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Clowse et al.[1] report that ferritin, oestradiol, and uric acid
level at mid-gestation may predict preterm delivery in systemic lupus
erythematosus (SLE) with mild-moderate disease activity. This is a well-
done study, but we believe that the authors fail to fully address the
effect of antiphospholipid antibodies. The author states that four
patients tested positive for antiphospholipid antibodies....
Clowse et al.[1] report that ferritin, oestradiol, and uric acid
level at mid-gestation may predict preterm delivery in systemic lupus
erythematosus (SLE) with mild-moderate disease activity. This is a well-
done study, but we believe that the authors fail to fully address the
effect of antiphospholipid antibodies. The author states that four
patients tested positive for antiphospholipid antibodies. However, the
details of which specific antiphospholipid antibodies and total number of
patients tested for antiphospholipid antibody were not mentioned in this
article. A previous prospective study demonstrated that lupus
anticoagulant was the strongest predictor of adverse pregnancy outcomes in
patients with SLE.[2] In addition, considering a previous study which
reported that approximately 40% of SLE patients have antiphospholipid
antibodies, the number of patients testing positive for antiphospholipid
antibodies is relatively low in the study by Megan et al.[3] We suspect
that there may be a measure of selection bias, or alternatively, a portion
of patients who in whom antiphospholipid testing was not performed. As the
study included patients with unclear antiphospholipid antibodies profiles
and substantially lower rates of antiphospholipid antibody positivity, it
is uncertain whether their results are widely generalizable.
References
1. Clowse MEB, Wallace DJ, Weisman M, et al. Predictors of preterm birth
in patients with mild systemic lupus erythematosus. doi:
10.1136/annrheumdis-2012-202449.
2. Lockshin MD, Kim M, Laskin CA, et al. Prediction of adverse pregnancy
outcome by the presence of lupus anticoagulant, but not anticardiolipin
antibody, in patients with antiphospholipid antibodies. Arthritis Rheum
2012;64(7):2311-2318.
We read with interest the report by Galloway et al on the risk of skin and
soft tissue infections (including shingles) in patients exposed to TNF
antagonists from the BSRBR [1]. In the light of our recently published
systematic literature review of the risk of shingles in rheumatoid
arthritis (RA) patients, we would like to address several issues raised in
the report [2]. The authors state that the inci...
We read with interest the report by Galloway et al on the risk of skin and
soft tissue infections (including shingles) in patients exposed to TNF
antagonists from the BSRBR [1]. In the light of our recently published
systematic literature review of the risk of shingles in rheumatoid
arthritis (RA) patients, we would like to address several issues raised in
the report [2]. The authors state that the incidence of shingles is
1.6/100 patient-year (PY) in anti-TNF cohort compared to 0.8/100PY in
nbDMARD group. However, it is well established that RA patients have an
inherently higher risk of shingles irrespective of treatment modality [3].
In a retrospective analysis of data from a US managed care database (n
=122,272) and a UK general practice research database (n =38,621), an
increased risk of shingles was found among all patients with RA compared
with the general population (in the US, adjusted HR 1.91, 95% confidence
interval [95% CI] 1.80-2.03; in the UK, adjusted HR 1.65, 95% CI 1.57-
1.75) [4]. In one study addressing this issue, shingles incidence rates in
RA patients were 14.5 cases per 1,000 PY (9 cases of shingles in 187
patients) and 1.3-4.8 cases per 1,000 PY in the general population. In
this study, no cases of systemic dissemination or further episodes of
shingles infection were observed in the RA patients despite 27.4 years of
cumulative follow up among patients who continued on MTX [5]. Thus the
higher risk of shingles seen in patients on anti TNF agents in BSRBR might
be a reflection of active RA as it is these patients who are most likely
to receive TNF inhibitors.
The authors' recommendation of shingles vaccination prior to
commencing TNF antagonists has a number of limitations. Firstly the uptake
of vaccines in RA patients, as authors suggested, is poor [6]. Secondly,
most of these patients would have failed on nbDMARDs thus requiring rapid
escalation of therapy. The BSR states that live vaccines (such as the
shingles vaccine) should be given at least two weeks, and preferably four
weeks, prior to immunosuppressive therapy [7]. The ACR recommends
avoidance of live viral vaccine preparations with "all biologic agents",
but does not specify whether live vaccines are safe with MTX [8]. EULAR
state that live attenuated vaccines should be avoided whenever possible in
immunosuppressed patients with autoimmune inflammatory rheumatic diseases.
However, they suggest that VZV, shingles and MMR vaccines might be
exceptions to the rule and may be considered in the 'mildly
immunosuppressed' [9].
If a patient were to be vaccinated whilst receiving MTX to avoid
treatment delay (as suggested by EULAR), data is conflicting as to its
efficacy [9]. The CDC ACIP states that patients vaccinated whilst on
immunosuppressive therapy should be considered non-immune and should be
revaccinated at least 3 months after their therapy is discontinued [10].
Secondly, the shingles vaccine should be given at least two weeks (and
preferably one month) prior to receiving immunosuppressive medications
[11]. This would delay further the initiation of anti-TNF treatment for a
patient with aggressive disease and would be contrary to the 'treatment to
target' model.
