|Year : 2022 | Volume
| Issue : 2 | Page : 118-123
Experience with macrophage activation syndrome associated with systemic lupus erythematosus: A single-center study from Pakistan
Saira Elaine Anwer Khan1, Roshila Shamim2, Asadullah Khan3, Shabnam Batool1, Muhammad Zeeshan Aslam2
1 Department of Rheumatology, Shalimar Medical Complex, Lahore, Pakistan
2 Department of Rheumatology, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, Pakistan
3 Department of Rheumatology, Bolan Medical College Quetta, Quetta, Pakistan
|Date of Submission||07-Oct-2021|
|Date of Acceptance||18-Dec-2021|
|Date of Web Publication||08-Apr-2022|
Dr. Asadullah Khan
Department of Rheumatology, Bolan Medical College Quetta
Source of Support: None, Conflict of Interest: None
Objective: The objective of the study was to evaluate the clinical, laboratory manifestations, and associations of macrophage activation syndrome (MAS) in a cohort of Pakistani patients with systemic lupus erythematous and to compare it with a well-characterized cohort of active systemic lupus erythematosus (SLE) without MAS.
Materials and Methods: Patients with a diagnosis of SLE admitted from January 2017 to July 2019 were retrospectively reviewed. MAS ascertained by either clinical criteria or bone marrow biopsy were studied. Demographics, clinical, and laboratory parameters of MAS patients were evaluated and compared with a cohort of non-MAS active SLE.
Results: A total of 305 patients of SLE were evaluated, out of these 18 patients had a diagnosis of MAS, making a MAS prevalence of 5.9%. Mean age of the patients was 27.25 ± 10.16 years. Female comprised 13 (72%) of MAS group. Fever was the most common clinical presentation (100%), followed by splenomegaly (38.9%) and lymphadenopathy (33.3%). At least 5 (27.8%0 patients had MAS as their initial manifestation. Anemia (88.9%), thrombocytopenia (88.9%), leukopenia (72%), and pancytopenia (55.6%) were prominent laboratory parameters. Mean serum ferritin of 1584 ng/ml and mean triglyceride of 270 mg/dl were reported. On comparing with non-MAS cohort; younger age, fever, lymphadenopathy, splenomegaly, mucocutaneous features, any type of cytopenia, high aspartate aminotransferase (AST), low albumin, and lactate dehydrogenase, all showed significant association with MAS (P < 0.05).
Conclusion: Fever and associated cytopenias coupled with raised AST are strong predictors of MAS in patients with SLE.
Keywords: Hemophagocytic lymphohistiocytosis, systemic lupus erythematosus, macrophage activation syndrome
|How to cite this article:|
Anwer Khan SE, Shamim R, Khan A, Batool S, Aslam MZ. Experience with macrophage activation syndrome associated with systemic lupus erythematosus: A single-center study from Pakistan. Indian J Rheumatol 2022;17:118-23
|How to cite this URL:|
Anwer Khan SE, Shamim R, Khan A, Batool S, Aslam MZ. Experience with macrophage activation syndrome associated with systemic lupus erythematosus: A single-center study from Pakistan. Indian J Rheumatol [serial online] 2022 [cited 2022 Aug 12];17:118-23. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/118/342748
| Introduction|| |
Macrophage Activation Syndrome, a potentially fatal complication of hyperinflammation resulting from “Cytokine Storm,” is seen complicating many rheumatological conditions which include systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), rheumatoid arthritis, Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, and Sjogren's syndrome.,, In lupus, MAS creates a “MASsacre” by being hidden, with excellent camouflage. Many features of MAS overlap with both lupus disease flare and infection. This results in underdiagnosis and development of a storm that becomes very difficult and nearly impossible to control.
Proposed by Wolf et al. in 1991, for the first time as “Acute Lupus Hemophagocytic Syndrome,” MAS clinically manifests as fever, cytopenias, hepatosplenomegaly, elevated liver enzyme levels, hypertriglyceridemia, and hyperferritinemia, A characteristic bone marrow finding, which often, but not always, reveals numerous morphologically normal looking macrophages exhibiting hemophagocytic activity.
With no clear-cut diagnostic standards or classification criteria for MAS in Lupus as well as lack of standardized care or treatment guidelines. The majority of the times, MAS remains a major cause of morbidity and mortality in SLE.,, The mainstay of treatment is steroids and steroid-sparing agents, while in refractory patients, intravenous immunoglobulin (IVIG), cyclophosphamide, and plasma exchange have provided inconsistent results.,, Recently, different biologic agents have been used, but none showed proven beneficial results.
