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New EULAR treatment guidelines in hip osteoarthritis were recently
reviewed [1]. The recommendations are allegedly based on top level
scientific (grade 1a) data, and advocate the use of paracetamol (US:
acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs),
including selective cyclooxygenase 2 inhibitors (coxibs), in
osteoarthritis of the hip. We interpret the underlying data differently...
New EULAR treatment guidelines in hip osteoarthritis were recently
reviewed [1]. The recommendations are allegedly based on top level
scientific (grade 1a) data, and advocate the use of paracetamol (US:
acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs),
including selective cyclooxygenase 2 inhibitors (coxibs), in
osteoarthritis of the hip. We interpret the underlying data differently:
The review [1] states that due to a lack of studies evaluating
paracetamol in hip osteoarthritis alone, recommendations rely on studies
that also include osteoarthritic conditions in other joints. A review of 4
placebo-controlled trials demonstrated an effect size (ES) of 0.21 (0.02-
0.41)[2]. Two small (n=50 and n=60) trials could not be pooled for lack of
data. Thus, ES calculations are from 2 trials, where the smallest reported
no significant effect, leaving us with a final sample of 387 patients. The
EULAR review does not mention that a recent large (n=779) knee
osteoarthritis trial reported a non-significant effect of paracetamol
corresponding to a miniscule 0.8 mm on a visual analogue pain scale
(VAS)[3]. Together, available data clearly demonstrate a lack of effect of
paracetamol in large joint osteoarthritis.
Concomitant with the withdrawal of rofecoxib (Vioxx), and an
increasing awareness that other coxibs may also induce serious
cardiovascular toxicity, EULAR recommend the use of coxibs as second line
treatment after paracetamol for patients at risk for gastrointestinal
adverse effects1. However, no references to randomised controlled trials
(RCTs) or systematic reviews on efficacy are given. To our knowledge only
two RCTs evaluate the use of coxibs in hip osteoarthritis alone. A Pfizer-
funded trial with valdecoxib [4] found a difference over placebo of only
1.6 from a baseline value of 10.8 on the WOMAC subscale of pain, which
corresponds to a modest 7.9 mm on VAS. Similar results were found for
celecoxib in another Pfizer-funded trial [5]. These results are well below
the threshold of 15 mm on VAS which defines minimal clinically important
differences [6]. On the other hand, pivotal questions regarding the safety
of coxibs remain unresolved. In our view, this calls for caution and
suggests that the use of these drugs should be suspended until
comprehensive safety data for all coxibs are available.
The EULAR review states that NSAIDs are effective, but that adverse
effects may counter their benefit1. This conclusion is based on one
systematic Cochrane review [7] which allegedly included 14 placebo-
controlled trials. The ES for pain relief was 0.69 (95% CI 0.12-1.26).
However, the cited Cochrane review does not include a single study
published after 1994. It is not based on 14 placebo-controlled trials, but
on 14 placebo-controlled comparisons. The number of included placebo-
controlled trials was 3-three-(with 9, 146, and 104 patients,
respectively) of 2-8 weeks duration. The given ES of 0.69 was calculated
from the results of a single 8-week trial (n=146)(8), which reported a
mean difference over placebo corresponding to 10 mm on VAS.
To our knowledge, no further hip-specific RCTs with NSAIDs have been
published except the two coxib trials mentioned above, where groups of
patients treated with naproxen were included. The efficacy for naproxen in
these trials was not significantly different from that of the coxibs. A
recent analysis of 23 trials on the efficacy of NSAIDs (including coxibs)
in knee osteoarthritis demonstrated a small effect of therapy on pain
corresponding to 10.1 mm on VAS [9], which is too modest to be of any
clinical significance in the average patient. No long term trials (>13
weeks) have demonstrated beneficial effects of NSAIDs over placebo in hip
or knee osteoarthritis. Although all NSAIDs may induce serious adverse
effects, relevant safety issues cannot be addressed from short term
studies. In our view, it is highly likely that long term use of NSAIDs,
including coxibs, do more harm than good in patients with osteoarthritis
of the hip.
We support the EULAR guidelines initiative as a positive contribution
for evidence based care of patients with arthritis. However, we believe
that some of the recommendations are erroneous and misleading. In general,
lack of hard data to estimate treatment effects is a common problem.
However, in ostearthritis there is a plethora of data. In our view, the
available information unequivocally demonstrates that standard
pharmacological interventions with paracetamol and NSAIDs, including
coxibs, cannot be recommended for the osteoarthritic patient.
References
(1). Zhang W, Doherty M, Arden N, et al. EULAR evidence based
recommendations for the management of hip osteoarthritis: report of a
task force of the EULAR Standing Committee for International Clinical
Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2004: 2004.028886.
