When Cytopenia Changes the Diagnosis: Anti-MDA5 Dermatomyositis, Rapidly Progressive Interstitial Lung Disease, and Macrophage Activation

Based on: Ishikawa K, Nunomura S, Horiuchi K, Ito S, Yabe I. Early recognition of a macrophage activation-associated hyperinflammatory state in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapidly progressive interstitial lung disease: a case report. Journal of Medical Case Reports. 2026.
DOI: 10.1186/s13256-026-06507-9

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The Clinical Problem

A 59-year-old Japanese woman presented with six weeks of progressive dyspnea and a skin rash. During the same period, she developed intermittent fever and progressive proximal muscle weakness.

At admission, her temperature was 37.9 °C, respiratory rate 16 breaths/min, and oxygen saturation 94% on room air. Examination demonstrated Gottron's sign, reverse Gottron's sign, periungual inflammation, bilateral basal crackles, and proximally predominant weakness graded 3/5 on the Medical Research Council scale.

At first glance, this looks like an inflammatory myopathy with pulmonary involvement.

But the case soon becomes more complicated.

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Clinical Reasoning: Step 1

What syndrome should be recognized first?

The combination of:

• characteristic dermatomyositis skin findings,

• proximal muscle weakness,

• progressive respiratory symptoms, and

• bilateral pulmonary abnormalities

should immediately raise concern for dermatomyositis complicated by interstitial lung disease.

The pulmonary process deserves particular attention. In certain dermatomyositis phenotypes, lung disease can progress rapidly and dominate the clinical course.

Pause and consider

What additional finding would substantially narrow the dermatomyositis phenotype?

The answer is a myositis-specific antibody.

Laboratory testing revealed a strongly positive anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody titer of 1150 index, with a reference value of less than 32. Other myositis-specific antibodies were negative.

This finding substantially changes the clinical risk assessment.

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Clinical Reasoning: Step 2

Can dermatomyositis be present with normal muscle enzymes?

Despite clinically significant weakness, the patient's:

• creatine kinase was 68 U/L, and

• aldolase was 5.0 U/L,

both within their respective reference ranges.

Normal muscle enzymes should therefore not be allowed to outweigh the rest of the syndrome.

Electromyography demonstrated findings consistent with active myopathy, while skin biopsy showed vacuolar degeneration of the epidermal basal layer with perivascular inflammatory cell infiltration, supporting the diagnosis of dermatomyositis.

Clinical pearl

The biochemical severity of muscle injury does not necessarily parallel the clinical severity of anti-MDA5 dermatomyositis.

In this case, the diagnostic synthesis depended on the phenotype as a whole rather than on creatine kinase elevation.

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Clinical Reasoning: Step 3

How severe is the pulmonary involvement?

Pulmonary function testing demonstrated a markedly reduced percent predicted vital capacity of 34.9%.

Chest CT showed bilateral ground-glass opacities predominantly involving the lower lobes.

The combination of progressive dyspnea, markedly impaired vital capacity, CT abnormalities, and anti-MDA5 antibody positivity supported the diagnosis of:

Anti-MDA5 antibody-positive dermatomyositis complicated by rapidly progressive interstitial lung disease.

This is already a high-risk clinical situation.

Treatment was initiated with intravenous methylprednisolone at 1 g/day for three days, followed by tacrolimus. Intravenous cyclophosphamide was planned as part of intensive combination immunosuppressive therapy.

But then another diagnostic signal appeared.

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Clinical Reasoning: Step 4

The clue that should not be dismissed: cytopenia

At presentation, laboratory testing already showed mild cytopenias:

• white blood cells: 3,400/µL

• hemoglobin: 9.9 g/dL

• platelets: 135 × 10³/µL

Ferritin was also elevated at 601 ng/mL.

CT incidentally demonstrated splenomegaly.

Subsequent laboratory testing showed worsening cytopenia:

• white blood cells: 1,700/µL

• hemoglobin: 9.5 g/dL

• platelets: 127 × 10³/µL

The authors considered the degree of cytopenia disproportionate to the expected clinical course and performed bone marrow aspiration before cyclophosphamide was administered.

