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Diagnosis of MAS Hinges on Lab FindingsB Y B R U C E J A N C I N
FROM A SYMPOSIUM SPONSORED BY THE AMERICAN
COLLEGE OF RHEUMATOLOGY
SNOWMASS, COLO. – Macrophage activation syn-drome is a challenging diagnosis whose most usefulclues are to be found in the laboratory report.
Suspect the life-threatening diagnosis of macrophageactivation syndrome (MAS) in a patient with virtuallyany form of active rheumatologic disease who becomesacutely ill with a sharp drop in both erythrocyte sedi-mentation rate and platelet count in the presence of apersistently high C-reactive protein and escalating lev-els of serum D-dimers, urged Dr. Alexei A. Grom.
Another suggestive laboratory feature is marked hy-perferritinemia. Patients with MAS often have a serumferritin level in excess of 10,000 ng/mL, Dr. Grom saidat the meeting.
Moreover, while normally 60%-80% of serum ferritinis glycosylated, in MAS it’s typically less than 20%. Thismakes measurement of serum glycosylated ferritin auseful diagnostic tool, noted Dr. Grom, a pediatricrheumatologist at Cincinnati Children’s Hospital Med-ical Center.
Assessment of serum levels of soluble CD163 and sol-uble interleukin-2-receptor-alpha chains can also helppin down the diagnosis. They are strikingly elevated inMAS, and not in many other conditions. Extreme hy-pertriglyceridemia is another characteristic feature of thesyndrome.
The central feature of MAS, he continued, is un-controlled expansion of cytotoxic CD8 cells secreting
cytokines that stimulate macrophages to exhibit he-mophagocytic activity.
Indeed, hemophagocytic activity on the part of high-ly activated macrophages is the hallmark of MAS.Identification of hemophagocytic macrophages in thebone marrow confirms the diagnosis. Unfortunately, of-ten this finding is not present early in the course of thedisease.
This macrophage hemophagocytosis explains theextreme hyperferritinemia seen in MAS. Free hemo-globin is released as erythrocytes are phagocytized. Thiscreates a need to boost ferritin production in order to
sequestrate the free iron, he explained. Three cardinal features of the massive systemic in-
flammatory response that defines MAS are liver dys-function, cytopenias, and coagulopathy consistentwith disseminated intravascular coagulation. Howev-er, like hemophagocytic macrophages in the bonemarrow, these features often are not of much help inmaking an early diagnosis. Overt cytopenia is seen onlyin the late stages of MAS.
Abnormal liver function tests and laboratory evi-dence of coagulopathy can also occur in a flare of sys-temic juvenile idiopathic arthritis – and since 80% of pe-diatric MAS occurs in patients with SJIA, hepaticdysfunction and coagulopathy are not useful in mak-ing the distinction.
The clinical presentation of MAS includes persistentfever, impressively enlarged lymph nodes, prominenthepatosplenomegaly, and a hemorrhagic rash featuringbruising, then purpura, followed by mucosal bleeding.Many patients also develop mental status changesand/or seizures.
These clinical features can be viewed as largely a con-sequence of a cytokine storm involving increased in-terferon-gamma, granulocyte macrophage colony–stimulating factor, tumor necrosis factor-alpha, and in-terleukin-1, -6, and -18.
No trigger is identifiable in the majority of cases ofMAS. When a trigger is found, it is most commonly aninfection with Epstein-Barr virus or cytomegalovirus.
MAS has a 10%-20% mortality. The death rate is de-clining in pediatric patients because of increasing aware-
Continued on following page
20 PEDIATRIC RHEUMATOLOGY A P R I L 2 0 1 1 • R H E U M AT O L O G Y N E W S
Bone marrow specimen shows macrophagehemophagocytosis in a patient with systemicjuvenile idiopathic arthritis and MAS.
