Maillefert and colleagues have reported an interesting study
concerning the possible relationship between hepatitis C virus
(HCV)infection and rheumatoid arthritis (RA).[1] They found a 0.65 %
prevalence of HCV infection in 309 patients with RA, which is similar to
that reported in the general French population.[2] They concluded that
HCV infection can not be implicated in the pathogenesis of RA. HCV
in...
Maillefert and colleagues have reported an interesting study
concerning the possible relationship between hepatitis C virus
(HCV)infection and rheumatoid arthritis (RA).[1] They found a 0.65 %
prevalence of HCV infection in 309 patients with RA, which is similar to
that reported in the general French population.[2] They concluded that
HCV infection can not be implicated in the pathogenesis of RA. HCV
infection is a major public health concern.[3]
Since its discovery it has
been associated with some autoimmune diseases such as mixed
cryoglobulinemia[4] and sicca syndrome.[5] It as also been reported a
significant association between HCV infection and psoriatic arthritis in
an Italian study.[6]
In the last two years we evaluated the presence of HCV infection in 72
consecutive patients with RA. All the patients fulfilled the ACR criteria
for RA. All of them were screened for the presence of anti-HCV antibodies
even in the absence of any data suggestive of liver disease as a standard
procedure before the initiation of treatment with methotrexate or other
immunosuppressive agents. Cases with positive serology were further
evaluated for HCV-RNA with a RT-PCR method. Our patients were 70.8%
females, had a mean age of 57.9 years (range 21-77 y), and 56.9% were
positive for the rheumatoid factor. We found evidence of HCV infection
(anti-HCV plus HCV-RNA positivity) in 5 patients (6.9%). As control
patients we used a group of 47 patients with other rheumatological
diseases observed in the same period that were screened for HCV infection
on the same basis and with the same methods. These patients were 59.6%
females and had a mean age of 53 years (range 21-82 y). We found evidence
of HCV infection in 4 of them (8.5%).
We found a rather high prevalence of HCV infection in our RA patients.
However, we observed the same prevalence in our control goup.
Epidemiological studies have shown high prevalence of HCV infection even
in the general population from some Italian areas.[7,8] Therefore, our
data seem to confirm the absence of correlation between HCV infection and
RA. The great variability in the prevalence of HCV infection in different
geographical areas and patient subpopulations[9] must be taken into
account when evaluating the possible role of HCV in systemic diseases in
order to avoid wrong conclusions.
References
(1) Maillefert JF, Muller G, Falgarone G, Bour JB, Ratovohery D, Dougados
M, et al. Prevalence of hepatitis C virus infection in patients with
rheumatoid arhritis. Ann Rheum Dis 2002; 61: 635-7.
(2) Dubois F, Desenclos JC, Mariotte N, Goudeau A. Hepatitis C in a French
population-based survey, 1994: seroprevalence, frequency of viremia,
genotype distribution, and risk factors. Hepatology 1997; 25: 1490-6.
(3) Sharara AI, Hunt CM, Hamilton JD. Hepatitis C. Ann Intern Med 1996;
125: 658-68.
(4) Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection
in type II cryoglobulinemia. N Engl J Med 1992; 327: 1490-5.
(5) Jorgensen C, Legouffe MC, Perney P, Coste J, Tissot B, Segarra C, et
al. Sicca syndrome associated with hepatitis C virus infection. Arthritis
Rheum 1996; 39: 1166-71.
(6) Taglione V, Vatteroni ML, Martini P, Galluzzo E, Lombardini F, Delle
Sedie A, et al. Hepatitis C virus infection: prevalence in in psoriasis
and psoriatic arthritis. J Rheumatol 1999; 26: 370-2.
(7) Guadagnino V, Stroffolini T, Rapicetta M, Costantino A, Kondili LA,
Menniti-Ippolito F, et al. Prevalence, risk factors, and genotype
distribution of hepatitis C virus infection in the general population: a
community-based survey in southern Italy. Hepatology 1997; 26: 1006-11.
(8) Coppola RC, Masia G, Pradat P, Trepo C, Carboni G, Argiolas F, Rizzetto
M. Impact of hepatitis C virus infection on healthy subjects on an Italian
island. J Viral Hepat 2000; 7: 130-7.
(9) Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences
and temporal trends. Sem Liver Dis 2000; 20: 1-16.
Zhang and colleagues reported in a recent metaanalysis of randomised trials that placebo is very effective in the treatment of osteoarthritis (OA), especially for pain, stiffness and self-reported function.[1] In addition Zhang et al. concluded:” Important determinants of the magnitude
of effect appear to be the baseline severity, the expected strength of the treatment, the route of delivery and the sample...