Pause and consider

In a patient with:

• fever,

• splenomegaly,

• cytopenia,

• hyperferritinemia, and

• severe systemic inflammatory disease,

what additional process should enter the differential diagnosis?

The major concern is macrophage activation/hemophagocytic hyperinflammation.

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Clinical Reasoning: Step 5

The bone marrow changes the case

Bone marrow examination demonstrated hemophagocytosis by activated macrophages.

This was an important finding, but it did not establish a definitive diagnosis of macrophage activation syndrome.

According to the authors, the patient fulfilled four of the eight HLH-2004 criteria:

1. fever,

2. splenomegaly,

3. hyperferritinemia, and

4. bone marrow hemophagocytosis.

She therefore did not satisfy the required threshold for definitive hemophagocytic lymphohistiocytosis/macrophage activation syndrome by those criteria.

That distinction is central to the reasoning in this case.

The appropriate conclusion was not:

"The patient had definite MAS."

Rather, the clinical and bone marrow findings suggested a:

macrophage activation-associated hyperinflammatory state.

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The Diagnostic Pivot

This is the key teaching moment.

A clinician could have viewed the fever, ferritin elevation, pulmonary deterioration, and systemic inflammation as manifestations of severe anti-MDA5 dermatomyositis alone.

The worsening cytopenia and splenomegaly suggested that something more might be occurring.

Bone marrow hemophagocytosis then supplied additional evidence of macrophage activation even though formal diagnostic criteria for MAS were not fulfilled.

The case therefore illustrates a recurring principle in clinical reasoning:

Diagnostic criteria define syndromes, but evolving physiology may become clinically important before the full criteria are satisfied.

In this patient, the authors used the totality of the findings rather than waiting for overt MAS to develop.

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Clinical Reasoning: Step 6

Should treatment wait until diagnostic criteria are fulfilled?

The clinical problem was no longer simply anti-MDA5 dermatomyositis with RP-ILD.

The patient had severe lung disease together with evidence suggesting systemic macrophage activation.

Given the progressive interstitial lung disease and suspected hyperinflammatory state, treatment was intensified.

The patient received:

• high-dose intravenous methylprednisolone,

• oral tacrolimus,

• plasma exchange,

• and subsequently intravenous cyclophosphamide after hematologic recovery.

According to the clinical course figure, treatment ultimately included:

• three courses of methylprednisolone pulse therapy,

• oral tacrolimus,

• five sessions of plasma exchange, and

• six doses of intravenous cyclophosphamide administered biweekly.

Plasma exchange was introduced early with the goal of reducing circulating inflammatory mediators and anti-MDA5 antibodies.

Importantly, the case report describes the improvement following this treatment strategy; it does not establish that any single intervention caused the favorable outcome.

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Clinical Reasoning: Step 7

What happened?

The patient improved progressively.

By the 12-week follow-up:

• cytopenias had improved,

• percent predicted vital capacity increased from 34.9% to 56.1%,

• muscle strength improved from MRC 3/5 to 4/5, and

• the patient remained clinically stable without relapse during the reported follow-up period.

Ferritin and anti-MDA5 antibody levels also decreased over the clinical course, and dyspnea resolved.

The trajectory shown in the authors' clinical-course figure is particularly instructive: inflammatory markers, antibody level, pulmonary function, and clinical symptoms evolved in parallel as treatment intensified.

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What Was the Final Diagnosis?

The most precise formulation is:

Anti-MDA5 antibody-positive dermatomyositis complicated by rapidly progressive interstitial lung disease, with a macrophage activation-associated hyperinflammatory state demonstrated by bone marrow hemophagocytosis.

The authors deliberately stopped short of labeling the hyperinflammatory process as definite macrophage activation syndrome because the full HLH-2004 criteria were not satisfied.

That diagnostic restraint is important.

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Differential Diagnosis at the Critical Decision Point

When cytopenia developed in this patient, several possibilities required consideration.

1. Severe anti-MDA5 dermatomyositis itself

Systemic inflammation and severe RP-ILD could explain fever and clinical deterioration.