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A P R I L 2 0 1 1 • W W W. R H E U M AT O L O G Y N E W S . C O M PEDIATRIC RHEUMATOLOGY 21
ness of the syndrome and consequentearlier diagnosis and initiation of treat-ment.
“I think that in adult rheumatologythis condition is still relatively unrecog-nized. My adult rheumatology col-leagues in Cincinnati believe that manyof these patients end up with a diagno-sis of culture-negative sepsis,” he said.
It is crucial to understand that rough-ly one-third of patients with MAS willexperience recurrent episodes.
For this reason, Dr. Grom provides pa-tients with a letter explaining their con-dition in the event they should have arecurrence while out of town, necessi-tating a visit to an emergency depart-ment where physicians may be MAS in-experienced.
Dr. Grom declared having no relevantfinancial interests. ■
Continued from previous page
MAS Treatment Failures Stir Controversy B Y B R U C E J A N C I N
FROM A SYMPOSIUM SPONSORED BY THE
AMERICAN COLLEGE OF RHEUMATOLOGY
SNOWMASS, COLO. – Treatment ofmacrophage activation syndrome with a combination of high-dose cortico-steroids and cyclosporine is quite effec-tive in the majority of cases if started suf-ficiently early; it’s what to do for theothers where the controversy arises, ac-cording to Dr. Alexei A. Grom.
One reasonable option is to use the In-ternational Histiocyte Society treatmentprotocol for hemophagocytic lympho-histiocytosis, a hematology/oncologydisorder bearing clinical similarities tomacrophage activation syndrome (MAS).This protocol entails supplementing cor-ticosteroids and cyclosporine with etopo-side (VP-16), a mitotic inhibitor and an-tineoplastic agent used in treating avariety of cancers. Etoposide is em-ployed to induce apoptosis of activatedphagocytic macrophages and other im-mune cells, he said at the symposium.
But while etoposide is a reasonablenext step, the drug’s numerous short-and long-term side effects – including se-vere myelosuppression leading to fatalsepsis – have caused many physicians tolook for alternatives. Among the morepromising are antithymocyte globulinand rituximab, said Dr. Grom, a pediatricrheumatologist at Cincinnati Children’sHospital Medical Center.
Antithymocyte globulin depletes Tcells, including CD8 cells, and mono-cytes. Numerous case reports describesuccessful use of this agent in treatingMAS.
The rationale for using rituximab, a po-tent depleter of B cells, applies to patientswith Epstein-Barr virus–induced MAS.Because of the immune dysfunction pre-sent in MAS, these patients develop per-sistent viral infection harbored chiefly byB cells. Dr. Grom has used rituximab suc-cessfully in patients with Epstein-Barrvirus–triggered MAS, and he suspectsthat this approach may also be very ef-
fective in the setting of MAS associatedwith systemic lupus erythematosus.
The increased level of tumor necro-sis factor present in MAS has prompt-ed numerous attempts to use etaner-cept and other anti–tumor necrosisfactor biologics. Results have beenlargely disappointing.
“Personally, I think we should stayaway from TNF-alpha antagonists inMAS,” the pediatric rheumatologist said.
The efficacy of interleukin-1 and -6 in-hibiting agents in systemic juvenile idio-pathic arthritis (SJIA) makes them ap-pealing agents for the treatment of MAS,because MAS episodes are often trig-gered by flares of SJIA. However, case re-ports involving the interleukin-1 in-hibitor anakinra have yielded mixedresults, and to date there is very little ex-perience with interleukin-6 inhibitionin MAS.
First-line treatment of MAS by Dr.Grom and his Cincinnati colleagues be-gins with high-dose steroids, typically 3-5 days of intravenous methylpred-nisolone pulses at 30 mg/kg per daybefore dropping down to 2-3 mg/kg intwo or three divided doses. Cyclosporineis dosed at 2-5 mg/kg in two divided dos-es, usually given intravenously.
Dr. Grom said he had no relevant fi-nancial disclosures. ■
