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.
I read with interest the study by Martinez-Zammora et al. (1), which reported an increased incidence of thrombotic events in patients with antiphospholipid syndrome with recurrent spontaneous abortion (APS-RSA
group) in comparison with 3 different control groups. Although their conclusions seem to be valid, some comments may be appropriate.
This study is labeled as 'case-control', but it is actual...
I read with interest the study by Martinez-Zammora et al. (1), which reported an increased incidence of thrombotic events in patients with antiphospholipid syndrome with recurrent spontaneous abortion (APS-RSA
group) in comparison with 3 different control groups. Although their conclusions seem to be valid, some comments may be appropriate.
This study is labeled as 'case-control', but it is actually a retrospective cohort study. Case-control studies have a different design, where researchers select cases and controls based on the presence or absence of the outcome, respectively, and look back in time for
disproportionate exposures (2). Cohort studies follow groups defined by different exposures and observe the incidence of the outcomes. In the retrospective cohort design, the researcher starts the study at the time
follow-up has already been completed (3). This kind of mislabeling of study design has been frequently observed in medical journals, and may cause confusion among readers (2).
Given that this is a cohort study, the relative risk (RR) should have been calculated instead of the odds ratio. Odds ratios frequently generate larger differences between exposed and non-exposed groups (especially when
dealing with non-rare events), therefore overestimating the observed effect (4). However, considering the longer follow-up time of the APS-RSA group in comparison to the tRSA and uRSA groups, perhaps the incidence rate ratio (5) would be more adequate than the RR to compare de risk of
thrombosis in this study.
The authors should have made the exclusion criteria (like history of thrombotic events previously to the beginning of the follow-up period) clearer in methods. Also, the plotting of the Kaplan-Meier curves seems to
be inaccurate, since the curves that represent cumulative incidences in the tRSA and uRSA groups should have ended when the patients with longer permanence in the cohort were censored or had presented an event (6). In the abstract, the reporting of "12 year cumulative thrombotic incidence rate" gives the wrong idea that the mean follow-up time was 12 years.
Despite the problems of analysis and reporting, this study has adequate internal validity and problably external validity (albeit only Spanish Caucasian individuals were included), representing an advance in
the knowledge about the antiphospholipid syndrome.
References
1. Martinez-Zamora MA, Peralta S, Creus M, et al. Risk of thromboembolic events after recurrent spontaneous abortion in antiphospholipid syndrome: a case-control study. Ann Rheum Dis 2011 [Epub ahead of print].
2. Grimes DA. "Case-control" confusion: mislabeled reports in obstetrics and gynecology journals. Obstet Gynecol 2009;114:1284-6.
3. Euser AM, Zoccali C, Jager KJ, et al. Cohort studies: prospective versus retrospective. Nephron Clin Pract 2009;113:214-7.
4. Case LD, Kimmick G, Paskett ED, et al. Interpreting measures of treatment effect in cancer clinical trials. Oncologist 2002;7:181-7.
5. Pearce N. Effect measures in prevalence studies. Environ Health Perspect 2004;112:1047-50.
6. Clark TG, Bradburn MJ, Love SB, et al. Survival analysis part I: basic concepts and first analyses. Br J Cancer 2003;89:232-8.
Does Rheumatoid Synovitis Activity Vary During The Day? A sonographic
and Doppler evaluation.
A. Lhoste-Trouilloud1, B. Pereira2, M. Couderc3, S Mathieu3 , M. Soubrier3
1 Radiology; 2DRCI; 3 Rheumatology Department, CHU Gabriel Montpied,
Clermont-Ferrand, France
Dear Editor,
We read with interest the report of Semerano et al who describe a diurnal variation of power Doppler ultrasonography in the met...
Does Rheumatoid Synovitis Activity Vary During The Day? A sonographic
and Doppler evaluation.