Zhang and colleagues reported in a recent metaanalysis of randomised trials that placebo is very effective in the treatment of osteoarthritis (OA), especially for pain, stiffness and self-reported function.[1] In addition Zhang et al. concluded:” Important determinants of the magnitude
of effect appear to be the baseline severity, the expected strength of the treatment, the route of delivery and the sample size”.[1] But neither Zhang et al. nor Bijlsma and Welsing in the accompanying editorial discussed the impact of acetaminophen (paracetamol) on the placebo effect.
[1, 2]
Current guidelines emphasize paracetamol as the first-line therapy, when pharmacological agents are needed, [3, 4] and paracetamol (500 mg up to 4000 mg) is used as rescue medication in nearly all OA trials. In a recent trial on retention on treatment with lumiracoxib and celecoxib, in which a maximum dose of 2 g paracetamol was permitted, rescue medication was used by 79.5% to 81.3% of the patients. [5] Individuals with greater baseline level of OA pain or use of a limited form of treatment would be
more likely to utilize rescue therapy. This was the case in the Glucosamine/chondroitinArthritis Intervention Trial (GAIT), which allowed up to 4000 mg of paracetamol daily as rescue analgesia. Patients with moderate-to-severe pain used 1.9 ± 1.9 to 2.5 ± 2.2 tablets (500 mg) per day at the end of follow-up compared to 1.4 ± 1.6 to 1.7 ± 1.8 tablets in patients with mild pain. [6] A meta-analysis of randomised controlled trials reported that paracetamol is effective in relieving pain due to OA when used in a fixed dose between 2000 mg and 4000 mg and that paracetamol
has a higher response rate than placebo. [7] The effect size (ES) of 0.21 is small but statistically significant. A most recent Cochrane systemic review concluded that paracetamol is superior to placebo in OA with an
improvement from baseline of 5%, an absolute change of 4 points on a 0 to 100 pain scale and a number needed to treat (NNT) ranging from 4 to 16. [8]
Altogether, paracetamol may be the missing link to explain at least partially the high placebo rate in pain and OA trials not seen in other medical conditions. [9] Indeed, Zhang et al. reported in their metaanalysis that only 15 trials analysed did not allow rescue medications. The effect size (ES) was 0.71 without rescue medication compared to 0.51 in all trials (n=193) and 0.03 in trials with untreated controls (n=14), which suggest to me that rescue medication can mask the efficacy of the active treatment. But rescue medication use is not
assessed sequentially along with other variables in OA trials and mostly limited or no data are available from published trials on the starting dose, final dose, dose over time of paracetamol rescue medication and the
percentage of patients who used rescue medication during the study. However, without comprehensive data on active use of rescue medication from all or most of the studies in OA, final conclusions in regard to the determinants of placebo effect are fairly speculative.
References
1. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716-23.
2. Bijlsma JW, Welsing PM. The art of medicine in treating osteoarthritis:I will please. Ann Rheum Dis 2008;67:1653-55.
3. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905-1915.
4. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including
Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003;62:1145-55.
5. Fleischmann R, Tannenbaum H, Patel NP, Notter M, Sallstig P, Reginster JY. Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: a randomised controlled
trial in patients with osteoarthritis. BMC Musculoskelet Disord 2008;9:32.
6. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.
7. 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;63:901-7.
8. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257.
9. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–602.
The work carried out by the authors on calcium and the cardiovascular
risk is of primary importance. We thank the authors for questions and
comments on the SEKOIA study, safety being a primary concern for us.
The number of emergent adverse events reported in SEKOIA study was similar
in the 3 treatments groups: 85.8%, 87.9% and 86.5% in the SrRan 1g, SrRan
2g and placebo groups as well as the number...
The work carried out by the authors on calcium and the cardiovascular
risk is of primary importance. We thank the authors for questions and
comments on the SEKOIA study, safety being a primary concern for us.
The number of emergent adverse events reported in SEKOIA study was similar
in the 3 treatments groups: 85.8%, 87.9% and 86.5% in the SrRan 1g, SrRan
2g and placebo groups as well as the number of serious emergent adverse
events: 17.0%, 16.5% and 17.4%, respectively. The adverse reactions
considered by the investigators as related to the study drug were similar
to those reported in osteoporotic patients: diarrhea (3.3%, 6.6% and 2.7%,
respectively), nausea (2.0%, 2.7% and 1.8% respectively), and headache
(1.6 in each SrRAn group and 0.7% in the placebo group). Regarding
cutaneous safety, 16.3% of the patients reported a skin disorders in the
SrRan 2g group compared to 12.4% and 12.2% in the SrRan 1g group and in
the placebo group, respectively which is in line with the incidence of
skin reaction in osteoporotic patients. No cases of DRESS, SJS or TEN were
reported.
