Little data has addressed the issue of male fertility on anti TNF Therapy. The recent article by Villiger and colleagues in this journal suggested that sperm quality of patients with spondyloarthritis receiving long term anti TNF inhibition therapy was comparable to that in healthy
controls and imputed reassurance for male patients treated with anti TNF therapy for fatherhood.
Little data has addressed the issue of male fertility on anti TNF Therapy. The recent article by Villiger and colleagues in this journal suggested that sperm quality of patients with spondyloarthritis receiving long term anti TNF inhibition therapy was comparable to that in healthy
controls and imputed reassurance for male patients treated with anti TNF therapy for fatherhood.
We report herein one of our AS patients whose sperm count decreased precipitously while treated with infliximab, without other DMARDs, correlating with infertility while under treatment.
A 50 years old male was diagnosed 4 years earlier to have AS.
Diagnosis was based on symptoms of inflammatory lower back pain and limitation of spinal motion, with imaging support of sacroilitis on MRI study. After failure of prolonged NSAID treatment he was started on anti TNF therapy. His treatment was changed several times due to incomplete response to treatment. During his treatment period the patient was evaluated at the hospital's IVF unit for suspected infertility and tested for sperm count routinely.
The patient was started first on etanercept 25 mg twice weekly with his first sperm count after 3 months of treatment 6 million/cc. Due to secondary failure, after 16 months treatment was switched to adalimumab 40mg twice monthly, and then after another 6 months to infiximab 400 mg once every 8 weeks. Three months after initiating infliximab the sperm count was 2 million; three months later it had decreased to 0.2 million/cc, and then 0.1 million/cc three months later. At that point infiximab was discontinued, despite a positive clinical response to
treatment, due to suspected effect of the treatment on the sperm count.
Six months after discontinuing infliximab, the sperm count rose to one million and soon thereafter his wife became pregnant without resorting to IVF.
TNF has been shown to have a positive role in the male gonadal tract with an effect on germ cell apoptosis. However at high tissue concentration, adverse effects on spermatogenesis have also been noted.
Villiger et al showed that the sperm quality of patients with inactive disease treated with anti TNF therapy is comparable to that of healthy controls. Yet an earlier letter by La Montagna et al showing no alterations in serum follicle stimulating hormone, luteinising hormone,
prolactin, and testosterone levels testing 3 fertile male patients on anti TNF therapy for treatment of ankylosing spondylitis, described asthenoazoospermia in two patients, potentially related to anti TNF therapy.
The possible negative effect of active inflammatory disease on gonadal dysfunction is appreciated. In the present case, despite successful inhibition of active disease by infliximab, it was discontinuation of the drug which led to increased sperm count which was translated into improved fertility. We believe that caution is advised and the possibility of such an effect should be taken into consideration when male infertility is suspected in patients treated with anti TNF agents.
Further large studies are needed to fully explore the effect of anti TNF agents on male fertility.
We thank Drs Ugurlu and Seyahi for their comments and request for
clarification regarding the development of the skin thickness progression
rate. For the purpose of this study, we included only patients with early
diffuse scleroderma at the time of the first Pittsburgh evaluation (<2
years duration).
We defined diffuse cutaneous disease as skin thickening proximal to the
elbows or knees (upper arms, thighs or trunk) o...
We thank Drs Ugurlu and Seyahi for their comments and request for
clarification regarding the development of the skin thickness progression
rate. For the purpose of this study, we included only patients with early
diffuse scleroderma at the time of the first Pittsburgh evaluation (<2
years duration).
We defined diffuse cutaneous disease as skin thickening proximal to the
elbows or knees (upper arms, thighs or trunk) on physical examination at
the time of the first Pittsburgh evalutions.
In our model building process we assessed for correlations and
interactions between al variables significant at a p-value of 0.20 in the
bivariate model, and performed stepwise multivariable logistic regression.
By using a larger critical value we intended to included all potentially
useful variables and thus hoped to have a better predictive model.
