Fever and rhabdomyolysis in a recent traveler: A case report of an uncommon presentation of anti-synthetase syndrome

Abstract

Anti-synthetase syndrome is a rare systemic autoimmune disease characterized by aminoacyl-tRNA synthetase autoantibodies. As an overlap disease, it can present heterogeneously with Raynaud’s phenomenon, rash, arthritis, interstitial lung disease, or myositis. Rhabdomyolysis is not commonly seen. Diagnosis of anti-synthetase syndrome is based on autoantibody positivity and clinical presentation and may be supported by muscle biopsy. We describe an unusual case of a 28-year-old woman with anti-Jo-1 anti-synthetase syndrome presenting with isolated rhabdomyolysis without lung or skin involvement. Our case also describes concurrent influenza infection as a potential trigger for anti-synthetase syndrome. This case illustrates the variability and potential severity of this rare syndrome.

Introduction

Idiopathic inflammatory myopathies (IIM) are a group of autoimmune myopathies often accompanied by widespread organ dysfunction. ¹ Anti-synthetase syndrome (ASyS) is a rare IIM subtype. It may present variably with myositis, arthritis, interstitial lung disease (ILD), Raynaud’s phenomenon, fever, or a dermatomyositis-like rash. “Mechanic’s hands” may be a pathognomonic sign. ¹ Autoantibodies in ASyS target aminoacyl-tRNA synthetases, including Jo-1, PL-7, PL12, OJ, KS, Zo, and YRS/HA. ² Treatment involves immunosuppression with glucocorticoids and disease-modifying antirheumatic drugs.

Rhabdomyolysis is a clinical syndrome of organ dysfunction resulting from muscle damage. It can variably cause myoglobinuria, kidney injury, compartment syndrome, weakness, myalgia, or electrolyte abnormalities. The most common driving etiologies of rhabdomyolysis are trauma, exertion, toxins, drugs, or infection. Viral causes include influenza, HIV, and SARS-CoV-2. ³ While muscle inflammation causing rhabdomyolysis has been observed in some subtypes of IIM, ⁴ it is uncommonly reported in ASyS.

Case

A previously healthy 28-year-old woman presented with 6 weeks of fever, low back pain, and arthralgias after 2 months of travel throughout Central America and Mexico. The patient reported no past medical history and denied any family or personal history of autoimmune disease.

Vital signs showed fever (103.2°F), tachycardia (140 bpm), and hypotension (86/51 mmHg).

Physical examination revealed 3/5 muscle strength in all four extremities. Bilateral PIP joint swelling and tense subcutaneous edema in the bilateral forearms and lower legs were noted. Pulmonary examination was normal. No rashes, mechanic’s hands, or Raynaud’s phenomenon were present.

Serum studies were notable for normal white blood cell count, anemia with hemoglobin of 8.7 g/dL (12.0–16.0), decreased sodium of 132 mmol/L (136–145), elevated aspartate transaminase of 1258 units/L (5–34), elevated alanine aminotransferase of 648 units/L (10–60), and elevated creatine kinase (CK) of 15,499 units/L (29–168). Creatinine was normal. Urinalysis showed large blood, but only occasional red blood cells.

A nasopharyngeal swab rapid antigen test was positive for influenza B.

Serum cytomegalovirus IgM, Epstein–Barr virus PCR and herpes simplex virus PCR testing were negative. Blood smear and blood cultures were negative.

Serum rapid 4th generation HIV Ab/Ag test was initially positive; however, confirmatory HIV-1/HIV-2 RNA nucleic acid testing was non-reactive.

A clinical diagnosis of rhabdomyolysis was made based on myoglobinuria, tense subcutaneous edema, myalgias, and weakness. The patient received IV fluids and supportive care. However, by day 2, she developed oropharyngeal dysphagia, indicating severe weakness. Despite modest initial improvement in CK levels, the patient’s CK began to rise again by day four of admission (Figure 1).

Figure 1.

Line graph of serum creatine kinase (CK) levels from admission through 10-month follow-up correlated with inflammatory myositis diagnostic workup and treatment demonstrating therapeutic response to immunosuppression.

Beginning on day 4 of admission, she was empirically given pulse-dose methylprednisolone IV 1000 mg due to rising CK levels and concern for IIM. Antibody testing was sent, and magnetic resonance imaging (MRI) was performed to assess the pattern and extent of myositis and guide muscle biopsy for the highest yield.

Contrast MRI of bilateral femurs on day 6 of admission demonstrated T2-hyperintense signal in the lower extremity musculature, consistent with diffuse systemic myositis (Figure 2). Bilateral, symmetric muscle edema of the proximal muscle groups, particularly the thigh and pelvic girdle is highly suspicious for IIM. By contrast, infectious myositis or metabolic myopathies typically present with asymmetrical and patchy or focal involvement. Muscle biopsy of the quadriceps was performed to definitively exclude other etiologies, including influenza myositis. Hematoxylin and Eosin and Masson trichrome staining demonstrated multifocal perivascular and endomysium inflammation with mixed lymphocytes and scattered necrosis, consistent with IIM.

Figure 2.

T2-weighted axial views of bilateral lower extremity musculature taken day 6 of admission demonstrating extensive hyperintense signal throughout the bilateral thigh musculature involving the quadriceps, adductor, and hamstring muscle groups with prominent fluid signal along the intramuscular fascia consistent with diffuse systemic myositis.