When specifically focusing on cardiac safety, a similar incidence of
cardiac events was reported in the 3 treatment groups: 5.5%, 5.7% and
5.8%, respectively. Five cases of serious myocardial infarction were
reported in the 2g group while 1 case was reported in the SrRan 1g group
and in the placebo group. All events occurred in patients with major
cardiovascular risk factors or comorbidities. All patients were suffering
from hypertension from several years and all but one were overweight or
obese. Among the strontium-ranelate treated patients, all presented
additional risks factors such as hypercholesterolemia, diabetes, or
previous or family myocardial ischaemia. Based on this small number of
events and on the presence of numerous comorbidities, it seemed difficult
at the time of the results to formally conclude to a higher risk of MI
with SrRan. These results were then submitted to the European agency and
were part of the routine benefit-risk assessment of the strontium
ranelate. When applying at posteriori, the newly contraindication of the
European agency to the SEKOIA population (i.e. when excluding patients
with pathology at baseline corresponding to the newly defined
contraindications: uncontrolled hypertension, thromboembolic events
including deep vein thrombosis and pulmonary embolism, ischaemic heart
disease, peripheral arterial disease and/or cerebrovascular disease), the
number of MI become comparable between the 3 treatment groups: 1 event in
the SrRan 1g group, 2 in the SrRan 2g group and 1 in the placebo group,
demonstrating that the contraindications are effective to minimize the
cardiac risk in this population of OA patients.
We read with interest the article by Dr Kvien and colleagues
concerning cyclosporine–A (CsA) versus parenteral gold salts (PGS) in
early rheumatoid arthritis (RA).[1] The authors concluded that both drugs
had similar results on radiological progression of the disease, while CsA
was associated with severe side effects especially hypertension and renal
function impairment. We would like to make some comme...
We read with interest the article by Dr Kvien and colleagues
concerning cyclosporine–A (CsA) versus parenteral gold salts (PGS) in
early rheumatoid arthritis (RA).[1] The authors concluded that both drugs
had similar results on radiological progression of the disease, while CsA
was associated with severe side effects especially hypertension and renal
function impairment. We would like to make some comments concerning the
CsA efficacy and side effects.
It is known that CsA man cause hypertension and may increase serum
creatinine levels. On the other hand, renal disease in RA patients may be
influenced by many factors, such as: long disease duration, previous
disease modifying antirheumatic drugs (DMARDs) usage, the intake of non
steroidal anti–inflammatory drugs (NSAIDs), the dose of CsA given and even
the usage of other drugs which interfere with CsA renal function.[2,3]
Considering the above parameters, 42% of CsA patients in Dr Kvien study
received other DMARDs and were also allowed to receive NSAIDs during the
study. In addition, in some patients the dose of CsA was 5 mg/kg body
weight. We believe that the above parameters may influence blood pressure
and renal function in CsA treated patients. To avoid this inconvenience,
it is better to treat early RA patients with CsA and small doses of
steroids. Indeed, we have reported a prospective two year randomised trial
in early RA patients using small doses of CsA (3 mg/day) and 7.5 mg of
prednisone per day, versus methotrexate (MTX). We found that the efficacy,
tolerability and safety were similar between the two drugs.[4] In
addition, in a long term follow up study for 42 months, we found similar
results and no radiological deterioration in both groups.[5] In the above
long term trial, 27% of CsA treated patients developed side effects. Eight
of them (15%) had hypertension, which was managed very well with
nifedipine 10 mg/day. A total of 7 patients (14%) discontinued the study
due to side effects, one because of uncontrolled hypertension, three because
of gingival hyperplasia, and three because of severe hyperthrichosis.[5]
Furthermore, none of our patients increased the serum creatinine more than
30% from the baseline levels and none of them discontinued the study due
to renal function deterioration. In addition to that, in a recent study
from our group, we investigated the effectiveness, toxicity, and drug
survival in a long term observational trial in early RA patients. After 12
years of follow up, the longest drug survival time was seen in MTX treated
patients, followed by CsA without significant differences between these
two drugs. Finally, PGS and D–penicillamine had the most serious adverse
drug reaction and the lowest drug survival time.[6]
Thus, considering the pathophysiology of RA and the role of CD4+
T–cells in its pathogenesis,[7] we believe that CsA has a place in the
treatment of early RA patients, but it will be given as monotherapy or in
combination therapy with small doses of steroids or/and MTX but without
the use of NSAIDs.
References
(1) Kvien TK, Zeidler HK, Hannonen P, Wollheim FA, Førre Ø, Hafström I, et
al. Long term efficacy and safety of cyclosporin versus parenteral gold in
early rheumatoid arthritis: a three year study of radiographic
progression, renal function, and arterial hypertension. Ann Rheum Dis
2002;61:511–6.
