Arthritis Cure

🔥+ Arthritis Cure 09 Jul 2020 The products used in these natural remedies are very easy to find. ... Black pepper has long been known to aid in pain relief and swelling ...

Arthritis Cure Other symptoms and signs associated with joint pain include swollen joints, joint redness, and stiffness. ... Take the Gout Quiz to learn all about this painful. ... There are over 100 types of arthritis, including osteoarthritis, rheumatoid ... Connective tissue disease is when the body's connective tissues come under attack, ...

Skip to main content

Arthritis Curehow to Arthritis Cure for Advanced Search

EditorialEditorial
JØRGEN JEPPESEN
The Journal of Rheumatology April 2011, 38 (4) 595-597; DOI: https://doi.org/10.3899/jrheum.110006

This article has a correction. Please see:

Low-grade chronic inflammation has been proposed to play a central role in atherosclerosis1,2, as well as in other types of vascular damage, and measuring the level of inflammatory markers in the blood can provide prognostic information regarding cardiovascular disease (CVD) risk1,2. A serum level of C-reactive protein (CRP), determined with a high-sensitivity assay, is at the moment the best studied inflammatory marker, and CRP has been used to enhance risk prediction based on Framingham risk score and Reynolds risk score in apparently healthy women and men1,2,3.

In this issue of The Journal, Provan and colleagues4 report interesting data regarding the putative role of low-grade chronic inflammation in CVD with special reference to the well established increased CVD risk seen in patients with rheumatoid arthritis (RA)5. Provan and colleagues4 studied a cohort of a little more than 100 patients with RA, and they found that serum levels of CRP above the median (> 3.80 mg/l) at baseline were associated with increased central artery stiffness at followup 15 years later. As increased central or large artery stiffness is a well established marker of increased CVD risk6, Provan and colleagues4 speculate that poor control of RA, as reflected by higher levels of CRP, and thereby accompanying inflammatory damage to the elastic arteries, may explain the increased CVD risk seen in patients with RA. As a consequence, they discuss that early active disease management by use of disease modifying antirheumatic drugs to control inflammation may help to reduce the risk of later CVD in patients with RA. However, although it certainly would be desirable if tight control of the inflammatory processes caused by RA would eventually lead to a decreased risk of CVD in RA patients5, things may be somehow more complicated than initially thought. Thus, higher serum CRP levels in RA patients may be caused by other factors than the inflammatory rheumatic disease7,8, and further, studies using Mendelian randomization have shown that genetically elevated levels of CRP are associated neither with increased CVD risk9 nor with measures of aortic stiffness10, suggesting that the inflammatory biomarker used by Provan and colleagues4 is merely a risk marker rather than a causal factor in the disease processes that eventually lead to clinical CVD, in patients with and without RA for that matter.

Before discussing the above issues in more detail, it is worthwhile to briefly consider the concept of low-grade inflammation1,2,3,11. Normal human serum contains CRP concentrations less than 10 mg/l, and it is generally accepted that mild inflammation and viral infections cause elevation of CRP in the 10–40 mg/l range, while active inflammation and bacterial infections produce levels of 40–200 mg/l12. With the development of high-sensitivity CRP assays capable of measuring the very the 1 last update 2020/07/09 low CRP levels normally found in human serum (0.1–2.5 mg/l), it was possible to show that apparently healthy individuals, who had serum CRP levels between ∼2 and 10 mg/l, had a substantially increased risk of CVD, independently of all well established traditional CVD risk factors1,2,3. As the increased CVD risk could be identified within the serum CRP range otherwise considered to be normal, the concept of a low-grade inflammatory state evolved1,2,3,11. In this context, it is worth repeating that the median serum CRP level of the RA patient population studied by Provan and colleagues4 was 3.80 mg/l, i.e., within the low-grade inflammation range and not in the high-grade inflammation range11.Before discussing the above issues in more detail, it is worthwhile to briefly consider the concept of low-grade inflammation1,2,3,11. Normal human serum contains CRP concentrations less than 10 mg/l, and it is generally accepted that mild inflammation and viral infections cause elevation of CRP in the 10–40 mg/l range, while active inflammation and bacterial infections produce levels of 40–200 mg/l12. With the development of high-sensitivity CRP assays capable of measuring the very low CRP levels normally found in human serum (0.1–2.5 mg/l), it was possible to show that apparently healthy individuals, who had serum CRP levels between ∼2 and 10 mg/l, had a substantially increased risk of CVD, independently of all well established traditional CVD risk factors1,2,3. As the increased CVD risk could be identified within the serum CRP range otherwise considered to be normal, the concept of a low-grade inflammatory state evolved1,2,3,11. In this context, it is worth repeating that the median serum CRP level of the RA patient population studied by Provan and colleagues4 was 3.80 mg/l, i.e., within the low-grade inflammation range and not in the high-grade inflammation range11.

