MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes

Abstract

Objectives: To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome.

Methods: A total of 39 patients with CAPS, including 5 FCAS, 16 MWS and 18 CINCA syndrome, received anti-IL-1 therapy. All patients with CINCA and 12 with MWS were treated with IL-1Ra (anakinra), 14 patients with MWS with a monoclonal anti-IL-1β antibody (canakinumab) and patients with FCAS received IL-1 Trap (rilonacept). During serial clinical visits serum amyloid A, C-reactive protein, erythrocyte sedimentation rate and MRP8/14 serum levels were analysed.

Results: Untreated patients with CAPS had significantly elevated MRP8/14 values. In response to treatment there was a significant reduction of MRP8/14 levels in CINCA (2,830 (range 690 - 8,480) ng/ml to 670 ng/ml, p < 0.001) and MWS patients (anakinra-treated: 4,390 (1790 - 9780) ng/ml to 1,315 ng/ml (p = 0.003); canakinumab-treated: 3,000 (500 - 13060) ng/ml to 630 ng/ml (p=0.001)). However, in many patients with CAPS, MRP8/14 levels were still elevated compared with healthy individuals, reflecting residual disease activity. However, canakinumab-treated patients with CAPS showed normalised MRP8/14 levels, suggesting control of phagocyte activation.

Conclusions: Monitoring of cellular systems involved in inflammatory cascades of the innate immunity was successfully applied to the IL-1-driven CAPS diseases. This is the first study illustrating different states of subclinical disease activity in all types of CAPS depending on the type of anti-IL-1 therapy. MRP8/14 is a sensitive biomarker for monitoring disease activity, status of inflammation and response to IL-1 blockade in patients with CAPS.

Figure 1

Interleukin (IL-1) blockade in patients with Muckle–Wells syndrome (MWS): anakinra versus canakinumab. (A) Serum concentrations of MRP8/14 (myeloid-related proteins); (B) ESR (erythrocyte sedimentation rate); (C) CRP (C-reactive protein) and (D) SAA (serum amyloid A) were determined in anakinra- (N=12) and canakinumab-treated patients with MWS (N=14) at baseline, short-term (day 14 in anakinra-treated patients, and day 8 in canakinumab-treated patients) and last follow-up (4–19 months in anakinra-treated patients, and 6–15 months in canakinumab-treated patients). The scatter plot depicts the measured values for each patient. Horizontal grey line indicates mean. Dashed grey lines indicate the upper limit of healthy individuals (MRP < 450 ng/ml, ESR < 20 mm/h, CRP < 0.5 mg/dl, SAA < 10 mg/l).

Figure 2

Individual follow-up of patients with chronic infantile neurological, cutaneous and articular (CINCA) syndrome treated with anakinra. (A) Serum concentrations of MRP8/14 (myeloid-related proteins); (B) ESR (erythrocyte sedimentation rate); (C) CRP (C-reactive protein) and (D) SAA (serum amyloid A) in 18 patients with CINCA before starting of interleukin 1 receptor antagonist (IL-1Ra; anakinra) treatment at baseline, after 3 months of treatment, after 12 months of treatment and at last follow-up (18 months). The scatter plot depicts the measured values for each patient. Horizontal line indicates mean. In general, MRP8/14 serum levels and the other inflammatory markers mirror the clinical response to treatment after starting anakinra therapy. Nevertheless, none of the inflammation markers normalise (and are less than the cut-off point of healthy controls as indicated by the grey dashed line) in a substantial proportion of patients.

Figure 3

Individual follow-up of patients with familial cold autoinflammatory syndrome (FCAS) treated with interleukin 1 (IL-1) Trap. (A) Serum concentrations of MRP8/14 (myeloid-related proteins); (B) ESR (erythrocyte sedimentation rate); (C) CRP (C-reactive protein) and (D) SAA (serum amyloid A) in five patients with FCAS before starting IL-1 Trap (rilonacept) treatment at baseline, after 3 months of treatment, after 6 months of treatment and at last follow-up (24–32 months). The measured values are heterogeneous in the five patients and have a trend to decrease after the start of treatment. Nevertheless, significant differences cannot be seen in this small number of patients. The scatter plot depicts the measured values for each patient. Horizontal line indicates mean. Dashed grey line indicates the upper limit of healthy individuals (MRP < 450 ng/ml, ESR <20 mm/h, CRP < 0.5 mg/dl, SAA < 10 mg/l).