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.
Competing Interest: None
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 twicedaily 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.
We have with great interest read the letter by Mäkinen, Hannonen and Sokka in the July issue of the ARD, 2008 (1). The authors make the point that the sex differences in remission rates assessed by DAS28 in patients with early RA reported by us (2,3) may be spurious due to the fact that DAS 28 does not take into account gender differences in erythrocyte sedimentation rate (ESR). Consequently they propose tha...
We have with great interest read the letter by Mäkinen, Hannonen and Sokka in the July issue of the ARD, 2008 (1). The authors make the point that the sex differences in remission rates assessed by DAS28 in patients with early RA reported by us (2,3) may be spurious due to the fact that DAS 28 does not take into account gender differences in erythrocyte sedimentation rate (ESR). Consequently they propose that we calculate ACR remission rates from our data to see whether the sex differences found by DAS28 will remain or disappear. However, we already addressed this question in our study (3). We quote from the results section:
“To investigate whether the sex difference in remission rate would also be evident in the presence of more stringent criteria, the clinical criteria described by Mäkinen et al. were applied. (4).” “By these criteria, remission at 2 years was achieved by 17.8% of the women and 26.8% of the men (p=0.005), remission by 5 years by 21% of the women and 28.5% of the men (p=0.039) and remission achieved both at 2 and 5 years by 9.5% of women and 16.4% of men (p=0.013). Thus, by these stringent
remission criteria, overall remission rates were considerably lower than those by the DAS28 criterion, but the significant sex difference remained.”
Admittedly, these clinical criteria are not equal to the ACR criteria (5), but they do take the gender differences in ESR into account.
However, the ACR criteria were not applied in our study (3). Therefore we have reviewed our data. 552 of the 698 patients had values for all variables included in the ACR criteria (no swollen, no tender joint, painVAS ≤10 mm, morning stiffness ≤ 15 min, ESR ≤30 mm in women and ≤ 20 mm in men, fatigue excluded). The results show that 10.4% of the women and 16.2% of the men met all five criteria at 5 years, p=0.048. Thus, our data show gender differences in remission rates also when strict criteria are applied and when gender differences in ESR are accounted for.
These data lead to some considerations. Looking at the individual patients, it becomes evident that unacceptably many patients are erroneously classified as non-remitters by the ACR criteria. E.g., the presence of a single tender joint in association with no swollen joint, normal ESR, morning stiffness 5 minutes and pain VAS 5 mm would hardly be regarded as evidence of ongoing active disease. Several more plausible explanations to a single tender joint would instead be considered.
Likewise, an ESR of 36 mm in a woman without swollen and tender joints, morning stiffness and pain (VAS 2 mm) would rather be assigned to some other cause than active RA. Furthermore, classifying a patient with only a pain VAS of 13 mm or only a morning stiffness of 30 minutes in absence of other criteria does not seem to warrant a judgment of no remission. Such patients were numerous enough in our study to question the clinical relevance of the ACR criteria.
References
1. Mäkinen H, Hannonen P, Sokka T. Sex: a major predictor of remission as measured by 28-joint disease activity score (DAS28) in early rheumatoid arthritis? Ann Rheum Dis 2008;67:1052-3.
2. Tengstrand B, Ahlmén M, Hafström I, for the BARFOT Study Group. The influence of sex on rheumatoid arthritis: A prospective study of onset and outcome after 2 years. J Rheumatol 2004;31:214-22.
3. Forslind K, Hafström I, Ahlmén M, Svensson B for the BARFOT Study Group. Sex: a major predictor of remission in early rheumatoid arthritis? Ann Rheum Dis 2007;66:46-52.
4. Makinen H, Kautiainen H, Hannonen P, Sokka T. Frequency of remissions in early rheumatoid arthritis defined by 3 sets of criteria. A 5-year followup study. J Rheumatol 2005;32:796-800.
5. Pinals RS, Masi AT, Larsen RA, and the subcommittee for criteria of remission in rheumatoid arthritis of the American Rheumatism Association diagnostic and therapeutic criteria committee. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum
1981;24:1308–15.
We read with the great interest the paper by Garces et al. Anti-tumour necrosis factor agents and lipid profile: a class effect? [1] In this study the investigators showed the different effect on lipid profile between infliximab and etanercept in patient with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We would like to present the similar study in RA patients treate...
