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
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.
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...
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...
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...
Dear Editor,
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 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...
Pages