We agree that in the Table 2 the 95% confidence interval for the
prediction of mortality by anti-RNA polymerase III antibody should not be
0.40 - 1.94. Instead, it should be 0.40 - 0.94. We apologize for this
error.
While we collected information on the patient's referral area and
assessed its potential impact on the model (section entitled clinical
information), all US systemic sclerosis patients were included regardless
of their residence location.
To the editor,
We read with interest the article by Domsic et al (1) in which they report
that skin thickness progression rate (STPR) could predict mortality and
early internal organ involvement in diffuse scleroderma (dSSc). There are
few points that we would like to address:
1)Authors included only patients with diffuse skin involvement at the time
of initial evaluation and measured STPR prospectively in 826 patients wit...
To the editor,
We read with interest the article by Domsic et al (1) in which they report
that skin thickness progression rate (STPR) could predict mortality and
early internal organ involvement in diffuse scleroderma (dSSc). There are
few points that we would like to address:
1)Authors included only patients with diffuse skin involvement at the time
of initial evaluation and measured STPR prospectively in 826 patients with
dSSc followed between 1980 and 2005. However, they do not tell us how they
defined the degree and the extent of skin involvement used as inclusion
criteria. This information would be useful in interpretation of the STPR.
2)They used variables that were significant at the level of p < 0.2 in
the univariate analysis for stepwise multivariable logistic regression. It
is rather obvious that a variable with a low statistical significance
would be even less significant when used in a logistic regression.
3)In Table 4, the p value for anti-RNA polymerase III antibody in
predicting mortality was found to be 0.02. However the 95 % confidence
intervals were calculated as 0.40 - 1.94. We think that there might be an
error in this calculation.
4)The authors report that multivariable regression model was not affected
by patients' referral area whether greater or less than 100 miles from
Pittsburgh. However at the Methods they state that they only included
patients who were living within 100 miles of Pittsburgh. This point should
be clarified.
Reference
1) Domsic RT, Rodriguez-Reyna T, Lucas M, Fertig N, Medsger TA Jr. Skin
thickness
progression rate: a predictor of mortality and early internal organ
involvement in diffuse scleroderma. Ann Rheum Dis. 2011;70:104-9.
In a recent issue of ARD, Wildi and colleagues reported results of a randomized trial and suggested that chondroitin sulfate slowed the rate of cartilage loss in osteoarthritic knees over 6 months (1). We have a number
of concerns.
The authors controlled for age and bisphosphonate use between treatment groups, but these are not known to be associated with cartilage loss. In contrast, these authors a...
In a recent issue of ARD, Wildi and colleagues reported results of a randomized trial and suggested that chondroitin sulfate slowed the rate of cartilage loss in osteoarthritic knees over 6 months (1). We have a number
of concerns.
The authors controlled for age and bisphosphonate use between treatment groups, but these are not known to be associated with cartilage loss. In contrast, these authors and others (2;3) have reported that meniscal damage, high BMI and malalignment do increase the risk of
cartilage loss, yet the authors provide no information about the comparability of treatment groups on these factors and do not control for them in analyses. This is especially critical in such a small trial, when
randomization often fails to produce a balance in prognostic factors.
Differences in cartilage loss between treatment groups were reported for the lateral but not medial femorotibial compartment, but the authors do not state whether study participants had lateral or medial disease.
Generally a greater proportion of OA patients has medial disease, and therefore one wonders about the clinical value of preventing cartilage loss in a clinically likely unaffected compartment.
No significant difference in bone marrow lesion (BML) scores or synovitis was detected at the end of the randomized trial (6 months).
Difference reported at 12 months must thus be due to changes during the second 6 months, when both groups were taking chondroitin. This suggests no effect of treatment on BMLs.
In the placebo group, the authors report rates of change over 6/12 months between -1.8%/-4.0% (trochlea) and -6.8%/-9.3% (medial femoral condyle). These rates are 4-fold higher than those reported in the OA Initiative (4) and other observational studies (3;5). The authors state
that the two trained readers were blinded to treatment and examination time point, except for baseline. Could partial unblinding to time sequence or treatment have affected the results?
