Fluticasone Reduces CRP in COPD

To the Editor.

I have read the observational study by Sin and colleagues (1) and an accompanying editorial by Calverley (2) published in the AJRCCM. It remains unclear whether the C-reactive protein (CRP) in these patients was elevated as a consequence of their COPD or whether it was due to concomitant atherosclerosis or coronary artery disease. second, there is still uncertainty whether elevated concentrations of CRP are causally related to the increased risk for cardiovascular complications or are merely a consequence of this elevated risk. In addition, the questions of whether elevated CRP levels reflect the degree of the underlying atherosclerosis or plaque vulnerability or might be related to other environmental or infectious stimuli, or whether CRP can directly influence platelet aggregation or coagulation, are unanswered. In contrast to Dr. Sin’s speculation, there is little evidence that a reduction in CRP will lead to an improvement in outcome of COPD. In my view, the most important aspect missed by Drs. Sin and Calverley is the point that one could argue the converse. Corticosteroids could alter markers of systemic inflammation without any therapeutic benefit. A reduction in CRP by fluticasone or prednisolone is not necessarily “likely to have clinical relevance” and may not “improve health and/or cardiovascular outcomes in patients with COPD” as Dr. Sin suggests. In fact, the opposite might be the case: Monakier and colleagues (3) have recently suggeted that rofecoxib, a COX-2 inhibitor, lowers CRP (mean reduction by > 50%, namely, 0.84 mg/dL at 1 month and 1.3 mg/ dL at 3 months; baseline 1.33 3.99 mg/dL) and interleukin-6 levels significantly. The authors speculate that this “may translate into reduction of acute coronary events” (3). Despite these presumably beneficial actions of rofecoxib, this drug has recently been withdrawn from the market because its long-term use (> 1 year) might be associated with an increase in cardiovascular and cerebrovascular morbidity (4). What seems to appear obvious or “logical” in medicine may not be so. Observational studies such as the one by Dr. Sin and colleagues should be analyzed carefully, and allegations about possible “salutary effects” of corticosteroids “on cardiovascular morbidity and mortality in COPD” (1) should not be based on such studies. I am afraid that Dr. Sin’s study does not add clinically relevant information to the question of whether corticosteroids reduce mortality in COPD. Long-term interventional studies are clearly needed.

Conflict of Interest Statement: J.C.V. received euro4,000 from GlaxoSmithKline (GSK) for speaking at conferences sponsored by this company and euro3,000 for serving on an Advisory Board for GSK, and received euro25,000 in 2003-2004 from GSK as research grants.

J. CHRISTIAN VIRCHOW

University of Rostock

Rostock, Germany

References

1. Sin DD, Lacy P, York E, Man SFP. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:760-765.

2. Calverley P. Are inhaled corticosteroids systemic therapy for chronic obstructive pulmonary disease? [editorial]. Am J Respir Crit Care Med 2004;170:721-722.

3. Monakier D, Mates M, Klutslein MW, Balkin JA, Rudensky B, Meerkin D, Tzivoni D. Rofecoxib, a COX-2 inhibitor, lowers C- reactive protein and interleukin-6 levels in patients with acute coronary syndromes. Chest 2004;125:1610-1615.

4. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351: 1709-1711.

From the Authors:

There is a marked scarcity of data regarding the systemic bioactivity of inhaled fluticasone in chronic obstructive pulmonary disease (COPD). Although interesting, Lee and Lipworth’s data (1) on 2 mg per day of fluticasone in COPD are unlikely to be germane to our study, as we achieved all of the reductions in C-reactive protein (CRP) in our cohort with only 1 mg per day of fluticasone (2). Previous data from Brutsche and coworkers (3) indicate that systemic availability of fluticasone with 1 mg per day is small, particularly in patients with reduced forced expiratory volume in one second or in those with compromised diffusion capacities. For example, in patients with carbon monoxide transfer coefficients of less than 80% of predicted (which would be the case for most patients with COPD), systemic availability of fluticasone was less than 10%. Whether such small amounts of systemically absorbed fluticasone can significantly reduce CRP is open to question. We believe this to be unlikely, since the magnitude of CRP reduction observed with fluticasone (1 mg/d) was similar to that achieved by 30 mg per day of prednisone in our study (2). Nevertheless, future studies are needed to clearly delineate the exact mechanism(s) through which inhaled fluticasone and other corticosteroids exert their action on CRP and other relevant systemic proteins and cytokines in COPD.