Thus, after this brief comment on the concept of low-grade inflammation1,2,3,11, it is time to discuss putative causes of the persistent low-grade inflammation that may be found in some apparently healthy women and men1,2,3, including patients with well controlled RA or mild disease activity13. Initially, it was thought that this low-grade inflammatory state was mainly the result of minor chronic insults such as smoking, chronic bronchitis, chronic gingivitis, and persistent bacterial infections with microorganisms such as Helicobacter pylori and Chlamydia pneumoniae1,2,14, but from the mid-1990s it became clear that higher serum levels of CRP were also closely associated with overweight and many of the metabolic factors closely associated with the overweight condition14,15. Thus, although increasing age, smoking, symptoms of chronic bronchitis, H. pylori and C. pneumoniae infections, all associate with raised serum concentrations of CRP within the low-grade inflammation range14,15, the relationships between serum CRP levels and metabolic variables, such as body mass index, waist circumference, plasma glucose, prevalence of type 2 diabetes, blood pressure, prevalence of hypertension, plasma triglyceride, serum insulin levels, and estimates of insulin resistance have been found to be as strong as the relationships between serum CRP levels and the aforementioned factors14,15. Further, it is noteworthy that higher serum levels of CRP in addition to CVD predict new-onset hypertension and new-onset type 2 diabetes1. As a likely mechanistic link between overweight and increased synthesis of CRP by the liver, it has been shown that human subcutaneous adipose tissue secretes interleukin 6 (IL-6) in vivo16, and it has been estimated that ≈30% of the total circulating concentrations of IL-6 originate for adipose tissue in healthy subjects16. So, adipose tissue is indeed an active proinflammatory organ. In this context, in discussing “metabolic inflammation” versus inflammation caused by inflammatory diseases, it is noteworthy that human subcutaneous adipose does not secrete tumor necrosis factor-α (TNF-α)16. With respect to lifestyle habits other than smoking, which, as mentioned above, are associated with increased serum concentrations of CRP8,14, it is important to note, regarding RA patients and low-grade inflammation, that higher serum CRP levels are negatively correlated with level of physical activity8, as significantly lower physical activity levels were reported among women with RA in the Nurses Health Study17.

Arthritis Curehow to Arthritis Cure for Therefore, is it possible that metabolic factors and lifestyle risk factors discussed above, rather than the rheumatic disease itself, could explain the low-grade inflammation state found in Provan and colleagues’ RA patients at baseline in 1992, or at least partly explain the condition? The answer to this question is simple: we do not know. Thus, Provan and colleagues4 do not provide the readers of The Journal with any baseline information about their RA patient cohort related to prevalence of metabolic risk factors and lifestyle risk factors. In particular, missing baseline information about estimates of overweight and body composition, level of physical activity, smoking habits, blood pressure levels, serum insulin levels, and estimates of insulin resistance, all factors reported in various studies to be relatively closely correlated with both serum CRP levels and large artery stiffness8,18,19, makes the results reported by Provan and colleagues difficult to interpret in depth discussing presence of low-grade inflammation in patients with RA. The relevance of this point is further highlighted by a recent report in The Journal by Crowson and colleagues20, that patients with RA were found to have significantly increased waist circumference and elevated blood pressure status compared with controls, and although the results in the medical literature are not entirely consistent, several articles have been published describing that patients with RA have a higher prevalence of metabolic disturbances, in particular hypertension and insulin resistance7. In this context, it is interesting that Chung and colleagues7 found that RA patients with insulin resistance had significantly higher serum CRP levels compared with insulin-sensitive RA patients [median (interquartile range): 6 mg/l (3–14) vs 3 mg/l (3–9); p = 0.01]. Further, it is of note that in a study by Rosenvinge and colleagues21 RA patients with active disease showed marked insulin resistance compared with well matched controls, but the level of insulin resistance was not influenced by anti-TNF-α therapy despite marked reductions in serum levels of CRP, which changed from the high-grade to the low-grade inflammation range. Thus taken together, it is likely that “metabolic inflammation” also contributes to raised serum CRP levels in the low-grade inflammation range in RA patients with well controlled or mild disease activity.