We read with the great interest the paper by Garces et al. Anti-tumour necrosis factor agents and lipid profile: a class effect? [1] In this study the investigators showed the different effect on lipid profile between infliximab and etanercept in patient with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We would like to present the similar study in RA patients treated with infliximab and etanercept. We recruited 38 women, age matched with active RA to the study. The total plasma cholesterol, HDL, LDL and TG levels were measured before and after 12 months of treatment with both TNF-&[alpha] inhibitors. The results are summarized in table 1.
We did not observe any statistically significant changes in the lipid profile after 12 months of therapy with etanercept, however the TG levels after 12 months of treatment had the tendency to decrease. The patients treated with infliximab had at 12 months of the treatment. the statistically significant lower HDL level (p=0,003) and higher TG level (p=0,03) than at baseline. Reduction of HDL and elevation of TG levels was for the first time observed by Cauza et al [2] after 6 weeks of therapy with infliximab in patients with RA and PsA, that it is in agreement with results of our study. Popa et al. [3] showed that the long-term therapy of infliximab can lead to pro-atherogenic pattern of the plasma lipids concentration. Seriolo et al. [4] observed a group of 22 patients with RA treated with etanercept. After 48 week of the treatment the investigators did not observe any significant changes in lipid levels as compared to the baseline. In our study the final HDL level was lower than in the baseline and the TG level was higher than the baseline respectively. The reason of this changes is not fully elucidated. We may speculate that the changes in cholesterol levels in patients with RA treated with TNF-&[alpha] inhibitors may be caused by the influence of this drugs on cytokines network and the adipocytokines. It is known, that the one of adipocytokines – adiponectin has a stream on insulin resistance and lipids metabolism. Low level of adiponectin correlates negatively with low HDL and positively with high TG level. [5] Recently we published the brief report on increased adiponectin levels in patient with RA treated with etanercept. [6] The serum HDL and TG levels remained unchanged during the 3 month study. That may suggest differences in lipid influence between infliximab and etanercept. In the recently published study of Gonzalez-Gay et al. [7] the investigators didn't observed changes in adiponectin levels upon infliximab therapy. The adiponectin concentration partially negatively correlated with TG/HDL ratio, TC/HDL ratio and high fasting plasma glucose levels, and was independent of CRP (C-reactive protein) levels and BMI (body mass index). It is especially important in the light of the results of the study suggesting changes in lipid profile toward pro-atherogenic reduction of HDL after treatment with infliximab. This changes perhaps have no impact on gross cardiovascular risk in patients with RA and effective suppression of inflammation contributes significantly to reduction of cardiovascular risk.
References
1. Garces SP, Parreira Santos MJ, Vinagre FMR, Roque RM, da Silva JAC: Anti-tumour necrosis factor agents and lipid profile: a class effect? Ann Rheum Dis 2008;67:893-4.
2. Cauza E, Cauza K, Hanusch-Enserer U, Etemad M, Dunky A, Kostner K. Intravenous anti-TNF-alpha therapy leads to elevated triglyceride and reduced HDL-cholesterol levels in patients with rheumatoid arthritis and psoriatic arthritis. Wien Klin Wochenschr 2002;30:1004-7.
3. Popa C, van den Hoogen FHJ, Radstake TRD, Netea MG, Eijsbouts AE, den Heijer M et al. Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis. Ann Rheum Dis 2007;66:1503-7.
4. Seriolo B, Paolino S, Ferrone C, Cutolo M. Long-term effects of etanercept treatment on lipid profile in patients with rheumatoid arthritis. Ann Rheum Dis 2007 http://ard.bmj.com/cgi/eletters/66/7/958#921:22 Oct 2007.
5. Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, Matsubara K et al. Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clin Sci 2002;103:137-42.
6. Lewicki M, Kotyla P, Kucharz E. Etanercept increases adiponectin level in woman with rheumatoid arthritis. Clin Rheumatol 2008;27:1337-8.
7. Gonzalez-Gay MA, Llorca J, Garcia-Unzueta MT,
Gonzalez-Juanatey C, De Matias JM, Martin J et al. High-grade inflammation, circulatin adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis. Clin Exp Rheumatol 2008;26:596-603.
