HMGB1) were elevated and showed a significant correlation with the burden of granulomatous inflammation in patients with Granulomatosis with polyangiitis (GPA or Wegener) (1). The same group has previously published data suggesting that HMGB1 is a marker of GPA and that HMGB1 is not detec...
Dear editor,
Rituximab (RTX) is an effective alternative for rheumatoid arthritis patients that failed or are unable to tolerate treatment with anti-TNF agents. The approved dose of RTX for rheumatoid arthritis is 1000 mg given 14 days apart. However, an analysis of the results of recent studies may indicate that the 500 mg dose is equally effective and less expensive.
The 2 year results of the IMAGE...
Dear editor,
We read with interest the article by Houssiau, et al [1], which provided evidence that mycophenolate mofetil (MMF) was not significantly superior to azathioprine (AZA) in preventing renal flares in European patients with lupus nephritis (LN), with a renal relapse rate of 19%, 25% in the MMF, AZA group, respectively. However, inconsistency exists compared with other studies up to now [2-5]. Recently...
Dear editor,
We are writing in response to 'Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumor necrosis factor alpha therapy' by Lan, et al[1]. We performed a similar retrospective study in the rheumatoid arthritis and the spondyloarthritis patients comorbid with chronic hepatitis B treated by anti-tumor ne...
Dear Editor,
We read with interest the meta-analysis of registries and prospective observational studies conducted by Mariette and colleagues on the risk of malignancies in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) antagonists. (1) Their meta-analysis highlights the complexity surrounding this important clinical issue, when TNF antagonists are considered for patients with RA with...
Wang-Dong Xu, Yu-Jing Zhang, Hai-Feng Pan, Dong-Qing Ye*
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China;
*Correspondence: Dong-Qing Ye, M.D, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China,
E-mail: yd...
Dear Editor,
We read with interest the retrospective case-control study by de Jong et al.(1) The authors found an intriguing association between statin use and development of rheumatoid arthritis (RA). Some comments regarding the methodology and authors statements, may be appropriate.
Evaluating treatment effects in observational studies can be problematic as prognostic factors influencing treatment decisions...
Dear Editor,
The study by Feydy and colleagues1 clearly evidences the importance of controls for assessment of the significance of clinical/radiologic observations/signs. Their eloquent study appropriately challenges the preconceived notion that enthesitis or enthesial reaction is an identifier for spondyloarthropathy2-5 and confirms the perceptions derived from studies of human skeletal collections.6,7 Those studies...
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