For the classification of axial spondyloarthritis (axSpA) Assessment of SpondyloArthritis international Society (ASAS) criteria are to be applied in patients with back pain of > 3 months and age at onset of back pain <45 years who have:
(1) Sacroiliitis on imaging (definite sacroiliitis according to modified New York criteria OR active {acute}) inflammation on MRI highly suggestive of sacroiliitis assoc...
For the classification of axial spondyloarthritis (axSpA) Assessment of SpondyloArthritis international Society (ASAS) criteria are to be applied in patients with back pain of > 3 months and age at onset of back pain <45 years who have:
(1) Sacroiliitis on imaging (definite sacroiliitis according to modified New York criteria OR active {acute}) inflammation on MRI highly suggestive of sacroiliitis associated with axSpA PLUS any one or more of the 11 features defined for axSpA;
OR
(2) The presence of HLA B27 PLUS two or more of the 11 features defined for axSpA. [1,2]
It is not easy to remember all the 11 features defined for axSpA. Therefore, in clinical practise one needs an 'instrument' to simplify remembering these 11 features. I suggest the following simple method to memorize these 11 features. It has worked well in our rheumatology clinic:
yoUr (uveitis) Patient (psoriasis) has:
A - Arthritis
B - Back pain
C - Crohn's/colitis
D - Dactylitis
E(x2) - enthesitis; elevated CRP
F - Family history
G - Good response to NSAIDs
H - HLA B27
I am sure that rheumatologists will find it easy to memorize the 11 features of axSpA with the help of this 'instrument'.
References
1. Rudwaleit M, van der Heijde D, Landewé R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777-83.
2. Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68;ii1-ii44.
We have read with interest the article by Knevel et al, entitled “Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study” published on-line on March 22, 2012.1 The authors describe an elegant candidate gene study using four datasets of European rheumatoid arthritis (RA) patients with longitudinal radiological data, which let them conclude that genetic...
We have read with interest the article by Knevel et al, entitled “Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study” published on-line on March 22, 2012.1 The authors describe an elegant candidate gene study using four datasets of European rheumatoid arthritis (RA) patients with longitudinal radiological data, which let them conclude that genetic variants in IL15 are associated with the intensity of radiological progression in RA.
With a different approach, we have recently reported data suggesting that serum-IL15 (sIL15) could be a potential biomarker of severe disease for patients with early arthritis,2 and then we demonstrated that those with increased levels of the cytokine may require earlier and more intensive treatment, based on two major findings: first, early arthritis patients with increased sIL15 levels at baseline (30% of the study population) presented higher disease activity throughout follow-up; second, rheumatologists—blinded to sIL15 levels— prescribed treatment with DMARDs and glucocorticoids more intensively to these patients than to those with normal or low IL15 levels.3 Hence, the findings from the genetic study by Knevel et al. add further evidence for IL15 as a marker of severity in RA.
In addition, we would like to share new data that may contribute to the better understanding of the relation between IL15 and radiological progression. It has been described that IL15 can mediate the development of osteoclasts 4 through the induction of IL17 5 6 that, in turns, promotes RANKL production 7 8. Based on these findings, we have analyzed whether the amounts of RANKL and osteoprotegerin (OPG) in serum correlated with sIL15 in 102 early arthritis patients from our cohort in which blood samples from 376 visits have been analysed for either marker. We measured OPG concentration by using a DuoSet kit from R&D Systems (Abingdon, United Kingdom), and total RANKL serum levels through a specific kit from Apotech (Epalinges, Switzerland), following the manufacturer recommendations. We fitted multivariable models adjusted for repeated measures (xtgee command of Stata 12) to find correlates of either RANKL or OPG.
