Dear Editor,

The severity of rheumatoid arthritis (RA) is highly variable between patients and currently known risk factors explain only part of this variance.(1) Much research is dedicated to identify additional new risk factors. Such factors may shed light on the processes underlying progression of RA and many risk factors together may enable risk stratification and individualized treatment of RA.

With interest we read the study by Moller et al, showing that RA- patients with anaemia have more severe radiological progression.(2) Although anaemia in RA is generally considered to be a consequence of chronic inflammation, this recent study -based on RA patients included in the Swiss SCQM-database- observed that the association between anaemia and joint damage was independent of the association between disease activity (measured with the DAS28ESR and cDAI) and joint damage. This led to the presumptions that anaemia in RA captures disease processes that are unmeasured by established disease activity markers (e.g. subclinical inflammation) and that evaluation of the haemoglobin level may help to identify patients with rapid radiological progression.

Since in science replication of findings is relevant to ascertain the validity, we evaluated the association between anaemia at first presentation and disease severity over 7 years in 676 early RA patients included in the Leiden Early Arthritis Clinic.(1) Two outcome measures were studied. First, radiological progression; 3502 sets of hand and feet radiographs were made with yearly intervals and scored according to the Sharp-van-der-Heijde method by one reader (ICC 0.91).(3) Second, disease persistency was assessed by evaluating its counterpart, achieving DMARD- free sustained remission.(4) Analyses were done using multivariate normal regression analysis and cox regression.(5) All analyses were adjusted for age, gender and treatment strategy.(1) The haemoglobin level was determined at first presentation. The WHO definitions for the presence and severity of anaemia were used.(6)

24.1% of the RA-patients had anaemia at first presentation. These patients were older and had a higher swollen joint count (SJC), ESR and CRP (Table 1). Patients with anaemia had more severe joint damage progression (beta 1.03, p 0.012, indicating a 1.03 higher rate of joint destruction per year, which equals 1.037= 23% more joint damage after 7 years). Similar to M?ller et al, we also adjusted for ESR, SJC and RF; this did not affect the association (beta 1.03, p 0.040) (Figure 1A). When evaluating the three haemoglobin categories a "dose-dependent" effect was observed (beta 1.03, p 0.002). Also this association was significant after adjusting for ESR, SJC and RF (beta 1.02, p 0.032) (Figure 1B). All analyses remained significant when the CRP was included as covariate instead of the ESR (data not shown).(7) Patients with anaemia tended to achieve DMARD-free remission less often than patients without anaemia (HR 0.57, 95% CI 0.34-0.95, p 0.031), also after adjusting for ESR, SJC and RF (HR 0.59, 95% CI 0.34-1.02, p 0.056) (Figure 1C).

Analysis on this population-based inception cohort revealed that within RA anaemia is independently associated with radiographic progression. As clinical inflammation in RA may predominantly affect the feet,(8) we evaluated a 66-SJC that -in contrast tot the DAS28ESR and cDAI used by Moller et al- included the MTP-joints. Nonetheless, also we observed that anaemia independently predicted disease severity. This may indicate that anaemia indeed reflects subclinical inflammation. Future studies are required to unravel this association.

Table 1 Characteristics of RA patients per haemoglobin category. Table available on the monthly Epage.

Figure 1. Joint destruction (Sharp-van der Heijde scores) and DMARD- free sustained remission curves over 7 years follow-up in RA patients, categorized according to the presence (A, C) or severity (B) of anaemia. Figure available on the monthly Epage.

References

(1) de Rooy DP, van der Linden MP, Knevel R, et al. Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic? Rheumatology (Oxford) 2011;50:93-100.

(2) Möller B, Scherer A, Forger F, et al. Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis: a prospective cohort study. Ann Rheum Dis Published Online First: 16 March 2013. doi:10.1136/annrheumdis-2012-202709

(3) Knevel R, Krabben A, Brouwer E, et al. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multicohort study. Ann Rheum Dis 2012;71:1651-7.

(4) van der Woude D, Young A, Jayakumar K, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 2009;60:2262-71.

(5) Knevel R, Tsonaka R, Cessie SL, et al. Comparison of methodologies for analysing the progression of joint destruction in rheumatoid arthritis. Scand J Rheumatol Published Online First: 20 February 2013. doi:10.3109/03009742.2012.7286182013

(6) WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.1) (http://www/who.int/vmnis/indicators/haemoglobin.pdf, accessed [March 2013]).