Literature review is full of case reports and case series. In a study from China, clinical characteristics, laboratory parameters, histopathologic features, treatment, and outcome of MAS complicating SLE in 32 patients from six centers was studied retrospectively to facilitate timely diagnosis and immediate therapeutic intervention. However, similar studies are lacking in the subcontinent. The recent COVID-19 pandemic has further heightened interest in “Cytokine Storm”.
Our only hope to tame this storm is by understanding not only its presentations but also response to treatment in our local population. We here present our experience with MAS in SLE at a rheumatology center, focusing on clinical and laboratory manifestation unique to our population as well as, the response to different treatment regimens. We further aim to compare MAS patients with a well-constructed matched control group of non-MAS SLE patients to look for unique characteristics and response.
| Materials and Methods|| |
We conducted a retrospective data analysis of all SLE patients admitted to rheumatology department from January 2017 to July 2019 after approval from the Institutional Review Board (Institutional Review Board no FMH-04-2019-IRB-615-M).
The patients in whom diagnosis of MAS was either biopsy proven or based on 2016 classification criteria for macrophage activation syndrome proposed by European League against Rheumatism/American College of Rheumatology, were included in the study. The Criteria define MAS as a patient with fever and high Ferritin, having any two of the followings: low platelets (<150 × 109/mL), high triglycerides (>50U/L), transaminitis (aspartate aminotransferase [AST] >50/L), and low fibrinogen (fibrinogen <360 mg/mL). Patients with incomplete records of clinical or laboratory features mandatory in diagnostic criteria of MAS were excluded. Patients with any prior comorbid condition or medical illness leading to functional impairments, e.g., neurological impairment, psychiatric problems, chronic renal diseases, chronic liver diseases, and malignant diseases were also excluded from the analysis.
We reviewed the clinical records of the patients for:
- Demographic data: age, gender, mode of admission, admission in specific monitored facility (medical ward, high dependency unit, and intensive care unit)
- Clinical manifestation of lupus with current presenting symptoms
- Diagnostic criteria of MAS
- Disease activity of SLE assessed by Modified SLEDAI 2000
- Laboratory parameters including blood workup, serology, inflammatory markers, and histopathology of bone marrow
- Outcomes of the patients were evaluated as length of hospital stay, any morbidity, need for mechanical ventilation, and mortality
- In addition, MAS cohort was then compared with another well-matched cohort of active SLE patients without MAS.
Statistical analysis was performed using Version 25.0. All the categorical variables were presented in the form of frequency and percentage, whereas quantitative variables were presented in the form of mean ± standard deviation. Comparison of categorical data between two groups was by Chi-square test. For continuous data, Student's t-test was employed, along with the Mann–Whitney U test when the data did not follow a normal distribution. Stratification of the data was done for gender. Logistic regression model was applied for clinical associations using Chi-square tests with P < 0.05 considered statistically significant.
| Results|| |
A total of 305 lupus patients were reviewed during the study period. MAS was diagnosed in 18 patients, making a prevalence of 5.9%. From these 305 cases, 84 patients including all MAS cases, with adequate records were then considered for the study, making it a case–control study comprising 18 cases and remaining 66 controls.
Among MAS cohort, nine (50%) patients were admitted directly into intensive care unit, three (16.7%) in high dependency unit, and remaining six (33.3%) in medical wards. About 11 patients (61%) presented to the emergency department, while the remaining were admitted through outpatient department. Females comprised 72.2% (n = 13) of the cohort, with female-to-male ratio of 7.2:1. The mean age of patients was 21.50 ± 2.5 years. With borderline significance, male patients had a younger age as compared to female (P = 0.18).