In addition, the safety of vaccination must be considered with
respect to both the immune dysfunction of RA itself and potential
immunosuppression if administered during MTX therapy. A theoretical
possibility exists, for example that stimulating a deregulated immune
system may cause deleterious effects [12]. As such, EULAR suggest that
vaccination in patients with autoimmune inflammatory rheumatic disease
should ideally be administered when the disease is quiescent [9].
A more pragmatic approach would be to rely on post-exposure
management thereby removing the issues posed above as well as
circumventing deviation from the current model of early aggressive therapy
of RA. An option would be vaccination following exposure as with varicella
zoster vaccine. However, no data exists regarding shingles vaccine post-
exposure. An alternative could be administration of VZIg following
exposure to shingles or VZV, although estimations of its efficacy vary.
Levin et al found only 20% of immunocompromised children developed
clinical varicella if VZIg was administered within 96 hours of exposure
[13]. However, Evans et al reported that 56% of immunosuppressed patients
developed clinical varicella with post-exposure VZIg [14].
We conclude that at this point in time it is premature to recommend
VZ vaccination for RA patients prior to starting biologic therapy.
References
1. Galloway JB, Mercer LK, Moseley A et al. Risk of skin and soft
tissue infections (including shingles) in patients exposed to anti-tumour
necrosis factor therapy: results from the British Society for Rheumatology
Biologics Register. Ann Rheum Dis. 2013;72:229-234
2. Zhang N, Wilkinson S, Riaz M, et al. Does methotrexate
increase the risk of varicella or herpes zoster infection in patients with
rheumatoid arthritis? A systematic literature review. Clin Exp Rheumatol.
2012;30(6):962-71
3. Glück T, Müller-Ladner U. Vaccination in patients with chronic
rheumatic or autoimmune diseases. Clinical infectious diseases: an
official publication of the Infectious Diseases Society of America. 2008;46(9):1459-65.
4. Smitten AL, Choi HK, Hochberg MC, et al. The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis rheum 2007;57(8):1431-8.
5. Antonelli MA, Moreland LW, Brick JE. Herpes zoster in patients with
rheumatoid arthritis treated with weekly, low-dose methotrexate. The
American journal of medicine. 1991;90(3):295-8.
6. Zhang J, Delzell E, Xie F, et al. The use, safety, and effectiveness of
herpes zoster vaccination in individuals with inflammatory and autoimmune
diseases: a longitudinal observational study. Arthritis Res Ther
2011;13:R174
7. BSR. Vaccinations in the immunocompromised person -Guidelines for the
patient taking immunosuppressants, steroids and the new biologic
therapies. 2002
8. Guidelines for the management of rheumatoid arthritis: 2002 Update.
Arthritis rheum 2002;46(2):328-46.
9. van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann rheum dis 2011;70(3):414-22.
10. ACIP. Recommendations of the Advisory Committee on Immunization
Practices (ACIP): Use of Vaccines and Immune Globulins in Persons with
Altered Immunocompetence. MMWR. 1993;42(RR-4).
11. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster:
recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR. Recommendations and reports: Morbidity and mortality weekly
report. Recommendations and reports / Centers for Disease Control. 2008
;57(RR-5):1-30; quiz CE2-4.
12. Wraith DC, Goldman M, Lambert PH. Vaccination and autoimmune disease:
what is the evidence? Lancet 2003;362(9396):1659-66.
13. Levin MJ, Nelson WL, Preblud SR et al. Clinical trials with
varicella-zoster immunoglobulins. London: Academic Press Inc., Ltd; 1986.
14. Evans EB, Pollock TM, Cradock-Watson JE, et al. Human anti-
chickenpox immunoglobulin in the prevention of chickenpox. Lancet. 1980;315(8164):354-6.
I congratulate the research team from Rotterdam for the high quality study
design of the tREACH study, but their conclusions are over-stated [1].
Their quotation of the literature is incomplete, referring to studies that
have studied initial combination DMARDs plus corticosteroid (BeSt,
FinRACo, COBRA) but excluding those studies that do not support their
conclusions. There have been two previously publ...
I congratulate the research team from Rotterdam for the high quality study
design of the tREACH study, but their conclusions are over-stated [1].
Their quotation of the literature is incomplete, referring to studies that
have studied initial combination DMARDs plus corticosteroid (BeSt,
FinRACo, COBRA) but excluding those studies that do not support their
conclusions. There have been two previously published randomised
controlled trials comparing step up and initial combination triple DMARD
therapy which show no sustained benefit of initial triple therapy.
