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.
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...
Pages