Recent eLetters

Dear Editor,

We read with interest the paper of M Sebastianni et al about the predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis(1). The authors suggest that the CSURI score "can represent a feasible and reliable clinical tool in the routine evaluation of patients". However, we feel this report raises serious issues concerning the reproducibility of the methodology. When calculating the score, the number of capillaries ("N") was the most important predictive index. The definition of the "N" is clearly detailed and the clinicians have to count "all the capillaries detectable in the entire distal front line, including capillaries placed at different levels". The measurement was illustrated in figure 1 and we noticed that that the author were counting 13 capillaries on the panel C as specified in the legend.

However, the same picture was used 3 years ago, when the same authors described the score(2), excepted that the picture was a little larger and included one more capillary on the right of the picture, and the authors counted only 11 capillaries. We were surprised about such a huge difference in capillary counting, especially in didactic pictures which have the aim to illustrate the methodology of the score. This difference may be induced by the difficulty of defining the "entire distal front line". It also reflects the difficulty of capillary counting using native videocapilaroscopy that could be overcome by using fluorescent dyes. It is difficult to estimate the extrapolation of this error on the score MxD/N2 but, it seems clear that the reproducibility of the CSURI remains questionable. Although the aim to build-up an informative and easy to use capillaroscopic score is a highly valuable purpose, the reproducibility of such measurements remains a stumbling stone difficult to get round.

References

1. Sebastianni M, Manfredi A, Vukatana G, et al. Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study. Ann Rheum Dis 2012;71:67-70.

2. Sebastiani M, Manfredi A, Colaci M, et al. Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. Arthritis Rheum 2009;61:688-94.

Conflict of Interest:

none

Dear Editor,

The maintenance of serum calcium within normal limits is important to sustain life. In vitamin D deficiency calcium cannot adequately be absorbed by the intestinal mucosa. The lack of both of these important players in bone health and can bring about secondary hyperparathyroidism[1].

The excess PTH, among other things, stimulates osteoclastogenesis[2] and liberates calcium from the skeleton to maintain an adequate serum calcium level[3]. The recent study by Boumans, et al., (2012)[4] finding that rituximab inhibits osteoclastogenesis raises a significant question: what impact does this have on maintaining serum calcium, especially in patients with secondary hyperparathyroidism? Vitamin D deficiency is described as endemic[5]; additionally people with rheumatoid arthritis (RA) have consistently low levels[6], and agents used, such as corticosteroids deplete vitamin D levels. In turn calcium cannot be absorbed and instead must be taken from the bone and the increase in PTH is the mechanism by which this occurs. In one study of 850 men with RA[6] the prevalence of insufficiency (below 75 nmol/L (30 ng/mL)) was 84% and deficiency (below 50 nmol/L (20 ng/mL)) was 43%. Also, after adjustment, hypovitaminosis D was more common in those with anti-cyclic citrullinated peptide antibody positivity and those who are non-white; deficiency was independently associated with greater joint tenderness and higher high sensitivity CRP. Indeed, in a recent study[7] of rituximab patients, all were vitamin D deficient with levels below 50 nmol/L (20 ng/mL). The study apparently did not measure PTH or calcium levels.

The calcium aspect of rituximab does not appear to have been studied, but a concern is that hypocalcaemia may result and cardiac or skeletal muscle problems could follow. As far as the author is aware, calcium measurement is not a part of any routine blood draws in rituximab therapy in RA. The mere prospect that hypocalcaemia may occur should induce us to think of preventive strategies. One approach may be similar to that used with bisphosphonates: to ensure calcium levels are adequate and that the patient is taking a source of vitamin D before therapy. To be more accurate, 25-hydroxy vitamin D can be measured and we can ensure it is above 75 nmol/L (30 ng/mL). This is because it takes levels between 75-80 nmol/L (30-32 ng/mL) to suppress PTH and a level above 85 (34 ng/mL) for intestinal calcium absorption to be optimised[5]. In the elderly, levels above 122 nmol/L (49 ng/mL) may be required to suppress PTH to what is considered normal in young adults[8].