(2). Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen)
reduce the pain of osteoarthritis? A meta-analysis of randomised
controlled trials. Ann Rheum Dis 2004.
(3). Miceli-Richard C, Le Bars M, Schmidely N, Dougados M. Paracetamol
in osteoarthritis of the knee. Ann Rheum Dis 2004;63:923-930.
(4). Makarowski W, Zhao WW, Bevirt T, Recker DP. Efficacy and safety of
the COX-2 specific inhibitor valdecoxib in the management of
osteoarthritis of the hip: a randomized, double-blind, placebo-controlled
comparison with naproxen. Osteoarthritis Cartilage 2002;10:290-6.
(5). Kivitz AJ, Moskowitz RW, Woods E, et al. Comparative efficacy and
safety of celecoxib and naproxen in the treatment of osteoarthritis of the
hip. J Int Med Res 2001;29:467-79.
(6). Tubach F, Ravaud P, Baron G, et al. Evaluation of clinically
relevant changes in patient- reported outcomes in knee and hip
osteoarthritis: the Minimal Clinically Important Improvement. Ann Rheum
Dis 2004.
(7). Non-aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) for
osteoarthritis of the knee [15 p) (16 ref 12 bib) (Update Software, online
or CD-ROM, updated quarterly program]: The Cochrane Library (Oxford),
2001.
(8). Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the
treatment of osteoarthritis of the hip. Arthritis Rheum 1994;37:529-36.
(9). Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Non-steroidal
anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in
osteoarthritic knee pain: meta-analysis of randomised placebo controlled
trials. BMJ 2004;329:1317-.
We read with a great interest article by McInnes and colleagues [1]
concerning the beneficial properties of statins in patients with
rheumatoid arthritis.
HMG-CoA reductase inhibitors are widely used
compounds introduced primarily as effective cholesterol lowering agents.
With time, it has been recognised that effects of statins go far
beyond only lipid lowering properties and nowadays they a...
We read with a great interest article by McInnes and colleagues [1]
concerning the beneficial properties of statins in patients with
rheumatoid arthritis.
HMG-CoA reductase inhibitors are widely used
compounds introduced primarily as effective cholesterol lowering agents.
With time, it has been recognised that effects of statins go far
beyond only lipid lowering properties and nowadays they are recognized as
pleiotrophic effects.
Mc Innes and co-authors [1] put the emphasis to these pleiotrophic
properties of HMG-CoA inhibitors and their possible application in the
treatment of patients with rheumatoid arthritis. The other papers
indicatng the need to correct lipid abnormalities in lupus erythematosus
were published recently [2].
As it was elegantly reviewed by the Authors, interaction with cytokine
mediated pathways via prenylation of signal proteins may alter the course
of rheumatoid arthritis. This effect is separated from lipid lowering
properties, but obviously lowering cholesterol level augments pleiotrophic
action of statins. We can agree with the Authors that in spite of
recognition the problem of accelerated atherosclerosis, there is
relatively lack of studies and trials performed on human that prove
beneficial effect of HMG -Co A reductases inhibitors in humans.
In this place, we would like to share our own experience with statins in
patients with other systemic disorder akin in some aspects to rheumatoid
arthritis, systemic lupus erythematosus (SLE). According to the results
obtained in our pilot study with simvastatin (Zocor MSD) in the patients
with mild or moderate lupus activity, we showed that simvastatin in a dose
of 20 mg/day significantly reduced TNF-a concentration in sera patients
with SLE. The effect could be seen just after 4 weeks of treatment and was
independent from the initial cholesterol level. Lowering effect of TNF-a
was associated with a decrease in lupus activity measured with SLEDAI.
This suggest relatively significant anti-inflammatory potential of statins
and very fast mode of action. The drug activity can be explained by
limitation of systemic inflammation, restoration of endothelial function,
lowering of cholesterol level as well as the direct immunosupresive and/or
immunomodulatory effects [3,4].
Since rheumatoid arthritis and SLE share the similar pattern of
inflammation, they could be recognised as independent risk factors for
atherosclerosis. As it was described by Urowitz and colleagues bimodal
pattern of mortality with late peak that is dependent on atherosclerosis
and its complication will probably allow us to seek for more aggressive
scheme of lipid lowering treatment [5].
With use of statins, we are
given the excellent opportunity to suppress inflammation, normalise lipid
profile and probably decrease the doses of classical immunosupressive
agents. We also believe that promising results of pilot trials in human
will give way to the big multicentre international trial to prove statins
efficacy in large group of patients [6].
References
(1). McInnes IB, McCarey DW, Sattar N. Do statins offer therapeutic potential
in inflammatory arthritis? Ann Rheum Dis 2004; 63: 1535-1537
(2). Wajed J, Amad Y, Durrington PN, Bruce IN. Prevention of cardiovascular
disease in systemic lupus erythemtosus - proposed guidelines for risk
factor management. Rheumatology 2004; 43: 7-12
(3). O'Driscal G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A
reductase inhibitor, improves endothelial function within 1 month.
