We read with interest the recent article by Pavelka and colleagues [1] and the accompanying editorial by van Vollenhoven [2] regarding dose escalation of infliximab in the treatment of patients with rheumatoid arthritis (RA). Pavelka and colleagues evaluated infliximab dose escalation in patients who had initially responded (based on the criteria of an improvement of 1.2 in the 28-joint count Disease Activ...
We read with interest the recent article by Pavelka and colleagues [1] and the accompanying editorial by van Vollenhoven [2] regarding dose escalation of infliximab in the treatment of patients with rheumatoid arthritis (RA). Pavelka and colleagues evaluated infliximab dose escalation in patients who had initially responded (based on the criteria of an improvement of 1.2 in the 28-joint count Disease Activity Score [DAS28]) but who failed to achieve DAS28 remission (DAS28 score of < 2.6) after 12 months. Patients were randomly assigned to either ontinue
receiving 3 mg/kg or increase their dose to 5 mg/kg. The results showed that the mean change from baseline to 1 year in the DAS28 score was not significantly different between the treatment groups.
We agree with the editorial that this study is an important addition to the medical literature, as it is the first controlled, randomized, double-blinded study evaluating infliximab dose escalation conducted after
our double-blinded, prospective, dose-escalation study, the START trial.[3] However, we cannot fully agree with the conclusions in this article and the accompanying editorial, which suggest that the study provides definitive proof that infliximab dose escalation is not useful under any circumstances. Although some of the study limitations were discussed by Pavelka and colleagues as well as by van Vollenhoven (e.g., additional dose adjustment above 5 mg/kg was not permitted), the following
important limitations were not discussed.
First, to be eligible to participate in the study, patients must have received infliximab 3 mg/kg for at least 12 months; whereas, current EULAR treatment guidelines suggest that patients should be evaluated every 3 months and have their treatment adjusted whenever clinical response is inadequate,[4] which generally reflects actual clinical practice. Thus, the study entry criteria may have excluded patients who would have been
more likely to benefit from dose escalation, such as those who switched to another therapy or received a dose increase before 12 months. This left fewer patients in the study population who might have benefitted from a
dose increase. In addition, the baseline mean swollen joint count was 4.5, which may be too low to show a difference between two dosages that differ by only 2 mg/kg. No information on baseline median swollen joint
count and tender joint count was provided, which is more meaningful in a population that is not normally distributed.
Second, the primary study endpoint was the mean change in DAS28 score, which may not be the most sensitive efficacy measure for evaluating dose escalation given that the majority of RA patients do not need infliximab dose escalation. In the START trial, only 30% of patients met
the criteria for dose escalation, and approximately half of these patients needed an infliximab dose higher than 5 mg/kg to achieve a response.[3]
Evaluating “the proportion of patients achieving a specific level of response” such as the EULAR response, low disease activity, or DAS28 remission would have been a more sensitive endpoint in this situation. A recently published, randomized, double-blind study (RISING Study) showed that a significantly greater proportion of nonresponders who received dose escalation achieved EULAR responses than those who did not receive dose escalation.[5] Although the number of nonresponders who received dose escalation in the RISING study was smaller than that of the study reported by Pavelka and colleagues, the study design and evaluation period in the RISING study were more consistent with the EULAR treatment recommendations
and clinical practice.
Third, the article by Pavelka and colleagues did not report the C-reactive protein (CRP) concentration at baseline; however, it is evident from Figure 3 of their article that the CRP concentration at study period
week 0 was substantially lower in the 5-mg/kg group than in the 3-mg/kg group. We have shown in our START trial that all 7 nonresponders to infliximab dose escalation had low CRP concentrations at baseline.[3]
Thus it is possible that the 5-mg/kg group had more patients who were less likely to respond to infliximab dose escalation than the 3-mg/kg group.
Furthermore, 18 patients (25%) in the 3-mg/kg group were noncompliant with the study treatment compared with 4 patients (6%) in the 5-mg/kg group.