The authors used a FISP sequence to assess BMLs (6). FISP is a Gradient Recalled Echo (GRE) sequence that is insensitive to BMLs (7) due to trabecular magnetic susceptibility or T2* effects (also see consensus
statements by OMERACT (Outcome Measures in Rheumatology Clinical Trials) and OARSI (Osteoarthritis Research Society International) (8)). Why did the authors not use T2-, proton density-, or intermediate-weighted FS FSE
sequences as has been recommended?
Further, the authors used non fat-suppressed T1-weighted and T2-weighted axial GRE type sequences to assess peripatellar synovitis. These sequences are prone to chemical shift artifacts that hinder accurate
differentiation from other peripatellar structures, such as the retinaculae or fat (9). In figure 1 of their paper, the arrows do not depict the exact location of measurement, nor do they differentiate fluid from synovium, retinaculum or fat. Few non-enhanced MRI sequences have been described that can delineate the synovial membrane from adjacent structures, and none have been validated against a gold standard of either
histology or contrast-enhanced MRI (10). Could the authors provide validation data for their method to provide evidence that what they are measuring is actually synovium?
References
1. Wildi LM, Raynauld JP, Martel-Pelletier J, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis
patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis 2011 Mar 1.
2. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann Rheum Dis 2008;67(5):683-8.
3. Sharma L, Eckstein F, Song J, et al. Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees. Arthritis Rheum 2008;58(6):1716-26.
4. Hunter DJ, Niu J, Zhang Y, et al. Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative. Ann.Rheum Dis 2009;68(3):349-56.
5. Le Graverand MP, Buck RJ, Wyman BT, et al. Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon-Schuss radiography. Ann Rheum Dis 2010;69(1):155-62.
6. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al. Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes. Arthritis Res Ther
2006;8(1):R21.
7. Roemer FW, Hunter DJ, Guermazi A. MRI-based semiquantitative assessment of subchondral bone marrow lesions in osteoarthritis research. Osteoarthritis Cartilage 2009;17(3):414-5.
8. Peterfy CG, Gold G, Eckstein F, et al. MRI protocols for whole-organ assessment of the knee in osteoarthritis. Osteoarthritis Cartilage 2006;14 Suppl A:A95-111.
9. McGibbon CA, Bencardino J, Palmer WE. Subchondral bone and cartilage thickness from MRI: effects of chemical-shift artifact. MAGMA 2003;16(1):1-9.
10. Hayashi D, Roemer FW, Katur A, et al. Imaging of Synovitis in Osteoarthritis: Current Status and Outlook. Semin Arthritis Rheum 2011 Feb 2.
We read with great interest the article of Petri et al [1] addressing the important issue of the effects of statins on vascular disease of patients with systemic lupus erythematosus (SLE). This randomized clinical trial showed no benefit of atorvastatin in the progression of subclinical atherosclerosis in 200 patients with SLE, most of them with normal lipid levels. This result is of high clinical relevance,...
We read with great interest the article of Petri et al [1] addressing the important issue of the effects of statins on vascular disease of patients with systemic lupus erythematosus (SLE). This randomized clinical trial showed no benefit of atorvastatin in the progression of subclinical atherosclerosis in 200 patients with SLE, most of them with normal lipid levels. This result is of high clinical relevance, however, some questions regarding the homogeneity of both treatment arms may limit its
interpretation.
There were no differences between both groups in the frequency of hypertension and diabetes mellitus, the proportion of men, the age at recruitment or the baseline lipid levels. However, there is no mention to smoking. Moreover, treatments received by the patients up to recruitment or during the study period are not reported.