Saunders et al found no superiority of triple therapy (MTX, SSZ and
HCQ) when compared to step up therapy if delivered within the context of
an intensive management strategy. This study recruited patients with high
disease activity (DAS28>5.1) with a longer disease duration; patients
were reviewed patients monthly, and given bridging IM corticosteroid and
IA corticosteroid injections when required. The study was smaller (n=96)
and did not have sufficient power to detect a small difference in mean
change in DAS28, but the trend at 12 months favoured step-up therapy
(difference [95%CI] in mean change in DAS28 = 0.5 [-0.2, 1.1]). [2]
Within the context of a less intensive management strategy, Moreland
et al demonstrated that early superiority of triple therapy over initial
MTX monotherapy was not sustained following 'step up' to triple therapy in
patients with a sub-optimal response to MTX monotherapy. Moreover, this
study showed no clinical advantage to stepping up from MTX monotherapy to
MTX/etanercept rather than to triple therapy. [3]
The tREACH study demonstrated an early, statistically significant
superiority with initial combination therapy but the authors do not
discuss the clinical significance of this difference - they identified
that on average the DAS fell by 0.39 more with initial combination therapy
but this value is comfortably within the reported measurement error of DAS
of 0.6 units [4]. Whether this very small difference in change in DAS is
of any clinical significance may be answered by long term follow up of the
tREACH study.
It is important to assess all the evidence available before making
recommendations based on a single study. The tREACH study suggests that
initial triple therapy may yield a slightly larger reduction in DAS, but
not all other studies support this conclusion. Given our current
knowledge, it remains appropriate to offer patients with recently
diagnosed RA either initial combination therapy or a step-up regimen.
Crucially, whichever strategy is chosen by the patient, he/she should be
reviewed frequently, assessed carefully and treated intensively with the
aim of reaching low disease activity or remission.
References
1. P H de Jong, J M Hazes, P J Barenregt et al. Induction therapy
with a combination of DMARDs is better than methotrexate therapy" first
results of the tREACH trial. Ann Rheum Dis 2013;72:72-78
2. S A Saunders, H A Capell, A Stirling et al. Triple therapy in Early
Active Rheumatoid Arthritis. Arth Rheum 2008;58:1310-1317
3. L W Moreland, J R O'Dell, H Paulus et al. A randomized comparative
effectiveness study of oral triple therapy versus etanercept plus
methotrexate in early aggressive rheumatoid arthritis: The Treatment of
Early Aggressive Rheumatoid Arthritis trial. Arth Rheum 2012;64:2824-2835
4. AM van Gestel, M L L Prevoo, M A van't Hof, et al. Development and
validation of the European League against Rheumatism response criteria for
Rheumatoid Arthritis. Arth Rheum 1996;39:34-40
2nd Propedeutic Dept of Internal Medicine, Hippokration GH,
Thessaloniki, Greece
Dear Editor,
We read with great interest the article by Genovese et al on the
effect of the BAFF antagonist tabalumab in rheumatoid arthritis patients
with inadequate response to TNFa blockade. The res...
2nd Propedeutic Dept of Internal Medicine, Hippokration GH,
Thessaloniki, Greece
Dear Editor,
We read with great interest the article by Genovese et al on the
effect of the BAFF antagonist tabalumab in rheumatoid arthritis patients
with inadequate response to TNFa blockade. The results of this study
indicated a moderate effect of tabalumab early (week 6/ week 9) after
initiation of therapy, both in terms of clinical as well as laboratory
markers of disease activity, which however was not significantly sustained
later on in the course of treatment (week 16).
In the previous decade, biological therapies that target the B cell have
become established in the treatment of rheumatoid arthritis and theories
regarding a possible connection of seropositivity and an enhanced
peripheral compartment of memory cells have emerged. [1] Interestingly,
not all biological B-cell targeted treatments have proved to be equally
effective in rheumatoid arthritis.
Our group published recently the observation that TNF antagonism
(infliximab) does not significantly affect the levels of BAFF in
previously biologically naive rheumatoid arthritis patients, regardless of
the presence or absence of seropositivity. [2] Prompted by the results of
Genovese et al we attempted to reanalyze our data to investigate whether
BAFF levels could represent a biomarker to predict flare of the disease
and potentially response to anti-BAFF therapy. We recategorized the
patients included in the study in responders and non-responders and
compared the effect of antiTNF treatment on BAFF levels in each individual
patient, pre and post treatment, in the two separate categories.
Responders were identified as the patients whose DAS28 value decreased by
at least 1.2 units post treatment with infliximab.
There wasn't any statistical significant correlation between impact on
DAS28 and Baff difference in the total sample (Spearman test r=0.454), in
the responders group (Spearman test r=0.391) and in the non-responders
group (Spearman test r=0.541). Within the non-responders group,
seronegative patients had comparable levels of BAFF pre- and post
treatment, while in seropositive patients, BAFF levels appeared to
decrease post TNFa antagonism, p=0.046. It needs however to be stressed
out that a. the number of the patients is small for a safe conclusion to
be drawn, and b. the BAFF measured in this study represents only the
soluble and not the membrane bound molecule.
It would be of great interest to know whether the authors looked at BAFF
levels during their study. Another issue to be addressed would be the
prevalence of specific BAFF promoter polymorphisms among responders and
non-responders to tabalumab, which have been associated with disease
severity in the presence or absence of increased serum BAFF levels. [3,4]
The pathogenesis of rheumatoid arthritis is complex and leads to a wide
diversity of disease phenotypes and the role of BAFF in the development
and treatment of the disease, as well as the physiological meaning of
exogenous pharmaceutical interventions have not become fully clarified.
The interplay of soluble cytokines and membrane bound receptors and its
clinical outcome may only be elucidated when all involved partners have
been identified and the individual intermolecular interactions have become
mapped.