Circulation 1997: 95: 1126-31
(4). Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins slectively
inhibit leukocyte function antigen-1 by binding to a novel regulatory
integrin site. Nat Med 2001; 7: 687-692.
(5). Urowitz MB, Bookman AAM, Kocher BE, et al. The bimodal mortality in SLE.
Am J. Med 1976; 60: 221-225
(6). Abud- Mendoza C, de la Fuente H, Cuevas-Orta E, et al. Therapy with
statins in patients with refractory rheumatic diseases: a preliminary
study. Lupus 2003; 12: 607-611
Patient selection can affect required sample sizes and outcomes in
randomised clinical trials and the optimal selection may depend on how the
tested drug differentially affects patients. Bruynesteyn K et al. [1,2]
have investigated these effects in rheumatoid arthritis based on an
outcome measure of radiological damage progression.
An absolute reduction (AR) drug which reduces the expe...
Patient selection can affect required sample sizes and outcomes in
randomised clinical trials and the optimal selection may depend on how the
tested drug differentially affects patients. Bruynesteyn K et al. [1,2]
have investigated these effects in rheumatoid arthritis based on an
outcome measure of radiological damage progression.
An absolute reduction (AR) drug which reduces the expected number of
new erosions per year by, say, 2 in all patients irrespective of their
initial erosive risk is conceivable. Similarly, a relative reduction (RR)
drug which reduces the expected number of new erosions per year by, say,
20% in all patients is also conceivable, thus by, say, 1 new erosion per
year in medium risk patients and by, say, 3 new erosions in high risk
patients.
However, the authors’ absolute and relative risk reduction drug
models (ARR, RRR, respectively) differ from those described above in that
they reduce the risk of the number of new erosions exceeding a pre-
determined limit, smallest detectable change, by absolute or relative
amounts [1]. Although valid as means of quantifying the effect of drugs
[3,4], ARR and RRR are not appropriate statistical models of drug action.
In fact, the authors’ ARR model represents a drug which reduces the number
of new erosions in ‘high’ and ‘low’ risk patients by similar absolute
amounts but is 50% less effective in patients at ‘medium’ risk of disease
progression. It is this inappropriate drug model which gives rise to the
statement (1): “From a statistical point of view, it would be wise to
avoid groups of patients with an average prior risk (of disease
progression) …. such patient groups provide less statistical power, as
compared to trials with patient groups with a low or a high prior risk”
rather than any valid reason to avoid enrolling average risk patients.
In a realistic absolute reduction (AR) drug model, the ‘medium’ risk
group is the optimum choice (representing patients with progression
critically near the pre-determined on/off event limit, Table 1.2 in [1]).
If the drug effect is averaged across all patients, results for an AR drug
are unaffected by patient selection. Thus the article inadvertently
highlights the caution required if on/off events, as opposed to group
averaged results, are used as outcome measures in trials.
Within the limits of such an evaluation, re-examination of the given
trial results [1] using corrected AR, RR models, indicate that:
methotrexate in combination with cyclosporin A is a pure RR drug, reducing
the occurrence of erosions in patients in proportion to their initial
risk; whilst the combination therapy in the COBRA trials follows a mixed
AR/RR model, reducing the occurrence of erosions more in high risk
patients than in low risk patients but not as much as might be expected by
their relative risk. Both studies confirm that patients at medium and high
risk of radiological disease progression are the optimum choice in
clinical trials where radiological damage is the outcome.
R
References
(1). Bruynesteyn K, Wanders A, Landewé R, van der Heijde D. How the
type of risk reduction influences required sample sizes in randomised
clinical trials. Ann Rheum Dis 2004; 63:1368-1371.
(2). Bruynesteyn K, Landewé R, van der Linden S, van der Heijde D.
Radiography as primary outcome in rheumatoid arthritis: acceptable sample
sizes for trials with 3 months follow-up. Ann Rheum Dis 2004; Published
Online First 22/03/2004. doi:10.1136/ard.2003.014043.
(3). Osiri M, Suarez-Almazor ME, Wells GA, Robinson V, Tugwell P.
Number needed to treat (NNT): implication in rheumatology clinical
practice. Ann Rheum Dis 2003; 62:316-321.
(4). Rothwell PM. Can overall results of clinical trials be applied to
all patients?[see comment]. Lancet 1995; 345:1616-1619.
There has been growing interest in studies evaluating the
effects of
various disease modifying agents on endothelial dysfunction in patients
with rheumatoid arthritis due to the predictive value of such properties
on endothelial function on increased or decreased risk of cardiovascular
events. We, therefore, read with great interest the article by Doctors
Ferraciolo and Gremese in the June 2004 issue...