The authors did not elaborate on the nature of this noncompliance. If 25% of patients received higher dose of infliximab (de facto dose escalation) or other treatment adjustments to improve clinical response, then the
decrease in CRP level and DAS28 score in the 3-mg/kg group could be attributed to this noncompliance, depending on how data from these noncompliant patients were handled in the analysis. It would be interesting to know how the outcome would have been affected if an efficacy measure that does not include CRP (e.g., CDAI) had been used to
evaluate an appropriately selected study population. The actual infliximab dose received in the 3-mg/kg group ranged from 2.7 to 5.5 mg/kg and from 3.3 to 6.3 mg/kg in the 5-mg/kg group. The difference in response rates
between the two groups could easily be eliminated if some patients in the 3-mg/kg group who would have responded to dose escalation actually received infliximab 5.5 mg/kg instead and if some patients in the 5-mg/kg group who would have responded to dose escalation, only received 3.3 mg/kg of infliximab and consequently did not respond.
Fourth, radiographic progression was not evaluated by Pavelka and colleagues. Results from both the ATTRACT [6] and the RISING [5] studies have indicated that higher doses of infliximab inhibit radiographic progression more effectively than lower doses.
We applaud the efforts of Professor van Vollenhoven to educate rheumatologists on the phenomenon of regression to the mean, which is inevitable given the waxing and waning nature of RA disease activity.
Nonetheless, if infliximab dose escalations were unnecessary for all patients, there would be no reason to expect a relationship between the need for dose escalation and infliximab trough serum concentrations. The results of the START study showed that some patients who required dose escalation had inadequate serum concentrations of infliximab (lower than that of patients who did not require dose escalation), and these patients responded after their serum infliximab concentrations were increased by dose escalation.[3] This is further illustrated in Figure 1A-C herein, which shows that the mean trough serum infliximab concentrations for patients who received dose escalations in START were below those of patients who did not require dose escalation at any time (Figure 1A, 1B,
and 1C). Trough serum concentrations for patients who required multiple dose escalations reached those of patients who did not require dose escalation at the final dose increase after which response was achieved
(except nonresponders; Figure 1D). A relationship between serum infliximab concentrations and response has also been demonstrated in the ATTRACT study [6] and most recently in the RISING study.[5] Despite the limitations of these studies, their findings indicate that some patients
receiving 3 mg/kg every 8 weeks have an insufficient infliximab serum concentration and may be more likely to respond to a higher dose or a shorter dosing interval.
Some patients, however, do not respond to an increased dose. In the START trial, 7 patients met the criteria for double-blinded dose escalation but did not respond even after 4 dose escalations and despite having adequate serum infliximab concentrations (Figure 1D). These patients had normal CRP concentrations at baseline, suggesting that they did not have active inflammation. Durez and colleagues [7] also showed that patients requiring dose escalation had higher levels of CRP and higher joint counts at baseline. We do not advocate the measurement of
serum infliximab concentrations to determine the need for dose escalation due to high individual variability.[6] However, as indicated by the studies mentioned above,[3, 6] a careful clinical evaluation may allow for the identification of patients who would benefit from dose escalation.
Finally, Pavelka and colleagues reported an increased rate of nonserious adverse events in the 5-mg group compared with the 3-mg group.
The clinical significance of these events is unclear. The rates of serious adverse events and serious infections did not differ between treatment groups. This is consistent with the results of the START trial in which
patients with dose escalation did not have increased rates of serious adverse events or serious infections.[3] Since dose escalation in selected patients only served to increase the serum trough concentrations to values comparable to those in patients who do not require dose
escalation, we postulated that the risks of serious infection and serious adverse events would not be increased in patients who received dose escalation.
The results from the study reported by Pavelka and colleagues are important but are not the final verdict on the issue of infliximab dose escalation. Rather than abandon dose flexibility altogether, efforts must be made to distinguish patients who would benefit from dose escalation from those who would not benefit. Rheumatologists must be cognizant of
the regression to the mean phenomenon, but clearly some patients require dose escalation, and physicians should be given the flexibility to optimize treatment for these patients. Academic clinicians, practicing physicians, and the pharmaceutical industry must collaborate to further
elucidate the optimal use of infliximab and other treatments for RA.
Figure
Figure 1: Mean (± standard deviation) trough serum infliximab
concentrations for patients in the START study who were eligible to
receive dose escalations. Serum levels before and after the last dose
escalation, when patients achieved a clinical response, are shown.