(7) Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68:954-60.

(8) Knevel R, Kwok KY, de Rooy DP, et al. Evaluating joint destruction in rheumatoid arthritis: is it necessary to radiograph both hands and feet? Ann Rheum Dis 2013;72:345-9.

Conflict of Interest:

None declared

Dear Editor,

We thank Clockaerts and colleagues for their thoughtful commentary on our paper and will address a number of their comments. They expressed concern regarding lack of verification of our data related to statin use, duration of use, and dosage, and indicated these data were based on self- report. While we acknowledged in our paper[1] that we did not have dosage data, the verification was that participants brought their medications with them during yearly follow-up visits and we were able to confirm that statins were prescribed for these patients. This approach was not as valid as a pill count but, in our view, is more rigorous than self-report.

Clockaerts and colleagues accounted for duration of statin use by examining effects for those with 1-119 days, 120-364 days and 365 days or greater of statin use at 50% or more of the recommended daily dosage. Our approach was to use the yearly follow-up visit prescription data indicating 0, 1, 2, 3 or 4 years of statin use to examine the effects on changes in OA structural progression, pain and function. While we did not have dosage data, we believe that our approach reasonably accounted for differing durations of statin usage in our sample. In the end, an assumption of compliance was made in both studies[1,2] that medications were taken as prescribed.

In our opinion, neither our study[1] nor the work of Clockaerts et al[2] provides convincing evidence of a subgroup(s) who might be most responsive to OA-related benefits, if any, of statins. Clockaerts and colleagues suggested it is more plausible that statins could be useful in the early as compared to later stages of OA. They went on to recommend studies of statin use in persons with Kellgren and Lawrence (KL) scores of 0 at baseline. While we did not conduct subgroup analyses, we had 684 persons in our sample who had a baseline KL grade of 0 on one knee and 1,286 who had a baseline grade of 0 or 1 in at least 1 knee. If an association between statin use or duration of use and OA disease progression existed for patients with either no or very mild disease of at least one knee, the random intercept analyses in the structural equation models would have detected these relationships. No associations were found. When describing their analyses for persons with and without KL scores of 0, Clockaerts and colleagues reported that "when we used those separate definitions of incidence and progression, we found similar results."p645 It is not clear to us why Clockaerts and colleagues suggest statins may be more effective DMOADS for persons with either no or mild OA.

Clockaerts et al correctly indicated that we did not report the occurrence of muscle pain in our sample. They also suggested that muscle pain is an important side effect of statins and should be taken into account when considering pain scores for OA; the implication would be that, if statins caused muscle pain, then statin-related muscle pain might interfere with knee OA pain and function measures. On further reflection, this appears unlikely. First, our pain measure asked the participant to "rate the pain that you've had in your right/left knee during the past 7 days," requesting a focal pain report, not a more generalized pain assessment. Second, Clockaerts et al cite the work of Armitage who summarized potential adverse musculoskeletal effects of statin use including myopathy (defined as muscle symptoms accompanied by muscle enzyme elevation 10-fold-or-higher above the upper limit of normal) or myalgia (muscle symptoms with enzyme elevation up to 10-fold) [3]. Armitage indicated myopathy is a rare event particularly for standard doses, about 11 per 100,000 person-years of follow-up. Given that we had approximately 3,000 person-years of statin use in our study, we suspect myopathy influences were minimal (less than one represented in our panel). Regarding myalgia risk, Armitage reviewed several randomized trials that failed to support the assertion that statins cause myalgia or muscle cramps. For example, in one trial, the frequency of unexplained muscle pain or weakness was 32.9% in simvastatin-treated subjects and 33.2% in placebo-treated subjects[4]. Symptoms of myalgia are frequent among patients in the age ranges commonly needing cholesterol-lowering therapy, but the causal relationship of statins to myalgia is unsupported.

Thus, given the focused pain questions, the very low anticipated frequency of true myopathy and absence of evidence that statins are causally associated with myalgia, we suspect that any misreporting of muscle symptoms as knee OA pain and reduced function would likely have occurred in both statin-treated and statin-untreated groups about equally.

We agree that additional study is needed and we fully endorse the recommendation by Clockaerts and colleagues that future studies of the potentially protective effects of statins on OA incidence and progression should be targeted toward sub-groups who are most likely to benefit. Unfortunately, our study does not assist in identifying a subgroup whose osteoarthritis may be more likely to respond favorably to statins.