There has been growing interest in studies evaluating the
effects of
various disease modifying agents on endothelial dysfunction in patients
with rheumatoid arthritis due to the predictive value of such properties
on endothelial function on increased or decreased risk of cardiovascular
events. We, therefore, read with great interest the article by Doctors
Ferraciolo and Gremese in the June 2004 issue of Annals of the Rheumatic
Diseases [1].
We found the message of the article is clear about the role
of TNF blockade, particularly concerning reductions in cardiovascular
risk. There unfortunately is a misquotation of the literature in the
section entitled TNF Blockers and Cardiovascular and Cardiovascular Risk.
The sentence "Data in rheumatoid patients have shown that etanercept (TNF
RII 75 Fc-IgG fusion protein) in the short term has positive effects on
the physiology of the endothelium (30) but not in those with longlasting
disease (31)" is incorrect. In fact, reference 30 refers to a study by
Hurlimann, et al. [2] of 11 patients with long-standing RA, which
demonstrated 28% improvement (p=0.018) in endothelial-dependent vascular
function after 12 weeks of infliximab therapy that appeared to be additive to the effects of methotrexate. A recent study by Gonzalez-Juanatey, et
al.[3] similarly reported that infliximab treatment provides significant
improvement (p=0.02) in endothelial-dependent vascular function in
patients with long-standing disease who are treated for longer than 1
year.
In another series of experiments, Booth et al. [4] demonstrated
significant improvement in endothelial-dependent function (p=0.004) in a
population of anti-neutrophil cytoplasmic antibody-positive patients with
systemic vasculitis who were treated with infliximab while receiving stable concomitant doses of cyclophosphamide, mycophenolate mofetil or
prednisolone. Improvement in endothelial-dependent vascular function, when examined on a background of methotrexate therapy, has not been observed
with etanercept with either short or long-term therapy. The study cited bythe authors by Hansel, et al., [5] demonstrated no increased effectiveness of etanercept alone on endothelial dysfunction when compared with that of
methotrexate alone.
We appreciate the opportunity to provide this correction and
look
forward to the authors' response.
References
(1). Ferraccioli GF, Gremese E. Autoantibodies and thrombophilia
in RA:
TNF alpha and TNF alpha blockers. Ann Rheum Dis 2004;63:612-615.
(2). Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et
al. Anti-tumor necrosis factor alpha treatment improves endothelial
function in patients with RA. Circulation 2002;106:2184-2187.
(3). Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-
Porrua C,
Llorca J, Gonzalez-Gay MA. Active but transient improvement of endothelial
function in rheumatoid arthritis patients undergoing long-term treatment
with anti-TNF-alpha antibody. Arthritis & Rheumatism 2004;51:447-
450.
(4). Booth AD, Jayne DRW, Kharbanda RK, McEniery CM, Mackenzie
IS,
Brown J, Wilkinson IB. Infliximab improves endothelial dysfunction in
systemic vasculitis: a model of vascular inflammation. Circulation 2004;
109:1718-23
(5). Hansel S, Lassig G, Pistrosch F, Passauer J. Endothelial
dysfunction in young patients with long-term rheumatoid arthritis and low
disease activity. Atherosclerosis 2003;170:177-80.
We thank Dr Godinho and his co-authors for their report about
usefulness of anakinra in the treatment of refractory adult onset Still’s
disease (AOSD).
Not all the patients with AOSD have a similar disease course: 4 different
disease patterns (monocyclic systemic, monocyclic chronic articular,
polycyclic systemic and polycyclic chronic articular) have been described
[1]. On the other hand, c...
We thank Dr Godinho and his co-authors for their report about
usefulness of anakinra in the treatment of refractory adult onset Still’s
disease (AOSD).
Not all the patients with AOSD have a similar disease course: 4 different
disease patterns (monocyclic systemic, monocyclic chronic articular,
polycyclic systemic and polycyclic chronic articular) have been described
[1]. On the other hand, cytokine profiles are not well defined in all the
subsets of AOSD [2].
We would describe our experience with 2 additional cases of AOSD,
diagnosed according to Yamaguchi criteria [3] and treated with anakinra: 1
case with monocyclic systemic disease course had a favourable response,
whilst the second patient with a polycyclic chronic articular disease
course did not show any benefit from anakinra.
The first patient, a 43–year-old Italian woman with monocyclic systemic
disease was admitted to our Division in July 2003 with fever (39° C),
evanescent rash, pharyngodynia and arthralgia. Laboratory findings showed
leukocytosis (WBC 25,460/mm3), increased ESR (104 mm/1sth), CRP
(29.4mg/dl) and serum ferritin levels (12,287mg/l). Treatment was started
with prednisolone (75mg/day, reduced after 3 weeks to 25mg/day),
indomethacin (100mg/day), and methotrexate (15mg/weekly im).