(2) Boers M. Renal disorders in rheumatoid arthritis. Semin Arthritis Rheum
1990;20:57–68.
(3) Altman RD, Perez GO, Sfakianakis GN. Interaction of cyclosporine A and
non steroidal anti–inflammatory drugs on renal function in patients with
rheumatoid arthritis. Am J Med 1992;93:396–402.
(4) Drosos AA, Voulgari PV, Papadopoulos IA, Politi EN, Georgiou PE, Zikou
AK. Cyclosporine A in the treatment of early rheumatoid arthritis. A
prospective, randomized 24–month study. Clin Exp Rheumatol
1998;16:695–701.
(5) Drosos AA, Voulgari PV, Katsaraki A, Zikou AK. Influence of cyclosporin
A on radiological progression in early rheumatoid arthritis patients: a
42–month prospective study. Rheumatol Int 2000;19:113–8.
(6) Papadopoulos NG, Alamanos Y, Papadopoulos IA, Tsifetaki N, Voulgari PV,
Drosos AA. Disease modifying antirheumatic drugs in early rheumatoid
arthritis: a longterm observational study. J Rheumatol 2002;29:261–6.
(7) Choy EH, Panayi GS. Cytokine pathways and joint inflammation in
rheumatoid arthritis. N Engl J Med 2001;344:907–16.
RA is a systemic disease and Sarzi-Puttini and colleagues have to be
praised for investigating the effects of anti-TNF therapy on the
circulating IGF system rather than the usual measures of disease activity,
joint damage and disability. However, their conclusions are based on
false assumption that serum myoglobin is a marker of the muscle catabolism
characteristic of rheumatoid cachexia.
RA is a systemic disease and Sarzi-Puttini and colleagues have to be
praised for investigating the effects of anti-TNF therapy on the
circulating IGF system rather than the usual measures of disease activity,
joint damage and disability. However, their conclusions are based on
false assumption that serum myoglobin is a marker of the muscle catabolism
characteristic of rheumatoid cachexia.
In my opinion the authors have confused accelerated muscle protein
breakdown (a cardinal feature of cachexia) with skeletal muscle
degeneration which occurs only in the relatively few patients complicated
by rheumatoid myositis. In the vast majority of patients with RA muscle
wasting is caused by increased muscle proteolysis and, possibly, reduced
muscle protein synthesis. As correctly described in many of the references
cited by Sarzi-Puttini and colleagues, these alterations in muscle protein
turnover are caused by increased expression of inflammatory cytokines such
as TNF, and corticosteroid treatment. Cytokines and corticosteroids can
act directly on skeletal muscle tissue or indirectly through alterations
in the levels and biological actions of anabolic hormones such as IGF-I or
anti-anabolic factors such as myostatin. What the authors seem to ignore
is that this muscle protein breakdown is an intracellular process in which
the ubiquitin-proteasome system degrades muscle proteins into their
constituent amino acids which are then exported in the circulation where
they can be used to synthesise acute-phase proteins in the liver (the so
called muscle-liver connection).
The presence in the circulation of
relatively large and intact muscle proteins such as myoglobin and creatine
kinase is, on the contrary, indicative of skeletal muscle tissue
damage/necrosis. This completely different process is seen in healthy
people few days after unaccustomed eccentric exercise, rabdomyolisis and
degenerative muscle diseases such as muscle dystrophy and myositis. In
these conditions muscle atrophy is mainly caused by loss of muscle fibres
while in cachexia muscle wasting is secondary to muscle fibre atrophy with
no reduction in muscle fibre number.
As serum myoglobin can not be used as a marker of the actions of IGF-I on
muscle protein metabolism in RA patients, the concomitant presence of high
serum levels of myoglobin and IGF-I in the corticosteroid-treated patients
can not be interpreted as evidence of IGF-I resistance.
Similarly, the
decrease in serum IGF-I in the context of stable levels of serum myoglobin
observed in the same group of RA patients when treated with adalimumab can
not be interpreted as a positive effect of this anti-TNF therapy on IGF-I
resistance. Therefore, the conclusions of Sarzi-Puttini and colleagues
should be revised to avoid confusion among readers. Further research on
the effects of IGF-I on proper measures of muscle protein metabolism are
necessary to demonstrate the presence of IGF-I resistance in RA patients
and the effects of anti-TNF and other treatments.
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment...
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment.
