Table 3 Characteristics of all studies included in the systematic review investigating cytokines in FMS patients.

Hader, 1991

Smythe

12/10

a) CD4+ T-lymphocytes from PBMC

b) T-cell culture; stimulation experiments with mitogens and measurement of IL-2 secretion

c) IL-2

FMS: higher concentration of mitogen was necessary to achieve optimal IL-2 secretion; peak time of IL-2 secretion was delayed.

Addition of calcium did not correct the reduction in IL-2 secretion in patients with FMS; addition of phorbole myristate acetate led to normal IL-2 secretion.

3d

2

0.4

Barth, 1999

Wolfe, 1985

12 FMS/6 rheumatoid arthritis or osteoarthritis controls/6 controls

a) supernatant of PBMC

b) self established double sandwich ELISA;

c) IL-4; IL-2; INFγ; GM-CSF; IL-5, IL-10

In vitro stimulation of PBMC with different L-tryptophan preparations: 6/12 FMS patients, 2/12 controls: IL-5 and IL-10 production

3d

4

0.1

Maes, 1999

ACR

21/33

a) serum

B) ELISA

c) IL-6, sIL-6 R, sIL-1R, IL-1RA

In FMS compared to controls:

IL-6↔

sIL-6R ⇑

sIL-1R ⇑

IL-1RA ⇑

3d

2

0.3

Pay. 2000

ACR

25 FMS/25 chronic musculoskeletal complaints/25 controls

a) serum

b) ELISA

c) IL-1β, TNF, IL-6

No difference for pro-inflammatory cytokines in FMS and controls.

3d

3

0.4

Wallace, 2001

ACR

56/56

Serum, PBMC

a) serum, PBMC, plasma

b) ELISA

c) IL-1β, IL-2, IL-6, IL-8, IL-10, sIL-2R, IL-1RA, IFNγ, TNF

In FMS compared to controls:

IL-1β, IL-2, IL-6, IL-8, IL-10, sIL-2R, IFNγ, TNF: ↔ in sera +PBMC

IL-1RA: ⇑ in serum

IL-8: ⇑ in plasma IL-1 RA, IL-6: ⇑ in PBMC

IL-6: ⇑ in PBMC of patients with disease duration > 2 years.

3d

3

0.5

Gür, 2002

ACR

81/32

a) serum

b) ELISA

c) IL-1, IL-2R, IL-6, IL-8

In FMS compared to controls:

IL-1 ↔

IL-2 R ⇑

IL-6 ↔

IL-8 ⇑

3d

2

0.4

Schwarz, 2002

ACR

17/17

a) serum

b) ELISA

c) IL-6

IL-6 ⇑ during tryptophan depletion in FMS

3d

4

0.3

Amel Kashipaz, 2003

ACR

22 FMS/CFS/19

a) PBMC

b) intracellular cytokine stain; flow cytometry

c) IL-1α, IL-6, IL-10, TNF

In FMS compared to controls:

IL-1α ↔

IL-6 ↔

IL-10 ↔

TNF ↔

3d

2

0.7

Salemi, 2003

ACR

53/10

a) skin biopsy

b) RT-PCR, IHC

c) IL-1β, IL-6, TNF

Detectable cytokines in FMS:

IL-1β (19/50)

IL-6 (14/51)

TNF (17/53)

None of the cytokines could be detected in control skin.

3d

2

0.7

Ardic, 2006

ACR

21/10

a) serum

b) ELISA

c) IL-1 (after balneo therapy)

After balneo therapy:

IL-1↓ in FMS

3d

3

0.2

Üçeyler, 2006

ACR

26/40

a) serum; whole blood

b) qRT-PCR;

ELISA

c) IL-2, IL-4, IL-8, IL-10, TNF, TGF-β1

In FMS compared to controls:

IL-2 ↔

IL-4 ⇓

IL-8 ↔

IL-10 ⇓

TGF-β1 ↔

TNF ↔

3d

4

0.8

Bazzichi, 2007

ACR

285/40 (16 rheumatoid arthritis cases, two Sjögren's syndrome cases, 16 systemic lupus erythematosus cases,

four systemic sclerosis cases, two undifferentiated connective-

tissue disease cases)/100

a) serum, plasma

b) ELISA

c) IL-1, IL-6, IL-8, IL-10, TNFα

No intergroup difference for cytokines.