After 2
months only little effects on both systemic and articular symptoms were
obtained. We prescribed anakinra (100 mg sc daily) recording, after 3
weeks, a decrease of serum CRP levels from 7.8 to 0.3 mg/dl, ferritin
levels from 3,058 to 129 mg/l, and WBC count from 13,580 to 5,850/mm3,
while haemoglobin increased from 9.4 to 12.3 g/dl along with defervescence
and improvement of arthralgia. After 10 months of treatment with anakinra
as monotherapy a slight leukopenia with netropenia occurred, but these
parameters returned to normal when anakinra was given every other day.
AOSD is still in remission.
The second patient, a 41 –year-old Italian man with polycyclic chronic
articular disease diagnosed in July 2000 based on fever, evanescent rash
and peripheral arthritis, was unsuccessfully treated with high dose
steroids and methotrexate and thereafter with leflunomide, cyclosporin,
intravenous immunoglobulins and all the TNFa antagonists. Both systemic
and articular symptoms did not ameliorate even following a 14 weeks
treatment with anakinra.
In the first case with monocyclic systemic disease, the treatment with
anakinra led to a rapid and persistent control of systemic symptoms and to
decrease of ESR, serum CRP, ferritin levels and WBC count. Noteworthy is
the significant decrease of serum ferritin levels which are considered as
a marker of AOSD activity [4].
References
(1). Cush JJ, Medsger TA, Jr, Christy WC, Herbert DC, Cooperstein LA. Adult
onset Still’s disease: clinical course and outcome. Arthritis Rheum 1987;
30: 186-94.
(2). Fujii T, Nojima T, Yasuoka H, Satoh S, Nakamura K, Kuwana M, et al.
Cytokine and immunogenetic profiles in Japanese patients with adult
Still’s disease. Association with chronic articular disease. Rheumatology
2001; 40:1398-404.
(3). Yamaguchi M, Ota A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwazaki
H, et al. Preliminary criteria for classification of adult Still’ disease.
J Rheumatol 1992;19:424-30.
(4). Akritidis N, Giannakakis I, Giouglis T. Ferritin levels and response to
treatment in patients with adult Still’s disease. J Rheumatol 1996; 23:
201-2.
We read with great interest the article by Topaloglu et al (Sep. 30
issue) [1] on the implication of the E148Q sequence variation in familial
Mediterranean fever (FMF). In our opinion, the best interpretation of this
study is not that E148Q is a disease-causing MEFV mutation, but, rather,
that this sequence variation is not involved in FMF, or more precisely
that the E148Q allele is not impli...
We read with great interest the article by Topaloglu et al (Sep. 30
issue) [1] on the implication of the E148Q sequence variation in familial
Mediterranean fever (FMF). In our opinion, the best interpretation of this
study is not that E148Q is a disease-causing MEFV mutation, but, rather,
that this sequence variation is not involved in FMF, or more precisely
that the E148Q allele is not implicated in the development of FMF.
Indeed, as no assay exists to date to evaluate the functional
consequences of the missense mutations identified in MEFV, it is worth
recalling that such sequence variations are considered as disease-causing
mutations on the basis of their high incidence in the homozygous or
compound heterozygous state in patients only, and not in healthy
relatives. This is the case for a few mutations including M694V, but not
for E148Q, as recently shown by a study that compared the allele and
genotype frequencies in a large group of patients of Sephardic Jewish
origin to those found in a control group consisting of healthy relatives
[2]. Most importantly, the study by Topaloglu et al. [1] underlines that
“the E148Q mutation is the one of the common mutations among the patients
with FMF with 3.5% allele frequency, the carrier frequency being found to
be 12% in the healthy Turkish population”. This data, therefore, not only
does not support the authors’ conclusion (given in the title of this
article), but rather strongly argues against the pathogenic role of E148Q
in FMF.
In addition, the inclusion criteria used by the authors are not clear
to us, since although the diagnosis of FMF was based on established
criteria [3], the authors mention the presence of E148Q in so-called
“asymptomatic patients” (4 of the 26 patients homozygous for E148Q) or
“quite symptomatic patients”; it seems to us, therefore, particularly
difficult to interpret the data presented in tables 1 (e.g. age at onset)
and 2 (frequency of phenotypic features). Furthermore, as the authors
identified several complex alleles involving E148Q in their population,
the patients with a “compound heterozygous genotype” (e.g. E148Q/M694V)
may actually carry a complex allele (E148Q-M694V) together with a normal
MEFV allele (N), and be, therefore, heterozygous at the MEFV locus (E148Q-
M694V/N). In this regard, although the implication of the sole E148Q
sequence variation as a disease-causing mutation is so far not
demonstrated, it is also worth mentioning a study that suggested the
effect of this sequence variation, when combined with V726A (i.e. complex
E148Q-V726A allele), in the clinical severity of the FMF disease [4].