In many studies SCC is registered along with basal cell carcinoma in non-melanoma skin cancer. However, the biological behaviour of these tumours is distinct and SCC can become extremely difficult to treat in certain patient subgroups, notably immunosuppressed patients.2 We suggest that the increased SCC rate among CD patients probably reflects the preferential use of azathioprine (AZA) for immune modulation in this group of patients compared to patients with all other diagnoses. Long term AZA is relatively well-tolerated in CD achieving sustained disease remission with an additional steroid-sparing effect.3 Thus recent treatment guidelines instigate AZA as an early treatment choice for CD patients.4 Moreover, among all other immunomodulatory strategies AZA is preferentially tested against biologicals in ongoing trials for patients with CD.5
However, AZA is a well established photocarcinogen too, as it increases the photosensitivity of the skin to ultraviolet A (UVA)6 through substitution of guanine for 6-thio-guanin in the DNA of patients under treatment. The accumulation of 6-thio-guanin moieties in the DNA of epidermal keratinocytes intensifies energy absorption at the DNA level with subsequent increased mutation and carcinogenesis rates.7,8 In transplanted patients the use of AZA has been associated with significant increase in the risk of skin malignancies,9,10 however the corresponding data concerning AZA-associated skin carcinogenesis in patients with inflammatory bowel diseases are not conclusive.11-13 Thus, in the light of the evidence of the recent adalimumab metaanalysis,1 the increased incidence of skin SCC among patients with CD becomes an important finding that merits further analysis.
The safety of biological therapies and their use is expanded as we learn to screen and be vigilant for acute infections. However, the next step will be to prevent long-term side-effects and from current experience with immunomodulation / immunosuppression regimes, non-melanoma skin cancer will be among the most perturbing ones.2,9,10 In this context the data of Burmester et al1 are also an important reminder that future studies should address explicitly the effect of the combination of biologicals and specific immunomodulatory drugs, like AZA, on skin carcinogenesis in order to ensure proper selection of combination regimens.
References
1. Burmester GR, Mease P, Dijkmans BAC, Gordon K, Lovell D, Panaccione R, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009. DOI:10.1136/ard.2008.102103.
2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17.
3. Prefontain E, Sutherland LR, MacDonald JK, Cepoiu M. Azathioprine or 6-mercapopurine for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000067. DOI: 10.1002/14651858.CD000067.pub2.
4. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomoulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130: 940-87.
5. Etchevers MJ, Aceituno M, Sans M. Are we giving azathioprine too late? The case of early immunomodulation in inflammatory bowel disease. World J Gastroenterol 2008;14:5512-8.
6. Perrett CM, Walker SL, O'Donovan P, Warwick J, Harwood CA, Karran P, et al. Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. Br J Dermatol 2008;159: 198-204.
7. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-4.
8. Zhang X, Jeffs G, Ren X, O’Donovan P, Montaner B, Perrett CM, et al. Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light. DNA Repair 2007;6:344-54.
9. Ulrich C, Stockfleth E. Azathioprine, UV light, and skin cancer in organ transplant patients – do we have an answer? Nephrol Dial Transplant 2007;22:1027-9.
10. Harwood CA, Attard NR, O'Donovan P, Chambers P, Perrett CM, Proby CM, et al. PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. Br J Cancer 2008;21:1276-84.
11. Austin AS, Spiller RC. Inflammatory bowel disease, azathioprine and skin cancer: case report and literature review. Eur J Gastroenterol Hepatol 2001;13:193-4.
12. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002;16:1225-32.
13. Maddox JS, Soltani K. Risk of nonmelanoma skin cancer with azathioprine use. Inflamm Bowel Dis 2008;14:1425-31.
Yoshida et al present an overview of different designs and 'failure
definitions' in biologic discontinuation studies in rheumatoid arthritis
(RA).[1] We feel it is a very important review, as the number of
discontinuation studies is increasing and therefore awareness of the
heterogeneity in these study designs as demonstrated in this review is
essential. We have however a few comments.
Firstly, one of...
Yoshida et al present an overview of different designs and 'failure
definitions' in biologic discontinuation studies in rheumatoid arthritis
(RA).[1] We feel it is a very important review, as the number of
discontinuation studies is increasing and therefore awareness of the
heterogeneity in these study designs as demonstrated in this review is
essential. We have however a few comments.