References
1.Roll P, Muhammad K, Schumann M, et al. RF positivity has
substantial influence on the peripheral memory B-cell compartment and its
modulation by TNF inhibition. Scand J Rheumatol. 2012 May;41(3):180-5.
doi: 10.3109/03009742.2011.645056. Epub 2012 Mar 9
2. Pyrpasopoulou A, Balaska E, Triantafyllou A, et al. B-cell
activating factor levels in rheumatoid arthritis patients in response to
treatment with biologics. J Interferon Cytokine Res. 2012 Jul;32(7):338-
40. doi: 10.1089/jir.2011.0118. Epub 2012 Apr 17.
3. Ruyssen-Witrand A, Rouanet S, Combe B, et al. Association between
-871C>T promoter polymorphism in the B-cell activating factor gene and
the response to rituximab in rheumatoid arthritis patients. Rheumatology
(Oxford). 2012 Dec 22. [Epub ahead of print]
4. Nossent JC, Lester S, Zahra D, et al. Polymorphism in the 5'
regulatory region of the B-lymphocyte activating factor gene is associated
with the Ro/La autoantibody response and serum BAFF levels in primary
Sjogren's syndrome. Rheumatology (Oxford). 2008 Sep;47(9):1311-6. doi:
10.1093/rheumatology/ken246. Epub 2008 Jul 10.
We read with interest the article by Doherty et al [1] where they
lament suboptimal care of patients with gout, as the majority are managed
by non-specialists. In 2005, we had surveyed non-rheumatologists on their
practices regarding the management of gout [2]. Of the 128 respondents,
52.3% were general practitioners (GPs). A significant proportion of
respondents were treating gout sub-optimally; 50% w...
We read with interest the article by Doherty et al [1] where they
lament suboptimal care of patients with gout, as the majority are managed
by non-specialists. In 2005, we had surveyed non-rheumatologists on their
practices regarding the management of gout [2]. Of the 128 respondents,
52.3% were general practitioners (GPs). A significant proportion of
respondents were treating gout sub-optimally; 50% would stop allopurinol
during an acute attack, once allopurinol was started, only 54.7% would
continue indefinitely and 15% would treat asymptomatic hyperuricemia.
As a result of this, in October 2008, the Malaysian Society of
Rheumatology and Ministry of Health, Malaysia, published the Clinical
Practice Guidelines on the Management of Gout (Gout CPG) which was made
available online [3] and in hard copy. To publicise the CPG, a series of
weekend rheumatology workshops were run, where the Gout CPG was a topic.
These are the results of a second survey done after the introduction of
the Gout CPG.
A cross-sectional self-administered questionnaire survey was carried out
among doctors attending these workshops. There were 9 workshops carried
out between April 2010 and February 2012. Participation in the survey was
voluntary.
366 questionnaires were handed out to the all participants of the
workshops on the last day, of which 296 (80.9%) were returned. 291 (98.3%)
of respondents stated that they treated gout, whose answers were further
analysed. With regards to specialty, 33.8% of the respondents were GPs,
46.7% Medical Officers (studying for post-graduate physician
qualifications) and 7.7% were general physicians. With regards to
experience, 29.3% had graduated less than 5 years ago, 21.7% between 5-10
years ago and 49% more than 10 years ago. Only 12.5% would stop previously
prescribed allopurinol during an acute attack, compared to 50% in the
previous study. Once started, 68.0% (compared to 54.7% previously) would
continue allopurinol indefinitely. Regarding urate levels while on
treatment, 11.3% would be satisfied with levels in the high normal (upper
third) range, 24.1% middle (middle third) range, 7.9% low normal (lower
third) range and 35.4% anywhere within the normal range. This is very
similar to the previous survey. 3.4% (compared to 15% previously) would
treat asymptomatic hyperuricemia.
There were no significant differences (p>0.05 on Kruskal-Wallis tests)
in the above management principles between the different specialties or
with regards to their years of experience.
As this was a self-administered questionnaire, there may be a variation
between theory and practice, but at least more doctors seemed to have the
correct theoretical knowledge after this series of workshops. The other
weakness is that this questionnaire was administered the day after the
lectures, so the information was fresh in the participants' memories but
may not be remembered long-term. However, all participants of the
workshops went home with a copy of the Gout CPG which they can use for
future reference.
We conclude that it is encouraging to note that following the introduction
of, and teaching on, the Gout CPG, non-rheumatologists are treating gout
more appropriately.
I read with great interest the paper by van Sijl et al., (1) a 3-year
longitudinal study by following patients with rheumatoid arthritis (RA) to
know the effect of the estimated renal function on cardiovascular (CV)
events. Out of 330 participants, 23 had CV event (7%). They mentioned the
study limitation of low statistical power derived from small number of CV
event and restriction of confounding va...
I read with great interest the paper by van Sijl et al., (1) a 3-year
longitudinal study by following patients with rheumatoid arthritis (RA) to
know the effect of the estimated renal function on cardiovascular (CV)
events. Out of 330 participants, 23 had CV event (7%). They mentioned the
study limitation of low statistical power derived from small number of CV
event and restriction of confounding variables for the analysis. This
limitation reflects to the number of independent variables in their study
presented in Table 2. Furthermore, sub-analysis by the stratification of
CV events was also limited.