Finally, the authors conclude that the symptomatic individuals
homozygous for E148Q should not be ignored. In our opinion, all
symptomatic individuals (i.e. patients) should not be ignored, regardless
of their MEFV genotype. In particular, all patients with a clinical
diagnosis of FMF should benefit from colchicine therapy; and in those
patients, the presence of two disease-causing mutations simply allows
diagnostic confirmation of MEFV-related FMF. As shown recently by means of
population genetics-based studies [5], a FMF-like condition that does not
result from mutations in MEFV indeed exists in all populations classically
affected by FMF, including patients of Turkish origin; in this latter
population, the proportion of patients with a clinical diagnosis of FMF
and whose disease phenotype does not result from MEFV mutations is at
least of 13% [5]. One cannot, therefore, exclude the possibility that the
few symptomatic individuals carrying the E148Q sequence variation
identified by Topaloglu et al. [1] have a FMF-like condition unrelated to
the MEFV gene.
References
(1). Topaloglu, R., Ozaltin, F., Yilmaz, E., Ozen, S., Balci, B.,
Besbas N., et al. E148Q is a disease causing MEFV mutation: a phenotypic
evaluation in patients with familial Mediterranean fever. Ann Rheum Dis
2004; Epub Sep 30.
(2). Tchernitchko, D., Legendre, M., Cazeneuve, C., Delahaye, A.,
Niel, F., and Amselem, S. The E148Q MEFV allele is not implicated in the
development of familial Mediterranean fever. Hum Mutat 2003; 22:339-340.
(3). Livneh, A., Langevitz, P., Zemer, D., Zaks, N., Kees, S., Lidar,
T., et al. Criteria for the diagnosis of familial Mediterranean fever.
Arthritis Rheum 1997; 40:1879-1885.
(4). Gershoni-Baruch, R., Brik, R., Shinawi, M., and Livneh, A. The
differential contribution of MEFV mutant alleles to the clinical profile
of familial Mediterranean fever. Eur J Hum Genet 2002; 10:145-149.
(5). Cazeneuve, C., Hovannesyan, Z., Genevieve, D., Hayrapetyan, H.,
Papin, S., Girodon-Boulandet, E., et al. Familial Mediterranean fever
among patients from Karabakh and the diagnostic value of MEFV gene
analysis in all classically affected populations. Arthritis Rheum 2003;
48:2324-2331.
We wish to comment on the conclusions of a study recently published
in Annals: A randomized controlled trial of intra-articular injection of
the carpometacarpal joint of the thumb in osteoarthritis (Ann Rheum Dis
2004: 63:1260-1263).
This study was designed as a randomized control
trial, which was powered to detect a difference "between the placebo and
steroid injection which was likely t...
We wish to comment on the conclusions of a study recently published
in Annals: A randomized controlled trial of intra-articular injection of
the carpometacarpal joint of the thumb in osteoarthritis (Ann Rheum Dis
2004: 63:1260-1263).
This study was designed as a randomized control
trial, which was powered to detect a difference "between the placebo and
steroid injection which was likely to be clinically significant was 20%"
(pg. 1261). Non parametric prospective power calculations established
that 45 patients were required in each group in order to detect a
difference with an alpha level of 5% and power of 80%. The authors are to
be commended for planning their study with this in mind. However, the
authors reported difficulty in recruitment which, rightly so, resulted in
the early termination of the project.
While the authors report the difficulty in recruitment to achieve
appropriate power, it appears that they have not considered the impact of
the under-recruitment on their results and therefore the conclusions that
they can draw from this study. The purpose of appropriate a-priori
powering of a study is to ensure that the chance of incorrectly accepting
a null hypothesis (i.e. a type II error) is sufficiently small. It is a
way of ensuring that a non-significant result is probabilistically likely
to be due to no difference between two groups.
Failure to reach the intended recruitment leads to difficulty in
interpreting studies with non-significant results. Two possible
explanations may be drawn from such non significant results:
1) There
may be no actual difference between the group or
2) There may indeed be a
difference, however the sample size was insufficiently large to detect
this.
Either way, this conundrum must be reflected in the discussion and
conclusions of the study.
As such, the authors of this article cannot claim, as they do in
their conclusions that "no clinical benefit was gained from inta-articular
steroids into the CMCJ...". At best, they can claim that there study, due
to the unfortunate, but very real problems associated with recruitment for
hand osteoarthritis trials, was unable to provide conclusive evidence to
evaluate whether steroids were effective.