RANKL serum levels were 3795 pg/ml (interquartile range[IQR]: 1464 – 10095) in patients with positive rheumatoid factor (RF+) and 1125 pg/ml (IQR: 569 – 2867) in those with negative RF (RF-), being the differences statistically significant at the multivariable analysis (β coefficient 5913 ± 1835 [RF+ vs RF-], p=0.001). In addition, RANKL was 2532 pg/ml (IQR: 912 – 7242) in patients with increased serum IL15 compared to 1441 pg/ml (IQR: 632 – 3920) in those with low levels of IL15, being significant the correlation between serum levels of these molecules (β coefficient 22.7 ± 11.3 [by pg/ml IL15], p=0.044). On the other hand, we did not observe any significant association between RANKL serum levels and age, gender, disease activity assessed by DAS28, ACPA, or OPG levels. Conversely, OPG serum levels were significantly associated with disease activity (β coefficient 337 ± 121, p=0.006) and age (β coefficient 70 ± 16.6, p <0.001.
We did not observe any significant association between OPG serum levels and either gender, rheumatoid factor, ACPA, or IL15 levels.
In conclusion, our findings, and those reported by Knevel et al. appear to harmonize. It would be interesting to know whether these genetic variants could conceivably explain the high baseline sIL15 values that we found in our early arthritis subpopulation, in association with severe disease and intensive therapy requirement.
References
1. Knevel R, Krabben A, Brouwer E, et al. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. Ann Rheum Dis 2012. doi:10.1136/annrheumdis-2011-200724
2. Lamana A, Ortiz AM, Alvaro-Gracia JM, et al. Characterization of serum interleukin-15 in healthy volunteers and patients with early arthritis to assess its potential use as a biomarker. Eur Cytokine Netw 2010;21(3):186-94.
3. Gonzalez-Alvaro I, Ortiz AM, Alvaro-Gracia JM, et al. Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis. PLoS One 2011;6(12):e29492.
4. Ogata Y, Kukita A, Kukita T, et al. A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol 1999;162(5):2754-60.
5. Gonzalez-Alvaro I, Ortiz Garcia AM, Dominguez-Jimenez C, et al. Inhibition of TNF and IL-17 production by leflunomide involves the JAK/STAT pathway. Ann Rheum Dis 2009;68(10):1644-50.
6. Ziolkowska M, Koc A, Luszczykiewicz G, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol 2000;164(5):2832-8.
7. Neumann E, Gay S, Muller-Ladner U. The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: new insights from animal models. Arthritis Rheum 2005;52(10):2960-7.
8. Schett G, Hayer S, Zwerina J, et al. Mechanisms of Disease: the link between RANKL and arthritic bone disease. Nature clinical practice. Rheumatology 2005;1(1):47-54.
We read with great interest the article by Wendling et al. published
online on January 4, 2012 in Annals of The Rheumatic Diseases, reporting a
case series of SAPHO patients treated with anakinra (1). Some time ago, we
firstly described a dysregulation of the P2X7 receptor-inflammasome axis
in a patient with SAPHO syndrome successfully treated with anakinra,
suggesting that interleukin-1 (IL-1) was very...
We read with great interest the article by Wendling et al. published
online on January 4, 2012 in Annals of The Rheumatic Diseases, reporting a
case series of SAPHO patients treated with anakinra (1). Some time ago, we
firstly described a dysregulation of the P2X7 receptor-inflammasome axis
in a patient with SAPHO syndrome successfully treated with anakinra,
suggesting that interleukin-1 (IL-1) was very likely involved in its
pathogenesis (2). These findings strengthened current evidence supporting
inclusion of SAPHO in the growing family of auto-inflammatory diseases.
Therefore, we fully agree with Wendling et al. on the fact that blocking
IL-1 with anakinra could be a therapeutic option in difficult cases of
SAPHO syndrome. The study by Wendling et al. further highlights the role
of IL-1 blockers in the treatment of SAPHO syndrome.
In this regard, it may be of great therapeutical interest to directly
target the intracellular mechanism of IL-1 maturation and release. It is
well known that IL-1 is processed and released by mononuclear phagocytes
through a mechanism requiring the assembly and activation of a cytoplasmic
complex named inflammasome. So far, no reliable blockers of the intrinsic
constituents of the inflammasome are available. On the contrary, several
druglike antagonists of an accessory inflammasome molecule, named P2X7,
have been developed by many pharmaceutical companies (3). P2X7 is a plasma
membrane receptor belonging to the P2 nucleotide receptor family, which is
expressed to high level by immune and inflammatory cells. P2X7 activation
triggers NLRP3-inflammasome activation and IL-1 and IL-18 processing and
release (4). P2X7 antagonists proved to be very potent blockers of IL-1
release in pre-clinical studies. Since 2011, about 20 Phase 1/Phase 2b
clinical studies have been performed, with various outcomes, to test
safety and efficacy of P2X7 blockers in patients affected by chronic
inflammatory diseases such as osteoarthritis, rheumatoid arthritis,
chronic obstructive pulmonary diseases (COPD) or Crohn' s disease. No data
are available in SAPHO. Our data and Wendling's now suggest that P2X7
blocking might be a useful option in the treatment of SAPHO (1,2).