Firstly, one of the difficulties in interpreting discontinuation studies
is that different protocols can be used, discontinuation protocol or dose
tapering protocols, and that interpretation is sometimes not
straightforward. This is exemplified by the misrepresentation of our study
in the review. This study is a down-titration and discontinuation trial
of infliximab in stable rheumatoid arthritis patients, in which we used a
dose tapering protocol.[2] We attempted to down-titrate infliximab until
stop in all patients unless a flare occurred. In 16% of all 51 patients,
infliximab could be discontinued. The review states however 0% in 12
patients. In 45% of the 51 patients the dose could be partially down-
titrated and in 39% no down-titration was possible due to flare after the
first down titration step. Additionally, we didn't have a variable follow
up duration, as stated in the review article, but 1 year for all included
patients.[2] This error underscores the difficulty in interpreting
different dose reduction study designs
A second remark we would like to make concerns the definition of 'failure'
after biologic discontinuation. The authors found heterogeneity across
studies with regard to definition of failure, with most of the included
studies in this review using a version of a DAS28-based failure
definition. We would like to point out a recently published paper in
OMERACT cooperation in this journal, validating a DAS28-based flare
criterion (delta DAS28>1.2 compared with baseline or delta DAS28>0.6
in case DAS28>3.2).[3] Of note, this was also the flare definition used
in our study, not delta DAS28-ESR>0.6 as mentioned in table 2. Use of
this validated flare criterion could lead to better comparison of results
between studies.
Finally, we would suggest to expand your search by using other databases
(Embase, Cochrane Central Register of Controlled Trials, trial registries)
and more search terms for discontinuation, as this should lead to a
higher yield in studies. For example, the STRASS study [4] is not
mentioned in this review, since it uses the term 'spacing'. This trial
however does study tapering until discontinuation.
In conclusion, Yoshida et al. address and illustrate, very thoroughly, two
important issues; differences in design and "failure definition" in
biological discontinuation studies. The heterogeneity across current
studies regarding these issues is demonstrated in a well-structured manner
and we agree with Yoshida et al. that standardized, and also validated,
definitions are important.
References
1. Yoshida K, Sung Y-k, Kavanaugh A, et al. Biologic discontinuation
studies: a systematic review of methods. Ann Rheum Dis 2013.
2. Van der Maas A, Kievit W, van den Bemt BJF, et al. Down-titration and
discontinuation of infliximab in rheumatoid arthritis patients with stable
low disease activity and stable treatment: an observational cohort study.
Ann Rheum Dis 2012;71:1849-54.
3. Van der Maas A, Lie E, Christensen R, et al. Construct and criterion
validity of several proposed DAS28-based rheumatoid arthritis flare
criteria: an OMERACT cohort validation study. Ann Rheum Dis 2012;0:1-6.
4. Fautrel B. Tapering TNF-Blockers in Established Rheumatoid Arthritis
Patients in DAS28 Remission: Results of a DAS28-Driven Step-Down Strategy
Randomized Controlled Trial [abstract]. Arthritis Rheum 2012;64
(Suppl):p4169-4170
Haara et al. recently published a study assessing epidemiological
aspects of osteoarthritis (OA) in Finland.[1] A finding of interest was
their identification of OA (in any finger joint) as a predictor of
cardiovascular death among men, with the authors suggesting an
undetermined metabolic factor as a mechanism. It may be that the
disability conferred by OA in the lower limbs delays presenta...
Haara et al. recently published a study assessing epidemiological
aspects of osteoarthritis (OA) in Finland.[1] A finding of interest was
their identification of OA (in any finger joint) as a predictor of
cardiovascular death among men, with the authors suggesting an
undetermined metabolic factor as a mechanism. It may be that the
disability conferred by OA in the lower limbs delays presentation of
patients with ischaemic heart disease due to lack of exertional symptoms.
Thus treatment to reduce risk is delayed. Additionally, some patients who
also have generalised OA and are less physically active may be at higher
risk of cardiac events.[2]
Occupation and levels of education have been used as surrogates of
social class.[3] Certain jobs that require repetitive movements or
heavier work intensity increase the risk of developing OA ,[4] although
occupation is not always linked to the development of hand OA.[5]
Generally, manual workers, whose jobs demand higher physical input, are
poorly paid compared to professionals.
Haara et al. found no link between duration of education and
osteoarthritis of the fingers but the association between OA and earlier
death may, nevertheless, be mediated by an effect of social class. Death
due to coronary disease is known to be associated with lower socioeconomic
groups. Another Finnish study noted higher incidence of myocardial
infarction in those of lower income, with higher pre-hospital, 28 day and
12 month mortality rates.[6] These higher rates may reflect differences in
prevalence and awareness of cardiac risk factors among the different
socioeconomic groups, which may also contribute to higher cardiovascular
death in men with OA.
References
(1) Haara MM, Manninen P et al. Osteoarthritis of finger joints in
Finns aged 30 or over: prevalence, determinants, and association with
mortality. Ann Rheum Dis 2003;62:151-8.
(2) Wagner A, Simon C et al. Physical activity and coronary event
incidence in N. Ireland and France. Circulation 2002;105:2247-52.