Reference
(1). Baskin L. Statistical interpretation can also bias research evidence.
BMJ 2003; Jun 28;326(7404):1453-5.
We thank Dr Chirinos for his interest in our article and appreciate
his comments [1].
We would disagree, however, with his suggestion that paired t-test is
only appropriately used to analyze repeated measurements before and after
an intervention in a single sample population. In our study the
statistical analysis by a paired t-test was decided before data collection
and based on the study d...
We thank Dr Chirinos for his interest in our article and appreciate
his comments [1].
We would disagree, however, with his suggestion that paired t-test is
only appropriately used to analyze repeated measurements before and after
an intervention in a single sample population. In our study the
statistical analysis by a paired t-test was decided before data collection
and based on the study design of cases and controls being closely matched
for five variables (i.e. sex, age, height, mean peripheral blood pressure
and heart rate).
We are very happy to provide the probability values for the
difference of the augmentation index between rheumatoid cases and healthy
controls, using paired/ unpaired statistical tests for normally and not
normally distributed data. These were 0.0284, 0.0245, 0.0422 and 0.0432
for paired t-test, Wilcoxon (matched pairs) test, unpaired t-test and Mann
-Whitney test, respectively.
The difference remains statistically significant and we would
therefore maintain that our study shows that arterial stiffness is indeed
increased in patients with rheumatoid arthritis, a finding which has
recently been confirmed both in patients with rheumatoid arthritis [2] and
those with systemic vasculitis [3].
References
(1). Chirinos AJ. Is arterial stiffness increased in rheumatoid
arthritis? Ann Rheum Dis 2004; (eLetter; 24 June).
(2). Wong M, Toh L, Wilson A, Rowley K, Karschimkus C, Prior D, Romas
E, Clemens L, Dragicevic C, Harianto H, Wicks I, McColl G, Best J, Jenkins
A. Reduced arterial elasticity in rheumatoid arthritis and the
relationship to vascular disease risk factors and inflammation. Arthritis
Rheum 2003;48:81-89.
(3). Booth AD, Wallace S, McEniery CM, Yasmin, Brown J, Jayne DR,
Wilkinson IB. Inflammation and arterial stiffness in systemic vasculitis:
a model of vascular inflammation. Arthritis Rheum 2004;50:581-588.
In the paper by Schmidt et al, measurements of the left and right
extremities of the same subjects seem to have been pooled to calculate
standard reference values for musculoskeletal ultrasonography [1].
However, it is common knowledge that right and left measurements are tied
and should not be mixed in order to get a larger “study sample”.
In the paper by Schmidt et al, measurements of the left and right
extremities of the same subjects seem to have been pooled to calculate
standard reference values for musculoskeletal ultrasonography [1].
However, it is common knowledge that right and left measurements are tied
and should not be mixed in order to get a larger “study sample”.
In the same paper, correlations have been used as measures of
agreement between two observers (inter-observer reliability). Correlations
are inappropriate for that purpose, however. Correlations express the
strength of association between the paired values, not the agreement
between them. Systemic variation between observers is a common phenomenon.
Moreover, the correlation is influenced by the distribution of data. A
large between-subject variation will lead to a high correlation. It is
clearly not reasonable to assess agreement by a statistical method that is
highly sensitive to the choice of the sample of subjects. Altogether, the
correlation may be high, when the agreement is poor. Calculating the
standard deviation of the differences between the pairs of measurements
would be more meaningful [2,3].
In the Schmidt et al paper, correlations were also used as measures
of repeatability (intra-observer reliability). The problems with
correlations are the same in this case. Furthermore, the correlation is
not very useful when the clinician wants to know whether a given change is
due to expected within-subject variation or to real change. Other measures
of repeatability have a more direct interpretation which can be applied to
individual measurements, for example limits of agreement calculated on the
basis of within-subject standard deviations [4,5].
References
(1). Schmidt WA, Schmidt H, Schicke B, Gromnica-Ihle E. Standard
reference values for musculoskeletal ultrasonography. Ann Rheum Dis 2004;
63: 988-94.
(2). Altman DG. Practical statistics for medical research. Chapman
& Hall, London, 1991.
(3). Bland JM, Altman DG. Statistics notes: measurement error and
correlation coefficients. BMJ 1996; 313: 41-2.
We read with great interest the article by Allanore et al, and
commend on their efforts in studying this important issue[1]. We would be
most grateful if the authors can help to clarify a few points.
Mean Deviation (MD) is the average of the numbers on the total
deviation plot with each value weighted according to the magnitude of the
normal range at that point. It signifies the over...
We read with great interest the article by Allanore et al, and
commend on their efforts in studying this important issue[1]. We would be
most grateful if the authors can help to clarify a few points.