Table 1 The serum TC (total cholesterol), HDL (high density lipoprotein), LDL (low density lipoprotein) and TG (triglycerides) levels in patients with RA treated with infliximab and etanercept before and after 12 month of therapy
Sir,
In their study, Lee et al (1) studied possible associations between anti-CCP titers and several markers of disease pathogenesis and activity of rheumatoid arthritis (RA)including the presence of erosions, CRP, ESR, disease duration and history of smoking. They report a significant association between anti-CCP titers and history of smoking. Authors are right that the vast majority of anti-CCP studies only deal with the
p...
Sir,
In their study, Lee et al (1) studied possible associations between anti-CCP titers and several markers of disease pathogenesis and activity of rheumatoid arthritis (RA)including the presence of erosions, CRP, ESR, disease duration and history of smoking. They report a significant association between anti-CCP titers and history of smoking. Authors are right that the vast majority of anti-CCP studies only deal with the
presence or absence of anti-CCP ("positivity" and "negativity"), but not the absolute concentrations (or titers) of this antibody. Yet, some patients exert only slightly elevated serum anti-CCP levels, whereas others have extremely high antibody concentrations. Lee et al have now linked quantitative anti-CCP production to smoking, and they also refer to recent publications suggesting a gene-environment interaction between HLA-
DRB1 alleles and smoking. Possible relationships between the presence of the shared epitope and anti-CCP antibody titers have not yet been published although Lee et al also think that "it is an enticing avenue for further research and these studies are ongoing".
As a matter of fact, we have recently assessed absolute serum anti-CCP levels in association with HLA-DRB1 in 53 Hungarian patients with RA (2).
Apart from confirming significant correlations between anti-CCP and HLA-DRB1*04 positivity (P<0.01), we also found significant association between HLA-DRB1*04 and absolute serum anti-CCP levels. Patients carrying one or two copies of HLA-DRB1*04 had significantly higher anti-CCP concentrations (530.0 +/- 182.6 U/ml) compared to DRB1*04 negative patients (56.8 +/- 27.4 U/ml) (P<0.01). The HLA-DRB1*01 allele did not show any association with anti-CCP levels. Regarding non-shared epitope HLA-DRB1 genotypes, HLA-DRB1*13 or DRB1*15-positive patients had significantly higher serum anti-CCP levels than patients carrying any other non-shared epitope DRB1 subtypes (P<0.01).
Thus, our results suggest a possible association between quantitative anti -CCP levels and HLA-DRB1*04 alleles, and possibly also with other DRB1 genotypes.
References
1. Lee DM, Phillips R, Hagan EM, Chibnik LB, Costenbader KH, Schur PH. Quantifying anti-CCP titer: clinical utility and association with tobacco exposure in patients with rheumatoid arthritis. Ann Rheum Dis
published online 21 Nov 2008; doi:10.1136/ard.2007.084509
2. Kapitány A, Szabó Z, Lakos G, Aleksza M, Végvári A, Soós L, Karányi Z, Sipka S, Szegedi G, Szekanecz Z. Associations between serum anti-CCp antibody, rheumatoid factor levels and HLA-DR4 expression in Hungarian patients with rheumatoid arthritis. Isr Med Assoc J 2008;10:32-36.
We write in response to a recent letter in the Annals describing a low vaccination rate among adults with systemic inflammatory disease [1].
Lanternier et al reported vaccination rates of 57% among patients with rheumatoid arthritis (RA) and found that the biggest barrier to vaccination was the failure of medical staff to recommend it! The authors conclude that all such patients should be tar...
We write in response to a recent letter in the Annals describing a low vaccination rate among adults with systemic inflammatory disease [1].
Lanternier et al reported vaccination rates of 57% among patients with rheumatoid arthritis (RA) and found that the biggest barrier to vaccination was the failure of medical staff to recommend it! The authors conclude that all such patients should be targeted for vaccination through a public health campaign.
We previously showed that vaccination rates can be significantly improved in a population with RA if this practice is adopted [2]. In addition we have recently demonstrated that such an approach can make a huge difference to outcome in such patients. The incidence of pneumonia in patients with RA is twice that of a control population and mortality is also doubled [3]. Since improving immunisation rates within our RA population we have recorded a major reduction in the number of RA patientsadmitted to hospital with pneumonia (from 36 in 2003 to a mean of 8 over each of the last 3 years). There has also been an impressive fall in the mortality of our RA patients from pneumonia with case fatality halving
from 22% to 11% over the same time period. Most of the small number of deaths have been in non-immunised patients.