References
1. Wendling D, Prati C, Aubin F. Anakinra treatment of SAPHO syndrome:
short-term results of an open study. Ann Rheum Dis doi:
10.1136/annrheumdis-2011-200743.
2. Colina M, Pizzirani C, Khodeir M, et al. Dysregulation of P2X7 receptor
-inflammasome axis in SAPHO sindrome: successful treatment with anakinra. Rheumatology 2010;49:1416-8.
3. Arulkumaran N, Unwin RJ, Tam FWK. A potential therapeutic role for P2X7
receptor (P2X7R) antagonists in the treatment of inflammatory diseases.
Expert Opin Investig Drugs 2011;20:897-915.
4. Ferrari D, Pizzirani C, Adinolfi E, et al. The P2X7 receptor: a key
player in IL-1 processing and release. J Immunol 2006;176:3877-3883.
We read with interest the paper of M Sebastianni et al about the predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis(1). The authors suggest that the CSURI score "can represent a feasible and reliable clinical tool in the routine evaluation of patients". However, we feel this report raises serious issues concerning the reproducibility of the methodology. When calculating the score, the num...
We read with interest the paper of M Sebastianni et al about the predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis(1). The authors suggest that the CSURI score "can represent a feasible and reliable clinical tool in the routine evaluation of patients". However, we feel this report raises serious issues concerning the reproducibility of the methodology. When calculating the score, the number of capillaries ("N") was the most important predictive index. The definition of the "N" is clearly detailed and the clinicians have to count "all the capillaries detectable in the entire distal front line, including capillaries placed at different levels". The measurement was illustrated in figure 1 and we noticed that that the author were counting 13 capillaries on the panel C as specified in the legend.
However, the same picture was used 3 years ago, when the same authors described the score(2), excepted that the picture was a little larger and included one more capillary on the right of the picture, and the authors counted only 11 capillaries. We were surprised about such a huge difference in capillary counting, especially in didactic pictures which have the aim to illustrate the methodology of the score.
This difference may be induced by the difficulty of defining the "entire distal front line". It also reflects the difficulty of capillary counting using native videocapilaroscopy that could be overcome by using fluorescent dyes. It is difficult to estimate the extrapolation of this error on the score MxD/N2 but, it seems clear that the reproducibility of the CSURI remains questionable. Although the aim to build-up an informative and easy to use capillaroscopic score is a highly valuable purpose, the reproducibility of such measurements remains a stumbling stone difficult to get round.
References
1. Sebastianni M, Manfredi A, Vukatana G, et al. Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study. Ann Rheum Dis 2012;71:67-70.
2. Sebastiani M, Manfredi A, Colaci M, et al. Capillaroscopic skin ulcer risk index: a
new prognostic tool for digital skin ulcer development in systemic sclerosis patients. Arthritis Rheum 2009;61:688-94.
Table 1 shows that PMR patients were significantly older than
comparison subjects. Yet age wasn't included in the univariate or
multivariate logistic regression models.
A personal bugbear around the misdiagnosis of PMR is the
misapplication of the label to relatively young patients without adequate
clinical due diligence to exclude mimicking conditions. Since the
incidence of PMR rises steep...
Table 1 shows that PMR patients were significantly older than
comparison subjects. Yet age wasn't included in the univariate or
multivariate logistic regression models.