References

1. Riddle DL, Moxley G, Dumenci L. Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis. Ann Rheum Dis. 2013;72:196-203.

2. Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis 2012;71:642-647.

3. Armitage J. The safety of statins in clinical practice. Lancet 2007;370:1781-1790.

4. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

Conflict of Interest:

We have no competing interests. This "response" is submitted in response to the comments by Clockaerts and colleagues who were responding to our paper published in ARD (Riddle et al. Associations Between Statin Use and Changes in Pain, Function and Structural Progression: A Longitudinal Study of Persons with Knee Osteoarthritis. ARD. 2013 Feb;72(2):196-203.

Dear Editor,

Vincent et al present a thorough review of available clinical research on antidrug antibodies to tumour necrosis factor blocking agents (1). We agree to a large extent with their interpretation of the data with regard to pathofysiology, assay characteristics and variation in drug and antidrug antibody serum levels. However, the conclusion that measurement of (anti)drug levels should therefore be used for clinical decision making in non-responding biological patients with inflammatory diseases to save costs, prevent adverse events and improve disease activity, including their proposed algorithm, seems flawed and is thusfar insufficiently supported by evidence. In our comment we will focus on RA, but for other inflammatory disease the same comments can be made.

Firstly, we would argue that the most promising application for therapeutic drug monitoring (TDM) to save costs or adverse events is not to predict response to the next treatment option in non responding patients, but rather to predict successful dose reduction and stopping in patients who are doing well. All treatment alternatives in non responding patients employ either another biologic or a higher dose of the same biologic, so even optimal channelling of patients can only lead to better disease control, not to saved costs or prevented adverse events. In patients doing well however, it could be possible to use TDM to optimise dose reduction or stopping compared to a trial and error strategy. This way, unnecessary flares and unneeded drug exposition (cost and adverse events) could be prevented.

Secondly, when TDM is done in non responding patients and a low serum drug level is found it is not sensible, at least in RA, to increase the dose as suggested. The better choice would be to change to another biologic, either TNF blocker or with another mechanism of action. Increasing the dose has a much lower chance of response in rheumatic diseases (2,3) and is associated with more adverse events and costs (4) than switching to another biological, and is therefore probably not cost effective. In addition to these arguments, there is also a lack of specific empirical data to support the proposed decision tree. The theoretical framework for TDM indicates that any test that is used for TDM in clinical practice should meet the following requirements: 1/ uncertainty exist on an important clinical outcome, 2/ a reliable and valid test is available that is strongly associated with this outcome and gives additional information about this outcome above simple test, 3/ the use of the test has treatment consequences and 4/ the use of the test is cost effective (adapted from Aarnoutse et al, 5). The proposed algorithm of Vincent et al does not fulfill these criteria. Firstly, increasing the dose in arm 1 is arguably not safe and (cost)effective. Also, arm 2 and 3 converge to the same treatment option, negating the possible value of testing. For arm 4, switching to another class of biological, a clearly higher post test chance of response has not been consistently demonstrated.

Finally and most importantly, the possible advantages of TDM in this context - better disease control - has never been demonstrated compared to usual tight control care.
The appropriate clinical study design to assess the value of TDM is a prediction cohort study in patients with either active disease and starting or switching a biological, or patients with low disease and withdrawing medication. After the clinical outcome has been measured prospectively, the sensitivity and specificity of baseline (anti)drug levels for (non)response measured using a validated test should be estimated using ROC analyses. Thereafter, prediction modelling including all other known predictors (eg clinical, CRP) should be done to determine the additive value of TDM above regular clinical tight control. A clear change from pretest to posttest chances should be demonstrated, expressed preferably in numbers needed to diagnose, and cost effectiveness measures should be provided. Finally, confirmation of the cost effectiveness in a so called diagnostic study - a randomised trial comparing test based treatment with usual care - would be considered to be the golden standard in proving the value of any diagnostic or prognostic test, including TDM. The current review describes 76 studies done in the last 13 years of which 36 in RA assessing (anti)drug levels for the five anti-TNF agents. These studies include basic labstudies, cross-sectional studies and longitudinal non interventional studies. Unfortunately, however, due to the specific design limitations, not one of these studies was able to provide test characteristics for an important clinical outcome, including sensitivity and specificity, and pretest and posttest chances, let alone cost effectiveness analyses. Of note, the cost effectiveness analysis of TDM in adalimumab done in RA patients by Krieckaert et al (6) is a Markov modeling study showing that TDM using adalimumab (anti)drug levels could be cost-effective, based on the presumption that (anti)adalimumab serum levels are predictive for successful dose reduction, and this has indeed yet to be established. Also, modeled TDM guided dose reduction was compared to no change in adalimumab treatment instead of the more valid comparison with clinically guided doses reduction.