Five (27.8%) patients presented with MAS as first manifestation of lupus. Besides MAS, other lupus manifestations included nephritis in 5 (27.8%), mucocutaneus in 5 (27.8%), neuropsychiatric manifestations in 3 (16.7%), and serositis in 2 (11.1%) of patients. Nephritis was more common in females although without statistical significance (P = 0.25). None of lupus manifestations had any significant association with gender (P > 0.05) [Table 1].
|Table 1: Baseline demographic and baseline characteristics of macrophage activation syndrome patients|
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Regarding clinical symptoms and signs, all patients with MAS had fever at the time of admission. In addition, lymphadenopathy was present in 6 (33.3%) patients, and splenomegaly (both clinically and ultrasound-proven) was present in 7 (38.9%) patients. On initial laboratory workup at the time of admission, anemia and thrombocytopenia were present in 16 (88.9%) each, while leukopenia in 13 (72.2%) patients. Ten (55.6%) patients had pancytopenia. Serum ferritin was above 1000 mcg/L in all patients, with a mean value of 1584.4 ± 208 ng/ml. Mean serum triglyceride level was 271 mg/dL, with higher mean values in males than females (P = 0.06). Bone marrow biopsy results were available in 7 (38.8%) patients, and the rest of the patients had refused to give consent for biopsy. In remaining patients, diagnosis of MAS was made by fulfilling the secondary HLH criteria of clinical and laboratory features., Minimum score achieved was 5/8 in clinical diagnosis group, while 6/8 in biopsy-proven group. NK-cell activity and soluble CD25 R levels records were not available for any patient. Except for higher TG levels in males compared to females, reaching near statistical significance (P = 0.06), no other clinical or laboratory feature had any association with gender [Table 1].
All patients with MAS were given pulse dose steroids (IV methylprednisolone acetate) of not <500 mg/day for 3 days, followed by oral steroids at 1 mg/kg/day dose tapered gradually. Thirteen (72.2%) patients received cyclosporin (Max. 2.5 mg/kg/day dose) as steroid-sparing agent. At least 3 (22.2%) received IV cyclophosphamide at 500 mg-750/m2 body surface area, as their initial diagnosis of lupus nephritis, and 2 (16.6%) patients received rituximab as immunosuppressant therapy. IV immunoglobulins in 2 (11.1%) and plasmapheresis in 3 (17%) were used salvage therapy to gain time. Coexisting infections were present in 7 (38.8%) patients, out of which 5 (27.7%) had pneumonia, 1 (5.6%) had UTI, and 1 (5.6%) had tuberculosis. Infections were treated according to local guidelines. Empiric antibiotics were given to control infections at physician discretion.
At least 8 (44.4%) patients required mechanical ventilation. With rigorous and multiarmed therapy, 13 (72.2%) patients were cured and discharged successfully, the mean duration of hospital stay was 28 ± 5 days. Mortality occurred in 5 (27.8%) patients during hospital stay.
On comparing MAS patients with non-MAS cohort of 66 patients, there was a significant association of MAS with age (P < 0.01), fever (P < 0.01), splenomegaly (P < 0.01), lymphadenopathy (P < 0.01), nephritis (P = 0.03), any type of cytopenia (P < 0.01), serum AST (P < 0.01), serum Albumin (P < 0.01), and serum lactate dehydrogenase (LDH) (P < 0.05). Besides, arthritis and lupus nephritis showed a significant association with lupus flare instead of MAS [Table 2].
|Table 2: Comparison of patients with macrophage activation syndrome with a nonmacrophage activation syndrome patient cohort|
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| Discussion|| |
In our study, the prevalence of MAS in SLE was 5.9%. Most patients were young with a mean age of 27.25 ± 10.16 years. There was expected female preponderance with 13 (72%) of total MAS patients. Fever was the most common clinical presentation (100%) followed by splenomegaly (38.9%) and lymphadenopathy (33.3%). At least 5 (27.8%) patients had MAS as their initial manifestation. Anemia (88.9%), thrombocytopenia (88.9%), leukopenia (72%), and pancytopenia (55.6%) were prominent laboratory parameters. On comparing with non-MAS cohort, younger age, fever, lymphadenopathy, splenomegaly, mucocutaneous features, any type of cytopenia, high AST, low albumin, and LDH, all showed a significant association with MAS with P < 0.05.
The prevalence of MAS in this study was 5.9% which is close to the results of Fukaya et al. (4.6%). Tsuji et al., however, reported a higher prevalence of hemophagocytosis in SLE in their retrospective data analysis (9.1%). This high prevalence is likely an overestimation due to inclusion bias, as they only included patients with high liver function tests in inclusion criteria. Although the study's primary outcome was mainly the evaluation of etiology of deranged LFTs in SLE, it does give an insight of the association of deranged LFTs before the development of hemophagocytosis and can be evaluated in further prospective studies.