Chronic treatment with glucocorticoids may increase the risk of developing atherosclerosis. In the general population, doses above 7.5 mg/day of prednisone used during 1 to 5 years increased the risk of cardiovascular
disease [2]. In 539 patients with SLE from the Hopkins Lupus Cohort [3], cardiovascular damage was associated with prednisone therapy, either the cumulative dose (coronary artery disease) or the use of doses over 60 mg/day (stroke). On the other hand, the antiinflammatory effects of prednisone may have beneficial effects on the progression of atherosclerotic plaques [4].
Antimalarials may have a beneficial effect on the lipid profile of patients with rheumatoid arthritis and SLE, especially those treated with steroids [5-10]. In a previous study by Petri et al [6] studying 264 SLE
patients of the Baltimore Lupus Cohort, HCQ was associated with lower serum cholesterol levels in the longitudinal regression analysis. The authors calculated that HCQ was able to "balance" the adverse effect of 10mg of prednisone on cholesterol levels. Roman et al found a significant
negative association between the use of HCQ and the presence of carotid plaques in 197 SLE patients [4]. Although data on this issue are conflicting, a beneficial affect of antimalarial therapy on the development and progression of atherosclerosis cannot be excluded [11].
Thus, to fully understand the clinical applicability of the results of this study [1], patients included in both therapeutic arms should prove homogeneous in terms of the proportion of those smoking and receiving treatment with prednisone and hydroxychloroquine.
References
1. Petri MA, Kiani AN, Post W, et al. Lupus
Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 2010 Dec 21:[Epub ahead of print].
2. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141(10):764-770.
3. Zonana-Nacach A, Barr SG, Magder LS, et al. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum 2000;43(8):1801-1808.
4. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349(25):2399-2406.
5. Rahman P, Gladman DD, Urowitz MB, et al. The
cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 1999;26(2):325-330.
6. Petri M, Lakatta C, Magder L, et al. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 1994;96(3):254-259.
7. Hodis HN, Quismorio FP, Jr., Wickham E, et al. The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J Rheumatol 1993;20(4):661-665.
8. Wallace DJ, Metzger AL, Stecher VJ, et al.
Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 1990;89(3):322-326.
9. Munro R, Morrison E, McDonald AG,et al. Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis 1997;56(6):374-377.
10. Costedoat-Chalumeau N, Leroux G, Piette J-C, et al. Antimalarials and systemic lupus erythematosus. In: Lahita RG, Tsokos G, Buyon JP, Koike T. Systemic lupus erythematosus. Elsevier. 5th Edition 2010;1061-81.
11. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69(1):20-28.
Dixon et al have performed a careful nested case-control study of the risk of non-serious infections associated with glucocorticoid use in elderly RA patients. Their methodology is impeccable, and the limitations of the study are clearly discussed.
Importantly, and to my satisfaction, they stress that confounding by indication cannot be ignored, although they posit that such confounding cannot complet...
Dixon et al have performed a careful nested case-control study of the risk of non-serious infections associated with glucocorticoid use in elderly RA patients. Their methodology is impeccable, and the limitations of the study are clearly discussed.
Importantly, and to my satisfaction, they stress that confounding by indication cannot be ignored, although they posit that such confounding cannot completely explain the effects found.
My main gripe is with the importance attached to these and other observational studies on the risks of glucocorticoid therapy, compared to the potential benefits (eg. improved quality of life and slowing of the
progression of disability), and risks of other treatments. For instance, a revealing sentence at the end of the results section reads as follows:
"Gastric acid-suppressive drug prescription (proton pump inhibitors or H2 blockers) in the 45 days before the index date was associated with an increased risk of NSI (aRR 1.36, 1.30 to 1.43)."
Although not the object of research, this risk is close to double that reported for glucocorticoids. With use of acid-suppression almost endemic above a certain age, it is perhaps legitimate to ask where the focus of our attention should be regarding this common adverse event.
We have read with interest the letter of Rech et al. on 3 patients with adult's Still disease (ASD) who experienced systemic and arthritis improvement while being treated with tocilizumab (TCZ) (1).
