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• Anti-inflammatory cytokine activity in pregnant women with rheumatoid arthritis
  Roberto Gerli
  Published on: 16 February 2005

• Published on: 16 February 2005

  Anti-inflammatory cytokine activity in pregnant women with rheumatoid arthritis

  • Roberto Gerli, Associate Professor
  • Other Contributors:
    • Elena Bartoloni Bocci, and Claudio Lunardi

  Dear Editor,

  We read with interest the analysis of pro- and anti-inflammatory cytokines in pregnant women with chronic inflammatory arthritis, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and ankylosing spondylitis, recently described by Oestensen et al [1].

  Besides direct measurement of cytokine serum levels, they analysed the levels of soluble CD30 (sCD30), a surface protein...

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  Dear Editor,

  We read with interest the analysis of pro- and anti-inflammatory cytokines in pregnant women with chronic inflammatory arthritis, such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and ankylosing spondylitis, recently described by Oestensen et al [1].

  Besides direct measurement of cytokine serum levels, they analysed the levels of soluble CD30 (sCD30), a surface protein released by CD30+ T cells which have been associated with the production of Th2-type anti-inflammatory cytokines (in particular IL-4 and, in part, IL-10) [2,3]. High levels of sCD30, that could represent, therefore, an indirect marker of counter-regulatory cell activity, have been described in several chronic inflammatory rheumatic disorders, including RA [3,4]. In their study, however, Oestensen et al. did not find any differences in sCD30 serum levels between RA and control non-pregnant women. Moreover, in contrast to the expected finding of increased sCD30 levels during pregnancy, that usually provides beneficial effect on RA disease activity, a progressive decrease of serum levels in the course of pregnancy was observed, although median of sCD30 from all sera of RA pregnant women demonstrated higher levels than those from non-pregnant RA and control subjects. These apparently conflicting data may be explained by some observations. High serum levels of sCD30 in RA, particularly in patients with circulating rheumatoid factor, have been confirmed in different studies, but the sCD30 concentration reported is very wide [4-7]. Indeed, the median value we found in a large series of 148 RA patients was 79.7 U/ml, significantly different from the values of age- and sex-matched healthy controls (19.1 U/ml, p<_0.001 but="but" ranging="ranging" from="from" _9.5="_9.5" to="to" _515="_515" u="u" ml.="ml." p="p"/> Longitudinal evaluations performed in several of these patients usually showed steady levels over time in subjects with stable disease activity, but showed significant changes after starting remission-inducing treatments, such as anti-TNFa-blockade (unpublished data). It is important to note, however, that these changes are essentially observed in subjects with medium-high levels of sCD30, whereas low basal values remain persistently stable irrespective of disease activity.

  In the Oestensen’s study, median of sCD30 values in non-pregnant women is rather low and this may be due to both low number and different selection of the patients, for example prevalent inclusion of patients with seronegative RA, mild disease or in remission. In addition, the pooling of samples from the three trimesters of pregnancy may be misleading and, in our opinion, the very low number of pre-pregnant women does not allow to draw any conclusion. Finally, the inclusion in RA group of patients with JIA may be not correct due to possible different roles exerted by CD30+ T cells in the JIC subgroups [6]. The persistently low levels of sCD30 in the longitudinal evaluation are in agreement with the observation of stable values of sCD30 when they are around the normal range and the slight decrease may be due in fact to enhancement of plasma volume due to pregnancy, as suggested by the Authors. This finding is in line with our analysis in two RA women followed-up before and during pregnancy, whose sCD30 values remained firmly below 25 U/ml also after delivery (Table 1). On the contrary, an increase of sCD30 values was observed during pregnancy in other 4 RA patients with basal sCD30 levels ranging from 60 to 348 U/ml. The increase was already observed in the first trimester and persisted until the delivery. The lack of correlation of sCD30 circulating levels and disease activity scores in the Oestensen’ RA cohort is not surprising, since an inverse correlation between an inflammation marker, such as C-reactive protein, and sCD30 has been found only in patients with early disease and high sCD30 serum levels before starting disease modifying anti-rheumatic drugs. [8]

  Although we are unable to explain the reasons of the absence of significant levels of sCD30 in a subset of RA patients, the high levels found in 4 of our 6 pregnant patients support the postulated counter-regulatory role of CD30+ T cells in RA. In addition, these findings point out the complex cytokine network characterizing RA synovitis, where spontaneous or physiological events, such as pregnancy, and/or treatment-induced prevalence of pro- or anti-inflammatory activity lead to disease flare or remission. [9] In this setting, we agree with Oestensen’s statement that simultaneous evaluation of markers not only of Th2-, but also of Th1-type cytokine-producing lymphocytes actively involved in RA synovitis, such as CD26+ cells,10,11 may help to better define the imbalance present in rheumatoid synovial microenvironment.

  References

  (1). Oestensen M, Foerger F, Nelson JL, et al. Pregnancy in patients with rheumatic diseases : Anti.inflammatory cytokines increase in pregnancy and decrease post-partum. Ann Rheum Dis Published Online First November 11, 2004. doi:10:1136/ard.2004.029538.

  (2). Gerli R, Pitzalis C, Bistoni O, et al. CD30+ T cells in rheumatoid synovitis: mechanisms of recruitment and functional role. J Immunol 2000;164:4399-407.

  (3). Gerli R, Lunardi C, Vinante F, et al. Role of CD30+ T cells in rheumatoid arthritis: a counter-regulatory paradigm for Th1-driven diseases. Trends Immunol 2001;22:72-7.

  (4). Gerli R, Muscat C, Bistoni O, et al. High levels of the solubile form of CD30 molecule in rheumatoid arthritis (RA) are expression of CD30+ T cells involvement in the inflamed joints. Clin Exp Immunol 1995;102:547-50.

  (5). Ichikawa Y, Yoshida M, Yamada C, et al. Circulating soluble CD30 levels in primary Sjögren’s syndrome, SLE and rheumatoid arthritis. Clin Exp Rheumatol 1998;16:759-60.

  (6). de Kleer M, Kamphuis SM, Rijkers GT, et al. The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum 2003;48:2001-10.

  (7). Okamoto A, Yamamura M, Iwahashi M, et al. Pathophysiological functions of CD30+ CD4+ T cells in rheumatoid arthritis. Acta Med Okoyama 2003;57:267-77.

  (8). Gerli R, Bistoni O, Lunardi C, et al. Solubile CD30 in early rheumatoid arthritis as a predictor of good response to second-line therapy. Rheumatology 1999;38:1282-4.

  (9). Gerli R, Lunardi C, Pitzalis C. Unmasking the anti-inflammatory cytokine response in rheumatoid synovitis. Rheumatology 2002;41:1341-5.

  (10). Muscat C, Bertotto A, Agea E, et al. Expression and functional role of 1F7 (CD26) antigen on peripheral blood and synovial fluid T cells in rheumatoid arthritis patients. Clin Exp Immunol 1994;98:252-6.

  (11). Gerli R, Muscat C, Bertotto A, et al. CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis. Clin Immunol Immunopathol 1996;80:31-7.

  Table 1: Serum levels of sCD30 (U/ml) in 6 RA patients before, during and after pregnancy

  		Pregnancy Trimester
  Patients	Pre-pregnancy	1st	2nd	3rd	Post partum (2ms)
  1	15	12	16	10	22
  2	24	18	21	11	23
  3	60	84	79	102	56
  4	94	162	158	199	86
  5	348	405	483	306	257
  6	106	137	111	214	173

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  Conflict of Interest:
  None declared.

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