|Year : 2022 | Volume
| Issue : 2 | Page : 149-152
Clinical characteristics and outcomes of macrophage activation syndrome among patients attending a rheumatology tertiary care center in North India
Rasmi Ranjan Sahoo1, Manesh Manoj2, Prashant Bafna2, Kasturi Hazarika2, Anupam Wakhlu1
1 Clinical Immunology and Rheumatology Services, Apollomedics Super Speciality Hospitals, Lucknow, Uttar Pradesh, India
2 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||05-Apr-2021|
|Date of Acceptance||08-Jul-2021|
|Date of Web Publication||24-May-2022|
Prof. Anupam Wakhlu
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Macrophage activation syndrome (MAS) is a potentially fatal condition complicating several rheumatologic disorders. This retrospective analysis studied the clinical characteristics and outcomes of patients diagnosed with MAS from a rheumatology tertiary care center.
Methods: Pediatric and adult patients diagnosed with rheumatologic disorders and fulfilling the 2016 European League against Rheumatism/American College of Rheumatology classification criteria for MAS associated with systemic juvenile idiopathic arthritis (sJIA) or the hemophagocytic lymphohistiocytosis (2004) criteria, as appropriate, were included over a period of 1 year. Detailed clinical history and laboratory parameters were extracted from the patients' records. Treatment details, duration of hospitalization, and outcomes were recorded.
Results: The study included nine patients (five males and four females) with a median age of 27 years, range 10–48 years. The median duration of illness was 6 months, range 2–60 months. Five patients were diagnosed with systemic lupus erythematosus, two patients with adult-onset Still's disease, and one each with sJIA and sarcoidosis. Infection (three patients), malignancy (one patient), and uncontrolled or aggressive disease (five patients) were recognized as the possible precipitating factors. Three patients had pancytopenia at presentation, whereas bicytopenia was observed in five patients. Hemophagocytosis on bone marrow biopsy was seen in seven patients. The median duration of hospital stay was 3 weeks, range 2–4 weeks. High-dose steroids were administered to all patients, along with oral cyclosporine in seven patients. One patient was given weekly etoposide infusion for unabated MAS. Two patients expired.
Conclusion: Prompt diagnosis and aggressive treatment strategy are pivotal for improving prognosis in MAS complicating rheumatologic disorders.
Keywords: Adult onset, hemophagocytic, lymphohistiocytosis, rheumatic diseases; still's disease
|How to cite this article:|
Sahoo RR, Manoj M, Bafna P, Hazarika K, Wakhlu A. Clinical characteristics and outcomes of macrophage activation syndrome among patients attending a rheumatology tertiary care center in North India. Indian J Rheumatol 2022;17:149-52
|How to cite this URL:|
Sahoo RR, Manoj M, Bafna P, Hazarika K, Wakhlu A. Clinical characteristics and outcomes of macrophage activation syndrome among patients attending a rheumatology tertiary care center in North India. Indian J Rheumatol [serial online] 2022 [cited 2022 Jul 4];17:149-52. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/149/345901
| Introduction|| |
Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous disorder characterized by immune dysregulation and cytokine storm leading to a hyperinflammatory state. The historical classification of primary and secondary HLH has been revised by the North American Consortium for Histiocytosis experts, and “HLH disease” and “HLH disease mimics” have been proposed under the broad group “HLH syndrome.” The HLH disease includes familial HLH due to genetic mutations, malignancy-associated HLH, HLH associated with rheumatologic disorders (macrophage activation syndrome [MAS]), HLH associated with immunocompromised states, iatrogenic HLH, and HLH not associated with other specific conditions.
Several autoimmune and autoinflammatory rheumatic diseases can be complicated by MAS, including systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease, and periodic fever syndromes. Among these disorders, MAS occurs more commonly in sJIA, with an estimated prevalence of 10%. The actual burden is still unknown, as hemophagocytosis was increasingly diagnosed on bone marrow aspiration of sJIA patients without overt manifestations of MAS. The prevalence is on the rise for other rheumatic diseases, including juvenile SLE (jSLE), with one study reporting approximately one-quarter of patients diagnosed with MAS.