We would like to add that a previously published cohort study has reported the results of a tocilizumab treatment in all ASD patients treated in France with TCZ during a three-year period, after failure...
We have read with interest the letter of Rech et al. on 3 patients with adult's Still disease (ASD) who experienced systemic and arthritis improvement while being treated with tocilizumab (TCZ) (1).
We would like to add that a previously published cohort study has reported the results of a tocilizumab treatment in all ASD patients treated in France with TCZ during a three-year period, after failure to all available therapies (2).
To be eligible to receive off-label TCZ for ASD in France between July 2006 and July 2009, patients had to be enrolled in a specific protocol of the French Agency for the Safety of Health Products (AFSSAPS).
The study population consisted of patients who fulfilled the Yamagushi criteria for ASD (3) and who had to present persistent active arthritis and/or systemic involvement resistant to therapies including
corticosteroids, methotrexate, anakinra and anti-TNFa drugs. Data were collected prospectively from physicians in charge of the patients. All patients receiving at least one infusion of TCZ during the study period were evaluated. The main outcome measures were the EULAR improvement criteria and resolution of systemic symptoms at 3 and 6-month follow-up (4).
Fourteen patients suffering from intractable refractory ASD were included in the cohort. All had chronic arthritis; radiological examination showed irreversible joint damage in eight patients. All patients had experienced failure or intolerance with methotrexate and
anakinra and twelve with at least one anti-TNF drug. At baseline, all patients were receiving prednisone at a mean dose of 23.3 mg/day. Based on a 28 joint count, mean tender joints were 10.5, swollen joints 7.9 and the mean DAS28 was 5.61. At baseline, in addition to arthritis, recurrent
systemic involvement, including fever and rash, was present in seven patients. Median ESR was 36.5 mm/1st hour and CRP was 5.2 mg/dL.
Eleven patients successfully completed the 6-month study. One withdrew due to necrotizing angiodermatitis, another due to chest pain at each TCZ infusion and a third due to systemic flare. A rapid resolution of systemic manifestations and arthritis was observed in most cases. The mean DAS28 dropped from 5.61 to 3.21 and 2.91 at 3 and 6-month follow-up visits, respectively. A good EULAR response was achieved in 64% (9/14) of patients at three and six months. EULAR remission (DAS28<2.6) was
achieved in 36% of patients (5/14) at three months and in 57% (8/14) at six months. The good EULAR response observed in two thirds of patients at three months was due to improvement of all disease activity scores: at six months, there was a 60% improvement in the number of tender joints, the number of swollen joints and the mean visual assessment score for patient global health. Resolution of systemic symptoms, including fever and eruption, was observed for 86% of patients (6/7) at three and six months.
Moreover, the mean prednisone dose was reduced to a mean of 13.0 mg/day at three months and to a mean of 10.3 at six months.
Thus, in most of our patients with refractory disease, response to TCZ treatment was rapid and sustained. The high observed rate (57%) of arthritis remission at six months is of particular interest in these patients. Of the seven patients with active systemic features at the start of TCZ treatment, all but one showed resolution of these symptoms.
Notably, TCZ had a corticosteroid-sparing effect since these meaningful improvements were observed despite a 56% mean reduction in corticosteroid dose after starting treatment.
We conclude that our cohort of patients with refractory ASD has demonstrated that an IL-6 inhibiting therapeutic approach TCZ was effective against systemic involvement of the disease in almost all patients and led to arthritis remission in half the patients, showing a
marked corticosteroid-sparing effect and an acceptable tolerance profile.
TCZ is a promising new treatment which should be further evaluated in ASD.
References
1. Rech J, Ronneberger M, Englbrecht M, et al. Successful treatment of adult-onset Still'S disease
refractory to TNF and IL-1 blockade by IL-6 receptor blockade. Ann Rheum Dis 2011;70:390-2.
2. Puechal X, de Bandt M, Berthelot JM, et al.
Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken) 2011;63:155-9.
3. Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19:424-30.
