Schnitzler Syndrome Presenting as a Fever of Unknown Origin with Elevated Alkaline Phosphatase Levels

Abstract

Schnitzler syndrome (SchS) is a rare, acquired, autoinflammatory disease that is sometimes associated with a fever of unknown origin (FUO). Elevated alkaline phosphatase (ALP) stemming from abnormal bone remodeling is a characteristic laboratory finding of SchS and is included in the diagnostic criteria. However, its utility as a clue to the diagnosis of SchS has been under-emphasized. We herein report a case of SchS presenting with a FUO and highly elevated ALP concentration, which led to repeated, unnecessary liver biopsies.

Introduction

Schnitzler syndrome (SchS) is a rare, acquired, chronic, autoinflammatory disease characterized by chronic urticaria, monoclonal (IgM or sometimes IgG) proteins, bone lesions, and clinical or biological signs of inflammation (1). The precise pathophysiology is still unknown, but interleukin-1β (IL-1β)-mediated and neutrophil-dominated inflammation is thought to be the principal mechanism (1). Although the Strasbourg criteria have a high sensitivity and specificity of 81-93% and 97-100%, respectively (1,2), diagnosing SchS remains challenging because of its rarity and the low level of awareness about the disease among clinicians (3).

SchS can cause a fever of unknown origin (FUO), and the time from the onset to the diagnosis is reportedly five years or more in many cases (4,5). This protracted interval may lead to some patients missing the opportunity to receive highly effective therapy, including anti-IL-1 receptor antagonists, such as anakinra (3). The early diagnosis and treatment are thus important for preserving the patient's quality of life and avoiding potentially serious complications, including hematological malignancies and AA amyloidosis (6,7), but the tips and pitfalls in diagnosing SchS have not been discussed sufficiently.

The Strasbourg criteria include an elevated level of alkaline phosphatase (ALP), a basic laboratory feature of SchS, as an objective finding of abnormal bone remodeling (Table). However, the actual importance of a high ALP level for diagnosing SchS has not been made clear.

Table.

Strasbourg Diagnostic Criteria for Schnitzler’s Syndrome (1).

Obligate criteria
•	Chronic urticarial rash+
•	Monoclonal IgM or IgG
Minor criteria
•	Recurrent fever*
•	Objective findings of abnormal bone remodeling with or without bone pain†
•	A neutrophilic dermal infiltrate on skin biopsy‡
•	Leukocytosis and/or elevated CRP §
Definite diagnosis if two obligate criteria AND at least two minor criteria if IgM, and three minor criteria if IgG
Probable diagnosis if two obligate criteria AND at least one minor criterion if IgM, and two minor criteria if IgG

*A valid criterion if objectively measured. Must be >38°C, and otherwise unexplained. Occurs usually - but not obligatory - together with the skin rash.

†As assessed by bone scintigraphy, MRI or elevation of bone alkaline phosphatase.

‡Corresponds usually to the entity described as neutrophilic urticarial dermatosis; absence of fibrinoid necrosis and significant dermal edema.

§Neutrophils >10,000/mm³ and/or CRP >30 mg/L.

We herein report a case of SchS manifesting a FUO with markedly elevated ALP levels, which led to unnecessary, repeated liver biopsies. The findings in the present case suggest that a high ALP level in SchS can be at once a diagnostic clue and a pitfall leading to an unnecessary liver biopsy.