Our data, together with experiences elsewhere [4], have combined to persuade a number of professional groups to write a letter to Sir Liam Donaldson, Chief Medical Officer in England, recommending that patients with RA be listed among the priority groups for vaccination each autumn.
We strongly agree with our colleagues from France that such an approach should be actively pursued to help reduce avoidable morbidity and mortality in this highly susceptible population.
References
1. Lanternier F, Henegar C, Mouthon L, Blanche P, Guillevin l and Launay C. Low influenza vaccination rate among adults receiving immunosuppressive therapy for systemic inflammatory disease. Ann Rheum Dis 2008;67:1047.
2. Doe S, Pathare S, Kelly CA, Heycock C, Binding J and Hamilton J. Uptake of influenza vaccinations in patients on immunosuppressive agents for rheumatological disease: a follow up audit of the influence of secondary care.
Rheumatology 2007;46:715-6.
3. Coyne P, Hamilton J, Heycock C, Saravanan S, Coulson E and Kelly CA. Acute lower respiratory tract infections in patients with rheumatoid arthritis. J Rheumatology 2007;34:1832-7.
4. Wolfe W, Caplan L, Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalisation for pneumonia: associations with prednisone,disease-modifying antirheumatic drugs and anti-tumour necrosis factor therapy. Arthritis Rheum 2006;54:628-34.
As it was mentioned in multiple manuscripts related to the topic several different possibilities could explain why the patients develop enlarged lymph nodes. Among those are indolent lymphomas, lymphatic hyperplasia and aggressive lymphomas, including both Hodgkin’s lymphoma
and large B-cell lymphoma, which are usually associated with Epstein-Barr infection, The other possibilities include Castelman’s D...
As it was mentioned in multiple manuscripts related to the topic several different possibilities could explain why the patients develop enlarged lymph nodes. Among those are indolent lymphomas, lymphatic hyperplasia and aggressive lymphomas, including both Hodgkin’s lymphoma
and large B-cell lymphoma, which are usually associated with Epstein-Barr infection, The other possibilities include Castelman’s Disease, Monoclonal Gammopathy and Gamma Heavy chain Disease. Most of these conditions regress
when immunosuppressive therapy- prednisone and ethotrexate are discontinued.
We observed 2 cases of IRREVERSIBLE mixed cellularity Hodgkin’s Disease developed by patients treated with methotrexate for Polymyositis.
First case, a 65 year old African American Female presented to the Emergency Room with generalized weakness and weight loss. She was also
found to have inguinal lymphadenopathy. The patient received multiple courses of Methotrexate in the past. Biopsy of the lymph node showed Hodgkin’s disease. At that time methotrexate was stopped and 3months later her lymph nodes decreased in size, the patient clinically improved and was able to get back to her normal routine. However, in another month she felt lymph nodes in the groin again. Cat/Pet scan showed diffuse extension of the disease despite the fact that she never resumed Methotrexate. Repeat biopsy confirmed mixed cellularity Hodgkin’s Disease.
Second case, a 70 year old white male with past medical history of Polymyositis, currently in remission came for evaluation complaining of loss of appetite and insomnia; he also reported 20 pound weight loss over
6 month. Screaning Cat scans revealed bilateral symmetrical mediastinal lymphadenopathy. Lymph node biopsy showed mixed cellularity Hodgkin’s disease. The patient had IgG antibodies against Epstein-Barr virus
suggestive of resent viral infection. Though the patient did receive several immunosuppressive drugs in the past he was off methotrexate for at least a year. We made a decision to initiate chemotherapy. Even if lymphoma was induced by methotrexate it would be unlikely to expect it to regress on its own at this moment.
Cases of IRREVERSIBLE Lymphoma are not as well characterized in the literature as the ones that regress when medications are stopped. We think that this issue remains underreported, so that the treatment scheme is not
clear at this moment.
We were interested in the finding by Atherton and colleagues of an association between current vitamin D status and chronic widespread pain (CWP)[1]. The authors conclude: “Follow-up studies are needed to evaluate
whether higher vitamin D intake might have beneficial effects on CWP risk”.
We are completing a large randomised, placebo-controlled trial on vitamin D and can contribute preliminary re...