Our study was concerned with the possible systemic antiinflammatory effects of corticosteroids. We share Dr. Virchow’s caution in not overinterpreting the clinical implications of our data. We agree that CRP and other markers of systemic inflammation are imperfect surrogates for future morbidity and mortality in COPD, and we cannot assume that the reductions in these levels will necessarily lead to improved clinical outcomes. However, the comparison of inhaled corticosteroids to rofecoxib is neither fair nor justified. In spite of rofecoxib’s beneficial effects on CRP, there were many high-quality studies (even before the APPROVe study [4]) that had indicated their potential harm (5). Moreover, there was a sound physiologic basis for their ability to increase cardiovascular risks (6). In contrast, inhaled corticosteroids have been linked with improved cardiovascular outcomes (7) and sound experimental evidence for their potential efficacy in reducing cardiovascular events (8-10). Thus, our study data must be interpreted in the context of the entire body of evidence. The results from the TORCH trial and a metaanalysis of mortality experience in the previous placebo-controlled studies will provide definitive data on whether inhaled corticosteroids do or do not reduce mortality in COPD (11).

Conflict of Interest Statement: D.D.S. received honoraria for speaking engagements from AstraZeneca in 2003 for $4,000 and in 2004 for $3,000 and from GlaxoSmithKline (GSK) in 2003 for $4,000 and in 2004 for $8,000 and has also received unrestricted research funding as either the principal investigator or coprincipal investigator from GSK in 2002 for $100,000, in 2003 for $80,000, and in 2004 for $1.5 million, and has also received $3,500 from GSK for consultancy work; P.M. received $4,000 per annum from Merck Frosst Canada Inc. for Advisory Board function from 2001-2003 and $2,000 from GSK for 2003 and a medical school grant to attend the 2003 ATS meeting and has received as co-principal investigator a medical school grant from GSK, $140,000, and from Merck, $2.45 million until 2003, and a medical school grant is being negotiated and a consultation is still in progress with GSK, and was invited to speak at an AstraZeneca sponsored scientific meeting in April 2004 with all travel expenses paid by the hosting company; P.L. received $1,000 in 2004 for an invited lecture at St. Paul’s Hospital Vancouver sponsored by Merck Frosst Canada and also received 30% of $60,000 for an unrestricted research grant from Abbott Laboratories in 2001-2002; E.Y. was on the CSK Medical Advisory Board from 2002 to 2003 but is no longer a member of this board (last meeting was in November 2003) and did not receive monetary payment.

DON D. SIN

PAUL MAN

University of British Columbia

Vancouver, British Columbia, Canada

PAIGE LACY

ERNEST YORK

University of Alberta

Edmonton, Alberta, Canada

References

1. Lee DK, Lipworth BJ. The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease. Br J Clin Pharmacol 2003;57:388-392.

2. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:760-765.

3. Brutsche MH, Brutsche IC, Munawar M, Langley SJ, Masterson CM, Daley-Yates PT, Brown R, Custovic A, Woodcock A. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000;356:556-561.

4. Topol EJ. Failing the public health: rofecoxib, Merck, and the FDA. N Engl J Med 2004;351:1707-1709.

5. Jni P, Nartey L, Med D, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative metaanalysis. Lancet 2004;364:2021-2029.

6. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2:879-890.

7. Suissa S, Assimes T, Brassard P, Ernst P. Inhaled corticosteroid use in asthma and the prevention of myocardial infarction. Am J Med 2003; 115:377-381.

8. Poon M, Gertz SD, Fallon JT, Wiegman P, Berman JW, Sarembock IJ, Taubman MB. Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits. Atherosclerosis 2001;155:371-380.

9. Marumo T, Schini-Kerth VB, Brandes RP, Busse R. Glucocorticoids inhibit superox\ide anion production and p22 phox mRNA expression in human aortic smooth muscle cells. Hypertension 1998;32:1083-1088.

10. Sakai M, Biwa T, Matsumura T, Takemura T, Matsuda FI, Anami Y, Sasahara T, Kobori S, Shichiri M. Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. Arterioscler Thromb Vasc Biol 1999;19:1726-1733.

11. Calverley P. Are inhaled corticosteroids systemic therapy for chronic obstructive pulmonary disease? [editorial]. Am J Respir Crit Care Med 2004;170:721-722.

Copyright American Thoracic Society May 15, 2005