Case Report

A 60-year-old man was referred to our hospital with a 1-year history of a fever, malaise, and chronic rash. Nineteen months before presentation, he began experiencing recurrent urticaria. The urticaria was slightly pruritic and mostly present on his trunk and limbs sparing the face, palms, and soles. The urticaria occurred several times per month and was not associated with cold exposure. Individual lesions persisted for several days. Four months later, he began experiencing a persistent fever of around 38.0°C. An intensive diagnostic work-up, including four sets of blood cultures, whole body contrast-enhanced computed tomography (CT), transthoracic echocardiography, upper and lower endoscopy, a bone marrow biopsy, a skin biopsy, and two percutaneous liver biopsies, produced no remarkable findings. He denied sore throat, headache, abdominal pain, arthralgia, and bone pain. His medical history was unremarkable. He was a non-smoker and drank only socially. Five months before presentation, he began prednisolone 1 mg/kg/day for clinically diagnosed adult-onset Still disease (AOSD). However, the treatment failed to improve his symptoms despite a slight decrease in his C-reactive protein (CRP) and ALP levels (Fig. 1). The prednisolone was tapered to 10 mg/day by the time of his current presentation.

Figure 1.

Clinical course of the patient. CRP: C-reactive protein, ALP: alkaline phosphatase, PSL: prednisolone, TCZ: tocilizumab

On presentation, the patient reported fatigue, but his vital signs were normal. A physical examination revealed urticaria on the trunk and extremities. The rest of the physical examination was unremarkable. Laboratory tests revealed elevated ALP levels at 515 U/L (normal: 106-322) U/L with no other liver enzyme abnormalities, leukocytes 11.2 (normal: 3.3-8.6) ×10⁹/L, CRP 7.52 (normal: 0.00-0.14) mg/dL, ferritin 278.1 (normal: 50-200) ng/mL, and erythrocyte sedimentation rate 126 (normal: 2-10) mm/h. ¹⁸F-fluorodeoxyglucose positron emission tomography-CT (FDG-PET-CT) revealed an increased but diffuse fluorodeoxyglucose uptake in the spine, pelvis, and femur (Fig. 2), suggesting that the source of the elevated ALP was the bone rather than the liver. Additional serum protein electrophoresis demonstrated IgG lamda monoclonal protein (Fig. 3).

Figure 2.

FDG PET-CT revealing a diffuse increased fluorodeoxyglucose uptake in the spine, pelvis, and femur (arrows)

Figure 3.

Serum protein electrophoresis with immunofixation showing monoclonal IgG lambda bands (asterisks).

SchS was definitively diagnosed based on the Strasbourg criteria (Table). Colchicine 1 mg/day was initially administered but had no effect. Tocilizumab 520 mg (8 mg/kg) biweekly was then administered because IL-1 receptor antagonists are unavailable for SchS treatment in Japan at present, and tocilizumab is considered a promising alternative therapy (5,6,8). The response to tocilizumab was very good, and the longstanding fever, malaise, and urticaria decreased several days after the start of the treatment. The CRP and ALP values also normalized (Fig. 1). Remission was maintained with tocilizumab monotherapy for two years after the start of treatment, but IgG lamda monoclonal protein was still positive at two years after the initiation of tocilizumab therapy.

Discussion

The diagnosis of SchS is often challenging and is made several years after the disease onset, even if the patient presents typical symptoms (4,5). A combination of features characteristic of the syndrome is thought to be the key to the diagnosis, but as the clinical signs of SchS are without exception non-specific, laboratory test findings are also important diagnostic clues. The presence of monoclonal IgM or IgG is an obligate component in SchS, but serum protein electrophoresis is usually not included in a routine work-up for a FUO (9). In contrast, ALP is almost routinely measured and may thus serve as a clue for recognizing the possibility of SchS in the differential diagnosis of a FUO.

Elevated ALP is most commonly caused by bone and liver disorders. In patients with SchS, it is thought to stem from increased bone metabolism, and 68% patients with the disease complain of bone pain (1). In our case, bone lesions were detected by FDG-PET-CT despite the absence of bone pain and arthralgia, suggesting that increased bone metabolism can be subclinical and that bone imaging tests may be useful even when patients do not have any apparent, musculoskeletal symptoms. The assessment of ALP isoenzyme or other bone metabolic markers may also be useful for determining the source of elevated ALP although they were unable to be measured in the present case. Furthermore, it is worth noting that two liver biopsies were performed in the present case in response to the elevated ALP because liver biopsies are generally considered to be useful in determining the cause of a FUO with increased ALP (10,11). However, clinicians should keep SchS in mind as a possible, albeit rare, cause of a FUO with elevated ALP stemming from abnormal bone remodeling to avoid unnecessary liver biopsies.