As mentioned above, studies using Mendelian randomization have shown that genetically elevated serum levels of CRP are associated neither with increased CVD risk9 nor with measures of aortic stiffness10, suggesting that CRP is merely a risk marker rather than a causal factor in the disease processes that eventually lead to clinical CVD. Thus, when discussing “metabolic inflammation” versus inflammation caused by rheumatic diseases, it would have been interesting if Provan and colleagues4 had measured inflammatory cytokines in the blood, such as IL-6 and TNF-α, and had shown that baseline levels of these inflammatory cytokines were also associated with increased central artery stiffness at followup 15 years later.

So, what is the lesson to be learned from the article by Provan and colleagues4 and the present article: elevated serum CRP levels above > 3.80 mg/l are associated prospectively with increased large artery stiffness, an established risk factor for CVD6; physicians caring for the 1 last update 2020/07/09 patients with RA should consider the presence of metabolic CVD risk factors, possibly requiring pharmacological or nonpharmacological treatment, as well as uncontrolled rheumatic disease in RA patients with raised serum CRP levels within the low-grade inflammation range, a view supported by experts in the field5.So, what is the lesson to be learned from the article by Provan and colleagues4 and the present article: elevated serum CRP levels above > 3.80 mg/l are associated prospectively with increased large artery stiffness, an established risk factor for CVD6; physicians caring for patients with RA should consider the presence of metabolic CVD risk factors, possibly requiring pharmacological or nonpharmacological treatment, as well as uncontrolled rheumatic disease in RA patients with raised serum CRP levels within the low-grade inflammation range, a view supported by experts in the field5.