The limitation in the total number for logistic regression analysis
was simulated with some modifications to improve statistical power (2).
Furthermore, Peduzzi et al. (3) conducted a Monte Carlo study to evaluate
the effect of the number of events per variable (EPV) on the outcome of
logistic regression analysis. As a conclusion, EPV value less than 10 has
some problems on the regression coefficients such as the fragility of the
sample variance. In addition to the number of events, EPV should also be
considered for the logistic model to keep validity of the outcome. I
understand that there is an opposite opinion that EPV value less than 10
is also acceptable in some situations in logistic regression analysis (4),
but I think there is no gold standard to select appropriate simulation
model to check the validity.
On this point, results presented by van Sijl et al. have some
problems to be accepted. Among 23 participants with CV event, 8 different
diagnoses were made. Because of the limitation in the number of CV events,
they compiled them as one dependent variable for logistic regression
analysis. Three independent variables for Model 1, presented in Table 2,
were used including estimated renal function. When conventional risk
factors or RA-related factors were added, four independent variables were
used for the analysis. Although they did not use these confounding
variables simultaneously, the maximum number of independent variables for
logistic regression analysis should be limited within three (3).
van Sijl et al. also described that uric acid should also be included
for the analysis, which is one of the recently discovered markers of both
renal dysfunction and CV disease in patients with RA. But EPV should be
kept 10 or higher by making longer follow-up or handling of larger sample
sizes to keep stable risk estimation. As the study design presented by van
Sijl et al. is unique, the author recommends adding satisfactory number of
events for logistic regression analysis to keep validity of the outcome.
References
1. van Sijl AM, van den Oever IA, Peters MJ, et al. Subclinical renal
dysfunction is independently associated with cardiovascular events in
rheumatoid arthritis: the CARRÉ Study. Ann Rheum Dis. 2012;71(3):341-
4.
2. Novikov I, Fund N, Freedman LS. A modified approach to estimating
sample size for simple logistic regression with one continuous covariate.
Stat Med. 2010;29(1):97-107.
3. Peduzzi P, Concato J, Kemper E, et al. A simulation study of the
number of events per variable in logistic regression analysis. J Clin
Epidemiol. 1996;49(12):1373-9.
4. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per
variable in logistic and Cox regression. Am J Epidemiol. 2007;165(6):710-
8.
Dear Editor, Gremese et al. conclude from the real life prospective study
performed in three early arthritis clinics that 12 weeks disease duration
and an early intervention with DMARD represent the most significant
opportunities to reach remission of RA. Moreover, it is supposed that vera
early rheumatoid arthritis (VERA) represents a window of opportunity in
terms of cost saving.
Dear Editor, Gremese et al. conclude from the real life prospective study
performed in three early arthritis clinics that 12 weeks disease duration
and an early intervention with DMARD represent the most significant
opportunities to reach remission of RA. Moreover, it is supposed that vera
early rheumatoid arthritis (VERA) represents a window of opportunity in
terms of cost saving.
A high level of confidence in the diagnosis of RA early in its course
is mandatory for the validity of any study. But experts often disagree
about diagnoses and discrepancies may be considerable among
rheumatologists confronted with early arthritis [1]. In the present
observational study all the subjects diagnosed as having early RA and VERA
fulfilled the 1987 classification criteria for RA at the first visit and
also retrospectively met the new 2010 RA classification criteria.
Notwithstanding misclassification may be an important confounder which
might have affected the results significantly. Multiple studies recently
indicated that the 2010 RA classification criteria have a considerable
risk of false positive and false negative classification of early
arthritis as RA [2]. In the present study 148 (20.8%) of 711 subjects
initially diagnosed with RA were classified as VERA. It is striking that
the subjects collected in the early arthritis cohort 2 (EAC 2) were
positive for rheumatoid factor and anti-CCP in only 35.7% and 26.7%,
respectively. How many of the subjects in the follow-up with VERA were
collected from EAC 2? Moreover, it would be interesting to know how many
of the subjects with VERA who had a follow-up assessment were positive for
rheumatoid factor and/or anti-CCP in each of the three EAC. Were all
patients tested for HLA-B27? A proportion of patients with early
undifferentiated arthritis (UA) , particularly patients with
oligoarthritis, may have reactive arthritis (ReA) despite not having a
clear history of preceding infection [3 ]. In these cases, a thorough
search for offending organisms may be crucial. Additionally, sero-negative
early arthritis and UA very frequently go into spontaneous remission over
weeks and months. Estimates of prognosis from studies specifically
reporting outcomes for UA suggest that up to 60% of UA patients experience
remission and 10% to 40% have persistent disease activity, but remain
undifferentiated [3]. Therefore, such cases misclassified as RA might
distort the results of the multivariate logistic regression in which VERA
and DMARD treatment emerged as predictors of remission.
Altogether, it will be of critical importance for the judgment of the
validity of the present study to learn more how the issues referred where
addressed by the authors?
References
1.Berthelot JM, Klarlund M, McGonagle D et al. Lessons from an
international survey of paper cases of 10 real patients from an early
arthritis clinic. CRI (Club Rhumatismes et Inflammation) Group. J
Rheumatol 2001;28:975-81.