Profound systemic inflammation leads to cytopenias, liver dysfunction, and coagulopathy, resembling disseminated intravascular coagulation (DIC) and hyperferritinemia. Without prompt diagnosis and aggressive therapy, the disease progresses to multi-organ dysfunction with poor outcomes. The reported mortality rates vary depending on the underlying rheumatic disease and range from 8% to 23% in sJIA and from 5% to 35% in SLE.
The present study characterizes the clinical features and outcomes of MAS patients from a rheumatology tertiary care center.
| Methods|| |
This retrospective study included children and adult patients with MAS, attending the department of clinical immunology and rheumatology of a tertiary care referral center in North India from 2019-20 over a period of 1 year. Patients diagnosed with sJIA fulfilled the 2016 European League against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for MAS, whereas other patients satisfied HLH-2004 criteria. The diagnosis of the underlying rheumatic disease was as per the ACR, EULAR, or any other consensus criteria applicable to that disease. The study was conducted as per the Declaration of Helsinki statement for medical research recruiting human participants.
Detailed clinical history including the demographic characteristics, duration and diagnosis of the Connective tissue disorder (CTD), presenting manifestations, past and current medications, and possible precipitating factors were extracted from the patient records. Laboratory parameters noted included serum ferritin, lactate dehydrogenase, fibrinogen, and triglycerides. The presence or absence of hemophagocytosis on bone marrow aspiration was documented. Treatment details, duration of hospitalization, and outcomes were also recorded.
Statistical analysis was done using GraphPad Prism 5.01 (GraphPad Software, San Diego, CA, USA). Quantitative data were expressed as median and interquartile range, whereas qualitative data were expressed as frequency.
| Results|| |
The study included nine patients (two children and seven adults) with median age of 27 years, range 10–48 years. There were five males and four females. The median duration of illness was 6 months, range 2–60 months. Five patients were diagnosed with SLE (including one patient of jSLE), two patients with AOSD, and one each with sJIA and sarcoidosis.
In patients with SLE, MAS was the presenting manifestation in one patient, whereas the diagnosis was established during the disease course in others. Mucocutaneous and musculoskeletal manifestations were predominant among the SLE patients. Two patients had proteinuria <1 g/24 h without active urine sediments and one patient had myositis. One patient had cranial neuritis and was receiving monthly cyclophosphamide pulse. The patient with jSLE presented with fever, polyarthritis, cervical lymphadenopathy, and acute lupus erythematosus rash. The laboratory abnormality of the above patient included anemia, leukopenia, transaminitis, raised ESR, and CRP along with hyperferritinemia.
AOSD was diagnosed in two patients who mainly had fever and polyarthritis. One patient had skin rash. Pancytopenia was present in one patient, whereas the other patient had leukopenia and thrombocytopenia. ESR was normal with mildly elevated CRP. One patient had lung involvement in the form of patchy areas of ground-glass opacities on high-resolution computed tomography scan.
Sarcoidosis was diagnosed in one patient based on granulomatous myositis, transaminitis, and early interstitial lung disease. Tuberculosis was ruled out with negative acid-fast staining and MTB GeneXpert. This patient had severe pancytopenia, renal dysfunction, and jaundice, and ultimately succumbed to her illness.
Overall, three patients had pancytopenia at presentation, whereas bicytopenia was observed in five patients. One patient presented with severe thrombocytopenia and subsequently developed anemia. Hemophagocytosis on bone marrow examination was seen in seven patients; one patient reportedly had normal bone marrow and one report was unavailable.
[Table 1] summarizes the clinical characteristics and laboratory parameters of the patients.
|Table 1: Clinical characteristics and laboratory parameters of patients with macrophage activation syndrome (n=9)|
Click here to view
Infection was a possible triggering factor in three patients, with pneumonia in two patients (Klebsiella was isolated in the bronchoalveolar lavage fluid in one patient) and one patient had a subcutaneous abscess. Uncontrolled or aggressive disease activity per se was considered as the precipitating factor in five patients. T-cell lymphoma was detected in a patient of SLE with cranial neuritis (bilateral sixth and seventh nerves) and antiphospholipid antibody positivity, who was receiving steroid and monthly cyclophosphamide infusion.