However, the combination of worsening cytopenia, splenomegaly, elevated ferritin, and subsequent hemophagocytosis suggested an additional macrophage-activation component.

2. Macrophage activation syndrome/secondary HLH

The phenotype was suggestive, but the patient fulfilled only four of eight HLH-2004 criteria.

The authors therefore favored the more cautious designation of a macrophage activation-associated hyperinflammatory state.

3. Infection-triggered hyperinflammation

This could not be fully excluded.

EBV and CMV screening was not performed at initial presentation because treatment of the rapidly progressive lung disease was prioritized. The authors specifically identify the lack of initial EBV testing as a limitation.

CMV antigenemia was subsequently assessed because of diarrhea during intensive immunosuppression and was negative.

This uncertainty should remain part of the interpretation rather than being retrospectively removed.

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Why This Case Matters

Anti-MDA5 dermatomyositis with rapidly progressive ILD is already associated with substantial clinical risk.

The additional development of:

• cytopenia,

• increasing ferritin,

• splenomegaly, or

• other features suggesting disproportionate systemic inflammation

may indicate macrophage activation.

The important teaching point is not that every patient with anti-MDA5 disease and elevated ferritin requires bone marrow examination.

Rather, this case demonstrates how a change in the pattern of laboratory abnormalities can signal that the original diagnostic framework is no longer sufficient.

The worsening cytopenia was the clue that prompted the clinicians to reconsider the case.

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Clinical Pearls

1. Recognize the anti-MDA5 phenotype early.
Characteristic dermatomyositis skin findings combined with rapidly progressive lung disease should prompt consideration of anti-MDA5-associated disease.

2. Normal CK does not exclude clinically important dermatomyositis.
This patient had substantial proximal weakness despite normal creatine kinase and aldolase.

3. Follow trends, not isolated values.
The progression from mild to more pronounced cytopenia changed the clinical interpretation.

4. Hyperferritinemia is a clue, not a diagnosis.
Ferritin was elevated in this patient, but the diagnosis depended on its relationship to other clinical findings.

5. Splenomegaly can be diagnostically important.
The splenomegaly was incidentally identified on CT but became more meaningful once cytopenia and hyperferritinemia were considered together.

6. Hemophagocytosis does not automatically equal MAS.
Bone marrow hemophagocytosis supported macrophage activation, but the patient did not meet the complete HLH-2004 diagnostic criteria.

7. Diagnostic thresholds should not replace clinical judgment.
The authors interpreted the patient as having an evolving hyperinflammatory state rather than waiting for definitive MAS criteria to be fulfilled.

8. Preserve diagnostic uncertainty.
An infectious trigger could not be fully excluded because EBV and CMV screening was not performed at presentation.

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Potential Pitfalls

Pitfall 1: Anchoring on the pulmonary diagnosis

Once anti-MDA5 dermatomyositis with RP-ILD was established, subsequent abnormalities could easily have been attributed to the same disease.

Better approach: Reassess the working diagnosis when new findings do not fit the expected course.

Pitfall 2: Dismissing mild cytopenia

The initial abnormalities were not dramatic.

Better approach: Examine the trajectory. Worsening leukopenia was a major clue in this case.

Pitfall 3: Calling the patient "MAS" too early

Hemophagocytosis is compelling but is not synonymous with definitive macrophage activation syndrome.

Better approach: Apply formal criteria while recognizing that clinically important macrophage activation may precede fulfillment of those criteria.

Pitfall 4: Assuming treatment-response proves causality

Pulmonary function, muscle strength, ferritin, and cytopenias improved after multimodal treatment.

Better approach: Describe this as a temporal association in a single case rather than attributing the outcome to one specific component of therapy.

