Table 1 Included papers on diagnosis, biomarkers and treatment of MAS in sJIA patients
Authors | Year | Number of sJIA patients with MAS | Subject | Content | Evaluation design | Results | Conclusion | Limitations | LOE [13] |
|---|---|---|---|---|---|---|---|---|---|
Ravelli et al.[3] | 2005 | 74 | diagnosis | Diagnostic criteria of MAS | Comparative study | A set of preliminary clinical and laboratory criteria of MAS in sJIA. | Preliminary Ravelli criteria [Table 3]. | Not validated, lacks ferritin as parameter. | 3 |
Davi et al.[18] | 2014 | 362 | diagnosis | Assessment of performance of diagnostic guidelines | Retrospective study | The preliminary Ravelli criteria perform better than the HLH-2004 guidelines in differentiating MAS from active sJIA or infection (by adding ferritin as parameter). | The preliminary diagnostic criteria perform better than the HLH-2004 guidelines. | Retrospective study design, selection bias | 3 |
Minoia et al.[16] | 2014 | 362 | diagnosis | Disease features of MAS in sJIA | Descriptive study | Decreased platelet counts and increased ASAT, triglycerides, ferritin and LDH levels were the most common laboratory features during onset of MAS. Fever and organomegaly were the most frequent clinical symptoms. | The clinical spectrum of MAS in sJIA comprises frequently reported clinical and laboratory features. | Retrospectively collected data, possible selection bias. | 3 |
Minoia et al.[19] | 2015 | 362 | diagnosis | Clinical heterogeneity of MAS in sJIA | Descriptive study | Clinical and laboratory features of MAS in sJIA did not differ among patients registered from different geographic locations. | The clinical spectrum of MAS is comparable across patients from different geographic locations. | Retrospectively collected data, possible selection bias. | 3 |
Ravelli et al.[21] | 2015 | 362 | diagnosis | Cross-validated literature- and consensus based diagnostic guidelines for MAS in sJIA | Comparative study complemented with expert opinion | A final set of diagnostic (laboratory) criteria was approved based on the selection of best classification criteria through statistical analyses and consensus formation techniques with a higher sensitivity and specificity compared to the preliminary Ravelli criteria. | Best performing set of diagnostic criteria for MAS in sJIA [Table 3]. | Not prospectively validated, level of evidence low due to incorporation of expert opinion. | 3/4 |
Kostik et al.[22] | 2015 | 18 | diagnosis | Diagnostic criteria | Comparative study | Laboratory criteria were more precise in discriminating MAS from active sJIA than clinical variables. Eight widely available laboratory markers were selected as best for early identification of MAS. | Preliminary diagnostic criteria. | Retrospective, no evaluation of changes in laboratory parameters. | 3 |
Lehmberg et al.[23] | 2013 | 27 | diagnosis | Differentiating MAS in sJIA from HLH | Retrospective study | Generally available laboratory measures with accessory cut-off values to distinguish MAS complicating sJIA from primary HLH and virus-associated HLH (VA-HLH) were retrospectively identified. | Neutrophil counts >1.8 x 109/L, CRP >90 mg/L and sCD25 <7900 U/ml indicate MAS in sJIA rather than primary HLH or VA-HLH. | No control group, no cut-off points. | 3 |
Grom et al.[24] | 2002 | 7 | biomarkers | NK cell function | Comparative study | NK cell activity was decreased in all patients compared to healthy controls. Low NK cell activity was associated with decreased numbers of NK cells. | NK dysfunction is common in sJIA associated MAS | Small patient sample. | 3 |
Bleesing et al.[25] | 2007 | 7 | biomarkers | sCD25, sCD163 | Comparative study | sCD25 and sCD163 were significantly higher in the acute phase of MAS compared to untreated new-onset sJIA patients and correlated with disease activity. | sCD35 and sCD163 are promising biomarkers of MAS | Small number of patients, not validated | 3 |
Reddy et al.[26] | 2014 | 2 | biomarkers | sCD25, sCD163 as markers of subclinical MAS in active sJIA | Comparative study | Laboratory abnormalities associated with MAS were seen in active sJIA patients with elevated levels of sCD25 and to a lesser extend in patients with elevated levels of sCD163. | sCD25 might be a marker of subclinical MAS in active sJIA. | Only 2 MAS patients, not validated | 3 |
Gorelic et al.[27] | 2013 | 7 | biomarkers | FSTL-1, ferritin/ESR ratio | Comparative study | FSTL-1 levels during MAS are elevated compared to active sJIA. Elevated levels of FSTL-1 were associated with occult MAS, correlated with levels of sCD25 and ferritin and normalized after treatment. Ferritin/ESR ratio was superior to ferritin in discriminating MAS from new-onset sJIA. | Elevated levels of FSTL-1 might be a marker of occult MAS. | FSTL-1 is unspecific, small sample size, not validated | 3 |