We were interested in the finding by Atherton and colleagues of an association between current vitamin D status and chronic widespread pain (CWP)[1]. The authors conclude: “Follow-up studies are needed to evaluate
whether higher vitamin D intake might have beneficial effects on CWP risk”.
We are completing a large randomised, placebo-controlled trial on vitamin D and can contribute preliminary results to this debate. The ‘Vital D’ study has over 2,000 women aged 70+ years. The randomised
participants received an annual dose of either 500,000IU cholecalciferol or placebo and have received study medication for 3 to 5 years. A randomised subset of 100 participants had pathology taken at the time of
completing the SF-12 questionnaire, coinciding with autumn/winter and one-year after the final dose of study medication. Serum vitamin D (Diasorin) and parathyroid hormone (PTH) levels were measured using the RIA and ELISA
assays, respectively.
We analysed our data for an association between vitamin D status and the two pain-related questions from SF-12. Question 8 “During the past 4 weeks, how much did pain interfere with your normal work?” – answers are
categorical ranging from “not at all” to “extremely”; Question 12 “During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting friends and relatives etc)?” – participants selected a category ranging from “all of the time” to “none of the time”. Results were analysed by logistic regressions using log transformed data and age-adjusted where appropriate (Minitab™-15). Pathology samples from 97 participants are
available (54=active; n=43 placebo).
Serum vitamin D and PTH were both predictive of the amount of time that physical health or emotional problems interfered with social activities (p<0.001). Women with lower vitamin D and higher PTH were more likely to have ill health impact on their social activities. The
relationship was stronger for PTH than vitamin D (p=0.001 and p=0.041, respectively); the median PTH for women indicating higher impact of ill health on social activities was 7.1 pmol/L (IQR: 4.5 to 11.7) compared
with 4.4 pmol/L (IQR: 3.4 to 6.1) for those experiencing little interference through health problems. The corresponding vitamin D medians were 48 nmol/L (IQR: 42 to 80) compared with 53 nmol/L (IQR: 40 to 70).
Although we did not find a direct association between serum vitamin D or PTH with interference from pain (p=0.279 and p=0.132, respectively), response to the pain question was moderately and significantly correlated
to the amount of time that health problems interfered with social activities (Pearson correlation=0.4; p<0.000). Participants with more interference from pain were 2.3 (95% CI: 1.4, 3.8) times more likely to experience higher interference of social activities due to health problems.
The analysis suggests lower vitamin D and higher PTH levels are associated with reduced health-related quality of life. This association was stronger with PTH than vitamin D. Although our results did not demonstrate a direct association between vitamin D status and our index of pain, those with higher vitamin D and lower PTH levels (better vitamin D status) had less interference on social activity through physical ill health or emotional problems. Our results did not demonstrate a direct
link of vitamin D status with pain but rather an inferred effect through the relationship between pain and health status.
References
1. Atherton K, Berry D, Macfarlane G, Power C, Hypponen E. Vitamin D and chronic widespread pain in a white middle-aged British population: evidence from a cross-sectional population survey. Ann Rheum Dis 2008;Aug
12 [Epub ahead of print].
I read with great interest the article by Sulli et al[1] on scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients.
The capillary abnormalities occurring in scleroderma-spectrum disorders were described by Maricq et al over 30 years ago and include enlarged capillary loops, areas of avascularity and haemorrhages. Since than many cross-sectional studies...
I read with great interest the article by Sulli et al[1] on scoring the nailfold microvascular changes during the capillaroscopic analysis in systemic sclerosis patients.
The capillary abnormalities occurring in scleroderma-spectrum disorders were described by Maricq et al over 30 years ago and include enlarged capillary loops, areas of avascularity and haemorrhages. Since than many cross-sectional studies of nailfold capillaroscopy have been published, most of them being qualitative. Only a few longitudinal studies have been performed. Sulli et al concluded that their capillaroscopic score is a tool to quantify and monitor the scleroderma microvascular damage.
I would like to make some comments with respect to performance and definition:
1. each parameter was scored in the middle of the nailfold. For most of the parameters this is the most ideal location except for the giant loops, which manifest at the lateral edges of the nailfold, especially in the
early phase of scleroderma-like disorders[2]. In our experience it is preferred to include the entire nailfold.