We are currently aware of three studies in rheumatic diseases specifically designed to assess the value of TDM, two of which have not been published yet (7-9). These studies assessed respectively the predictive value of infliximab (anti) drug levels in RA patients to predict response after initiation, prediction of successful dose reduction, and in ankylosing spondylitis patients prediction of response after dose increase. Interestingly, all three studies failed to demonstrate any relevant contribution of TDM for clinical decision making in the respective contexts. Other studies are currently underway to further explore this for other biologicals in other diseases (e.g. DRESS study in RA, TAXIT study in IBD).
In conclusion, TDM has no proven value yet in biological treatment, and should not be advocated at this moment. The most promising context seems TDM guided dose reduction in patients doing well. We strongly support research in this field, as it might enable us to treat our patients better, resulting in optimal disease control, better safety, and lower costs. However, a proposed TDM algorithm should be logically sound and empirically tested with scrutiny. We can therefore wholeheartedly join Vincent et al in their plea for significant research investment in this topic, both for test development as well as execution of appropriate clinical studies.

References

1. Vincent FB, Morand EF, Murphy K, et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralizing agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013;72:165-78.

2. Pavelka K, Jarosov K, Such D, et al. Increasing the infliximab dose in rheumatoid arthritis patients: a randomised, double blind study failed to confirm its efficacy. Ann Rheum Dis 2009;68:1285-9.

3. van den Bemt BJF, den Broeder AA, Snijders GF, et al. Sustained effect after lowering high dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study. Ann Rheum Dis 2008;67:1697-701.

4. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275-85

5. Aarnoutse RE, Schapiro JM, Boucher CA, et al. Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs? Drugs 2003;63:741-53.

6. Krieckaert C, Nair SC, Nurmohamed MT, et al. Evaluating the cost-effectiveness of personalized treatment with adalimumab using serum drug level and anti-adalimumab antibodies in rheumatoid arthritis patients. Ann Rheum Dis 2012;71(suppl 3):104.

7. Inman RD, Davis JC Jr, Heijde D vd, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008;58:3402-12.

8. van der Maas A, van den Bemt BJF, van den Hoogen FHJ, et al. Baseline (anti-) infliximab serum trough levels do not predict successful down-titration or cessation of infliximab in Rheumatoid Arthritis patients with long term low disease activity. Submitted 2013.

9. van den Bemt BJF, den Broeder AA, Wolbink GJ, et al. The combination of disease activity and infliximab serum trough levels for early prediction of (non-) response to infliximab-treatment in patients with rheumatoid arthritis. Submitted 2013.

Conflict of Interest:

None declared

Dear Editor,

I read with great interest the study of different diagnostic ultrasound measures of median nerve volume in patients with carpal tunnel syndrome (CTS) by Dejaco et al. (1). It is of great value, in my opinion, that this study succeeded not only in highlighting the diagnostic value and good reliability of ultrasound determination of median nerve cross sectional area (CSA) in patients with suspected CTS, but also confirmed previously reported results on the value of Doppler ultrasonography in classifying the severity of CTS (2-4).
I would like though to draw attention to a subgroup of patients, with persistent clinical and electrophysiological signs of CTS and condition after unsuccessful carpal tunnel release (CTR). The etiology of the persistent neurological semiology is in most of the cases an incomplete release of the retinaculum flexorum. Traction neuropathy, real recurrent CTS and iatrogenic nerve lesions occur less frequently. Nerve conduction studies are a valuable tool in supporting the indication for a reoperation, if a preoperative examination exists, but are not able to demonstrate the exact cause of a failed CTR. Several ultrasonography studies after CTR (5-8) have all concluded that the functional outcome and the CSA of the median nerve, may provide clinicians with a tool to estimate the response of these patients to surgery and the indication for reoperation. The difficulty though to quantify pathological changes after CTR remains an important limitation of neuromuscular ultrasound in clinical practice.
I would like therefore to report the preliminary data of the clinical, electrophysiological and ultrasound follow-up of 10 patients (mean age 53.46, SD +/- 14.8, 2 women) with CTS, who underwent due to persistent neurological semiology CTR two times. Functional Status Scale (9) was used for the clinical evaluation, while distal motor latency (DML) and CSA of the median nerve (carpal tunnel inlet) were used as electrophysiological and ultrasound markers for the follow-up. In addition, a retrospective analysis of the already acquired power-doppler ultrasound images of the median nerve at carpal tunnel inlet has been performed, in order to calculate for each patient the power-Doppler score according to the study protocol from Dejaco et al. (1). According to the preliminary data of this study the CSA and the power- Doppler score at the inlet of the carpal tunnel seem to highlight well the functional recovery of the patients after the second CTR (Table 1). On the other hand, the DML values of the median nerve showed no statistical significant changes pre- and postoperarive, failing to resemble the clinical improvement of the patients. A possible explanation could be, that the edema caused by the chronic nerve compression and the consecutive increased endoneurial pressure may have lead to nerve ischemia. This pathophysiologic cascade leading to secondary ischemic neuropathy may result in the observed reduced nerve excitability.
Therefore, systematic, multicentre, prospective studies are needed to evaluate the applicability and diagnostic values of these findings and to understand the complex sonology of CTS.