A. Lhoste-Trouilloud1, B. Pereira2, M. Couderc3, S Mathieu3 , M. Soubrier3
1 Radiology; 2DRCI; 3 Rheumatology Department, CHU Gabriel Montpied,
Clermont-Ferrand, France
Dear Editor,
We read with interest the report of Semerano et al who describe a diurnal variation of power Doppler ultrasonography in the metacarpophalangeal joints of patients with Rheumatoid arthritis (RA) (1). They reported a higher activity in the morning than in the afternoon or evening which mirrors the circadian variation in joint stiffness and pain (1). We conducted a similar survey but obtained completely opposite results.
Sonographic evaluation with B-mode and Color Doppler using the same unit, with the same transducer and settings was performed twice, before 9 am and at 4 pm by a single experienced radiologist (ALT) in 27 patients with
definite (1987 ACR criteria) and active RA (DAS28 4.66 ? 1.32). 22 synovial areas were scanned on each wrist, hand and forefoot, including 15 joints and 7 tendon sheaths. "Synovitis" was defined as abnormal hypoechoic synovial hypertrophy. Synovial vascularization was visualized by color Doppler and scored semi-quantitatively from 0 to 3[0=normal (no detectable Doppler signal inside the joint); 1=mild (Doppler signal involving < 1/3 of synovium); 2=moderate (Doppler signal involving >
1/3 but < 2/3 of synovium); 3=marked (> 2/3 of synovium involved)].
Of the 1188 imaged joints and sheaths, 328 showed synovitis in the morning, and 381 in the afternoon (p = 0.05). This number increased in 20 patients, remained the same in 6, and decreased in one. This increase was
significant in right forth PIP (p = 0.02). There was a trend to increase in right second MCP (p = 0.08), but tenosynovitis was stable (p = 1). The activity of synovitis was modified in 26 patients. This change involved several joints in 21 patients, and only one in 5. Activity significantly increased in the left second MCP (p = 0.02) and right fifth MCP (p = 0.04) and had a tendency to increase in the third and fourth right PIP and in
the left radio-carpal joint (p = 0.08). Some inactive or mild synovitis (S0 and S1) may progress to moderate or marked (S2 or S3): This was significant in the second right MCP (p = 0.013) and in the combination of all explored hand and wrist joints of the right side (p = 0.002) and of the left side (p = 0.026). Our findings, unlike those of Semerano et al, show that the number and activity of synovitis do not follow a circadian
rhythm. The increase number of activity in the hands, preferentially the dominant hand, could be explained by regular daily use. Further data are needed to confirm with a larger cohort including patients in clinical remission. Sonography often shows active synovitis in patients who are considered to be in clinical remission (2-4). However in these studies sonographic evaluation was performed only in the dominant hand which, in our results, showed the most variation over the day (2-4). Future studies should be able to determine when and which joints should be analyzed in the sonographic follow-up of RA patients, in particular in those who are in remission.
References
1. Semerano L, Gutierrez M, Falgarone G, et al. Diurnal variation of power Doppler in metacarpophalangeal joints of patients with rheumatoid arthritis: a preliminary study. Ann Rheum Dis 2011;70:1699-700.
2. Brown AK, Quinn MA, Karim Z, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug -induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006;54:3761-73.
3. Saleem B, Brown AK, Keen H, et al. Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: a clinical and imaging comparative study. Arthritis Rheum 2009;60:1915-22.
4. Saleem B, Brown AK, Keen H, et al. Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments. Ann Rheum
Dis 2011;70:792-8.
We read with much interest the published article entitled 'Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and
meta-analysis' by Mariette et al [1]. Beyond any doubt, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus and psoriatic arthritis are associated with higher incidence of maligna...
We read with much interest the published article entitled 'Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and
meta-analysis' by Mariette et al [1]. Beyond any doubt, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus and psoriatic arthritis are associated with higher incidence of malignancy[2.3,4]. The exact pathophysiology involved is not well understood but inflammatory cells have been proven to produce tumor-
associated antigens [5].Besides, the gold standard of therapy in RA i.e. methotrexate is reported to increase the risk of developing malignancies such as lymphoma [6]. Thus, the development of malignancy in this setting
appears to be multifactorial. Both the disease and its treatment increase malignant potential. The investigators stated that the risk of developing recurrence or a new primary cancer in patients with previous malignancies
were similar in both the DMARD-treated patients and TNFi-treated patients but there was no comparison made between the two groups for subjects without previous history of malignancies.To a certain extent, this information may potentially influence the clinicians' decision of
switching over to TNFi after weighing the risks and benefits.