2. it is remarkable that the number of giant capillaries at follow-up is decreased as compared to the baseline values. Giant loops persisted in patients with scleroderma-like disorders in other studies[3]. Unfortunately, criteria for early systemic sclerosis and antibody profiles of the patients were lacking.
More longitudinal studies are needed to define prognostic value, especially in relation to clinical characteristics including specific organ involvement.
References
1. Sulli A, Secchi ME, Pizzorni C, Cutolo M. Scoring the nailfold microvacular changes during the capillaroscopic analysis in systemic sclerosis patients. Ann Rheum Dis 2008;67:880-884.
2. Maricq HR. Widefield capillary microscopy. Technique and rating scale for abnormalities in scleroderma and related disorders. Arthritis Rheum 1981;24:1159-65.
3. Ter Borg EJ, Piersma-Wichers G, Smit AJ, Kallenberg CG, Wouda AA. Serial nailfold capillary microscopy in primary Raynaud’s phenomenon and scleroderma. Semin Arthritis Rheum 1994;24:40-7.
Over the past decade musculoskeletal ultrasound (MSU) has recognised a growing interest among rheumatologists. Cumulating evidence demonstrating the benefit of performing MSU for both patients and rheumatologists has further increased the interest in this imaging modality (1,2). However, although MSU is a fast expanding area in
rheumatology, there is still not much information on crucial issues like training...
Over the past decade musculoskeletal ultrasound (MSU) has recognised a growing interest among rheumatologists. Cumulating evidence demonstrating the benefit of performing MSU for both patients and rheumatologists has further increased the interest in this imaging modality (1,2). However, although MSU is a fast expanding area in
rheumatology, there is still not much information on crucial issues like training process and proof of competency for the rheumatologist (1,2).
Hence, we welcome the latest article by Naredo et al. for formalising the MSU education in the context of a guideline for the rheumatologist. However the new guideline may implicate some practical issues:
i) The three level education is preferred rather than two level education.
This may lead to considerable cost implications for the attendants; especially for physicians coming from economically less advantaged countries. EULAR may need to develop additional bursary schemes to cover awider number of attendants. Tying the timing of the MSU course with the
annual EULAR congress may be practical for those who will attend both organisations but a onsiderable percentage of attendants may not be willing or able to attend the EULAR congress. Organising the MSU courses in countries where living and accommodation costs are less expensive may
suite both EULAR and the attendants from economically less advantaged countries.
ii) For the intermediate and advanced levels there is a limitation for attendance. Given the time and effort investment of the tutors and increasing demand for attending a EULAR MSU, will there be a selection process for attendance; if yes, how could this be implicated? EULAR may seek ways to accommodate an increased number of attendants for intermediate and advanced levels.
iii) There are already well designed and dedicated courses for MSU at a national level in many countries (3). Would a certificate of attendance from such courses enable one to apply for the next level of a EULAR course? Provided that these national courses are run by a recognised faculty by the EULAR, acceptance of an attendance certificate from a national MSU course may decrease the high demand for EULAR MSU courses. In this way, the limitation of attendance problem for the higher levels of the EULAR MSU course may partly be ameliorated.
iv) MSU examination is operator dependent; so is the education time needed for achieving the competency of this skill. It has been reported that a basic level of competency could be attained in a considerably short
period of dedicated work (4,5). There are already many rheumatologists who have had training of MSU through self-teaching and visiting experienced centres in MSU sonography. What would be the method of substantiating the
considerable effort, time and money for these rheumatologists? What will be the method for them to prove their dedicated work? Could these rheumatologists directly attend an advanced EULAR MSU course plus a competency exam or only an a competency exam?
MSU has the potential to improve the daily clinical practice of the rheumatologist. However it is both medically and ethically important to make sure that the clinician has achieved the necessary skills to perform
MSU. Establishing a standard training scheme is an important way forward for the future rheumatologist ultrasonographers.
References
1. Brown AK, O’Connor PJ, Roberts TE, et al. Recommendations for the musculoskeletal ultrasonography by rheumatologists: Setting global standards for best practice by expert consensus. Arthritis Rheum 2005;53:83-
92.
2. Brown AK, O’Connor PJ, Roberts TE et al. Ultrasonography for the rheumatologists: the development of specific competency based educational outcomes. Ann Rheum Dis 2006;65:629-636.