Multiple authors have reported MAS presenting as an initial manifestation of SLE.,,, MAS presenting at the onset of lupus poses a difficulty in earlier diagnosis and a delay in treatment due to its close mimicry with other possible diagnoses including infections, malignancy, and other rheumatic diseases. In our study, 27.8% (n = 5) of patients had MAS at their initial presentation of lupus. This finding is concordant to Liu et al. who presented 28.1% of cases manifesting MAS at onset of lupus.
Clinical features and laboratory parameters of our cohort showed similarities with previous studies elaborated in [Table 3].,,,,,, Important differences include younger age of SLE patients, lower age group of male patients as compared to female, and prominent pancytopenia in our cohort. Younger age at onset patients implies the earlier onset of MAS in SLE course and could also relate to increased lupus activity in men population in our study [Table 2]. High triglyceride levels were reaching significant association with male gender in our cohort (P = 0.06). Exploring further laboratory manifestation, at least 55.6% of patients presented with pancytopenia in our cohort. Although diagnostic criteria consider decrease in one or two cell lineages, pancytopenia should also be considered features of increased marrow activity in MAS and can be proposed that “SLE patients presenting with pancytopenia, MAS should be considered in differentials along with SLE flare, sepsis, and disseminated intravascular coagulation. Lamboto et al. reported a higher cardiac involvement in their study comprising myocarditis and heart blocks, which were not found in other studies including ours. A recent study by Naveen et al. reported similar laboratory and clinical findings in SLE-associated MAS. In the majority of the studies reported above, lupus flare along with infections was the most common triggers for MAS, emphasizing the importance of control of disease activity along with infection control.
|Table 3: Comparison of clinical and laboratory features of current study with previous cohorts|
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With regard to need of bone marrow biopsy for diagnosis, in our study, 11 (61%) patients did not undergo bone marrow biopsy. The overall score on HLH secondary diagnostic criteria (where the score of 5 mandatory for Diagnosis) in the bone marrow biopsy group was 6/8 compared to 5/7 in the group where bone marrow biopsy was not available, highlighting the importance of other clinical and laboratory features for MAS in the absence of or a delay in the reports of bone marrow biopsy.
An important reason of delay in diagnosis of MAS is its similarity with SLE flare. Similar features such as fever, cytopenia, and lymphadenopathy make flare the common entity coming to mind. On comparing MAS patients with non-MAS cohort with active flare, to our surprise, mucocutaneous manifestations had a significant association with MAS (P < 0.01) despite low SLEDAI score of such features. Lupus nephritis and arthritis on the other hand had a significant association with lupus flare and not MAS (P = 0.01 and 0.06, respectively). Laboratory features such as any cytopenia (including pancytopenia), hypoalbuminemia, High LDH, and raised AST all showed significant association with MAS compared to lupus flare (P < 0.05 for all). We propose these parameters along with raised serum ferritin levels, and triglyceride levels can be considered as a red flag for early diagnosis of MAS.
In the absence of standardized treatment guidelines for the management of MAS, all patients received pulse doses of IV steroids followed by high dose oral steroids and immunosuppressants (Cyclosporin and IV cyclophosphamide), rescue IVIG, and rituximab depending on patients' severity and treating physician discretion, although no treatment was superior to other in the current study in terms of decreasing mortality or morbidity.
At least 50% (n = 9) of our patients were admitted in intensive care unit out of which 44.4% required mechanical ventilation. The overall mortality rate was 27.8% (n = 5) that is analogous with the mortality rate previously reported.,,, Earlier diagnosis and multiprongs management are hence the keys to timely success. As proposed by Parodi et al. for juvenile SLE, beside doing a fever workup in a young lady with cytopenias, checking serum ferritin levels, can aid in early diagnosis.
The study has certain limitations in the form of small sample size, single-center study, retrospective analysis, and lack of comparison of treatment arms, along with risk of selection bias since it was not a population-based study. Despite these, the study does give a glimpse of this rarer complication of a rare disease. The comparison of MAS cases with controls and comparison of MAS at onset versus distant MAS concluded very novel significant associations that can be research questionnaire for future research.
| Conclusion|| |
MAS mimics lupus flare both in clinical features and laboratory findings of cytopenias. Fever with cytopenias coupled with raised AST and organomegaly are strong predictors of MAS and the presence of such features should raise suspicion of MAS. In addition, preliminary diagnosis based on clinical and laboratory features in the absence of bone marrow biopsy can pace the management of this dire complication of lupus.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]