ABSTRACT

A 23-year-old otherwise healthy female with family history of familial Mediterranean fever (FMF) in 2 siblings who are on colchicine presented with fever, pleuritis, pericarditis, peritonitis and multiple abscesses in the liver. Sampling from the liver abscess showed neutrophil predominance with no findings of granuloma, vasculitis, lymphoma or malignancy. Similarly, samples from peritoneum and pleural fluids are exudative and showed foamy histiocytes, polymorphonuclear leukocytes. No pathogens, including bacterial, viral and fungal agents, were grown in cultures. The inflamatuary markers were very high, and despite multiple antibiotherapy, the clinical status and biochemistry picture did not improve. After excluding malignancy and infection, the picture was evaluated as an autoinflammatory disease and steroid treatment was started as anti-inflammatory therapy. Anti-interleukin 1 was added to the treatment of the patient who showed a dramatic radiological and clinical response to the steroid, and the steroid dose was reduced. Genomic DNA sample isolated from peripheral blood test showed homozygous MEFV m694v gene mutation diagnosing the patient with FMF.

Introduction

Aseptic abscesses are deep-seated, round, and sterile lesions that are rich in neutrophils. They do not respond to antibiotic therapy but do respond to steroid therapy. These lesions are not well-known.^[1] On closer examination, we can say that sterile inflammation is at the center of the disease pathogenesis. Although the majority of patients respond dramatically to steroids, approximately half of these patients relapse during the period when the steroid dose is reduced. In such cases, there are case-based studies in the literature that state tumor necrosis factor (TNF) alpha inhibitors and interleukin-1 (IL-1) antagonists successfully keep the patient on remission, and protect them from the side effects of steroids.^[2,3]

Case Report

A 23-year-old otherwise healthy post-partum female with family history of familial Mediterranean fever (FMF) in 2 siblings who are on colchicine presented with fever, pleuritis, pericarditis, peritonitis and multiple abscesses in the liver (Figure 1). Prior to this, the patient had no FMF findings such as fever, abdominal pain, joint pain, chest pain, or rash.

Figure 1

Sampling from the liver abscess showed neutrophil predominance with no findings of granuloma, vasculitis, lymphoma or malignancy. Similarly, exudate and foamy histiocytes, as well as polymorphonuclear leukocytes, were observed in samples from the peritoneum and pleural fluids. No pathogens, including tuberculosis, salmonella, brucella, viruses, and fungi, were grown in cultures. Parameters sent from the patient to exclude differential diagnoses, such as vasculitis, other connective tissue disorders, antiphospholipid syndrome, sarcoidosis, tuberculosis, neutrophil phagocytosis disorder, and macrophage activation syndrome, were negative (Table 2). Despite multiple antibiotic therapies, the patient’s blood levels of procalcitonin, C-reactive protein, and sedimentary were very high, and the clinical status and biochemistry picture did not improve. Once malignancy and infection were excluded, with the preliminary autoinflammation diagnosis, steroid treatment was continued at a dose of 60 mg/day after 3 days of 1 g steroid infusion. Most of the abscesses in the liver regressed, and the pleural and pericardial effusion resolved (Figure 2). With the steroid taper to 30 mg/day, anakinra 100 mg/day was added to the treatment. Gradually, the steroid dose was reduced to 5 mg/day. At the first month of this treatment, the patient’s C-reactive protein and procalcitonin levels decreased (Table 2). Clinically, fever, pain, and fluid collection were not documented (Figure 3).

Table 2

Figure 2

Figure 3

Based on all of this data, the patient was evaluated as having aseptic abscess syndrome (AAS) in the background of an autoinflammatory disease which led to the diagnosis of FMF given the homozygous M694V mutation.