The differential diagnosis of SchS is broad, but AOSD is perhaps the most important because it is relatively common and shares many clinical features with SchS (12). Some SchS cases meet the Yamaguchi criteria and are initially treated as AOSD, as in the present case, but SchS generally responds poorly to steroid therapy. The possibility of SchS should be considered in cases of suspected AOSD that are recalcitrant to steroid therapy. In the present case, the absence of a sore throat, the presence of pruritus, and the relatively mild ferritin elevation compared with that typically seen in AOSD were other characteristics of SchS (12). Furthermore, a markedly elevated ALP level is rare in AOSD and marks another important difference between these two diseases (12). Cryopyrin-associated periodic syndrome (CAPS) is also a differential diagnosis of SchS (7,12). CAPS includes three clinical entities: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID). However, CAPS generally develops in childhood, while SchS usually develops in individuals ≥50 years old (7,12). The absence of characteristic symptoms of CAPS, including cold-triggered episodes, sensorineural hearing loss, and chronic aseptic meningitis, is also important for differentiating the two conditions (12,13). Furthermore, monoclonal proteins have not been reported in CAPS (7).

The present case demonstrated a significant clinical response to tocilizumab. Although IL-1 is believed to be the principal mechanism in SchS, and anakinra, a recombinant human IL-1 receptor antagonist, is widely regarded as the first choice of treatment for SchS (1,6), there are barriers to its use in some areas, including its cost, lack of availability, and lack of health insurance coverage. In Japan, IL-1 receptor antagonists are not available. Therefore, alternative treatments are desired, although a discussion with the patient and institutional consensus will be necessary for their administration. IL-6 is thought to be involved in the pathogenesis of SchS based on several previous reports in which patients demonstrated an excellent response to IL-6 inhibitors, as in as our case. IL-6 in SchS is produced by mast cells, neutrophils, and lipopolysaccharide-stimulated peripheral blood mononuclear cells (6,14). The details of IL-6 involvement in the pathogenesis of SchS are still unknown, but IL-6 may be associated with skin and systemic inflammation, stimulate the osteoclast function, and serve as a growth factor for B-lymphocytes, resulting in the growth, proliferation, and survival of myeloma cells (7). Serum IL-6 levels are elevated in patients with SchS and seem to correlate with disease activity (6,8). Furthermore, it is interesting to note that some cases of SchS show no response to anti-IL-1 but show an excellent response to anti-IL-6 treatment with tocilizumab (8), suggesting that at least two independent pathways - via IL-1 (common pathway) and via IL-6 (alternative pathway) - may play a relevant role in SchS, with both resulting in the same clinical picture (8).

Despite the drastic clinical improvement and remission in the present case, monoclonal protein continued to be detected even at two years after the start of tocilizumab therapy. This finding is in line with that of previous reports, which found that the monoclonal protein levels remained stable during anti-IL-1 and anti-IL-6 treatment (7,8). The clinical significance of the persistent monoclonal proteinemia in SchS remains uncertain but suggests that continuous follow-up and vigilance against the development of hematological disorders or AA amyloidosis are needed.

Conclusion

We encountered a case of SchS presenting with a FUO and high ALP. The presence of high ALP levels and FDG-PET-CT findings of an increased fluorodeoxyglucose uptake in bone are clues for diagnosing SchS. However, elevated ALP levels in SchS can also be a pitfall, prompting unnecessary liver biopsies to determine the cause of the FUO. Clinicians should consider the possibility of SchS whenever patients with a FUO present with markedly elevated ALP levels, symptoms atypical of AOSD, or a poor response to steroid therapy.

Consent to publish the details of the case was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).