(3) Davey Smith G, Hart C et al. Education and occupational social
class: which is the more important indicator of mortality risk? J Clin
Epidemiol Community Health 1998;52:153-60.
(4) National Institutes of Health Conference. Osteoarthritis: new
insights. Ann Intern Med 2000;133:635-46.
(5) Jones G, Cooley HM, Stankovich JM. A cross sectional study of the
association between sex, smoking and other lifestyle factors and
osteoarthritis of the hand. J Rheumatology 2002;29:1719-24.
(6) Salomaa V, Niemela M et al. Relationship of Socioeconomic Status to
the Incidence and Prehospital, 28-Day, and 1-Year Mortality Rates of Acute
Coronary Events in the FINMONICA Myocardial Infarction Register Study.
Circulation 2000;101:1913-8.
The excellent review by da Silva and colleagues (1) comprehensively
covers the range of glucocorticoid side effects and points out that more
research in this area is sorely needed. One area they don�t review and
which we have previously suggested should be considered as an adverse
effect (2) is that the use of steroids by both primary doctors and
rheumatologists so frequently preempts the use of...
The excellent review by da Silva and colleagues (1) comprehensively
covers the range of glucocorticoid side effects and points out that more
research in this area is sorely needed. One area they don�t review and
which we have previously suggested should be considered as an adverse
effect (2) is that the use of steroids by both primary doctors and
rheumatologists so frequently preempts the use of DMARDs in patients with
rheumatoid arthritis. Thus steroids are given, there is a rapid
symptomatic response and the patient is more comfortable. Whether they
then decline further treatment or whether the doctor fails to recommend it
is unclear to me. However there are numerous studies where rheumatoid
patients are receiving oral glucocorticoids but are not on DMARDs. (3 4 5)
In one of the Leflunomide studies this was true of enrolled patients even
with a disease duration of eight years (4). I realize that may not be
what most would recommend but it happens.
The other issue, and here I suspect I do disagree with some of the
authors, is efficacy.
While the articles by Kirwan at al (6) and Van Everdingen et al (7) did
suggest that when given with DMARDs there is a small disease modifying
effect, Capell et al (8) didn�t find this. All of the manuscripts
however, were convincing that at 2 years there was no persistent
symptomatic benefit in the steroid group. Thus, if it is to be used for
such symptomatic reasons, - and I believe this still is the principle
reason it�s prescribed, - then surely only short term use can be justified
(9).
References
1. JAP Da Silva, JWG Jacobs, JR Kowan, M Boers, KG Saag, LBS Ines
et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis;
published evidence of prospective trial data. AnnRheumDis 2006;65:285-293.
2. L Caplan, AS Russell, F Wolfe. Steroids for rheumatoid
arthritis: The honeymoon revisited (once again). J Rheumatol 2005;32:1863-5.
3. D. Lacaille, AH Anis, DP Buk, JM Esdaile. Gaps in care for
rheumatoid arthritis: a population study. Arthritis Care and Research 2004;53:241-248.
4. V Strand, S Cohen, M Schiff, A Weaver, R Fleischman, G Cannon et
al. Treatment of active rheumatoid arthritis with Leflunamide compared with placebo
and Methotrexate. Arch Int Med 1999;159:2542-2550.
5. LS Simon, AL Weaver, DY Graham, AJ Kivitz, PE Lipsky, RC Hubbard
et al. Anti-inflammatory upper grastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. J.AMA 1999;282:1921-8.
6. JR Kirwan, M Byron, P Dieppe, C Eastmond, J Halsey, P Hickling et
al. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The
arthritis and rheumatism council low dose glucocorticoid study group. N.Engl.J.Med
1995;333:142-146.
7. AA Van Everdingen, JWG Jacobs, DRS van Reesema, WJ Bijlsma. Low dose prednisone therapy for patients with early rheum arthritis, clinical
efficacy disease modifying properties and side effects. A randomized double blind
placebo controlled clinical trial. Ann Int Med 2002;136:1-12.
8. HA Capell, R Madhok, JA Hunter, D Porter, E Morrison, J Larkin et
al. Lack of radiological and clinical benefit over two years of low dose
Prednisone for rheumatoid arthritis: results of a randomized controlled trial. Ann Rheum Dis
2004;63:797-803.
9. KG Saag. Resolved low dose glucocorticoids are neither safe nor
effective for the long term treatment of rheumatoid arthritis. ArthRheum 2001;45:468-471.
While the debate on the existence of autoantibodies against the PDGF receptor is amplified by two publications (1, 2) that contradict the data published by Gabrielli and colleagues (3), we wish to point to one important detail in the paper of Balada et al (4).
