Macrophage Activation Syndrome Clinical Trial
Official title:
Comparison of Predictive Ability of New Candidate Criteria for Diagnosis of Macrophage Activation Syndrome
Macrophage activation syndrome(MAS) is a complication of bone marrow suppression,
coagulopathy and CNS dysfunction which occurs in rheumatic diseases. Normally the
(Hemophagocytic Lympho-Histiocytosis) HLH-2004 criteria is used to diagnose patients with
MAS. However this criteria is probably not sensitive and would probably be fulfilled quite
late into the disease. Thus there would be an unacceptable delay. Ravelli et al came up with
a different set of criteria based on data of patients reported in literature.
Systemic onset juvenile idiopathic arthritis (SoJIA) is the most common cause of MAS. MAS in
other rheumatic illnesses occurs in the setting on unbridled inflammation. In both SoJIA and
uncontrolled rheumatic disease the patient is liable to have high WBC counts and high
platelet counts. Bone marrow suppression which is one of the pathognomic features of MAS
would be picked up very late if absolute cut off values were utilized. Kelly et al used the
same arguments in their review to suggest that in MAS/Reactive hemophagocytic
lymphohistiocytosis(ReHLH), the trend of change in laboratory parameters would be more
useful than absolute cut offs. Hence the investigators propose new candidate criteria which
are based on trends of laboratory parameters and seek to determine their utility in
comparison to absolute cut offs of HLH or Ravelli criteria. The investigators also wanted to
determine that among the Ravelli criteria and HLH-2004 criteria, which were fulfilled
earlier in patients diagnosed as having MAS.
Study hypothesis:-Criteria which measure serial trend of laboratory parameters would be
fulfilled earlier than absolute cut offs when diagnosing MAS in patients with rheumatic
illness.
Abbreviations:- ANC:- Absolute neutrophil count DIC:- Disseminated intra-vascular
coagulation HLH:- Hemophagocytic lymphohistocytosis IAHS:- Infection associated
hemophagocytic syndrome MAS:- Macrophage activation syndrome MODS:- Multi-organ dysfunction
syndrome NK cell:- Natural Killer cells ReHLH:- reactive HLH SoJIA:- Systemic onset juvenile
idiopathic arthritis SLE:- Systemic lupu erythematosus WBC:- white blood cell count
Background and Introduction:- The first appearance in literature of description of patients
with what was later to be known as macrophage activation syndrome (MAS) is probably the
description of SoJIA patients who had a fulminant course with hepatic failure by Boone et
al1 and those with coagulopathy by Silverman et al2. However the term "macrophage activation
syndrome" (and Syndromes of inappropriate macrophage activation in childhood) was first used
in medical literature by French pediatricians and hemat-oncologists3-5. The credit for the
same is wrongly attributed to Stephen et al, who were actually the first to use the term in
"rheumatology" literature in their description of 4 SoJIA patients with this complication6.
It is evident from the quoted literature that MAS at the time of it's intial recognition as
a symptom complex or complication of rheumatic illness, was a universally fatal illness.
Since then our understanding of it's pathology and it's treatment has grown considerably.
The main defect in MAS is deficient NK cell activity. Hence a trigger which stimulates the
immune system leads to unchecked CD8+ T cell proliferation which persists even after
elimination of the trigger. These T cells secrete IFN-gamma which leads to macrophage
overstimulation. This in turn activates a cytokine storm production (TNF a, IL 1 and IL 6)
and phagocytosis of marrow elements by the marcophages, ultimately leading to MODS7. MAS
usually occurs in the setting of an untreated or inadequately controlled rheumatic disease
with severe systemic inflammation. The diagnosis is difficult particularly against this
background and therefore a high clinical suspicion is paramount.
Among the many rheumatic diseases MAS has been predominantly described associated with
SoJIA. The next most common rheumatic illness described has been SLE. The hallmarks of this
complication are Bone marrow suppression, DIC with abnormal bleeding, encephalopathy/
seizures, and hepatitis. MAS has been increasing been recognized to have similarities with
Class II histiocytic disorders or hemophagocytic lymphohistiocytosis (HLH). In the most
recent classification of these disorders Class II disorders have been further subdivided
into primary (due to a genetic defect), secondary (due to infections, malignancies,
immunodeficiency) and reactive (due to rheumatic diseases)8. The last category alludes to
MAS.
Rationale and justification:-The HLH disorders are diagnosed using the HLH criteria. However
as pointed out by Kelly et al9 and Ravelli et al10 use of this criteria to diagnose patients
with MAS (i.e. Reactive HLH) would lead to a unacceptable loss of sensitivity and
significant delay. Some components of the HLH criteria such as Soluble NK cell activity,
CD-25 values above normal for age, and molecular diagnosis consistent with HLH are neither
practical nor feasible in most clinical settings for a majority of rheumatology patients.
Ravelli et al came up with a different set of criteria for patients with MAS based on data
of patients reported in literature10. A comparison of the 2 criteria in a retrospective
longitudinal study11 (albeit with a very small sample size) showed that the Ravelli et al
criteria to be much more sensitive and enabled patients to be diagnosed much earlier than
when the HLH-2004 criteria was used. In both SoJIA and uncontrolled rheumatic disease the
patient is liable to have high WBC counts and high platelet counts. Bone marrow suppression
which is one of the pathognomic features of MAS would be picked up very late if absolute cut
off values were utilized. Kelly et al used the same arguments in their review to suggest
that in MAS/ReHLH, the trend of change in laboratory parameters would be more useful than
absolute cut offs.
Hence we propose new candidate criteria which are based on trends of laboratory parameters
which would probably be able to predict MAS earlier than absolute cut offs of laboratory
parameters.MAS has now undergone a name change (to Reactive HLH) and an image change (from
an universally terminal illness to a dreaded but treatable complication). Hence the need for
recognition and early diagnosis is more important today than ever before. In this era of
potent and novel immuno-modulatory medications, a sensitive criteria which would pick up
patients prone to develop MAS or in the process of developing MAS would give us the edge to
finally help us rein in this terrifying disease.
;
Observational Model: Case-Only, Time Perspective: Retrospective
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