3. Uson J, Naredo E. Snap-shot of the ultrasound school of the Spanish Society of Rheumatology. Rheumatismo 2005;57:1-4.
4. Filippuci E, Unlu Z, Farina A et al. Sonographic training: a self training approach. Ann Rheum Dis 2003;62:565-567.
5. Balint PV, Sturrock RD. Intraobserver repeatability and
interobserver reproducibility in musculoskeletal ultrasound imaging measurements. Clin Exp Rheumatol 2001;19:89-92.
We read with interest the article by van der Helm, which explores the relationship between Body Mass Index (BMI) and radiological damage in early rheumatoid arthritis (RA). We were particularly interested in the
finding that patients with baseline BMI lesser than 25 developed more erosive disease during follow-up than those with increased BMIs. This association was only observed in those patients who were...
We read with interest the article by van der Helm, which explores the relationship between Body Mass Index (BMI) and radiological damage in early rheumatoid arthritis (RA). We were particularly interested in the
finding that patients with baseline BMI lesser than 25 developed more erosive disease during follow-up than those with increased BMIs. This association was only observed in those patients who were positive for anti-cyclic
citrullinated peptide (anti-CCP) antibodies.
We wonder whether this finding may be confounded by cigarette smoking. We note from table 1 that smoking was more prevalent in the group of patients with a lower BMI. A recent study has highlighted that cigarette smoking is associated with low body mass index in rheumatoid
arthritis and an inverse relationship exists between pack years of smoking and percentage body fat(1). As cigarette smoking is also associated with more severe RA disease(2) we wonder whether adjusting for smoking in the
multivariate analysis might reduce the observed association between BMI and the development of erosions.
Smoking has been identified as a predictor of erosive disease in RA cohorts(2), although other studies have failed to observe an association(3). Cigarette smoking and increasing pack years of smoking are strongly associated with the development of RA and rheumatoid factor (RF) positive disease(4). Anti-CCP positive status, like RF, is a poor prognostic marker in RA and these patients are more likely to experience a more severe disease course(5). In addition an association has been identified between anti-CCP positivity and smoking(6). A number of studies have gone on to postulate a gene-environment interaction in this group. They hypothesise that in genetically susceptible patients, who carry the HLA-DRB1 shared-epitope alleles, smoking may trigger RA-specific immune reactions to citrullinated protein(6,7).
Most studies exploring the effect of smoking on radiological outcome have done so in patients with established RA, and there is little literature relating to smoking as a predictor of erosive disease in the early years of the RA process. Therefore, we feel that it is important to explore the potential effect of smoking on the development of erosions in early RA and suggest that smoking may confound the observed association between low BMI and radiological outcome in this cohort.
References
1. Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, Douglas KMJ, Nevill AM, Jamurtas AZ, Kita M, Koutedakis Y, Kitas GD. Cigarette smoking associates with body weight and muscle mass of patients with rheumatoid arthritis: a cross-sectional, observational study. Arthritis Research
& Therapy 2008;10:R59 (20 May 2008).
2. Saag KG, Cerhan JR, Kolluri S, Ohashi K, Hunninghake GW, Schwartz DA. Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis 1997;56:463-9.
3. Finckh A, Dehler S, Costenbader KH, Gabay C. Cigarette smoking and radiographic progression in rheumatoid arthritis. Ann Rheum Dis 2007;66:1066-71.
4. Manfredsdottir VF, Vikingsdottir T, Jonsson T, Geirsson AJ, Kjartansson O, Heimisdottir M, Sigurdardottir SL, Valdimarsson H, Vikingsson A. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology 2006;45:734-40.
5. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis 2004;63(9):1090-5.
6. Verpoort KN, Papendrecht-van der Voort, van der Helm-van Mil, Jol-van der Zijde CM, van Tol MJD, Drijfhout JW, Breedveld FC, Vries RRP, Huizinga TWJ, Toes REM. Association of smoking with the constitution of the anti-cyclic citrullinated peptide response in the absence of HLA-DRB1 shared epitope alleles. Arthritis Rheum 2007;56:2913-8.
7. Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006:54(1):38-46.
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Dear Editor,
We read with interest the article by van der Helm, which explores the relationship between Body Mass Index (BMI) and radiological damage in early rheumatoid arthritis (RA). We were particularly interested in the finding that patients with baseline BMI lesser than 25 developed more erosive disease during follow-up than those with increased BMIs. This association was only observed in those patients who were...
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