A personal bugbear around the misdiagnosis of PMR is the
misapplication of the label to relatively young patients without adequate
clinical due diligence to exclude mimicking conditions. Since the
incidence of PMR rises steeply with age, the relative probability that a
patient with PMR syndrome has "primary PMR" is high in the elderly, where
PMR cases outnumber rarer mimics. In young patients, where PMR is rare,
the relative probability that a case is actually a (rare, and potentially
dangerous) mimic is considerably higher.
I would submit the authors could usefully re-examine their date
regarding patient age and propose a more specific criteria set where a
higher age threshold is set from evidence.
The maintenance of serum calcium within normal limits is important to
sustain life. In vitamin D deficiency calcium cannot adequately be
absorbed by the intestinal mucosa. The lack of both of these important
players in bone health and can bring about secondary
hyperparathyroidism[1].
The excess PTH, among other things, stimulates osteoclastogenesis[2]
and liberates calcium from the skeleton t...
The maintenance of serum calcium within normal limits is important to
sustain life. In vitamin D deficiency calcium cannot adequately be
absorbed by the intestinal mucosa. The lack of both of these important
players in bone health and can bring about secondary
hyperparathyroidism[1].
The excess PTH, among other things, stimulates osteoclastogenesis[2]
and liberates calcium from the skeleton to maintain an adequate serum
calcium level[3]. The recent study by Boumans, et al., (2012)[4] finding
that rituximab inhibits osteoclastogenesis raises a significant question:
what impact does this have on maintaining serum calcium, especially in
patients with secondary hyperparathyroidism? Vitamin D deficiency is
described as endemic[5]; additionally people with rheumatoid arthritis
(RA) have consistently low levels[6], and agents used, such as
corticosteroids deplete vitamin D levels. In turn calcium cannot be
absorbed and instead must be taken from the bone and the increase in PTH
is the mechanism by which this occurs. In one study of 850 men with RA[6]
the prevalence of insufficiency (below 75 nmol/L (30 ng/mL)) was 84% and
deficiency (below 50 nmol/L (20 ng/mL)) was 43%. Also, after adjustment,
hypovitaminosis D was more common in those with anti-cyclic citrullinated
peptide antibody positivity and those who are non-white; deficiency was
independently associated with greater joint tenderness and higher high
sensitivity CRP. Indeed, in a recent study[7] of rituximab patients, all
were vitamin D deficient with levels below 50 nmol/L (20 ng/mL). The study
apparently did not measure PTH or calcium levels.
The calcium aspect of rituximab does not appear to have been studied,
but a concern is that hypocalcaemia may result and cardiac or skeletal
muscle problems could follow. As far as the author is aware, calcium
measurement is not a part of any routine blood draws in rituximab therapy
in RA. The mere prospect that hypocalcaemia may occur should induce us to
think of preventive strategies. One approach may be similar to that used
with bisphosphonates: to ensure calcium levels are adequate and that the
patient is taking a source of vitamin D before therapy. To be more
accurate, 25-hydroxy vitamin D can be measured and we can ensure it is
above 75 nmol/L (30 ng/mL). This is because it takes levels between 75-80
nmol/L (30-32 ng/mL) to suppress PTH and a level above 85 (34 ng/mL) for
intestinal calcium absorption to be optimised[5]. In the elderly, levels
above 122 nmol/L (49 ng/mL) may be required to suppress PTH to what is
considered normal in young adults[8].
Even if further studies show the inhibition of osteoclastogenesis by
rituximab is negligible and of little consequence in the development of
hypocalcaemia, the approach remains sound. This is because by ensuring
adequate levels of vitamin D and calcium, patients will be on the
strongest ground in ensuring bone health, along with the many benefits
that may result from improved vitamin D levels[9].
In sum, at a minimum we should consider measurement of calcium levels
and ensure a basic level of vitamin D input; alternatively, 25 (OH) D
levels should be measured to ensure a level above at least 75 nmol/L (30
ng/mL) and preferably above 100 nmol/L (40 ng/mL).
References
1. Aloia JF Feuerman M Yeh JK. Reference range for serum parathyroid hormone.
Endocr Pract 2006;12: 137-144.
2. Jacome-Galarza CE Lee SK Lorenzo JA et al. Parathyroid hormone regulates
the distribution and osteoclastogenic potential of hematopoietic
progenitors in the bone marrow. J Bone and Miner Res 2011;26: 1207-1216.