3d

3

0.2

Bazzichi, 2007

ACR

80/45

a) plasma

b) ELISA

c) IL-1, IL-6, IL-8, IL-10, TNF

IL-10, IL-8, TNF: FMS > controls

3c

3

0.9

Macedo, 2007

ACR

18/22

a) PBMC

b) automated biochip array; before and after 1.5 mg of dexamethasone per os

c) IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IFNγ, TNF

After dexamethasone: reduction of cytokines FMS > controls.

3d

2

0.4

Kaufmann, 2007

ACR

22/15 CRPS/37

a) T-cells

b) FACS analysis

c) IL-2, IFNγ, IL-4, IL-10

No difference in percentage of cytokine producing cells between FMS and controls.

3d

2

0.6

Togo,

2008

ACR

7/9

a) plasma

b) Beadlyte multi-cytokine assay

c) IL-10, IL-6, IL-8, IL-1, TNF

No difference between groups.

"FM patients showed a shift to increased IL-10 in the

nighttime compared to controls."

3d

2

0.8

Wang, 2008

ACR

20/80

a) serum

b) Bio-Plex cytokine assay

c) IL-6, IL-8, IL-10, IL-4, TNF

At baseline: IL-8 in FMS > controls; no difference for other cytokines.

3d

4

0.4

Zhang, 2008

ACR

92/69 family members/62 anonymous blood samples from blood bank

a) plasma

b) Cytokine Twenty-Five-Plex Antibody Bead Kit

c) MCP-1, Eotaxin, IP-10, IL-13, IL-5, IL-10, IL-1b, IL-2, IL-4, IL-6, IL-7, IL-8, IL-12, IL-15, IL-17, TNF, IFNa, IFNg, GM-CSF, MIG, MIP-1a, MIP-1b, IL-1ra, IL-2r

Eotaxin and MIP: FMS > controls

3d

3

0.5

Feng, 2009

ACR

100 FMS patients and family members/35 unaffected parents

a) plasma

b) Cytokine Twenty-Five-Plex Antibody Bead Kit

c) Eotaxin, MIP.1a, MCP-1, IP10, IL-12, IL-1β

Rare missense variants of the MEFV gene are associated with risk of FMS and are present in a subset of 15% of FMS patients. This subset had, on average, high levels of plasma IL-1b compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype.

3d

3

0.4

Blanco, 2010

ACR

63/49

a) skin

b) immuno-histochemistry

c) MCP-1, TNF

MCP-1: FMS < controls

3c

3

0.8

Blanco, 2010

ACR

79/59

a) plasma

b) sandwich enzyme immunoassay kits

c) IL-8, TNF, sTNF-RI, sTNF-RII, MCP-1

Patients with FMS have lower systemic levels of MCP-2 than controls.

3d

3

0.4

Hernandez, 2010

ACR

64/25

a) serum

b) ELISA

c) TNF, IL-1, IL-6

TNF: FMS < controls

IL-1: not detectable in FMS

IL-6: FMS > controls

3c

4

0.6

Iannucelli, 2010

ACR

51/25 tension type headache/15

a) serum

b) multiplex bead-based sandwich immunoassay

c) IL-1β, IL-1Rα, IL-4, IL-6, IL-8, IL-10, INFγ, TNF

FMS > controls: IL-1RA, IL-6, IL-10, TNF

3d

3

0.7

Ortega, 2010

ACR

9/9

a) PBMC

b) ELISA

c) IL-1β, TNF, IL-6, IL-10

For all cytokines investigated: higher values at baseline in FMS compared to controls; after aquatic exercise levels as in controls.

3d

3

0.3

Ross, 2010

ACR

24/none

a) serum

b) bead-based immunofluorescence assay

c) IL-1α, IL-1β, IL-1RA, IL-6, IL-8, IL-10, TNF

IL-6 and IL-8: FMS responders (i.e. GH response to exercise of ≥ 5 ng/mL) higher than FMS non-responders. For IL-1α vice versa.

4

1

0.2