Autoantibody testing demonstrated positive antinuclear antibodies with a speckled pattern at a 1:320 titer and a highly positive anti-Jo-1 antibody (>8.0 units), consistent with a diagnosis of ASyS.

High-resolution chest CT showed no evidence of ILD.

After 3 days of IV methylprednisolone, her CK decreased markedly, and her weakness improved to 4/5 muscle strength throughout. She was transitioned to oral prednisone 60 mg daily with a taper.

The patient received 2 doses of rituximab 1000 mg intravenously given 14 days apart as induction therapy for ASyS.

At outpatient follow-up 3 weeks after discharge, the patient had experienced marked clinical improvement with normal 5/5 strength in all four extremities on examination and no sequelae. CK levels had normalized by follow-up 10 months later. She remains on rituximab 500 mg IV every 6 months.

Discussion

ASyS was initially described in patients with myositis and lung fibrosis who have aminoacyl-tRNA synthetase autoantibodies. ⁵ Anti-Jo-1 is the most common autoantibody and has been observed in up to 88% of ASyS patients. ⁶ ASyS is hypothesized to be driven by B cells and plasma cells. ⁷

ASyS is rare even among IIM, with some estimates placing it at only 28% of IIM cases. ⁶ The incidence of anti-Jo-1 autoantibodies is only 1.5 per 100,000. ⁵ ASyS appears to affect female patients more than males, with a ratio of 2:1. ⁵ The average age of onset for ASyS is in the fifth to sixth decade of life, but it has been seen in younger patients, including children. ⁸

ILD, usually nonspecific interstitial pneumonitis (NSIP), organizing pneumonitis (OP), or NSIP/OP overlap, occurs in 67% to 100% of ASyS patients. However, lung involvement may develop at a different time course than other symptoms. Dermatomyositis-like rash is seen in 32%–44% of cases. CK varies in ASyS, but mean elevations are in the 4000 range. MRI evidence of myositis is seen in 65% of these cases. Muscle histology often shows mononuclear cell infiltrates and muscle fiber necrosis. ⁶

Anti-Jo-1 antibody tests in clinical practice demonstrate 96.9% sensitivity and 99.8% specificity. Thus, autoantibody testing is the best method for diagnosis and is unlikely to yield a false positive. ⁷

This case posed a diagnostic challenge given the presentation of fever, arthritis, and rhabdomyolysis in a patient with positive influenza B viral testing. Distinguishing viral from autoimmune myositis is crucial for identifying appropriate treatment.

Viral myositis is far more common than IIM and often presents with fever, headache, arthralgias, and myalgias. Rhabdomyolysis is more frequently seen in viral myositis. Myositis caused by influenza requires confirmation nasopharyngeal viral antigen testing. Biopsy is not necessary for the diagnosis of viral myositis but may be used to differentiate it from IIM. In viral myositis, biopsy shows muscle degeneration and necrosis without inflammatory infiltrates. ⁴

Viral infection itself, such as with SARS-CoV-2 virus, may also act as inciting factors for the presentation of ASyS. ⁹ Influenza infection may have served as the trigger for ASyS development in this case. However, to our knowledge, there are no published cases of ASyS triggered by influenza.

In this case, minimal response to supportive care, strong anti-Jo-1 antibody positivity, diffuse symmetric myositis on MRI, muscle biopsy findings of inflammatory infiltrate, and robust clinical response to immunosuppressive therapy indicate that rhabdomyolysis in our patient was driven by ASyS rather than other infectious or metabolic etiologies.

There are only a few reported cases in which ASyS has presented with rhabdomyolysis. In each of these cases, the patient demonstrated dermatologic and/or lung involvement prior to or at the time of diagnosis. In one case, a 42-year-old man presented with symptomatic ILD. He was found 6 months later to have myositis with CK levels up to 19,245 units and acute kidney injury. He was diagnosed as anti-Jo positive ASyS. ¹⁰ In a second case, a 64-year-old man presented with inflammatory arthritis, ILD, and myositis (CK level 5605 units) with acute kidney injury. He was diagnosed as anti-Jo positive ASyS. ¹¹ Similarly, a third case has been described as anti-OJ ASyS with rash, Raynaud’s phenomenon, and rhabdomyolysis; however, clinical details of rhabdomyolysis beyond elevated CK levels were not provided. ¹² All of these ASyS cases presented with other organ system involvement in addition to rhabdomyolysis. Conversely, our patient presented without ILD or cutaneous findings.

In our case, treatment was initiated with rituximab. Rituximab is a monoclonal antibody targeting CD20, which allows for the depletion of B cells. Both rituximab and intravenous immunoglobulin can be considered for the treatment of severe IIM. However, rituximab may be considered first-line for ASyS specifically due to its concurrent efficacy in ILD and inflammatory arthritis and its mechanism of action targeting B cells, which are thought to be for a significant role in pathogenesis. ¹³

Conclusion

In summary, this case highlights a novel presentation of ASyS, which contributes to growing knowledge of the rare condition. To enhance diagnosis, clinicians should maintain awareness of the varied presentations of ASyS. ASyS may rarely present as isolated rhabdomyolysis without lung or skin involvement. Furthermore, viral infection (including influenza) may serve as a trigger for ASyS development. There is a need for further reporting of the varied presentation of ASyS to better guide diagnosis and treatment.