4. van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 1998;41:1845-50.
We thank Dr. Ostergaard for the comment on the mentioned article on the ACR/EULAR classification criteria. As co-authors on that manuscript, we confirm that all points mentioned by the authors are correct:
- Only patients with a clinical synovitis, which is not clearly better explained by another disease entity are eligible for testing.
- MRI and US may be used to determine a more complete joint in...
We thank Dr. Ostergaard for the comment on the mentioned article on the ACR/EULAR classification criteria. As co-authors on that manuscript, we confirm that all points mentioned by the authors are correct:
- Only patients with a clinical synovitis, which is not clearly better explained by another disease entity are eligible for testing.
- MRI and US may be used to determine a more complete joint involvement AFTER the patient has been found eligible.
- Classification is usually a procedure in early disease. However, some problems may occur in the rare scenario of classification attempts in late disease, as patients may have become inactive. For those patients with a long history, but without a documentation of the domains, a standard radiograph may be used (as correctly mentioned in the e-letter).
- In case a patient with established/late disease brings documentation on the domains that show active classifiable disease in the past, classification can also be made retrospectively.
Although these issues are mentioned in the manuscript, we agree that it is certainly very important to re-emphasize, as they are critical to a correct classification. In this regard it is also very important to again stress that the classification criteria do include several aspects of isease activity, and that therefore, if a patient is then well treated, they will become negative again. This is, similar to the previous
criteria, NOT indicating that this patient does not have classified rheumatoid arthritis anymore.
Although, the construct of the new criteria will hopefully be a basis for classification of RA in the extended future, there is the possibility of amending these as new evidence is generated. This includes long term implications of MRI/US findings in patients with clear conventional radiographs, such as possibly evidenced by newer studies, some of which are cited by Dr Ostergaard.
One main objective of the classification committee was to provide criteria, which are to be usable world-wide, considering possible limited access to new imaging techniques or other, more advanced diagnostic tests, such as ACPA. The latter were therefore not asked for exclusively in the classification system. This thought on general feasibility should be kept in mind, even as hopefully convincing new evidence for new diagnostic
markers comes along.
I was interested in the study about CD27++ plasma cells by Ten Boekel et al., in which they evaluate longitudinal data of CD27++ plasma cells in systemic lupus erythematosus (SLE) patients. [1] There are many factors influencing the expression of peripheral CD27++ plasma cells in SLE patients, including infection and immunosuppressive drugs. [2,3] In our pervious study, although the expression of peripheral...
I was interested in the study about CD27++ plasma cells by Ten Boekel et al., in which they evaluate longitudinal data of CD27++ plasma cells in systemic lupus erythematosus (SLE) patients. [1] There are many factors influencing the expression of peripheral CD27++ plasma cells in SLE patients, including infection and immunosuppressive drugs. [2,3] In our pervious study, although the expression of peripheral CD27++ plasma cells was found to have correlation with SLE disease activity (SLE disease activity index, levels of anti-dsDNA, C3 and C4), bacterial or viral
infection seemed affect the expression of peripheral CD27++ plasma cells profoundly. [4] Further more, our unpublished data showed that SLE patients who received immunosuppressive therapy with leucopenia or suppressed bone marrow had persistent low percentage of peripheral CD27++ plasma cells, which could be explanation of non-consistent correlation between peripheral CD27++ plasma cells and SLE disease activity in the present study of Ten Boekel et al. Two major factors including bacterial or viral infection and administration of immunosuppressive drugs (such as azathiopurine, cyclophosphamide and rituximab) might affect the presentation of peripheral CD27++ plasma cells. When SLE patients have infection, peripheral CD27++ plasma cells should not be used to evaluate disease activity.
References
1. Ten Boekel E, Prins M, Vrielink GJ, et al. Longitudinal studies of the association between peripheral CD27++ plasma cells and systemic lupus erythematosus disease activity: preliminary results. Ann Rheum Dis 2010 Nov 12.