Patients who required dose escalation and responded to dose escalation had
lower mean serum concentrations than those who did not require dose
escalation.
References
1. Pavelka K, Jarosova K, Suchy D, et al.
Increasing the infliximab dose in rheumatoid arthritis patients: a randomised, double blind study failed to confirm its efficacy. Ann Rheum Dis 2009;68:1285-9.
2. van Vollenhoven RF. How to dose infliximab in rheumatoid arthritis: new data on a serious issue. Ann Rheum Dis 2009;68:1237-9.
3. Rahman MU, Strusberg I, Geusens P, et al.
Double-blinded infliximab dose escalation in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:1233-8.
4. Combe B, Landewé R, Lukas C, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34-45.
5. Takeuchi T, Miyasaka N, Inoue K, et al. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol 2009 Jul 22 [Epub ahead of print].
6. St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:1451-9.
7. Durez P, Van den Bosch F, Corluy L, Veys et al. A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks can be effective: a Belgian prospective study. Rheumatology (Oxford) 2005;44:465-8.
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.
The editorial of colleagues Kay and Westhovens on the 3 E project about use of methotrexate makes some excellent points on the position of methotrexate in our daily practice, especially in the first 2 paragraphs.
The fact that apparently methotrexate remains the initial preferred antirheumatic drug rests on perceived efficacy, an acceptable safety profile, and maybe predominantly on low...
The editorial of colleagues Kay and Westhovens on the 3 E project about use of methotrexate makes some excellent points on the position of methotrexate in our daily practice, especially in the first 2 paragraphs.
The fact that apparently methotrexate remains the initial preferred antirheumatic drug rests on perceived efficacy, an acceptable safety profile, and maybe predominantly on low costs. Our subanalysis of the BeSt trial has shown that, when aiming at low disease activity as preferred
treatment outcome, only 1/3 of patients continue to benefit from initial treatment with methotrexate in the first 2 years [1], and this proportion drops to ¼ after 5 years. The majority of the patients have to switch to
or add other drugs because of lack of efficacy of MTX, not because of toxicity.
Many trials, including the BeSt trial, have shown that at the group level, initial treatment with a combination of MTX and either prednisone or a TNF-blocking agent [2-7], is superior to treatment with MTX alone.
Disease activity decreases more rapidly in the groups treated with combination therapy, which results in less radiological damage progression. Many follow up studies have shown that the toxicity of these drugs is low or manageable.
From a theoretical point of view, it may be interesting to know what length of delay, while trying out initial treatment with methotrexate monotherapy, would not result in more damage progression. For individual patients there is more at stake than that. Most have already suffered for
some time from the symptoms of (developing) rheumatoid arthritis before they came to the rheumatologist’s office. The impact on their daily life, and that of their family members, is not to be underestimated. We have an
obligation to our patients to try to aim at clinical improvement as early as possible, which in general is best achieved with combination therapy.
In case of a good response, we can taper to monotherapy. For some this strategy will mean temporary overtreatment. For most, it will mean the best chance on early and prolonged benefit of our initial treatment
choice.
References
1. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YPM, van Zeben D, Kerstens PJSM, Gerards AH, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007;66:1356-1362.
2. Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350(9074):309-18.
3. Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.
Lancet 1999;353(9164):1568-73.
4. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363(9410):675-81.
5. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial
of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54(1):26-37.
6. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al.
Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146(6):406-15.
7. Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis
(COMET): a randomised, double-blind, parallel treatment trial. Lancet 2008;372(9636):375-82.
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.
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 European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group provided recommendations for standardization of future research on endothelial progenitor cells (EPCs)[1]. We support this
initiative, as the use of different protocols by different study groups in EPC research hampers substantial advancement in this field. However, we feel that some of the statements made by the EUSTAR gr...
The European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group provided recommendations for standardization of future research on endothelial progenitor cells (EPCs)[1]. We support this
initiative, as the use of different protocols by different study groups in EPC research hampers substantial advancement in this field. However, we feel that some of the statements made by the EUSTAR group lack scientific
evidence and must be put in proper context.