Mean Deviation (MD) is the average of the numbers on the total
deviation plot with each value weighted according to the magnitude of the
normal range at that point. It signifies the overall severity of the field
loss. Thus, a MD of -2 dB depression may indicate a 2 dB depression
everywhere in the field (not necessarily a glaucomatous field loss) or a
depression of 4 dB over half of the field (more specific for a
glaucomatous process). According to one of the commonly employed criteria
from Anderson [2] glaucomatous visual field defects may be defined by (1)
three or more adjacent points in an expected location of the central 24o
field, on the same side of the horizontal meridian, that have p <_5 on="on" the="the" pattern="pattern" deviation="deviation" pd="pd" plot="plot" one="one" of="of" which="which" must="must" have="have" p1.="p1." _2="_2" glaucoma="glaucoma" hemifield="hemifield" test="test" ght="ght" being="being" outside="outside" normal="normal" limits.="limits." _3="_3" corrected="corrected" standard="standard" cpsd="cpsd" with="with" p="p" _5.="_5." as="as" and="and" are="are" routine="routine" printout="printout" statistics="statistics" humphrey="humphrey" sita="sita" _24="_24" visual="visual" it="it" would="would" be="be" interest="interest" if="if" authors="authors" can="can" provide="provide" these="these" indices="indices" for="for" their="their" subjects="subjects" will="will" helpful="helpful" in="in" confirming="confirming" that="that" field="field" defect="defect" was="was" indeed="indeed" glaucomatous.="glaucomatous."/> In the absence of progression of glaucomatous visual field
loss, a patient having such field loss at a normal intraocular pressure
(IOP) is at the most a normal tension glaucoma suspect. The authors may
like to report any progression of glaucomatous visual field loss in the
future, which will truly define normal tension glaucoma.
We concur with the author that cup-disc ratio (CDR), if
measured vertically and > 0.7 in the absence of an extremely large or
tilted cup, usually suggest glaucomatous optic neuropathy. A CDR of >
0.3, however, will have much less bearing in indicating a glaucomatous
process. Studies have shown that vertical CDR must be interpreted with the
vertical disc diameter (VDD) [3]. For example, in normal population (glaucoma
eyes excluded) with VDD of 1.9 mm, the 50th percentile of vertical CDR is
0.55, with a 95th percentile at 0.74.
In addition, nowadays, the neuroretinal rim is regarded as more
important than the cup or CDR. The cardinal feature of glaucomatous optic
neuropathy is a loss of tissue from inner edge of the rim [4]. Other features
include rim notching, hemorrhage crossing the rim, undercutting of rim,
and asymmetry of rim between eyes, etc [4]. The authors may like to provide
these data in support of a glaucomatous optic nerve damage.
Finally, both eyes of each subject were used in analysis. Any effect
may be double-represented in the study population. This may be overcome by
including only one eye of each patient, or if both eyes are to be
included, using statistical means such as a generalized estimating
equation [5].
Reference
(1). Allanore Y, Parc C, Monnet D, Brezin AP, Kahan A. Increased
prevalence of ocular glaucomatous abnormalities in systemic sclerosis. Ann
Rheum Dis. 2004 Oct; 63(10):1276-8.
(3). Crowston JG, Hopley CR, Healey PR, Lee A, Mitchell P; Blue
Mountains Eye Study. The effect of optic disc diameter on vertical cup to
disc ratio percentiles in a population based cohort: the Blue Mountains
Eye Study. Br J Ophthalmol. 2004 Jun;88(6):766-70.
(4). South East Asia Glaucoma Interest Group (SEAGIG). Asia Pacific
Glaucoma Guidelines. 2004. p 21
(5). Katz J, Zeger S, Liang KY. Appropriate statistical methods to
account for similarities in binary outcomes between fellow eyes. Invest
Ophthalmol Vis Sci. 1994 Apr;35(5):2461-5.
Dear Editor,
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Dear Editor,
We thank Dr Chirinos for his interest in our article and appreciate his comments [1].
We would disagree, however, with his suggestion that paired t-test is only appropriately used to analyze repeated measurements before and after an intervention in a single sample population. In our study the statistical analysis by a paired t-test was decided before data collection and based on the study d...
Dear Editor,
In the paper by Schmidt et al, measurements of the left and right extremities of the same subjects seem to have been pooled to calculate standard reference values for musculoskeletal ultrasonography [1]. However, it is common knowledge that right and left measurements are tied and should not be mixed in order to get a larger “study sample”.
In the same paper, correlations have been...
Dear Editor,
We read with great interest the article by Allanore et al, and commend on their efforts in studying this important issue[1]. We would be most grateful if the authors can help to clarify a few points.
Mean Deviation (MD) is the average of the numbers on the total deviation plot with each value weighted according to the magnitude of the normal range at that point. It signifies the over...
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