REFERENCES

  1. for 1 last update 2020/07/09 1.1.
    1. Ridker Arthritis Curehow to Arthritis Cure for PM,
    2. Silvertown Arthritis Curehow to Arthritis Cure for JD
    . Inflammation, c-reactive protein, and atherothrombosis. J Periodontol 2008;79 Arthritis Curehow to Arthritis Cure for Suppl: for 1 last update 2020/07/09 15441544Arthritis Curehow to Arthritis Cure for 51.
  2. 2.
    1. Libby P,
    2. for 1 last update 2020/07/09 RidkerRidker PM,
    3. Arthritis Curehow to Arthritis Cure for Hansson GK,
    4. Leducq Transatlantic Network on Atherothrombosis
    . Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol the 1 last update 2020/07/09 20092009;54:212938.
  3. 3.
    1. Ridker Arthritis Curehow to Arthritis Cure for PM,
    2. Cook NCook N
    . Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham Risk Scores. Circulation 2004;109:19559.
  4. 4.
    1. Arthritis Curehow to Arthritis Cure for Arthritis Curehow to Arthritis Cure for the 1 last update 2020/07/09 ProvanProvan Arthritis Curehow to Arthritis Cure for SA,
    2. Arthritis Curehow to Arthritis Cure for Angel the 1 last update 2020/07/09 KKAngel the 1 last update 2020/07/09 KK,
    3. Semb AG,
    4. for 1 last update 2020/07/09 MowinckelMowinckel P,
    5. Agewall S,
    6. Atar D,
    7. et al.
    Early prediction of increased arterial stiffness in patients with chronic inflammation: a 15-year follow-up study of 108 patients with rheumatoid arthritis. J Rheumatol 2011;38:60612.
  5. 5.
    1. Pieringer H,
    2. Pichler Arthritis Curehow to Arthritis Cure for M
    . Cardiovascular morbidity and mortality in patients with rheumatoid arthritis: vascular alterations and possible clinical implications. Q J Med the 1 last update 2020/07/09 20112011;Arthritis Curehow to Arthritis Cure for 104:1326.
  6. 6.
    1. Willum-Hansen T,
    2. Staessen JA,
    3. Torp-Pedersen CTorp-Pedersen C,
    4. Rasmussen S,
    5. Thijs Arthritis Curehow to Arthritis Cure for L,
    6. Ibsen H,
    7. et al.
    Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 2006; for 1 last update 2020/07/09 113113:66470.
  7. 7.
    1. Chung CP,
    2. Oeser A,
    3. Arthritis Curehow to Arthritis Cure for Solus JF,
    4. Arthritis Curehow to Arthritis Cure for the 1 last update 2020/07/09 AvalosAvalos for 1 last update 2020/07/09 II,
    5. Arthritis Curehow to Arthritis Cure for Gebretsadik T,
    6. Shintani Arthritis Curehow to Arthritis Cure for A,
    7. et for 1 last update 2020/07/09 al.et al.
    Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis 2008;196:Arthritis Curehow to Arthritis Cure for 75663.
  8. 8.
    1. Jeppesen J,
    2. Hansen Arthritis Curehow to Arthritis Cure for TW,
    3. Olsen MHOlsen MH,
    4. Rasmussen S,
    5. Ibsen H,
    6. for 1 last update 2020/07/09 Torp-PedersenTorp-Pedersen C,
    7. Arthritis Curehow to Arthritis Cure for et al.
    C-reactive protein, insulin resistance and risk of cardiovascular disease: a population-based study. Eur J Cardiovasc Prev Rehabil Arthritis Curehow to Arthritis Cure for 2008;15:5948.
  9. 9.
    1. Zacho Arthritis Curehow to Arthritis Cure for J,
    2. Tybjaerg-Hansen A,
    3. Jensen JS,
    4. Grande P,
    5. Sillesen H,
    6. Nordestgaard BG
    . Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008;359:1897908.
  10. 10.
    1. Schumacher WSchumacher W,
    2. Cockcroft J,
    3. Timpson NJ,
    4. McEniery CM,
    5. Arthritis Curehow to Arthritis Cure for Gallacher J,
    6. Rumley ARumley A,
    7. et al.
    Association between C-reactive protein genotype, circulating levels, and aortic pulse wave velocity. Hypertension 2009;53:1507.
  11. Arthritis Curehow to Arthritis Cure for 11.
    1. Sattar N,
    2. McCarey DW,
    3. Capell H,
    4. McInnes IB
    . Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 2003;108:295763.
  12. 12.
    1. Clyne B,
    2. the 1 last update 2020/07/09 OlshakerOlshaker JS
    . The C-reactive protein. J Emerg Med 1999;17:101925.
  13. 13.
    1. Graf JGraf J,
    2. Scherzer RScherzer R,
    3. Arthritis Curehow to Arthritis Cure for Grunfeld C,
    4. Imboden J
    . Levels of C-reactive protein associated with high and very high cardiovascular risk are prevalent in patients with rheumatoid arthritis. PLoS One 2009;4:e6242.