Considering that the inclusion criteria considered patients with RA, PsA and ankylosing spondylitis, we feel that Table 1 under indication, should state the specific disease entity for all publications. The phrase
'rheumatic disease' is too general. Other rheumatic diseases such as systemic lupus erythematosus, takayasu arteriis and dermatomyositis have specific indications for TNFi especially in refractory cases. The investigators could have clarified the indication with the respective
authors.
To date, there are many different types of TNFi prescribed worldwide such as Infliximab, Etanercept and Adalimumab. In this meta-analysis, it would have been interesting and beneficial if the investigators had
studied the breakdown incidence of malignancy with each individual TNFi.
With reference to Table 2 on the rates of malignancies in TNFi patients, the information on the incidence rate per 1000 patients should have been subdivided into the 1st year of treatment with TNFi, 2nd year and subsequent years. It is vital for clinicians to identify when the incidence peaks in order to be more vigilant during follow-up.
We applaud the quality of the work and thank the editor for publishing such informative articles.
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 doi:10.1136/ard.2010.149419.
2. Husni ME, Mease PJ. Managing comorbid disease in patients with psoriatic arthritis. Cur Rheumatol Rep 2010;12:281-7.
3. Bernatsky S, Ramsey-Goldman R, Foulkes WD, et al. Breast, ovarian, and endometrial malignancies in systemic lupus erythematosus: a meta-analysis. Br J Cancer 2011;104:1478-81.
4. Chen YJ, Chang YT, Wang CB, et al. The risk of cancer in patients with rheumatoid arthritis: A nationwide cohort study in Taiwan. Arthritis Rheum 2011;63:352-8.
5. Szekanecz E, Andras C, Sandor Z, et al. Malignancies and soluble tumor antigens in rheumatic diseases. Autoimmun Rev 2006;6:42-7.
6. Matsui Y, Miura Y, Sugino N, et al.
Methotrexate-associated lymphoplasmacytic lymphoma complicated with type 2 cryoglobulinemia. Int J Haematol 2011;93:253-6.
We read with interest the recent article by Galloway et al. investigating septic arthritis (SA) in rheumatoid arthritis (RA) patients enrolled in the British Society for Rheumatology Biologics Register (BSRBR), who received anti tumour necrosis factor (anti-TNF) therapy.[1]
The results of their evaluation of data from the BSRBR indicated that anti -TNF therapy for RA is associated with a doubling of t...
We read with interest the recent article by Galloway et al. investigating septic arthritis (SA) in rheumatoid arthritis (RA) patients enrolled in the British Society for Rheumatology Biologics Register (BSRBR), who received anti tumour necrosis factor (anti-TNF) therapy.[1]
The results of their evaluation of data from the BSRBR indicated that anti -TNF therapy for RA is associated with a doubling of the risk for SA, and the authors recommended that physicians and surgeons assessing RA patients take into consideration this potentially life-threatening complication. In addition, the authors addressed the effect of orthopaedic surgery on the risk of SA occurring within 90 days after surgery.
To date, the results of studies on the association of perioperative anti-TNF therapy and risk for surgical site infections (SSIs) have been conflicting. Some studies on joint surgery in RA patients treated with anti-TNF therapy have failed to demonstrate any significant increase in the incidence of postoperative infection [2-4], while results of other studies have suggested that there were higher complication rates in patients treated with TNF blockers than in patients not treated with
blockers.[5, 6] In their evaluation of data from the BSRBR, Galloway et al. concluded that it was reassuring to see no evidence of increased risk of prosthetic joint SA, and that the rate of postoperative joint infection was not significantly influenced by anti-TNF therapy.
However, the authors reported that the strongest association of the occurrence of SA was with a history of orthopaedic surgery of a large joint at baseline, irrespective of whether SA developed in a prosthetic joint.