First of all, an EPC is defined as an immature cell, which is capable of differentiating into a mature endothelial cell. Investigators tried to define and characterize these cells in cultures of isolated mononuclear cells and by FACS analysis of blood mononuclear cells [2, 3]. However, so far, these experiments lack hard evidence for real endothelial
characteristics in vivo of all these cultured or FACS-phenotyped cells. Therefore, the description in the present article of two main subpopulations of EPCs with different origins, functions and morphological
characterization, has to be interpreted with caution.
As stated by the authors, the different EPC subpopulations gathered by the use of different culture conditions represent different aspects of EPC biology. The therapeutic use of these different EPC subpopulations may
even have different effects in vivo[4, 5]. Therefore, further research regarding the different EPC subpopulations acquired by these different methods is necessary before any recommendations can be made.
Although many of the recommendations made by the EUSTAR are based on accumulating evidence in the field of EPC research, some are based on the opinion of the EUSTAR expert panel alone. For example, coating cell culture wells with fibronectin and using the culture media EGM-2
(Clonetics, San Diego, California, USA). To the best of our knowledge, no study has shown the superiority of a single coating regimen or medium in the culture of EPCs. We fear that the important EUSTAR recommendation is
flawed by their statement regarding culture media and coating.
We think that more research is needed before any consensus can be reached regarding this subject and that the recommendations made by the EUSTAR are premature.
References
[1] Distler J, Allanore Y, Avouac J, Giacomelli R, Guiducci S, Moritz F, et al. EULAR Scleroderma Trials and Research group statement and recommendations on endothelial precursor cells. Ann Rheum Dis 2009;68:163-8.
[2] Rouhl R, van Oostenbrugge R, Damoiseaux J, Cohen Tervaert J, Lodder J. Endothelial Progenitor Cell Research in Stroke. A Potential Shift in Pathophysiological and Therapeutical Concepts. Stroke.2008;39:2158-65.
[3] Leone A, Valgimigli M, Giannico M, Zaccone V, Perfetti M, D'Amario D, et al. From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells. European Heart Journal 2009;30:890-9.
[4] Mobius-Winkler S, Hollriegel R, Schuler G, Adams V. Endothelial Progenitor Cells: Implications for Cardiovascular Disease. Cytometry Part A. 2009;75A:25-37.
[5] Mund J, Ingram D, Yoder M, Case J. Endothelial progenitor cells and cardiovascular cell-based therapies. Cytotherapy 2009;00:1-11.
We read with great interest the viewpoint written by P Emery et al entitled “Guidelines for initiation of antitumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe”.(1)
The Portuguese Society of Rheumatology issued its guidelines for the use of antitumour necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) for the first time in 2003....
We read with great interest the viewpoint written by P Emery et al entitled “Guidelines for initiation of antitumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe”.(1)
The Portuguese Society of Rheumatology issued its guidelines for the use of antitumour necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) for the first time in 2003. They have been regularly updated and the
last version was published in December 2007, in English in Acta Reumatologica Portuguesa, which is an open access journal, indexed to Medline/Pubmed and Thomson Scientific (2). In our view there are some particularities in these guidelines that could be of interest for further discussion by the medical community. Applying the same analyzing strategy used in the P Emery et al publication we would like to highlight that in the Portuguese guidelines there is no minimum disease duration requested
for the initiation of anti-TNF therapy in RA. However, patients are supposed to be on methotrexate (MTX) in a dose of at least 20mg/week for 3 months, or, in case of intolerance, toxicity or contraindication, after a
period of at least 6 months of other disease modifying anti rheumatic drug (DMARD). Thus, in practice, a period of no less than 3 months will elapse between diagnosis and theoretical eligibility for anti-TNF treatment.
Regarding the disease activity level required for treatment initiation the proposed threshold is a Disease Activity Score using 28 joint counts (DAS28) superior to 3.2. Nevertheless, if patients have a progressive
radiological or functional worsening, anti-TNF treatment can be considered even with a DAS28 score below 3.2. Treatment response should be assessed by DAS28 with the goal of reaching remission or low disease activity after
6 months of treatment. In addition, a switch to another drug should be performed if radiological progression or functional impairing is occurring. Though, if a patient had an initial DAS28 superior to 5.1 it is offered the possibility of staying on the same drug if the DAS28 score is persistently inferior to 4. Any of the approved anti-TNF treatment drugs can be used as first or second line treatments.