Shimizu et al.[8] | 2010 | 5 | biomarkers | IL-6, IL-18, neopterin for differentiating MAS in sJIA from VA-HLH or KD | Comparative study | IL-18 was significantly higher in MAS in sJIA compared to EBV-HLH or KD and correlated with measures of disease activity. IL-6 was higher in KD patients and neopterin was higher in EBV-HLH. | Serum cytokine profiles differ between MAS in sJIA, KD and EBV-HLH. IL-18 might be useful for differentiation of MAS in sJIA from HLH. | Small sample, not validated | 3 |
Shimizu et al.[12] | 2012 | 5 | biomarkers | IL-18, IL-6 during TCZ treatment | Comparative study | TCZ can suppress clinical symptoms of MAS. IL-18 and IL-6 were elevated during MAS in patients with and without TCZ and correlated with disease activity. | During TCZ treatment, monitoring IL-18 and IL-6 could be useful to disclose early MAS. | Only 5 MAS patients, not validated | 3 |
Yokota et al.[28] | 2015 | 14 | biomarkers | Changes in laboratory markers in patients with MAS receiving TCZ | Retrospective Descriptive study | Most patients had common laboratory features associated with MAS. | Clinical and laboratory features of MAS appear similar among patients with and without TCZ treatment. | No control group, retrospective | 3 |
Shimizu et al.[29] | 2015 | 15 | biomarkers | Serum IL-18 as biomarker for the prediction of MAS in sJIA | Comparative study | During active sJIA, IL-18 levels >47750 pg/ml predicted development of MAS. IL-6 levels in patients with MAS did not differ from IL-6 levels during active sJIA in absence of MAS. | Serum IL-18 levels > 47750 pg/ml might be a biomarker for MAS development | High cut-off values suggest low sensitivity | 3 |
Kounami et al.[30] | 2005 | 5 | biomarkers | urine β2-microglobulin | Descriptive study | Urinary β2-microglobulin levels increased during MAS. | Increases in urinary β2-microglobuline might be an indicator of MAS. | No control group, small sample size, not specific | 3 |
Sawhney et al.[6] | 2001 | 8 | treatment | steroids, CsA, eto | Case-series | Patients received steroids as part of a combinational regimen, of which >62% in combination with CsA. | High dose steroids in combination with CsA was effective in cases of MAS. | Small retrospective case-series | 3 |
Mouy et al.[35] | 1996 | 5 | treatment | steroids, CsA | Case-series | CsA monotherapy was effective in 7 episodes of MAS and was effective in 3 episodes of steroid-resistant MAS. | CsA can be effective as first or second line (mono) therapy. | Small retrospective case-series | 3 |
Stephan et al.[1] | 2001 | 18 | treatment | steroids, CsA, IVIG, eto | Case-series | CsA as initial monotherapy induced remission in 5 cases. CsA was effective in 6 cases of steroid-resistant MAS. Steroids were effective as first-line (mono) therapy. IVIG was not effective. | CsA and steroids were effective as first-line monotherapy or combined. | Small retrospective case-series | 3 |
Miettunen et al.[37] | 2011 | 8 | treatment | Anakinra | Case-series | Anakinra was effective in 8 cases of conventional therapy- resistant MAS. | Anakinra was effective in cases where initial therapy with steroids and CsA failed. | Small retrospective case-series | 3 |
Ramanan et al.[31] | 2004 | 3 | treatment | (pulse) steroids, eto | Case-series | Steroid monotherapy was effective in 3 patients with MAS with renal involvement. | Steroids can be effective as monotherapy in patients with renal involvement complicating MAS. | Small retrospective case-series | 3 |
Lin et al.[2] | 2012 | 4 | treatment | steroids, IVIG, CsA | Case-series | Prednisolone was effective as monotherapy or in combination with CsA. IVIG was not effective. | Patients responded well to steroids and CsA. | Small retrospective case-series | 3 |
Kounami et al.[30] | 2005 | 5 | treatment | steroids, IVIG, CsA | Case-series | All patients treated with CsA as first or second line therapy responded well. IVIG failed as first-line treatment. | CsA was effective as first-line (mono) therapy. | Small retrospective case-series | 3 |
Singh et al.[11] | 2011 | 6 | treatment | steroids, IVIG | Case-series | Four patients responded to high dose methylprednisolone, 1 patient recovered after addition of IVIG to steroids. | Steroids were effective as initial monotherapy. | Small retrospective case-series | 3 |
Cortis et al.[36] | 2006 | 9 | treatment | steroids, CsA, etanercept | Case-series | 7 cases of MAS responded to high dose steroids with or without CsA. In one patient, a third episode of MAS responded to etanercept when steroids and CsA failed. | Patients responded well to steroids and CsA. | Small retrospective case-series | 3 |
Zeng et al.[32] | 2008 | 13 | treatment | steroids, eto, VCR, IVIG | Case-series | Steroids were effective as first-line (mono) therapy. 1 patient responded to eto after steroids, CsA and IVIG failed. | Steroids were effective as first-line (mono) therapy. | Small retrospective case-series | 3 |
Nakagishi et al.[34] | 2014 | 3 | treatment | Dexamethasone palmitate | Case-series | All three patients were resistant to methylprednisolone but responded well to dexamethasone palmitate. | DexP can be effective in mps-resistant MAS. | Small case-series | 3 |