  14. 14.
    1. Mendall MAMendall MA,
    2. Arthritis Curehow to Arthritis Cure for Patel P,
    3. Ballam L,
    4. Strachan D,
    5. Northfield TC
    . C reactive protein and its relation to for 1 last update 2020/07/09 cardiovascular risk factors: a population based cross sectional studyC reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ 96;3110615.
  15. 15.
    1. Yudkin JS,
    2. Stehouwer the 1 last update 2020/07/09 CDCD,
    3. Emeis JJ,
    4. Arthritis Curehow to Arthritis Cure for Coppack SW
    . C-reactive protein in healthy subjects: associations for 1 last update 2020/07/09 with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol the 1 last update 2020/07/09 19991999;19:9728.
  16. 16.
    1. Mohamed-Ali V,
    2. Goodrick S,
    3. Arthritis Curehow to Arthritis Cure for Rawesh for 1 last update 2020/07/09 AA,
    4. Katz DR,
    5. Arthritis Curehow to Arthritis Cure for Miles JM,
    6. Yudkin JS,
    7. et al.
    Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997;82:4196200.
  17. 17.
    1. Solomon DH,
    2. Karlson EW,
    3. Arthritis Curehow to Arthritis Cure for Rimm EB,
    4. Cannuscio CC,
    5. Arthritis Curehow to Arthritis Cure for Mandl for 1 last update 2020/07/09 LALAMandl for 1 last update 2020/07/09 LALA,
    6. Manson JE,
    7. et al.
    Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation for 1 last update 2020/07/09 20032003;107:Arthritis Curehow to Arthritis Cure for 1303 the 1 last update 2020/07/09 77.
  18. 18.
    1. Arthritis Curehow to Arthritis Cure for McEniery CM,
    2. Arthritis Curehow to Arthritis Cure for the 1 last update 2020/07/09 YasminYasmin,
    3. Arthritis Curehow to Arthritis Cure for Maki-Petaja the 1 last update 2020/07/09 KMKM,
    4. McDonnell BJ,
    5. Munnery M,
    6. Hickson SS,
    7. et al.,
    8. Arthritis Curehow to Arthritis Cure for Anglo-Cardiff Collaboration Trial Investigators
    . The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: the Anglo-Cardiff Collaborative Trial (ACCT III). Hypertension 2010;56:591 for 1 last update 2020/07/09 77.
  19. 19.
    1. Hansen TW,
    2. Jeppesen J,
    3. Rasmussen SRasmussen S,
    4. Ibsen H,
    5. Arthritis Curehow to Arthritis Cure for Torp-Pedersen C
    . Relation between insulin and aortic stiffness: a population-based study. J Hum Hypertens the 1 last update 2020/07/09 20042004; for 1 last update 2020/07/09 1818:1 the 1 last update 2020/07/09 77.
  20. 20.
    1. Chung CP,
    2. for 1 last update 2020/07/09 OeserOeser A,
    3. Solus JF,
    4. Avalos I,
    5. Gebretsadik T,
    6. Shintani Arthritis Curehow to Arthritis Cure for A,
    7. et al.
    Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis for 1 last update 2020/07/09 20082008;196:75663.
  21. Arthritis Curehow to Arthritis Cure for the 1 last update 2020/07/09 21.21.
    1. Rosenvinge A,
    2. Krogh-Madsen Arthritis Curehow to Arthritis Cure for R,
    3. Baslund B,
    4. Pedersen BK
    . Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNF-alpha therapy. Scand J Rheumatol Arthritis Curehow to Arthritis Cure for 2007;36:916.
Arthritis Curehow to Arthritis Cure for
View Abstract
Sign In to Email Alerts with your Email Address

Thank you for your interest in spreading the word about The Journal of Rheumatology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
(Your Name) has forwarded a page to you from The Journal of Rheumatology
(Your Name) thought you would like to see this page from the The Journal of Rheumatology web site.
Low-grade Chronic Inflammation and Vascular Damage in Patients with Rheumatoid Arthritis: Don’t Forget “Metabolic Inflammation”
JØRGEN JEPPESEN
The Journal of Rheumatology Apr 2011, 38 (4) 595-597; DOI: 10.3899/jrheum.110006
Low-grade Chronic Inflammation and Vascular Damage in Patients with Rheumatoid Arthritis: Don’t Forget “Metabolic Inflammation”
JØRGEN JEPPESENJØRGEN JEPPESEN
Arthritis Curehow to Arthritis Cure for The Journal of Rheumatology Apr 2011, 38 Arthritis Curehow to Arthritis Cure for (4) 595-597; DOI: 10.3899/jrheum.110006 DOI: 10.3899/jrheum.110006
Arthritis Curehow to Arthritis Cure for Save to my folders