EULAR, ACR: Likely HLH/MAS should be met with immunomodulation while diagnosis continues
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Key takeaways:
- The points to consider advise beginning immunomodulatory therapy while diagnostic investigations continue.
- Multidisciplinary teams can help achieve better outcomes.
Patients with likely hemophagocytic lymphohistiocytosis or macrophage activation syndrome should begin immunomodulation while the diagnostic investigation continues, according to new EULAR/American College of Rheumatology guidelines.
“Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes characterized by fever, elevated ferritin and other markers of systemic inflammation, inappropriately low blood cell counts, disseminated intravascular coagulopathy, hepatitis, central nervous system (CNS) inflammation and high risk for progression to multiple organ dysfunction, shock and often death,” Bita Shakoory, MD, of the NIH, and colleagues wrote in Annals of the Rheumatic Diseases.
“Early identification and intervention can prevent organ failure and death,” they added. “Nevertheless, practice patterns in recognizing and managing these conditions vary widely.”
To draft new guidelines for the management of suspected HLH and MAS, Shakoory and colleagues formed an international task force following approval from ACR and EULAR. The task force consisted of pediatric and adult rheumatologists, hematologists and oncologists, immunologists, infectious disease specialists, three intensivists, a nurse, two patient representatives and three methodologists. The panel met for an in-person meeting in 2019 to determine the scope of the project and see which questions would be addressed by the effort.
For the literature review, task force members included studies published prior to November 2020. Upon completion of the review, important principles from the search were distilled into the overarching principles and guidelines. During a consensus meeting, members discussed each point and voted for their inclusion. On the first ballot, items required an 80% consensus for inclusion in the final manuscript. Points that did not reach 80% were further discussed and voted on, and admitted only if they broached 80%.
The effort resulted in six new overarching principles and 24 points to consider. The overarching principles follow:
- HLH/MAS symptoms present on a spectrum, and therapy may be needed even if the condition does not meet all of the classification criteria.
- Systemic hyperinflammation can progress to HLH or MAS.
- Systemic hyperinflation or HLH/MAS can happen in “nearly any inflammatory state.”
- It is imperative that modifiable contributors are investigated and addressed.
- HLH or MAS should be treated with urgency while considering inflammation degree and organ dysfunction.
- Patients with systemic hyperinflammation may receive aid from consulting experts in HLH or MAS.
The points to consider are divided into recognition, criteria, evaluating contributors, prognostic factors, treatment and disease monitoring. The recognition and early diagnosis points follow.
- Laboratory features that should lead investigators to consider HLH/MAS include persistent fever, elevated inflammation markers, low hemoglobin and platelet counts, liver dysfunction, coagulopathy, splenomegaly and CNS dysfunction.
- Patients at risk for progressing to HLF/MAS should have their ferritin levels checked.
- If ferratin is normal, but patients remain under suspicion, serial ferritin testing may be necessary.
- Other laboratory values that physicians should investigate include complete blood count with differential, liver panel values, fibrinogen, d-dimer, LDH and C-reactive protein.
- Specialized biomarkers can help clinicians investigate HLH and MAS.
The criteria and evaluating contributor points follow.
- There is no one set of criteria that can diagnose HLH/MAS in every situation.
- Investigators should be aware of diseases that are often linked to HLH/MAS.
- Genetic testing for suspected patients should be considered early.
- The decision to perform genetic testing should factor in the age, clinical features and laboratory findings.
- Patients who undergo genetic testing should do so with “next-generation” sequencing.
- Genetic counseling should be offered to patients who undergo genetic testing.
Points to consider regarding prognostics follow.
- Factors indicating a poor prognosis include underlying malignancy, CNS involvement, liver involvement, organ dysfunction and prolonged disease activity.
- In patients with probable HLH or MAS, a full neurological exam should be completed.
- CNS involvement evaluation should include brain MRI and cerebrospinal fluid examinations.
- In patients where HLH or MAS is suspected, brain evaluations should not stop systemic immunomodulating therapy.
Points to consider regarding treatment and monitoring follow.
- Patients who likely have HLH or MAS should begin immunomodulatory therapy while diagnostic investigation continues.
- The choice of which therapy to use should account for potential rapid progression and the risk for malignancy.
- Initial therapies may include glucocorticoids, anakinra (Kineret, SOBI) or IVIg.
- In addition to treating HLH or MAS, physicians should also manage patients’ underlying disease triggers.
- If the course of treatment is presumed to be lengthy, an infectious disease specialist should be consulted.
- In patients who are undergoing therapy and demonstrate worsening disease states, physicians should reconsider the initial diagnosis.
- Patients with systemic hyperinflammation should be monitored continuously for signs of progression to HLH or MAS.
- Clinical and laboratory markers should be evaluated every day, and systemic inflammation markers should be investigated at least every 2 weeks.
- A multidisciplinary team approach is the best way to monitor and treat patients with HLH or MAS.
“The HLH/MAS paradigm has evolved rapidly in response to genetic, biomarker, clinical and therapeutic insights,” Shakoory and colleagues wrote. “These insights reflect the diversity and intersection of contributors and suggest convergence on a shared HLH/MAS physiology and phenotype. These insights have also led to more diagnostic and therapeutic options while highlighting the wide spectrum of primary care and subspecialty providers who care for patients with early features of HLH/MAS.”
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