We agree with P Emery et al perspective that updated evidence based European Guidelines are needed for the use of anti-TNF therapy in RA. In our view this should be prepared with a wide basis of consensus from practicing clinicians all over Europe and ideally should be able to
encompass practical and precise recommendations on DAS28 thresholds, taking into account structural progression and functional impairment.
References
1. Emery P, Van Vollenhoven R, Ostergaard M, Choy E, Combe B, Graninger W, et al. Guidelines for initiation of antitumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe. Ann Rheum Dis 2009;68:456-9.
2. Rheumatoid Arthritis Study Group of the Portuguese Society of Rheumatology. Portuguese guidelines for the use of biological agents in rheumatoid arthritis- December 2007 update. Acta Reumatol Port 2007;32:363-6.
This review is very interesting. This review showed some evidence about the relationship between RA and cardiovascular risk. Statins are the most widely prescribed drugs, used for the treatment of
hypercholesterolemia and resulting cardiovascular diseases. Previous reports showed that mechanism by which statins may reduce vascular event rates relates to potential anti-inflammatory effects of these agents....
This review is very interesting. This review showed some evidence about the relationship between RA and cardiovascular risk. Statins are the most widely prescribed drugs, used for the treatment of
hypercholesterolemia and resulting cardiovascular diseases. Previous reports showed that mechanism by which statins may reduce vascular event rates relates to potential anti-inflammatory effects of these agents.
Inflammatory processes, in this regard, play a important role in the pathogenesis of atherosclerosis, and elevated plasma levels of markers of inflammation such as high sensitivity C-reactive protein (hs-CRP), serum
amyloid A, IL-6 and soluble intercellular adhesion molecule-1 have been shown to predict cardiovascular events. Statin has a role to inhibit an endothelial pro-adhesive and pro-inflammatory phenotype induced by
different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines. The important question is should we concern more about the cardiovascular risk in patients with RA? Should we give statin in patients
with RA?
Most patients with RA now receive a combination of DMARDs as the emphasis of treatment moves towards the induction of disease amelioration/remission together with tissue protection. A longitudinal studies are now required
to determine whether such benefits of statins translate into a significant reduction of the vascular risk end point in patients with RA.
We read with interest the article by Alvarez-Rodriguez L. and coworkers on “Circulating cytokines in active Polymyalgia Rheumatica”.[1]
The origin and the pathogenesis of PMR is still obscure despite decades of intense research. The main obstacle for investigating and understanding PMR pathogenesis is the apparent lack of a definite site where
inflammation occurs. The results and interp...
We read with interest the article by Alvarez-Rodriguez L. and coworkers on “Circulating cytokines in active Polymyalgia Rheumatica”.[1]
The origin and the pathogenesis of PMR is still obscure despite decades of intense research. The main obstacle for investigating and understanding PMR pathogenesis is the apparent lack of a definite site where
inflammation occurs. The results and interpretations put forward in the above mentioned paper raise a number of points which need to be addressed.
The authors confirmed the well known elevation of circulating IL-6 in active PMR patients and the dramatic fall after steroid treatment.[2-3]
More interestingly, the authors found no significant increase of IL-6 production by peripheral blood lymphocytes and monocytes both at single cell level and at PBMC culture supernatant release. Therefore the authors
suggest that IL-6 might be mainly produced in the inflamed tissue. Now we think some additional information should be presented.
First, while it is confirmed that other inflammatory cytokines are not elevated in active PMR [3], this is not true for other inflammatory molecules which can play a relevant role in the pathogenesis: chemokines
(CCL-5 RANTES) [4] and angiogenic growth factors (VEGF) [5] both of which again present a dramatic decrease after steroid treatment.
Second, the author state that the hypothesis of the systemic component of PMR was based on a single study which utilized only semiquantitative PCR.[2] Actually a few years ago we demonstrated that PBMC spontaneously release in culture higher amount of VEGF [5] than controls and, more interestingly, this heightened synthetic capacity was maintained also in corticosteroid treated patients, thus suggesting an activation state of circulating monocytes which is only partially steroid
sensitive.