3. Wallis DE Penckofer S Sizemore GW. The "sunshine deficit" and
cardiovascular disease. Circulation 2008;118: 1476-1485.
4. Boumans MJ Thurlings RM Yeo L et al. Rituximab abrogates joint destruction
in rheumatoid arthritis by inhibiting osteoclastogenesis. Ann Rheum Dis
2012;71: 108-113.
5. Cannell JJ Hollis BW Zasloff M et al. Diagnosis and treatment of vitamin D
deficiency. Expert Opin Pharmacother 2008;9: 107-118.
6. Kerr GS Sabahi I Richards JS et al. Prevalence of vitamin D
insufficiency/deficiency in rheumatoid arthritis and associations with
disease severity and activity. J Rheumatol 2011;38: 53-59.
7. Hasan E Olusi S Al-Awadhi A et al. Effects of rituximab treatment on the
serum concentrations of vitamin D and interleukins 2, 6, 7, and 10 in
patients with rheumatoid arthritis. Biologics 2012;6: 31-35.
8. Kinyamu HK Gallagher JC Rafferty KA et al. Dietary calcium and vitamin D
intake in elderly women: effect on serum parathyroid hormone and vitamin D
metabolites. Am J Clin Nutr 1998;67: 342-348.
9. Wilding PM Cardiovascular disease, statins and vitamin D. Br J Nurs
2012;21: 214-220.
We read with great interest the recent paper by Grayson et al., which
compared patterns of arteriographic lesions in patients with Takayasu's
arteritis (TAK) and giant cell arteritis (GCA).
Using a similar methodology as in a previous paper by our group (2),
Grayson et al. confirmed that arterial involvement is contiguous in the
aorta and usually symmetric in paired branch vessels for TAK,...
We read with great interest the recent paper by Grayson et al., which
compared patterns of arteriographic lesions in patients with Takayasu's
arteritis (TAK) and giant cell arteritis (GCA).
Using a similar methodology as in a previous paper by our group (2),
Grayson et al. confirmed that arterial involvement is contiguous in the
aorta and usually symmetric in paired branch vessels for TAK, and extended
these findings for GCA.
Because biomathematical pattern analysis of vascular lesions in
inflammatory diseases is a new concept, we believe a few additional
limitations should be underlined. First, both the study by Grayson et al.
as well as our previous work only considered vascular patterns present at
a given time point. Therefore, we were not able to incorporate the dynamic
progression of vascular lesions observed in these diseases, which is truly
a critical issue. Second, vascular patterns may be strongly influenced by
the delineation of vascular beds used for the analysis. For instance, we
distinguished femoral and iliac arteries and did not consider thoracic
aorta has a whole, while Grayson et al. used other subdivisions of the
vascular tree. Because underlying determinants of vascular targeting are
largely unknown, we believe it would be best not to regroup various
anatomical segments together. Third, classification models used by Grayson
et al. to distinguish between TAK and GCA have incorporated the age at
disease onset, which may be difficult to elicit in TAK where a long past
of non-specific and sometimes poorly recognized symptoms may precede a
more formal diagnosis.
While we believe that these novel methods will have important
implications for future classification of vasculitides, the finding that
TAK and GCA may exist on a spectrum within the same disease should be
interpreted with caution.
References
1. Grayson PC, Maksimowicz-McKinnon K, Clark TM, et al. Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis. Ann Rheum Dis 2012 Feb 10 (Epub ahead of print).
2. Arnaud L, Haroche J, Toledano D et al. Cluster analysis of arterial
involvement in Takayasu arteritis reveals symmetric extension of the
lesions in paired arterial beds. Arthritis Rheum 2011;63:1136-40.
A recent report by Hot and colleagues investigated the possible link
between the increased expression of IL-17 in rheumatoid diseases and the
high incidence of cardiovascular disorders in patients suffering these
pathologies.
To address this point the authors used an elegant approach that
combined in vitro cell functional studies with gene fingerprint analysis
by microarray. Consistent with...
A recent report by Hot and colleagues investigated the possible link
between the increased expression of IL-17 in rheumatoid diseases and the
high incidence of cardiovascular disorders in patients suffering these
pathologies.
