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.
We read the interesting paper of Dr. Gelinck and associates on the effect of anti-tumour necrosis factor-alpha (anti-TNF-á) therapy on the antibody response to influenza vaccination [1]. Although there was a modest impairment of the antibody response to the vaccination, the proportion of patients achieving a protective titer was not significantly diminished. However, we have oncerns on generalizing these res...
We read the interesting paper of Dr. Gelinck and associates on the effect of anti-tumour necrosis factor-alpha (anti-TNF-á) therapy on the antibody response to influenza vaccination [1]. Although there was a modest impairment of the antibody response to the vaccination, the proportion of patients achieving a protective titer was not significantly diminished. However, we have oncerns on generalizing these results to other segments of the population, particularly the elderly on statin therapy.
A novel immunomodulatory effect of statins is the ability to increasethe numbers and functionality of regulatory T cells (Tregs) in vivo by inducing the transcription factor forkhead box P3 [2]. Even though this
may result in plaque stability by attenuating effector T cell responses in the atheroma [3], it also may attenuate vaccination-specific T cell responses [4]. Interestingly, among those 65 years and older, the effectiveness of the influenza vaccine is significantly diminished [5] and
both humoral and cell-mediated influenza-specific responses are impaired compared to younger individuals [6]. Additionally, elderly individuals have an increase in peripheral Treg numbers [4]. Moreover, TNF-á inhibits
Tregs activity and, not surprisingly, anti-TNF-á therapy restores Tregs suppressive function [7].
Therefore it is highly plausible that among the elderly prescribed anti-TNF-alpha and/or statin therapy, Treg numbers and activity are significantly enhanced, resulting in a further diminution of the response to influenza vaccination. This is extremely important and needs to be
investigated, given the widespread use of statins and the increasing use of anti-TNF-alpha therapy among the elderly, whom are particularly vulnerable to the morbidity and mortality from influenza infection [5].
References
1. Gelinck LBS, van der Bijl AE, Beyer WEP, Visser LG, Huizinga TWJ, van Hogezand RA. The effect of anti-tumour necrosis factor á treatment on the antibody response to influenza vaccination. Ann Rheum Dis 2008;67:713-716.
2. Mausner-Fainberg K, Luboshits G, Mor A, Maysel-Auslender S, Rubenstein A, Keren G, George J. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 2008;197:829-839.
3. Mallat Z, Ait-Oufella H, Tedgui A. Regulatory T cell responses: potential role in the control of atherosclerosis. Curr Opin Lipidol 2005;16:518-524.
5. Jefferson T, Rivetti D, Rivetti A, Rudin M, DiPietrantonj C, Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 2005;366:1165-1174.
6. Deng Y, Jing Y, Campbell AE, Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol 2004;172:437-
3446.
7. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006;108:253-261.
We thank Dr Wissmann for the eLetter concerning Pneumocystis jiroveci pneumonia (PCP) to our article, "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.
We reported that PCP developed in 22 patients among 5,000 patients with RA treated with infliximab. The organism of Pneumocysits jiroveci was not i...
We thank Dr Wissmann for the eLetter concerning Pneumocystis jiroveci pneumonia (PCP) to our article, "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.
We reported that PCP developed in 22 patients among 5,000 patients with RA treated with infliximab. The organism of Pneumocysits jiroveci was not identified in any of the patients with PCP, but they have been
diagnosed as PCP by typical clinical manifestation such as dyspnea, fever, characteristic chest X-ray as well as chest CT findings showing diffuse alveolar shadows, and elevation of blood beta-D glucan. In addition, polymerase chain reaction for Pneumocystis jiroveci in sputa or alveolar lavage fluids has been analyzed, and the results were positive for 21 out of 22 patients diagnosed as having PCP.
Unfortunately, we did not routinely check the colonalization of PCP before starting infliximab. We agree that a screening for pneumocystis jiroveci and prophylactic treatment with cotrimoxazol before starting
infliximab treatment would be a useful method for prevention of PCP development.
In this regard, we routinely follow-up the blood beta-D glucan level as a monitoring of the expanding colonalization of Pneumocystis jiroveci. Although beta-D glucan is not specific for Pneumocystis jiroveci, as Dr. Wissmann pointed out, only few cases with severe fungal infection had been reported in the 5000 RA cohorts, while those with PCP was found in 0.4% of the patients. Consequently 117 RA patient (14 male and 105 female) treated with infliximab with 3mg/kg, at 0, 2, 6 week, followed by every 8 weeks, and observed for 30 weeks or more in our institution were checked for blood beta-D glucan level at every visit (Table 1). The patient demographics were follows: 24-71 years old (53.5 +/- 11.9; the mean +/- S.D.) and 3-624 contraction period months
(100.3 +/- 100.0; the mean +/- S.D.). MTX 8.8 mg/week, in average, has been administered together with infliximab, and prednisolone (6.3 +/- 2.6 mg/day; the mean +/- S.D.) was administered to 90 patients. At the time of screening before the introduction of infliximab, blood beta-D glucan
level was abnormally high in 2 patients (22.7 pg/mL and 27.4 pg/mL; normal less than 20 pg/mL). At week 14, 4 patients showed the elevation of blood beta-D glucan level, and prophylactic cotrimoxazol was initiated in 3 of them, which successfully decreased blood beta-D glucan level. The co-incidence of the peak in the elevation of blood beta-D glucan level in our patients with the development of PCP in 5,000 Japanese RA patients, as well as the efficacy of cotrimoxazol to beta-D glucan, collectively support a hypothesis that colonalization of
Pneumocystis jiroveci is not rare and PCP subsequently develops in Japanese RA patients with colonization of Pneumocystis jiroveci during treatment with infliximab.
Dear Editor,
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...
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...
Dear Sir
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...
Dear Editor
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...
Dear Editor,
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...
Dear Editor,
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...
Dear Sir,
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...
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...
Dear Editor,
We read the interesting paper of Dr. Gelinck and associates on the effect of anti-tumour necrosis factor-alpha (anti-TNF-á) therapy on the antibody response to influenza vaccination [1]. Although there was a modest impairment of the antibody response to the vaccination, the proportion of patients achieving a protective titer was not significantly diminished. However, we have oncerns on generalizing these res...
Dear Editor,
We thank Dr Wissmann for the eLetter concerning Pneumocystis jiroveci pneumonia (PCP) to our article, "Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.
We reported that PCP developed in 22 patients among 5,000 patients with RA treated with infliximab. The organism of Pneumocysits jiroveci was not i...
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