Even if further studies show the inhibition of osteoclastogenesis by rituximab is negligible and of little consequence in the development of hypocalcaemia, the approach remains sound. This is because by ensuring adequate levels of vitamin D and calcium, patients will be on the strongest ground in ensuring bone health, along with the many benefits that may result from improved vitamin D levels[9].

In sum, at a minimum we should consider measurement of calcium levels and ensure a basic level of vitamin D input; alternatively, 25 (OH) D levels should be measured to ensure a level above at least 75 nmol/L (30 ng/mL) and preferably above 100 nmol/L (40 ng/mL).

References

1. Aloia JF Feuerman M Yeh JK. Reference range for serum parathyroid hormone. Endocr Pract 2006;12: 137-144.

2. Jacome-Galarza CE Lee SK Lorenzo JA et al. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone and Miner Res 2011;26: 1207-1216.

3. Wallis DE Penckofer S Sizemore GW. The "sunshine deficit" and cardiovascular disease. Circulation 2008;118: 1476-1485.

4. Boumans MJ Thurlings RM Yeo L et al. Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis. Ann Rheum Dis 2012;71: 108-113.

5. Cannell JJ Hollis BW Zasloff M et al. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 2008;9: 107-118.

6. Kerr GS Sabahi I Richards JS et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 2011;38: 53-59.

7. Hasan E Olusi S Al-Awadhi A et al. Effects of rituximab treatment on the serum concentrations of vitamin D and interleukins 2, 6, 7, and 10 in patients with rheumatoid arthritis. Biologics 2012;6: 31-35.

8. Kinyamu HK Gallagher JC Rafferty KA et al. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. Am J Clin Nutr 1998;67: 342-348.

9. Wilding PM Cardiovascular disease, statins and vitamin D. Br J Nurs 2012;21: 214-220.

Conflict of Interest:

None declared

Dear Editor,

A recent report by Hot and colleagues investigated the possible link between the increased expression of IL-17 in rheumatoid diseases and the high incidence of cardiovascular disorders in patients suffering these pathologies.

To address this point the authors used an elegant approach that combined in vitro cell functional studies with gene fingerprint analysis by microarray. Consistent with several previous studies, including our own (1), the authors showed that IL-17A per se does not cause a significant inflammatory response in HUVEC while it greatly enhance the inflammatory properties of TNF?.

To investigate the functional consequences of these results the authors used a wide range of tests including endothelial cell migration and invasion. Most interestingly, they also showed that the conditioned medium of HUVEC stimulated with IL-17A with or without TNF? caused a significant increase in platelet aggregation.

These results further support our previous studies showing a proaggregant effect of IL-17A on both murine and human platelet aggregation (2). Like for endothelial cells, IL-17A alone did not influence platelet activation while it amplified the inflammatory effect of ADP. More specifically, IL-17A increased the primary reversible phase of ADP-induced platelet aggregation in a concentration-dependent manner.

The results presented by Hot et al. in Figure 6A show no difference between the conditioned medium of HUVEC treated with IL-17A or IL-17A + TNF? while in most of the other assays the combination of these two cytokines provided significant differences compared to the effects of IL- 17A alone. Thus it might be possible to hypothesize that the proaggregant effect observed might be due, al least in part, to a direct effect of IL- 17A still present in the medium. This could be easily addressed by adding an anti-IL-17A neutralizing antibody to the conditioned medium before the test on platelet aggregation.

References

1. Maione F, Paschalidis N, Mascolo N, et al. Interleukin 17 sustains rather than induces inflammation. Biochem Pharmacol 2009;77(5):878-87.

2. Maione F, Cicala C, Liverani E, et al. IL -17A increases ADP-induced platelet aggregation. Biochem Biophys Res Commun 2011;408(4):658-62.