To address this point the authors used an elegant approach that
combined in vitro cell functional studies with gene fingerprint analysis
by microarray. Consistent with several previous studies, including our own
(1), the authors showed that IL-17A per se does not cause a significant
inflammatory response in HUVEC while it greatly enhance the inflammatory
properties of TNF?.
To investigate the functional consequences of these results the
authors used a wide range of tests including endothelial cell migration
and invasion. Most interestingly, they also showed that the conditioned
medium of HUVEC stimulated with IL-17A with or without TNF? caused a
significant increase in platelet aggregation.
These results further support our previous studies showing a
proaggregant effect of IL-17A on both murine and human platelet
aggregation (2). Like for endothelial cells, IL-17A alone did not
influence platelet activation while it amplified the inflammatory effect
of ADP. More specifically, IL-17A increased the primary reversible phase
of ADP-induced platelet aggregation in a concentration-dependent manner.
The results presented by Hot et al. in Figure 6A show no difference
between the conditioned medium of HUVEC treated with IL-17A or IL-17A +
TNF? while in most of the other assays the combination of these two
cytokines provided significant differences compared to the effects of IL-
17A alone. Thus it might be possible to hypothesize that the proaggregant
effect observed might be due, al least in part, to a direct effect of IL-
17A still present in the medium. This could be easily addressed by adding
an anti-IL-17A neutralizing antibody to the conditioned medium before the
test on platelet aggregation.
References
1. Maione F, Paschalidis N, Mascolo N, et al. Interleukin 17 sustains rather than induces inflammation.
Biochem Pharmacol 2009;77(5):878-87.
2. Maione F, Cicala C, Liverani E, et al. IL
-17A increases ADP-induced platelet aggregation. Biochem Biophys Res
Commun 2011;408(4):658-62.
We read with great interest the manuscript from Kuwana and coworkers
related to the external validation of the EUSTAR recommendations on
endothelial progenitor cells (EPCs)(1, 2). The side-by-side comparisons of
methods for quantifying EPCs performed on 11 SSc patients and 11 age-
matched controls showed a statistically significant correlation between
EPC counts obtained by the MACS (enrichment of CD34+...
We read with great interest the manuscript from Kuwana and coworkers
related to the external validation of the EUSTAR recommendations on
endothelial progenitor cells (EPCs)(1, 2). The side-by-side comparisons of
methods for quantifying EPCs performed on 11 SSc patients and 11 age-
matched controls showed a statistically significant correlation between
EPC counts obtained by the MACS (enrichment of CD34+ cells by a magnetic-
activated cell sorter) and rosette methods when combined with fluorosphere
calibration (r=0.81, p<0.0001). These findings confirmed the validation
of EUSTAR recommendations and support the incorporation of a fluorosphere
technique into the EUSTAR recommendations. These data are of importance
because standardisation and reproducibility are critical issues in this
context.
Regarding the discussion part of the manuscript, it is stated that a
direct link between CD34+CD133+VEGFR2+ cell counts and "true EPCs" (also
called late outgrowth EPCs or endothelial colony-forming cells) is still
missing. In fact, we would like to remind that we already reported that
levels of circulating EPCs detected by flow cytometry were associated with
i) the formation of true EPC colonies and ii) with the delay before colony
appearance in patients with SSc (respectively p=0.02 and 0.006). In
addition, the number of true EPC colonies positively correlated with
levels of EPCs (R=0.73, p=0.0004) defined as Lin-7AAD-CD34+CD133+VEGFR2+
cells in patients with SSc (3). This correlation was not found with other
putative EPC populations (Lin-7AAD-CD133+VEGFR2+ and Lin-7AAD-CD34+VEGFR2+
cells), suggesting that the Lin-7AAD-CD34+CD133%VEGFR2+ should be
considered as the most suitable definition for EPC detection by flow
cytometry. These findings also support that late outgrowth EPCs are "true
EPCs" referring to the population detected by FACS.