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Clinical Timeline

Time point	Clinical development
Approximately 6 weeks before admission	Skin rash and progressive dyspnea develop; intermittent fever and proximal weakness follow
Admission	Gottron's and reverse Gottron's signs, periungual inflammation, basal crackles, MRC 3/5 proximal weakness
Initial laboratory evaluation	WBC 3,400/µL, hemoglobin 9.9 g/dL, platelets 135 × 10³/µL, ferritin 601 ng/mL, normal CK and aldolase
Initial investigations	Anti-MDA5 antibody 1150 index; %VC 34.9%; bilateral lower-lobe ground-glass opacities; splenomegaly; EMG consistent with active myopathy; skin biopsy supportive of dermatomyositis
Initial treatment	IV methylprednisolone followed by tacrolimus; cyclophosphamide planned
Subsequent course	WBC falls to 1,700/µL with persistent anemia and thrombocytopenia
Diagnostic pivot	Bone marrow aspiration demonstrates hemophagocytosis by activated macrophages
Treatment escalation	Plasma exchange initiated; cyclophosphamide given after hematologic recovery
12 weeks	Cytopenia improves; %VC rises to 56.1%; strength improves to MRC 4/5; clinically stable without reported relapse

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Five Questions for the Reader

Question 1

A patient with characteristic dermatomyositis skin findings and progressive proximal weakness has normal CK and aldolase. Which interpretation is most appropriate?

A. Dermatomyositis is excluded
B. Muscle disease is unlikely unless CK exceeds 1,000 U/L
C. Normal muscle enzymes do not exclude dermatomyositis in the appropriate clinical phenotype
D. The weakness should be assumed to be functional
E. The anti-MDA5 antibody result is irrelevant

Answer: C

Explanation: The patient had clinically significant proximal weakness with normal CK and aldolase. EMG and skin biopsy provided additional evidence supporting dermatomyositis.

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Question 2

Which combination most strongly prompted consideration of macrophage activation in this case?

A. Normal CK and positive anti-MDA5 antibodies
B. Dyspnea and ground-glass opacities alone
C. Cytopenia, hyperferritinemia, splenomegaly, and fever
D. Proximal weakness and Gottron's sign
E. Normal cardiac investigations

Answer: C

Explanation: The combination of worsening cytopenia, elevated ferritin, splenomegaly, and fever raised concern for a hyperinflammatory process beyond the underlying dermatomyositis.

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Question 3

Why did the authors not diagnose definitive macrophage activation syndrome?

A. Ferritin was normal
B. Bone marrow examination was normal
C. There was no fever
D. Only four of eight HLH-2004 criteria were fulfilled
E. Anti-MDA5 disease cannot be associated with macrophage activation

Answer: D

Explanation: Fever, splenomegaly, hemophagocytosis, and hyperferritinemia were present, but the full diagnostic threshold was not met. The authors therefore used the term macrophage activation-associated hyperinflammatory state.

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Question 4

What investigation provided the strongest direct evidence of macrophage activation?

A. Electromyography
B. Chest CT
C. Anti-MDA5 antibody testing
D. Bone marrow aspiration
E. Echocardiography

Answer: D

Explanation: Bone marrow aspiration demonstrated hemophagocytosis by activated macrophages.

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Question 5

What is the most appropriate interpretation of the patient's improvement after treatment?

A. Plasma exchange was definitively curative
B. Cyclophosphamide alone caused the recovery
C. The multimodal treatment strategy was followed by improvement, but causality from any individual intervention cannot be established from a single case
D. The improvement proves that definite MAS was present
E. Spontaneous recovery can be excluded

Answer: C

Explanation: The patient received corticosteroids, tacrolimus, plasma exchange, and cyclophosphamide. The subsequent clinical improvement is important, but this case cannot determine the independent efficacy of any single component.

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Clinical Take-Home Message

In anti-MDA5 antibody-positive dermatomyositis with rapidly progressive interstitial lung disease, new or worsening cytopenia—particularly when accompanied by hyperferritinemia and splenomegaly—should prompt consideration of macrophage activation-associated hyperinflammation.

This case also illustrates a broader lesson in clinical reasoning: a dangerous biological process may become apparent before a patient fulfills every element of a formal diagnostic classification system. The appropriate response is neither to ignore the criteria nor to overstate the diagnosis, but to integrate the trajectory, phenotype, laboratory findings, pathology, and clinical urgency.

Here, bone marrow hemophagocytosis provided an important clue that supported therapeutic escalation while the authors appropriately retained diagnostic uncertainty regarding definitive macrophage activation syndrome.

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