Conflict of Interest:

None declared

Dear Editor,

We thank the authors for their interest in our paper and extending the discussion about how we can best assess the safety of glucocorticoid therapy. Ongoing uncertainty about the safety of steroids - particularly at low doses - despite over sixty years of clinical experience illustrates this is not an easy challenge. Nonetheless, it is important to tackle given the continuing widespread use. We must move towards clearer numerical risks for multiple safety outcomes (1). The two study designs available to us to address steroid safety are randomized controlled trials (RCTs) and observational studies. Each has advantages and disadvantages. The great benefit of RCTs is randomised treatment, meaning each group has a balance of known and unknown variables at baseline. The authors suggest a literature review on the topic: a good idea that we have already undertaken (2). Unfortunately, on reviewing all published RCTs, there was great variability in the quality of reporting in the methods and heterogeneity in the results for safety outcomes, making it difficult to have confidence in the final result of the meta-analysis. Furthermore, the total number of patients eligible for inclusion was less than 2000 after more than 60 years' of glucocorticoid trials in rheumatoid arthritis (RA).

Observational studies offer the chance to look at larger numbers of patients, which is crucial to study infrequent serious adverse events. This approach also allows us to examine 'real-life experience', particularly over the long-term. There are, however, many challenges. First, glucocorticoid therapy is used dynamically, meaning that conventional models of risk-attribution make assumptions that we know not to be true. This was the motivation for the second publication where we showed that novel methods for modeling exposure that considered changes to dose with time provided a better fit than traditional models (3). Second, adherence to therapy is a problem in steroid safety, as we know patients can take either more or less prednisolone than is prescribed. Third, observational studies provide associations that may or not be causal. Our finding of an association between GC therapy taken several years ago and current infection risk does not necessarily mean this is a direct effect with long latency. Whilst it may be having a direct effect by influencing adaptive immune pathways, it may represent an indirect effect, perhaps by impairing barrier functions such as skin integrity, or reflect the delay in hypothalamic-pituitary-adrenal axis resetting after glucocorticoid suppression (4, 5). Past GC use may also be a marker of current active disease, which brings us onto the fourth and largest challenge: confounding by disease severity. GC prescriptions are tightly coupled to disease severity, making this a difficult problem. We agree administrative databases do not contain good measures of disease severity in RA, meaning residual confounding is likely. We acknowledged this in both papers, but in the first went on to show that the residual confounding could not explain all of the observed association (6). Interestingly, RCTs do not resolve entirely the problem of confounding by disease severity. Randomisation ensures the groups are matched for disease severity at baseline, but as patients in the treatment arm respond to GC therapy, they will have lower disease severity throughout much of the study. Any measured infection risk will thus represent a mixing of effects of the direct effect of GCs on infection (perhaps increasing risk) plus the effect of lower cumulative disease severity (reducing risk).

We agree with the authors that we must strive towards a clearer understanding of steroid safety through carefully designed studies. Unfortunately, we cannot resolve all challenges at once. The weighted cumulative dose model has now shown benefit in modelling time-varying doses, and will enable us to move towards individualised safety estimates for given patterns of GC use. We have studies funded that will examine the extent of adherence to glucocorticoid therapy within a national database, allowing quantification of the effect of self-adjusted therapy on safety estimates. In order to address confounding by disease severity (both in observational studies and RCTs), we need to have regular measurements of both disease severity and treatment. We can then use techniques such as marginal structural modelling (7). It is rare that large databases contain sufficient information for such analyses, but by linking national datasets that each contains components of the total required information, we can move beyond our current knowledge (8). We agree a large and pragmatic RCT would be valuable, assuming disease severity is measured carefully throughout and the design allows for variation in GC exposure, both between and within subjects, to reflect real-life patterns of GC use.

The associations reported in our papers must indeed be interpreted with caution, as we do not yet have solutions to all of the challenges of observational drug safety research. This leaves us with uncertainty about the safety of these widely used drugs. We believe it is important to continue to address this issue whilst, in parallel, attempting to address the methodological limitations.