The authors also state that studies conform to EUSTAR recommendations
should assess associations between EPC counts and clinical features. We do
agree that translational data are needed to establish the face validity of
a biomarker. We would like to highlight that studies assessing this issue
have been recently published. Indeed, we previously reported in a cohort
of 50 consecutiveSSc patients that low EPC counts (defined by Lin-7AAD-
CD34+CD133+VEGFR2+ cells) were associated with the higher Medsger's
severity score (p=0.01) and the presence of past and/or current digital
ulcers (p=0.03). In addition, we recently reported the results of a 3-year
prospective study aiming at the evaluation of the possible merit of
endothelial markers for the prediction of cardiac/vascular events in
patients with SSc, in particular ischaemic digital ulcers(4). By
multivariate Cox proportional analysis, circulating Lin-7AAD-
CD34+CD133+VEGFR2+ cells were identified as independent predictors of the
occurrence of new ischaemic ulcers (hazard ratio, HR: 2.33, 95% confidence
interval, CI 1.44-12.22, p=0.03) in association with increased serum
levels of placenta growth factor (HR: 7.95, 95% CI 2.09-30.10). Low EPC
levels were also predictive of the occurrence of cardiac and vascular
events, defined by an exploratory composite index (HR: 3.18, 95% CI: 1.19-
12.80). We believe that these data obtained through a prospective study
support the reliability and value of EPCs to evaluate vascular risk.
Indeed, these results at least suggest that EPC counts quantified by flow
cytometry, accordingly to EUSTAR recommendations, can be used to identify
SSc patients who are at risk of the development of digital ulcers.
Altogether, Kuwana's results together with data from our groupsupport the
use of EUSTAR recommendations for assessing EPCs, which can yet be used as
a biomarker for vascular risk and raise the critical importance of
angiogenesis and vasculogenesis in the devastating condition that is SSc.
References
1. Kuwana M, Okazaki Y. Quantification of circulating endothelial
progenitor cells in systemic sclerosis: a direct comparison of protocols.
Ann Rheum Dis 2012, in press.
2. Distler JH, Allanore Y, Avouac J, et al. EULAR Scleroderma Trials and Research group statement and
recommendations on endothelial precursor cells. Ann Rheum Dis 2009;68(2):163-8.
3. Avouac J, Juin F, Wipff J, et al.
Circulating endothelial progenitor cells in systemic sclerosis:
association with disease severity. Ann Rheum Dis 2008;67(10):1455-60.
4. Avouac J, Meune C, Ruiz B, et al.
Angiogenic biomarkers predict the occurrence of digital ulcers in systemic
sclerosis. Ann Rheum Dis 2012;71(3):394-9.
We thank the authors for their interest in our paper and extending
the discussion about how we can best assess the safety of glucocorticoid
therapy. Ongoing uncertainty about the safety of steroids - particularly
at low doses - despite over sixty years of clinical experience illustrates
this is not an easy challenge. Nonetheless, it is important to tackle
given the continuing widespread use. We must mov...
We thank the authors for their interest in our paper and extending
the discussion about how we can best assess the safety of glucocorticoid
therapy. Ongoing uncertainty about the safety of steroids - particularly
at low doses - despite over sixty years of clinical experience illustrates
this is not an easy challenge. Nonetheless, it is important to tackle
given the continuing widespread use. We must move towards clearer
numerical risks for multiple safety outcomes (1).
The two study designs available to us to address steroid safety are
randomized controlled trials (RCTs) and observational studies. Each has
advantages and disadvantages. The great benefit of RCTs is randomised
treatment, meaning each group has a balance of known and unknown variables
at baseline. The authors suggest a literature review on the topic: a good
idea that we have already undertaken (2). Unfortunately, on reviewing all
published RCTs, there was great variability in the quality of reporting in
the methods and heterogeneity in the results for safety outcomes, making
it difficult to have confidence in the final result of the meta-analysis.
Furthermore, the total number of patients eligible for inclusion was less
than 2000 after more than 60 years' of glucocorticoid trials in rheumatoid
arthritis (RA).
Observational studies offer the chance to look at larger numbers of
patients, which is crucial to study infrequent serious adverse events.
This approach also allows us to examine 'real-life experience',
particularly over the long-term. There are, however, many challenges.