2.Zeidler H. The need to better classify and diagnose early and very early
rheumatoid arthritis. J Rheumatol. 2012;39:212-7.
3.Hitchon CA, Peschken CA, Shaikh S, El-Gabalawy HS. Early
undifferentiated arthritis. Rheum Dis Clin North Am 2005;31:605-26.
We recently published a meta-analysis of malignancy rates reported
from prospective observational studies in patients treated with tumour
necrosis factor inhibitors (TNF-I). [1] Whilst there was no increase in
the rates of all-site malignancy or lymphoma, there was an increased risk
of non-melanoma skin cancer (NMSC) (1.45, 95% CI 1.15 to 1.76).
We recently published a meta-analysis of malignancy rates reported
from prospective observational studies in patients treated with tumour
necrosis factor inhibitors (TNF-I). [1] Whilst there was no increase in
the rates of all-site malignancy or lymphoma, there was an increased risk
of non-melanoma skin cancer (NMSC) (1.45, 95% CI 1.15 to 1.76).
The skin cancer analysis included data from an abstract from the
British Society for Rheumatology Biologics Register (BSRBR) [2] that has
since been published as a full paper with different estimates [3}. In the
BSRBR abstract, the adjusted hazard ratio (HR) in comparison to a control
cohort of patients treated with disease-modifying antirheumatic drugs
(DMARD), without a prior NMSC, was 1.7 (95% CI 0.9, 3.4). [2] The updated
analysis provided separate estimates for basal cell carcinoma (HR 0.95
[95% CI 0.53 to 1.71]) and squamous cell carcinoma (HR 1.16 [95% CI 0.35,
3.84]). [3]
Since the updated results were substantially lower than the value
reported in the BSRBR abstract, we revised our analysis to include the
updated data, to investigate whether our original conclusions regarding
the increased risk of skin cancer could be sustained.
In our revised analysis, the pooled risk estimate for NMSC in
patients treated with TNF-I was 1.33 (95% CI 1.06, 1.60).
Therefore, the revised analysis is consistent with our original
conclusion that treatment with TNF-I increases the risk of NMSC; although,
the lower confidence interval bound is only just above 1.0. These revised
results are still aligned with a meta-analysis of randomised controlled
trials across indications; although, here the increased risk of NMSC was 2
-fold (RR 2.02, 95% CI 1.11 to 3.95). [4]
Direct random effects meta-analyses were conducted in a frequentist
framework using Stata version 11. The level of heterogeneity was
determined using the I2 statistic
References
1. Mariette X, Matucci-Cerenic M, Pavelka K, et al. Malignancies
associated with TNF inhibitors in registries and prospective observational
studies: A systematic review and meta-analysis. Ann Rheum Dis.
2011;70:1895-1904.
2. Mercer LK, Galloway JB, Lunt M, et al. The Influence of Anti-TNF
Therapy Upon Incidence of Non-Melanoma Skin Cancer (NMSC) in Patients with
Rheumatoid Arthritis (RA): Results From the BSR Biologics Register (BSRBR)
Arthritis Rheum. 2009;60(Suppl 10):2062
3. Mercer LK, Green AC, Galloway JB, et al. The influence of anti-TNF
therapy upon incidence of keratinocyte skin cancer in patients with
rheumatoid arthritis: longitudinal results from the British Society for
Rheumatology Biologics Register. Ann Rheum Dis. 2012;71:869-874
4. 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;20:119-30 .
5. Askling J, ARTIS study group. Anti-TNF therapy and risk of skin cancer,
data from the Swedish ARTIS registry 1998-2006. Ann Rheum Dis.
2009;68:(Suppl 3) 423
6. Greenberg J, Strand V, Keystone E, et al. TNF Inhibitors (TNF-I) and
Risk of Malignancy in 8,072 RA Patients Followed Over 15,495 Patient
Years. American College of Rheumatology Annual Meeting. 2007;Abstract 282
7. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the
risk of malignancy: analyses from a large US observational study.
Arthritis Rheum. 2007;56:2886-2895.
Conflict of Interest:
XM has received research grants or honoraria from Bristol Myers Squibb, GSK, Pfizer and Roche
AR was an employee of Wyeth Europa and had held shares in Wyeth and currently has Pfizer share options and has undertaken consultancy work for UCB Pharma and Pfizer
PE has received research grants or honoraria from Bristol Myers Squibb, GSK, Pfizer and Roche
This work was undertaken without external funding
We read with interest the paper by De Jong PH et al.,(1) a single blinded clinical trial which reports that triple disease modifying antirheumatic drugs (DMARDs) induction therapy is better than methotrexate (MTX) monotherapy in early rheumatoid arthritis (RA).
Our Hospital is located in San Luis Potosí (Mexico) and our cohort includes low income patients without any opportunities for biological th...
We read with interest the paper by De Jong PH et al.,(1) a single blinded clinical trial which reports that triple disease modifying antirheumatic drugs (DMARDs) induction therapy is better than methotrexate (MTX) monotherapy in early rheumatoid arthritis (RA).