References

1. Hoes JN, Jacobs JW, Buttgereit F, et al. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nature reviews Rheumatology 2010;6:693-702.

2. Dixon WG, Suissa S, Hudson M. The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses. Arthritis Research & Therapy 2011;13:R139.

3. Dixon WG, Abrahamowicz M, Beauchamp ME, et al. Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis. Ann Rheum Dis 2012.

4. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. N Engl J Med 2005;353:1711-23.

5. McMaster A, Ray DW. Drug insight: selective agonists and antagonists of the glucocorticoid receptor. Nat Clin Pract Endocrinol Metab 2008;4:91-101.

6. Dixon WG, Kezouh A, Bernatsky S, et al. The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case-control study. Ann Rheum Dis 2011.

7. Thamer M, Hernan MA, Zhang Y, et al. Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560-4.

8. Suissa S. Assessing the safety of new arthritis drugs: are we there yet? J Rheumatol 2008;35:2295-7.

Dear Editor,

In October 2011, Beyer and colleagues published an interesting article on the use of tocilizumab as rescue treatment for 3 patients with giant cell arteritis(1). Their patients had a high systemic inflammatory response and involvement of the aorta and its main branches, showing Takayasu-like features. The authors noted that, perhaps, tocilizumab might be less effective for 'classical' giant cell arteritis (GCA) patients with limited cranial involvement. In other case reports, tocilizumab has also been used successfully in patients with giant-cell arteritis and elevated acute phase reactants(2). In a series of cases recently published by Seitz et al(3,4), interestingly, two of their patients had almost normal acute phase reaction before starting treatment with tocilizumab and they did respond quickly upon treatment. The results in these case reports may indicate a good correlation between recent advances in the understanding of the pathogenic mechanisms of GCA and the favorable response to tocilizumab. At least two distinct CD4+ T-cell subsets, namely Th17 and Th1 cells, promote vascular inflammation in GCA. Th17 cells are explicitly corticosteroid-sensitive. However, Th1 cells are corticosteroid-resistant and abnormal Th1 responses continue, unaffected by corticosteroids, identifying GCA as a long-term, chronic immune-mediated disease(5). Interferon-gamma, the signature cytokine produced by the Th1 cell lineage, is expressed in high amounts in patients who experiment ischaemic complications. Thus, a major therapeutic challenge in controlling GCA disease activity lies in persistent Th1 responses. A recent study(6) has shown that in peripheral blood of active GCA patients Th1 and Th17 cells are markedly expanded and regulatory T cells are decreased. In experimental models, interleukin-6 (IL-6) is a potent inhibitor of transforming growth factor beta (TGF-beta)-driven induction of Foxp3+ regulatory T cells(7). IL-6 not only suppresses the generation of these regulatory T cells, but together with TGF-beta, it also induces naive T cells to express interleukin-17 and to become pathogenic Th17 cells(7). Theoretically, given that IL-6 regulates the balance between Th17 and regulatory T cells(8), it is possible that blocking IL-6-induced intracellular signals by the anti-IL-6 receptor antibody tocilizumab ameliorates the function of regulatory T cells, thereby helping to bring the immune system into physiologic balance.

Thus, besides its possible use as a rescue treatment or steroid sparing agent, perhaps, tocilizumab could have an additional role in modifying the natural history of this disorder.

References

1.Beyer C, Axmann R, Sahinbegovic E, et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis 2011;70:1874-5.

2.Sciascia S, Rossi D, Roccatello. Interleukin 6 blockade as steroid- sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011;38:2080-1.

3.Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156.

4.Seitz M. Reply to the Letter to the Editor of Francisco Jose Fernandez-Fernandez et al. Swiss Med Wkly 2012;142:w13504.

5.Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol 2011;23:43-9.

6.Terrier B, Geri G, Chaara W, et al. IL-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum 2011 Dec 6. doi: 10.1002/art.34327.

7.Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8.

8.Korn T, Mitsdoerffer M, Croxford AL, et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2008;105:18460-5.