First, glucocorticoid therapy is used dynamically, meaning that
conventional models of risk-attribution make assumptions that we know not
to be true. This was the motivation for the second publication where we
showed that novel methods for modeling exposure that considered changes to
dose with time provided a better fit than traditional models (3). Second,
adherence to therapy is a problem in steroid safety, as we know patients
can take either more or less prednisolone than is prescribed. Third,
observational studies provide associations that may or not be causal. Our
finding of an association between GC therapy taken several years ago and
current infection risk does not necessarily mean this is a direct effect
with long latency. Whilst it may be having a direct effect by influencing
adaptive immune pathways, it may represent an indirect effect, perhaps by
impairing barrier functions such as skin integrity, or reflect the delay
in hypothalamic-pituitary-adrenal axis resetting after glucocorticoid
suppression (4, 5). Past GC use may also be a marker of current active
disease, which brings us onto the fourth and largest challenge:
confounding by disease severity. GC prescriptions are tightly coupled to
disease severity, making this a difficult problem. We agree administrative
databases do not contain good measures of disease severity in RA, meaning
residual confounding is likely. We acknowledged this in both papers, but
in the first went on to show that the residual confounding could not
explain all of the observed association (6). Interestingly, RCTs do not
resolve entirely the problem of confounding by disease severity.
Randomisation ensures the groups are matched for disease severity at
baseline, but as patients in the treatment arm respond to GC therapy, they
will have lower disease severity throughout much of the study. Any
measured infection risk will thus represent a mixing of effects of the
direct effect of GCs on infection (perhaps increasing risk) plus the
effect of lower cumulative disease severity (reducing risk).
We agree with the authors that we must strive towards a clearer
understanding of steroid safety through carefully designed studies.
Unfortunately, we cannot resolve all challenges at once. The weighted
cumulative dose model has now shown benefit in modelling time-varying
doses, and will enable us to move towards individualised safety estimates
for given patterns of GC use. We have studies funded that will examine the
extent of adherence to glucocorticoid therapy within a national database,
allowing quantification of the effect of self-adjusted therapy on safety
estimates. In order to address confounding by disease severity (both in
observational studies and RCTs), we need to have regular measurements of
both disease severity and treatment. We can then use techniques such as
marginal structural modelling (7). It is rare that large databases contain
sufficient information for such analyses, but by linking national datasets
that each contains components of the total required information, we can
move beyond our current knowledge (8). We agree a large and pragmatic RCT
would be valuable, assuming disease severity is measured carefully
throughout and the design allows for variation in GC exposure, both
between and within subjects, to reflect real-life patterns of GC use.
The associations reported in our papers must indeed be interpreted
with caution, as we do not yet have solutions to all of the challenges of
observational drug safety research. This leaves us with uncertainty about
the safety of these widely used drugs. We believe it is important to
continue to address this issue whilst, in parallel, attempting to address
the methodological limitations.
References
1. Hoes JN, Jacobs JW, Buttgereit F, et al. Current view of
glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nature
reviews Rheumatology 2010;6:693-702.
2. Dixon WG, Suissa S, Hudson M. The association between systemic
glucocorticoid therapy and the risk of infection in patients with
rheumatoid arthritis: systematic review and meta-analyses. Arthritis
Research & Therapy 2011;13:R139.
3. Dixon WG, Abrahamowicz M, Beauchamp ME, et al. Immediate and
delayed impact of oral glucocorticoid therapy on risk of serious infection
in older patients with rheumatoid arthritis: a nested case-control
analysis. Ann Rheum Dis 2012.
4. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. N Engl J Med 2005;353:1711-23.
5. McMaster A, Ray DW. Drug insight: selective agonists and
antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol
Metab 2008;4:91-101.
6. Dixon WG, Kezouh A, Bernatsky S, et al. The influence of systemic
glucocorticoid therapy upon the risk of non-serious infection in older
patients with rheumatoid arthritis: a nested case-control study. Ann Rheum Dis 2011.
7. Thamer M, Hernan MA, Zhang Y, et al. Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560-4.
8. Suissa S. Assessing the safety of new arthritis drugs: are we
there yet? J Rheumatol 2008;35:2295-7.
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