Therefore a peripheral activation of mononuclear cells may be present in active PMR, at least as far as the production of some inflammatory molecules is concerned.
Based on their results the authors suggest a IL-6 spillover hypothesis from the inflamed tissue. But they do not discuss which tissue can be involved. We and other have demonstrated that the synovium of the shoulder joint [6,7] and periarticular structures (bursae) [8] are site of
inflammation. In particular shoulder synovitis is characterized by macrophage and lymphocyte infiltrate and neoangiogenesis which are much less marked in steroid treated inactive patients.[6] In addition, local production of VEGF was documented by immunohistochemistry in shoulder synovial biopsies and the tissue expression was significantly reduced in treated cases.[5]
Thus we think that in active PMR both peripheral (circulating mononuclear cells) and tissue (synovitis) inflammatory components coexist: some inflammatory molecules are produced in both compartments (VEGF) while other seem to have a more restricted site of production. This is certainly true for the neuropeptide VIP [9] whose serum level are undetectable (R. Meliconi, personal observations) and might be true for IL-6.
Finally we agree IL-6 is a central molecule in PMR pathogenesis and it presents also a relevant prognostic value together with its soluble receptor [10], therefore the suggestion by Alvarez-Rodriguez and coworkers about the possible use of IL-6 blocking agent in PMR patients can be fully endorsed.
References
1. Alvarez-Rodríguez L, Lopez-Hoyos M, Mata C, Marin MJ, Calvo-Alen J, Blanco R, et al. Circulating cytokines in active polymyalgia rheumatica. Ann Rheum Dis Published Online First 1 March 2009. doi:10.1136/ard.2008.103663
2. Roche NE, Fulbright JW, Wagner AD, Hunder GG, Goronzy JJ, Weyand CM. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36:1286-1294.
3. Uddhammar A, Sundqvist K-G, Ellis B, Rantapää-Dahlqvist S. Cytokines and adhesion molecules in patients with polymyalgia rheumatica. Br J Rheumatol 1998;37:766-769.
4. Pulsatelli L, Meliconi R, Boiardi L, Macchioni P, Salvarani C, Facchini A. Elevated serum concentrations of the chemokine RANTES in patients with polymyalgia rheumatica. Clin Exp Rheumatol 1998;16:263-268.
5. Meliconi R, Pulsatelli L, Dolzani P, Boiardi L, Macchioni P, Salvarani C, et al. Vascular endothelial grow factor production in polymyalgia rheumatica. Arthritis Rheum 2000;43:2472-2480.
6. Meliconi R, Pulsatelli L, Uguccioni M, Salvarani C, Macchioni P, Melchiorri C, et al. Leukocyte infiltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid treatment. Arthritis Rheum 1996;39:1199-1207.
7. Frediani B, Falsetti P, Storri L, Bisogno S, Baldi F, Campanella V, et al. Evidence for sinovitis in active polymyalgia reumatica: sonographic study in a large series of patients. J Rheumatol 2002;29:123-130.
8. Salvarani C, Cantini F, Olivieri I, Barozzi L, Macchioni L, Niccoli L, et al. Proximal bursitis in active polymyalgia reumatica. Ann Intern Med 1997;127:27-31.
9. Pulsatelli L, Dolzani P, Silvestri T, De Giorgio R, Salvarani C, Macchioni P, et al. Synovial expression of vasoactive intestinal peptide in polymyalgia reumatica. Clin Exp Rheumatol 2006;24:562-566.
10. Pulsatelli L, Boiardi L, Pignotti E, Dolzani P, Silvestri T, Macchioni P, et al. Serum interleukin-6 receptor in polymyalgia reumatica: a potential marker of relapse/recurrence risk. Arthritis Rheum 2008;59:1147-1154.
Recently, I read an interesting article titled "Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus" published in ARD.
In this article, Cheng et al. reported increased plasma IL17 and IL23 and decreased IL22 in SLE patients, which may suggest their important and distinct roles in SLE pathophysiology [1]. Their re...
Recently, I read an interesting article titled "Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus" published in ARD.