Discussion

AAS is a part of the large group of diseases that form the topic of neutrophilic diseases. It is a condition in which tissues are infiltrated by neutrophils and granuloma/vasculitis symptoms are not observed. No microorganisms can be produced in tissue and blood cultures, and antibiotic response is not obtained.^[4] AAS is characterized by typical features that include regional, systemic, clinical, and biological abnormalities. The clinical presentation usually includes fever (90%), weight loss (50%), and visceral pain (67%). Abscesses are usually found in the spleen (97%), followed by the liver (40%), abdominal lymph nodes (48%), and pancreas (7%). When looking at extra-abdominal locations, lung (17%), brain (7%), superficial lymph nodes, and skin were observed.^[2,5] Considering the blood analysis of the cases, it was seen that 70% had neutrophilic hyperleucocytosis, 95% had high C-reactive protein levels, and 47% had increased liver enzyme levels. Lesions are sterile in terms of bacteria, fungi, parasitosis, and viral agents. In addition, antinuclear antibody, rheumatoid factor, antineutrophilic cytoplasmic antibody, and anti-phospholipid antibody levels are also negative.^[4]

AAS is often associated with other diseases that need to be investigated and treated. For example, chronic inflammatory bowel disease, relapsing polychondritis, spondyloarthropathy, neutrophilic dermatitis, monoclonal gammopathies, myelodysplasia, and sarcoidosis.^[6-10] The feature that makes this case interesting is that FMF has been detected as a result of this situation.

The specific criteria used in the diagnosis of AAS were radiologically demonstrated deep abscesses, neutrophilic cell dominance in the tissue samples taken from these abscesses, negative culture and serological results, no response to antibiotherapy and dramatic response to immunosuppressive therapy.^[11] AAS can occur in patients with FMF and is often misdiagnosed as infection. Failure to recognise this entity can lead to unnecessary morbidity and healthcare costs. AAS must be considered when patients develop deep abscesses that do not respond to conventional antibiotic therapy. The initial treatment of choice for AAS is high-dose intravenous glucocorticoids. Maintenance therapy should include a disease-modifying antirheumatic drug or biologically targeted agent or a combination of the two. The ideal regimen for maintenance therapy is still evolving. In patients placed on steroid maintenance therapy alone relapse occurred in some, but not all patients.^[12] Disease-modifying antirheumatic drugs (DMARDs) and biological targeted agents have been used as maintenance therapy. DMARDs that have been used to treat AAS include azathioprine, colchicine, cyclophosphamide, ciclosporin, methotrexate and mycophenolate mofetil. Biological targeted therapies that have been used include infliximab, adalimumab, etanercept, anakinra, canakinumab and tocilizumab.

In the literature, it is observed that many treatment recommendations for AAS are based on clinical observations and experiences instead of randomized controlled clinical research results. Steroids are the cornerstone of treatment.^[12,13] For 2-4 weeks, 0.5 mg/kg/day can be started orally or intravenously, and the dose can be gradually reduced according to the clinical response. The prognosis for AAS is variable, and to date, death from AAS has not been reported. However, 60% of patients presented with relapses and required chronic immunosuppressive therapy.^[2,4] In addition to steroids, relapse cases can be treated with azathioprine (2-3 mg/kg), pulse cyclophosphamide, or methotrexate. In these cases, the use of anti-TNF-alpha or recombinant IL-1 receptor antagonists and anti-IL-1B monoclonal antibodies may be considered when relapsed.^[14,15]

IL-1B is an essential cytokine of the innate immune system. It is produced from myeloid cells as pro-IL1B and converted into its active form, IL-1B, with caspase 1 activity. The activation of caspase 1 depends on the inflammasome pathway. Uncontrolled activation in the Caspase 1 and IL-1B pathways leads to systemic and multi-organ sterile inflammation. In autoinflammatory diseases, fever, arthritis, serositis, rash, and sterile abscesses are observed, while neutrophils and high acute phase reactants are used to monitor treatment response. In summary, the uncontrolled activation of the innate immune response can manifest itself with a clinical picture such as aseptic abscess, fever, and serositis, as in our case (inflammasome formation → caspase 1 activation → IL-1B release). Successful treatment modalities aimed at suppressing this pathway have been observed, where IL-1B plays a crucial role in the pathophysiology of aseptic abscess.

Conclusion

In conclusion, IL-1B blockade is a good treatment option in cases of AAS that require a high steroid dose and are not well controlled, as in our case.^[3]

Ethics

Informed Consent: Informed consent was obtained.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Concept: S.B., S.U., Design: S.B., S.U., Analysis or Interpretation: S.B., S.U., Literature Search: S.B., Writing: S.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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