2. Dorner T, Lipsky PE. Correlation of circulating CD27high plasma cells and disease activity in systemic lupus erythematosus. Lupus 2004;13:283-9.
3. Ten Boekel E, Siegert CE, Vrielink GJ, et al. Analyses of CD27++ plasma cells in peripheral blood from patients with bacterial infections and patients with serum antinuclear antibodies. J Clin Immunol 2007;27:467-76.
4. Yang DH, Chang DM, Lai JH, et al. Significantly higher percentage of circulating CD27(high) plasma cells in systemic lupus erythematosus patients with infection than with disease flare-up. Yonsei Med J 2010;51:924-31.
We read with great interest the article of Houssiau et al (1) that provide valuable information for the management of SLE patients with lupus nephritis. However, there is no mention on hydroxycloroquine (HCQ) use in their study. We and others strongly believe that management of SLE patients can be easily improved with more systematic use of this
inexpensive drug that has a high efficacy/toxicity ratio. HCQ...
We read with great interest the article of Houssiau et al (1) that provide valuable information for the management of SLE patients with lupus nephritis. However, there is no mention on hydroxycloroquine (HCQ) use in their study. We and others strongly believe that management of SLE patients can be easily improved with more systematic use of this
inexpensive drug that has a high efficacy/toxicity ratio. HCQ has demonstrated effectiveness in preventing SLE activity as well as in reducing the risk of damage accrual and in protecting against thrombotic events and diabetes (2, 3). Moreover, several observational cohort studies
have shown that antimalarial therapy is associated with longer survival of patients with SLE (2-4).
Regarding glomerulonephritis, three retrospective studies have suggested an effect of antimalarial therapy in the final outcome. The rate of complete renal remission in SLE patients treated with mycophenolate mofetil for membranous lupus nephritis was 5.2 times higher in those who were concomitantly treated with HCQ (95% CI: 1.2 - 22.2; p = 0.026) (4, 5). A case-control study showed that 94% of patients with lupus nephritis in prolonged remission were on HCQ, versus 53% of those not fulfilling criteria for complete remission (p=0.01) (6). A third study found that exposure to antimalarials before the diagnosis of lupus nephritis was negatively associated with the development of renal failure, hypertension, thrombosis and infection, and with a better survival rate at the end of
the follow-up (7). More recently, prospective data have confirmed the beneficial effects of antimalarials in patients with lupus nephritis: among 203 SLE patients included in the LUMINA cohort, HCQ had a strong protective effect in retarding renal damage occurrence even after
adjusting for possible confounding factors (8).
Finally, as emphasized by Houssiau et al, serum measures of the active metabolites of AZA or of MMF were not routinely performed in their study, leaving open the possibility that patients who failed on one or the other
drug were non-adherent to the medication. Due to the very long half life of HCQ, we have demonstrated that measurement of blood HCQ concentration is a reliable, simple, and objective method to detect noncompliant patients who are at high risk of further flares (9). In our experience, monitoring adherence to treatment with blood HCQ dosage is helpful to conduct specific interventions to improve compliance of patients and to avoid some flares. Additionally, in order to evaluate adherence to treatment in patients included in clinical trials, we suggest that this blood dosage should be included in the design of SLE trials.
References
1. Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;69(12):2083-9.
2. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69(1):20-8.
3. Shinjo SK, Bonfa E, Wojdyla D, et al. Antimalarial treatment may have a time-dependent effect on lupus
survival: data from a multinational Latin American inception cohort. Arthritis Rheum 2010;62(3):855-62.
4. Costedoat-Chalumeau N, Leroux G, Piette J-C, et al. Antimalarials and systemic lupus erythematosus. In: Lahita RG, Tsokos G, Buyon JP, Koike T. Systemic lupus erythematosus. Elsevier. 5th ?dition. 2010;1061-81.