In this article, Cheng et al. reported increased plasma IL17 and IL23 and decreased IL22 in SLE patients, which may suggest their important and distinct roles in SLE pathophysiology [1]. Their results is similar to our
previous reports which has been published Clinica Chimica Acta, we also observed decreased serum IL-22 level in SLE patients as compared to health controls, but did not found a correlation between serum IL-22 level and SLE disease activity index (SLEDAI)[2].
This study is interesting, they firstly reported the decreased plasma IL-22 level in SLE patients. However, I have several concerns: Firstly, this is a cross-sectional study, and because of the retrospective data collection, small number of patients and the lack of relation with
specific manifestations and glucocorticoid treatment. So the conclusion "increased plasma IL17 and IL23 and decreased IL22 in SLE may suggest their important and distinct roles in SLE pathophysiology"is not solid.
Secondly, the authors did not state the reproducibility of IL-17, IL-23 and IL-22 measurement, which should be described in methods section.
Thirdly, probably because of the small number of patients, they did not develop a regression analysis trying to show what others clinical aspect (previous treatment, other cytokines related to Th1 response, etc.) could be significant in this study, which is also a limitation in our previous study. Therefore, the results give an overall view about the role of IL22 in SLE but relevant clinical aspects have been left out. Lastly, "plasma samples were obtained under local ethics committee approved protocols and with informed consent" Should be clearly defined if the Plasma samples was obtained at the same point: SLE onset, or during disease's development, because serum IL-22 level may be changed at different disease stage.
In spite of these, a decrease in serum IL-22 levels in patients with SLE suggests that this cytokine might be implicated in the pathomechanisms of this disease.2 However, future studies with large samples and mechanism
studies are awaited to confirm this belief.
Acknowledgements
This work was partly supported by grants from the key program of
National Natural Science Foundation of China (30830089)
References
1. Cheng F, Guo Z, Xu H, Yan D, Li Q. Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 2009;68:604-6.
2. Pan HF, Zhao XF, Yuan H, Zhang WH, Li XP, Wang GH, et al. Decreased serum IL-22 levels in patients with systemic lupus erythematosus. Clin Chim Acta 2009;401:179-80.
Dear Editor,
We read with interest the recent article by Pavelka and colleagues [1] and the accompanying editorial by van Vollenhoven [2] regarding dose escalation of infliximab in the treatment of patients with rheumatoid arthritis (RA). Pavelka and colleagues evaluated infliximab dose escalation in patients who had initially responded (based on the criteria of an improvement of 1.2 in the 28-joint count Disease Activ...
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...
Dear editor,
The editorial of colleagues Kay and Westhovens on the 3 E project about use of methotrexate makes some excellent points on the position of methotrexate in our daily practice, especially in the first 2 paragraphs.
The fact that apparently methotrexate remains the initial preferred antirheumatic drug rests on perceived efficacy, an acceptable safety profile, and maybe predominantly on low...
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,
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 European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group provided recommendations for standardization of future research on endothelial progenitor cells (EPCs)[1]. We support this initiative, as the use of different protocols by different study groups in EPC research hampers substantial advancement in this field. However, we feel that some of the statements made by the EUSTAR gr...
Dear Sir,
We read with great interest the viewpoint written by P Emery et al entitled “Guidelines for initiation of antitumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe”.(1)
The Portuguese Society of Rheumatology issued its guidelines for the use of antitumour necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) for the first time in 2003....
Dear Editor,
This review is very interesting. This review showed some evidence about the relationship between RA and cardiovascular risk. Statins are the most widely prescribed drugs, used for the treatment of hypercholesterolemia and resulting cardiovascular diseases. Previous reports showed that mechanism by which statins may reduce vascular event rates relates to potential anti-inflammatory effects of these agents....
Dear Editor,
We read with interest the article by Alvarez-Rodriguez L. and coworkers on “Circulating cytokines in active Polymyalgia Rheumatica”.[1]
The origin and the pathogenesis of PMR is still obscure despite decades of intense research. The main obstacle for investigating and understanding PMR pathogenesis is the apparent lack of a definite site where inflammation occurs. The results and interp...
Dear Editor,
Recently, I read an interesting article titled "Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus" published in ARD. In this article, Cheng et al. reported increased plasma IL17 and IL23 and decreased IL22 in SLE patients, which may suggest their important and distinct roles in SLE pathophysiology [1]. Their re...
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