Our Hospital is located in San Luis Potosí (Mexico) and our cohort includes low income patients without any opportunities for biological therapy. Our induction therapy for early RA patients almost always includes 2-3 DMARDs and low dosage prednisone.
Recently, we evaluated 125 patients with RA that had been under stable treatment with biological therapy (BT) or > 3 DMARD (DMARDs combination) for at least a complete year before the evaluation for this study. Seventy six patients were under biologics and 49 on DMARDs combination. In both groups we evaluated clinical disease activity and ultrasound remission (UR) using DAS28; musculoskeletal ultrasounds (twelve-joint simplified power doppler ultrasonographic assessment)(2) UR was defined as when there was absence of power doppler activity in evaluated joints. Clinical remission was defined as a DAS28 score <2.6.(3).
Demographic characteristics were between BT (n=76) and DMARDs combination (n=49): women 68 vs 43 (p=0.766), mean age (years) 51.3 vs 48.9 (p=0.3), and evolution of the disease in years 14.7 vs 5.7 (p<0.0001). The combination group received methotrexate 94.7%, sulfazalacine 97.8%, antimalarial therapy 95.5% and prednisone 71.4%. The BT group received methotrexate (94.7%) and prednisone (56.6%). DAS 28 remission was achieved in 43.4% of BT group and 24.5% of DMARDs combination group (p= 0.03); of these, sixteen patients (48%) of BT and 4 (33%) of DMARDs combination achieved UR (p=0.055).
Our study and results from tREACH emphasize the benefit of triple therapy with DMARDs. Moreover, our results with power doppler emphasize that it is possible to achieve UR in patients using non-biological therapy, although we observed that more patients receiving BT than DMARDs reached UR De Jong et al, emphasize that the DMARDs combination decreases the number of patients requiring BT. We think that DMARDs combination for early RA is an excellent option for developing countries including Mexico; moreover, maybe it is also a good option for developed countries considering the cost of BT.(4)
We recognize that rheumatologists are influenced by medical information with scientific evidence, but most of these studies have been supported by pharmaceutical industries. Annual earnings were recently reported to exceed 30 billion dollars (USD) for biological therapy including adalimumab, etanercept, infliximab and rituximab.(5) In Mexico it is estimated that fewer than 2% of RA patients receive BT, probably due to the high cost of this therapy.(5)
Post-marketing studies, head to head including >3 DMARDs and BT that compare benefit, safety, direct and indirect costs may provide better options for the therapy selection.
References
1. de Jong PH, Hazes JM, Barendregt PJ, et al. Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial. Ann Rheum Dis. 2012. Epub 2012/06/09.
2. Naredo E, Rodriguez M, Campos C, et al. Validity, reproducibility, and responsiveness of a twelve-joint simplified power doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis. Arthritis Rheum 2008;59(4):515-22. Epub 2008/04/03.
3. Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford). 2004;43(10):1252-5. Epub 2004/07/09.
4. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012;379(9827):1712-20. Epub 2012/04/03.
5. Biologic drugs set to top 2012 sales. Nat Med. 2012;18(5):636. Epub 2012/05/09.
We read with great interest the letter from de Rooy et al. published in
the last issue of the Journal (1).
By analyzing the conclusions of this investigation in connection to
another recent report about the real onset of arthritis symptoms during
winter or spring and related more radiographic joint damage after 1 year,
it seems that the authors found slightly different results that need some...
We read with great interest the letter from de Rooy et al. published in
the last issue of the Journal (1).
By analyzing the conclusions of this investigation in connection to
another recent report about the real onset of arthritis symptoms during
winter or spring and related more radiographic joint damage after 1 year,
it seems that the authors found slightly different results that need some
comments (2).
As matter of fact, in Figure 2 of the study by de Rooy, it is evident that
both the highest percentage of rheumatoid arthritis (RA) patients with
symptom onset in each of the seasons (winter/spring), as well as the
effect of meteorologically defined seasons on radiographic damage
progression over 7 years of follow-up (however more then 1 year as in the
original study) are shown in both Dutch and Swedish RA patients.
Therefore, the results are very close to the results found by Mouterde et
al (2).
However, to obtain a more correct interpretation of the results and
related conclusions at least two important aspects must be considered (3).
First, differently from the Mouterde study referred to 1 year of follow-up
("short-term outcome" as reported in the title), when analyzing a longer
time (5-7 years of follow-up) as done by De Rooy, it is clear that the
therapeutical interventions adopted (conventional therapy for RA) may
obviously influence (alter) the progression of the disease and related
radiographic characteristics.
As consequence, the vitamin D deficiency effects even present short-term
outcome, are possibly lost during the long-term follow-up.
Second, by considering the obvious different vitamin D availability in the
different seasons, the authors should investigate (if possible) any
possible different therapeutical attitute in both centers to integrate the
vitamin D deficiency/efficiency by vitamin D analogs (i.e to treat
osteoporosis). The substitution treatment may once again interfere and
modulate the effects of the deficiency itself especially on long-term.
In fact, relationships between the circannual vitamin D status and the
disease behaviour are actually recognized in several rheumatic conditions,
including systemic lupus erythematosus, as well as RA (circannual
severity) (4,5).