5. Kasitanon N, Fine DM, Haas M, et al. Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus 2006;15(6):366-70.
7. Siso A, Ramos-Casals M, Bove A, et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus 2008;17(4):281-8.
8. Pons-Estel GJ, Alarcon GS, McGwin G, Jr., et al. Protective effect of hydroxychloroquine on renal damage in
patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61(6):830-9.
9. Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al. Very low blood hydroxychloroquine concentrations as an objective marker of poor adherence to treatment of systemic lupus erythematosus. Ann Rheum Dis 2007;66(6):821-4.
Dear Editor,
Little data has addressed the issue of male fertility on anti TNF Therapy. The recent article by Villiger and colleagues in this journal suggested that sperm quality of patients with spondyloarthritis receiving long term anti TNF inhibition therapy was comparable to that in healthy controls and imputed reassurance for male patients treated with anti TNF therapy for fatherhood.
We report herein one...
We thank Drs Ugurlu and Seyahi for their comments and request for clarification regarding the development of the skin thickness progression rate. For the purpose of this study, we included only patients with early diffuse scleroderma at the time of the first Pittsburgh evaluation (<2 years duration). We defined diffuse cutaneous disease as skin thickening proximal to the elbows or knees (upper arms, thighs or trunk) o...
To the editor, We read with interest the article by Domsic et al (1) in which they report that skin thickness progression rate (STPR) could predict mortality and early internal organ involvement in diffuse scleroderma (dSSc). There are few points that we would like to address: 1)Authors included only patients with diffuse skin involvement at the time of initial evaluation and measured STPR prospectively in 826 patients wit...
Dear Editor,
In a recent issue of ARD, Wildi and colleagues reported results of a randomized trial and suggested that chondroitin sulfate slowed the rate of cartilage loss in osteoarthritic knees over 6 months (1). We have a number of concerns.
The authors controlled for age and bisphosphonate use between treatment groups, but these are not known to be associated with cartilage loss. In contrast, these authors a...
Dear Editor,
We read with great interest the article of Petri et al [1] addressing the important issue of the effects of statins on vascular disease of patients with systemic lupus erythematosus (SLE). This randomized clinical trial showed no benefit of atorvastatin in the progression of subclinical atherosclerosis in 200 patients with SLE, most of them with normal lipid levels. This result is of high clinical relevance,...
Dear Editor,
Dixon et al have performed a careful nested case-control study of the risk of non-serious infections associated with glucocorticoid use in elderly RA patients. Their methodology is impeccable, and the limitations of the study are clearly discussed.
Importantly, and to my satisfaction, they stress that confounding by indication cannot be ignored, although they posit that such confounding cannot complet...
Dear Editori,
We have read with interest the letter of Rech et al. on 3 patients with adult's Still disease (ASD) who experienced systemic and arthritis improvement while being treated with tocilizumab (TCZ) (1).
We would like to add that a previously published cohort study has reported the results of a tocilizumab treatment in all ASD patients treated in France with TCZ during a three-year period, after failure...
Dear Editor,
We thank Dr. Ostergaard for the comment on the mentioned article on the ACR/EULAR classification criteria. As co-authors on that manuscript, we confirm that all points mentioned by the authors are correct:
- Only patients with a clinical synovitis, which is not clearly better explained by another disease entity are eligible for testing.
- MRI and US may be used to determine a more complete joint in...
Dear Editor,
I was interested in the study about CD27++ plasma cells by Ten Boekel et al., in which they evaluate longitudinal data of CD27++ plasma cells in systemic lupus erythematosus (SLE) patients. [1] There are many factors influencing the expression of peripheral CD27++ plasma cells in SLE patients, including infection and immunosuppressive drugs. [2,3] In our pervious study, although the expression of peripheral...
Dear Editor,
We read with great interest the article of Houssiau et al (1) that provide valuable information for the management of SLE patients with lupus nephritis. However, there is no mention on hydroxycloroquine (HCQ) use in their study. We and others strongly believe that management of SLE patients can be easily improved with more systematic use of this inexpensive drug that has a high efficacy/toxicity ratio. HCQ...
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