Table 1

Preoperative: FSS mean 25.6 (SD 5.2), CSA: mean 13.12mm2 (SD 1.5), DML: mean 8.9ms (SD 3.5), PDS: mean 1.2 (SD 0.42)

CTR-1: FSS: mean 23.2 (SD 4.3, p=0.2755), CSA: mean 12.5mm2 (SD 2.3, p=0.4844) DML: mean 8.3ms (SD 2.1, p=0.6476) PDS: mean 0.7 (SD 0.48, p=0.086)

CTR-2: FSS: mean 20.1 (SD 4.3,p=0.019) CSA: mean 11.2mm2 (SD 1.9, p=0.021) DML: mean 7.9ms (SD 4.1,p=0.5647) PDS: mean 0.6 (SD 0.51, p=0.01)

FSS = functional status scale CSA = cross sectional area (mm2) DML=distal motor latency (ms) PDS: Power Doppler Score SD = standard deviation CTR-1: First carpal tunnel release operation CTR-2: Second carpal tunnel release operation

Tables and Legends Table 1 Title: Overview of the clinical, electrophysiologic and sonographic follow up of the median nerve in the study group.

Legend: Statistical comparison of groups were performed with the help of Student's t test or. P-values < 0.05 were considered as statistically significant.

References

1. Dejaco C, Stradner M, Zauner D et al. Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography. Ann Rheum Dis 2012 Dec 4.

2. Ng ES, Ng KW, Wilder-Smith EP. Provocation tests in doppler ultrasonography for carpal tunnel syndrome. Muscle Nerve. 2012 Oct 2. doi: 10.1002/mus.23637.

3. Evans KD, Roll SC, Volz KR et al. Relationship between intraneural vascular flow measured with sonography and carpal tunnel syndrome diagnosis based on electrodiagnostic testing. J Ultrasound Med. 2012 May;31(5):729-36

4. Mohammadi A, Ghasemi-Rad M, Mladkova-Suchy N et al. Correlation between the severity of carpal tunnel syndrome and color Doppler sonography findings. AJR Am J Roentgenol. 2012 Feb;198(2):W181-4. doi: 10.2214/AJR.11.7012

5. Lee CH, Kim TK, Yoon ES et al. Postoperative morphologic analysis of carpal tunnel syndrome using high-resolution ultrasonography. Ann Plast Surg 2005;54:143-146.

6. Mondelli M, Filippou G, Aretini A. Et al. Ultrasonography before and after surgery in carpal tunnel syndrome and relationship with clinical and electrophysiological findings. A new outcome predictor? Scand J Rheumatol 2008;37:219-224.

7. Abicalaf CA, de Barros N, Sernik RA et al. Ultrasound evaluation of patients with carpal tunnel syndrome before and after endoscopic release of the transverse carpal ligament. Clin Radiol 2007;62:891-896

8. Kim JY, Yoon JS, Kim SJ et al. Carpal tunnel syndrome: Clinical, electrophysiological, and ultrasonographic ratio after surgery. Muscle Nerve. 2012 Feb;45(2):183-8.

9. Levine DW, Simmons BP, Koris MJ et al. A self-administered questionnaire for the assessment of severity of symptoms and functional status in carpal tunnel syndrome J Bone Joint Surg Am. 1993 Nov;75(11):1585-92.

Conflict of Interest:

None declared