The median duration of hospital stay was 3 weeks with a range of 2–4 weeks. Two patients expired. Pulse methylprednisolone (15 mg/kg for 3–5 days) was administered in six patients, dexamethasone (10 mg/m2 BSA) in seven patients, while two patients were managed with prednisolone (1–2 mg/kg). Oral cyclosporin (3 mg/kg) was given in seven patients and one patient required etoposide infusion.
| Discussion|| |
The present study highlights the clinical characteristics and outcomes of nine patients with MAS, being treated in a rheumatology clinic. SLE was the primary diagnosis in the majority of patients. This is possibly in keeping with the distribution of spectrum of disease seen in our center. SLE presenting as MAS is not uncommon, with one retrospective study reporting it in 46% of patients. Fever was present in all patients, whereas elevated levels of AST, LDH, CRP, and ferritin were observed in 94.7%, 92.3%, 84.5%, and 96% of patients in the above study, respectively. In our cohort, all patients with SLE had fever and elevated levels of AST, LDH, CRP, and ferritin. MAS may also be concomitantly encountered in jSLE. Sato et al. reported fever, leukopenia, hyperferritinemia, and increased AST to be more prevalent in jSLE with MAS, as compared to those without MAS. However, jSLE patients with MAS reportedly had frequent neurological symptoms in that study.
Increased prevalence of liver involvement and lymphadenopathy has been reported in MAS complicating AOSD. Our patients had transaminitis up to three times upper limit of normal, but none had lymphadenopathy. The study by Lenert and Yao found higher frequency of renal insufficiency, lung involvement, serositis, DIC, and shock in their cohort of seven patients with AOSD. Significantly low ESR values were also observed in the above study.
MAS secondary to sarcoidosis has been rarely reported. Both pulmonary and extrapulmonary disease have been associated with MAS. A systematic review of HLH in rheumatic patients revealed that 5 out of 421 patients had sarcoidosis.
In the present study, one patient of sJIA presented with MAS. The patient was on methotrexate for arthritis and subsequently developed thrombocytopenia, transaminitis, falling ESR, and high ferritin, suggesting a diagnosis of MAS. The bone marrow did not show evidence of hemophagocytosis. The diagnosis of MAS in sJIA is challenging because of the similarity of clinical features and laboratory abnormalities among the two conditions. The 2016 EULAR/ACR classification criteria included low cutoff values for ferritin, platelet count, AST, triglycerides, and fibrinogen, allowing for early diagnosis of MAS complicating sJIA.
The proposed triggering factors for MAS in rheumatologic disorders are poor control of disease activity, drugs (including biologics), and infections. A study of 362 patients diagnosed with sJIA complicated by MAS reported active disease in 51.7%, infections in 34.1%, and drugs including tocilizumab and canakinumab in 3.8% of patients as triggering factors.
High-dose steroids were administered to all patients, along with oral cyclosporin in seven patients. Two patients (sJIA and one SLE patient) improved with oral prednisolone (1–2 mg/kg weight). The patient with sarcoidosis was given weekly etoposide infusion for uncontrolled MAS.
There are no universally accepted treatment recommendations for MAS and management is usually guided by the HLH-2004 protocol. One study reviewed the diagnosis and treatment strategy for MAS in sJIA and recommended administration of high-dose corticosteroids with or without cyclosporin as first-line therapy, with anakinra, an interleukin-1 inhibitor, in select patients only.
Our study is limited by the small number of patients and its retrospective nature. We realized that a very careful documentation of the sequence of appearance of clinical features was important to detect precipitating factors or clinical features that could herald the development of MAS.
| Conclusion|| |
MAS can complicate rheumatic disorders, thus warranting a high index of suspicion for timely therapeutic intervention. It is challenging for the rheumatologist to differentiate features of MAS, from those that may be inherent to the CTD, like cytopenias and transaminitis. Early detection and aggressive treatment may possibly lead to better outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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