We previously reported that anti-TNF therapy was a likely cause of SSI development in RA patients following major orthopaedic surgery.[7] At that time, we diagnosed SSIs using the criteria for SSIs in the CDC recommendations for Prevention of Surgical Site Infection, 1999.[8] If we only included deep incisional SSI cases in our evaluation of SSIs, TNF blockers were not significant risk factors for acute SSI.
Therefore, as with the results of the study by Galloway et al., we also agree that the use of anti-TNF therapy does not definitely increase the risk for performing joint surgeries in RA patients. However, because we previously found that the use of TNF-blockers and long RA disease duration were associated with an increased risk of acute SSI in total joint arthroplasties (TJA) when SSI had been diagnosed using the criteria in the
CDC recommendations,[9] we believe that TJA should be performed and observed with caution for patients who are treated with anti-TNF therapy.
If an SSI occurs, especially in a prosthetic joint, patient prognosis is poor, because of difficulties in curing the infection. Periprosthetic joint infection is a devastating complication and is one of the leading causes of morbidity following prosthetic joint replacement with an increased risk of mortality.[10]
Moreover, whether or not anti-TNF therapy should be discontinued in RA patients undergoing elective orthopaedic surgery should be clarified.
More data are clearly needed, and additional studies must be performed to determine the effects of interrupting TNF blocker therapy prior to initiating surgical procedures.
References
1. Galloway JB, Hyrich KL, Mercer LK, et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis doi:10.1136/ard.2011.152769
2. Wendling D, Balblanc JC, Brousse A, et al. Surgery in patients receiving anti-tumour necrosis factor alpha treatment in rheumatoid arthritis: an observational study on 50 surgical procedures. Ann Rheum Dis 2005;64(9):1378-1379.
3. Talwalkar SC, Grennan DM, Gray J, et al. Tumour
necrosis factor alpha antagonists and early postoperative complications in patients with inflammatory joint disease undergoing elective orthopaedic surgery. Ann Rheum Dis 2005;64(4):650-651.
4. den Broeder AA, Creemers MC, Fransen J, et al. Risk factors for surgical site infections and other
complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: a large retrospective study. J Rheumatol 2007;34(4):689-695.
5. Ruyssen-Witrand A, Gossec L, Salliot C,et al. Complication rates of 127 surgical procedures performed in
rheumatic patients receiving tumor necrosis factor alpha blockers. Clin Exp Rheumatol 2007;25(3):430-436.
6. Giles JT, Bartlett SJ, Gelber AC, et al. Tumor necrosis factor inhibitor therapy and risk of serious
postoperative orthopedic infection in rheumatoid arthritis. Arthritis Rheum 2006;55(2):333-337.
7. Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications? Rheumatology (Oxford) 2010;49(2):341-347.
8. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol. 1999;20(4):250-278; quiz 279-280.
9. Momohara S, Kawakami K, Iwamoto T, et al. Prosthetic joint infection after total hip or knee arthroplasty in rheumatoid arthritis patients treated with nonbiologic and biologic disease-modifying antirheumatic drugs. Mod Rheumatol 2011 Feb 12.
10. Matar WY, Jafari SM, Restrepo C, et al.
Preventing infection in total joint arthroplasty. J Bone Joint Surg Am 2010;92 Suppl 2:36-46.
Conflict of Interest:
SM has received speaking fees and/or honoraria from Abbott Japan Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. KI has received speaking fees and/or honoraria from Abbott Japan Co., Ltd. and Mitsubishi Tanabe Pharma Corporation. The other authors have declared no conflicts of interest.
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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...
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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...
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Dear Editor,
We read with much interest the published article entitled 'Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis' by Mariette et al [1]. Beyond any doubt, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus and psoriatic arthritis are associated with higher incidence of maligna...
Dear Editor,
We read with interest the recent article by Galloway et al. investigating septic arthritis (SA) in rheumatoid arthritis (RA) patients enrolled in the British Society for Rheumatology Biologics Register (BSRBR), who received anti tumour necrosis factor (anti-TNF) therapy.[1]
The results of their evaluation of data from the BSRBR indicated that anti -TNF therapy for RA is associated with a doubling of t...
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