In addition, an increased disease severity and even risk of autoimmunity
in connection with vitamin D deficiency is also recognized and reported in
this Journal (6).
Therefore, it would be interesting for the authors and the readers to
revaluate the data on the light of the suggested comments.
References
1. de Rooy DPC, Andersson MLE, Knevel R, et al. Does the season at symptom onset influence the long-
term severity of radiographic joint destruction in rheumatoid arthritis?
Ann Rheum Dis doi:10.1136/annrheumdis-2012-201565
2. Mouterde G, Lukas C, Logeart I, et al. Predictors of radiographic
progression in the ESPOIR cohort: the season of first symptoms may
influence the short-term outcome in early arthritis. Ann Rheum Dis
2011;70:1251-6
3. Cutolo M. Rheumatoid arthritis: circadian and circannual rhythms in RA.
Nat Rev Rheumatol. 2011;5:500-2
4. Birmingham D, Hebert L, Song H et al. Evidence that abnormally large
seasonal declines in vitamin D status may trigger SLE flare in non-African
Americans. Lupus. 2012;21:855-64
5. Cutolo M, Otsa K, Laas K, et al. Circannual vitamin d serum levels and
disease activity in rheumatoid arthritis: Northern versus Southern Europe.
Clin Exp Rheumatol. 2006;24:702-4
6. Ritterhouse LL, Crowe SR, Niewold TB et al. Vitamin D deficiency is
associated with an increased autoimmune response in healthy individuals
and in patients with systemic lupus erythematosus. Ann Rheum Dis.
2011;70:1569-74
Dear Editor,
Clowse et al.[1] report that ferritin, oestradiol, and uric acid level at mid-gestation may predict preterm delivery in systemic lupus erythematosus (SLE) with mild-moderate disease activity. This is a well- done study, but we believe that the authors fail to fully address the effect of antiphospholipid antibodies. The author states that four patients tested positive for antiphospholipid antibodies....
Dear Editor,
We read with interest the report by Galloway et al on the risk of skin and soft tissue infections (including shingles) in patients exposed to TNF antagonists from the BSRBR [1]. In the light of our recently published systematic literature review of the risk of shingles in rheumatoid arthritis (RA) patients, we would like to address several issues raised in the report [2]. The authors state that the inci...
Dear Editor,
I congratulate the research team from Rotterdam for the high quality study design of the tREACH study, but their conclusions are over-stated [1]. Their quotation of the literature is incomplete, referring to studies that have studied initial combination DMARDs plus corticosteroid (BeSt, FinRACo, COBRA) but excluding those studies that do not support their conclusions. There have been two previously publ...
Triantafyllou Areti, Pyrpasopoulou Athina, Anyfanti Panagiota, Balaska Ekaterini, Aslanidis Spyros, Douma Stella
2nd Propedeutic Dept of Internal Medicine, Hippokration GH, Thessaloniki, Greece
Dear Editor,
We read with great interest the article by Genovese et al on the effect of the BAFF antagonist tabalumab in rheumatoid arthritis patients with inadequate response to TNFa blockade. The res...
Dear Editor,
We read with interest the article by Doherty et al [1] where they lament suboptimal care of patients with gout, as the majority are managed by non-specialists. In 2005, we had surveyed non-rheumatologists on their practices regarding the management of gout [2]. Of the 128 respondents, 52.3% were general practitioners (GPs). A significant proportion of respondents were treating gout sub-optimally; 50% w...
Dear Editor,
I read with great interest the paper by van Sijl et al., (1) a 3-year longitudinal study by following patients with rheumatoid arthritis (RA) to know the effect of the estimated renal function on cardiovascular (CV) events. Out of 330 participants, 23 had CV event (7%). They mentioned the study limitation of low statistical power derived from small number of CV event and restriction of confounding va...
Dear Editor, Gremese et al. conclude from the real life prospective study performed in three early arthritis clinics that 12 weeks disease duration and an early intervention with DMARD represent the most significant opportunities to reach remission of RA. Moreover, it is supposed that vera early rheumatoid arthritis (VERA) represents a window of opportunity in terms of cost saving.
A high level of confidence in t...
Dear Editor,
Dear Editor,
We recently published a meta-analysis of malignancy rates reported from prospective observational studies in patients treated with tumour necrosis factor inhibitors (TNF-I). [1] Whilst there was no increase in the rates of all-site malignancy or lymphoma, there was an increased risk of non-melanoma skin cancer (NMSC) (1.45, 95% CI 1.15 to 1.76).
The skin cancer analysis incl...
Dear Editor,
We read with interest the paper by De Jong PH et al.,(1) a single blinded clinical trial which reports that triple disease modifying antirheumatic drugs (DMARDs) induction therapy is better than methotrexate (MTX) monotherapy in early rheumatoid arthritis (RA).
Our Hospital is located in San Luis Potosí (Mexico) and our cohort includes low income patients without any opportunities for biological th...
Dear Editor,
We read with great interest the letter from de Rooy et al. published in the last issue of the Journal (1).
By analyzing the conclusions of this investigation in connection to another recent report about the real onset of arthritis symptoms during winter or spring and related more radiographic joint damage after 1 year, it seems that the authors found slightly different results that need some...
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