The protein that is sold by Upstate biologicals (now Millipore) and was used in the assay developed by Balada and colleagues corresponds to t...
While the debate on the existence of autoantibodies against the PDGF receptor is amplified by two publications (1, 2) that contradict the data published by Gabrielli and colleagues (3), we wish to point to one important detail in the paper of Balada et al (4).
The protein that is sold by Upstate biologicals (now Millipore) and was used in the assay developed by Balada and colleagues corresponds to the intracellular domain of the PDGF receptor alpha (from amino-acid 550 to the
end), fused to a N-terminal polyhistidine tag. Thus the antibodies detected in this report are, by definition, unable to bind to intact cells, by contrast to those described by Gabrielli and colleagues, which were shown to bind to the extracellular domain of the PDGF receptors. In other words, the two reports studied antibodies that recognize completely different epitopes. This has been overlooked in Balada’s conclusions.
In addition, the report does not include any control ruling out the possibility that the patient antibodies recognized the histidine tag instead of the PDGF receptor.
We believe that this point is a key to the understanding of Balada’s data, which may be misleading to scientists who are not familiar with receptor biochemistry.
References
1. Classen JF, Henrohn D, Rorsman F, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum 2009;60:1137-44.
2. Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145-51.
3. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-76.
4. Balada E, Simeón-Aznar CP, Ordi-Ros J et al. Anti-PDGFRa antibodies measured by non-bioactivity assays are not specific for systemic sclerosis. Ann Rheum Dis 2008;67:1027-1029.
Dear Editor
Maillefert and colleagues have reported an interesting study concerning the possible relationship between hepatitis C virus (HCV)infection and rheumatoid arthritis (RA).[1] They found a 0.65 % prevalence of HCV infection in 309 patients with RA, which is similar to that reported in the general French population.[2] They concluded that HCV infection can not be implicated in the pathogenesis of RA. HCV in...
Dear Editor,
Zhang and colleagues reported in a recent metaanalysis of randomised trials that placebo is very effective in the treatment of osteoarthritis (OA), especially for pain, stiffness and self-reported function.[1] In addition Zhang et al. concluded:” Important determinants of the magnitude of effect appear to be the baseline severity, the expected strength of the treatment, the route of delivery and the sample...
Dear Editor,
The work carried out by the authors on calcium and the cardiovascular risk is of primary importance. We thank the authors for questions and comments on the SEKOIA study, safety being a primary concern for us.
The number of emergent adverse events reported in SEKOIA study was similar in the 3 treatments groups: 85.8%, 87.9% and 86.5% in the SrRan 1g, SrRan 2g and placebo groups as well as the number...
Dear Editor
We read with interest the article by Dr Kvien and colleagues concerning cyclosporine–A (CsA) versus parenteral gold salts (PGS) in early rheumatoid arthritis (RA).[1] The authors concluded that both drugs had similar results on radiological progression of the disease, while CsA was associated with severe side effects especially hypertension and renal function impairment. We would like to make some comme...
Dear Editor,
RA is a systemic disease and Sarzi-Puttini and colleagues have to be praised for investigating the effects of anti-TNF therapy on the circulating IGF system rather than the usual measures of disease activity, joint damage and disability. However, their conclusions are based on false assumption that serum myoglobin is a marker of the muscle catabolism characteristic of rheumatoid cachexia.
In m...
Dear editor
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment...
Dear Editor,
Yoshida et al present an overview of different designs and 'failure definitions' in biologic discontinuation studies in rheumatoid arthritis (RA).[1] We feel it is a very important review, as the number of discontinuation studies is increasing and therefore awareness of the heterogeneity in these study designs as demonstrated in this review is essential. We have however a few comments. Firstly, one of...
Dear Editor
Haara et al. recently published a study assessing epidemiological aspects of osteoarthritis (OA) in Finland.[1] A finding of interest was their identification of OA (in any finger joint) as a predictor of cardiovascular death among men, with the authors suggesting an undetermined metabolic factor as a mechanism. It may be that the disability conferred by OA in the lower limbs delays presenta...
Dear Editor,
The excellent review by da Silva and colleagues (1) comprehensively covers the range of glucocorticoid side effects and points out that more research in this area is sorely needed. One area they don�t review and which we have previously suggested should be considered as an adverse effect (2) is that the use of steroids by both primary doctors and rheumatologists so frequently preempts the use of...
Dear Editor,
While the debate on the existence of autoantibodies against the PDGF receptor is amplified by two publications (1, 2) that contradict the data published by Gabrielli and colleagues (3), we wish to point to one important detail in the paper of Balada et al (4).
The protein that is sold by Upstate biologicals (now Millipore) and was used in the assay developed by Balada and colleagues corresponds to t...
Pages