A Chinese case series of Schnitzler syndrome and complete remission in one tocilizumab-treated patient

Schnitzler syndrome (SchS) is a rare acquired systemic autoinflammatory disease. The major clinical features of SchS are urticarial rash and monoclonal gammopathy, accompanied by fever, joint pain, and lymphadenopathy. There were few reports about SchS in Chinese population. Herein, we describe two patients with SchS in China and conducted a systematic literature review about SchS. Two Chinese Han patients were diagnosed as SchS in our department from 2017 to 2019. Their phenotype and genotype were carefully documented and studied. We also conducted a systematic literature review about SchS. There was one man (66 years old) and one woman (49 years old). Recurrent fever and urticarial rash occurred in both of them during the febrile attacks and normalized in asymptomatic intervals. Other manifestations included arthralgia, lymphadenopathy, and hearing loss. Hepatic cirrhosis and epilepsy were seen in the male patient. None of them had bone pain or family histories. Serum monoclonal IgM gammopathy was found in both patients. MyD88 gene mutation L258P was identified in the female patient. They were treated with tocilizumab and tripterygium wilfordii Hook F (TwHF) respectively, and both showed good response. The rarity and diversity of SchS make it difficult to be recognized. Anti-IL-6 agents may be alternative therapies when anti-IL-1 therapy is unresponsive or unavailable. Due to the case report, the effect of TwHF in the treatment of SchS should be further studied.


Introduction
Schnitzler syndrome (SchS) is a rare acquired systemic autoinflammatory disease, which was first described in 1972 by Liliane Schnitzler [1]. It always occurs in patients around 50 years. The main clinical features include urticarial rash and monoclonal gammopathy (usually of the IgM class, rarely IgG), accompanied by fever, bone/joint pain, and lymphadenopathy. Lymphoproliferative disorders and amyloidosis may happen in some patients with SchS [2,3]. Since the central pathogenesis of SchS is activation of innate immune system and release of interleukin (IL) -1 β, IL-1 antagonists are effective in about 90% patients with SchS [4].
SchS has been primarily reported in Caucasians [4] but hardly in the Chinese population. To our knowledge, this is the first case series of SchS in the Chinese patients with illustration of phenotype and genotype in English literature. We have the pre-printed article which can be accessed at https:// www.researchsquare.com/article/rs-13575/v1.

Patients and methods
From 2017 to 2019, two Chinese patients with SchS were identified based on the Strasbourg criteria [5]. According to the Strasbourg criteria, a definite diagnosis could be made when two obligate criteria and at least two minor criteria if IgM, and three minor criteria if IgG, were met. The complete medical records of these patients were established, and detailed data were collected and documented. Ethical approval for this study was approved by the Institutional Review Board of Peking Union Medical College Hospital and performed according to the Declaration of Helsinki. Informed consents were obtained from both participants. Whole exome sequencing by Next Generation Sequencing was performed in the Center for Genetic Testing, Joy Orient Translational Medicine Research Centre Co., Ltd., Beijing, China.
Articles were identified through PubMed database search utilizing the search string "Schnitzler syndrome" or "Schnitzler's syndrome." Case reports, case series, and abstracts with no published articles were excluded. All identified articles were read in full, with relevant information extracted and summarized.

Patient 1
A 66-year-old Chinese Han man presented with recurrent urticarial rash for 11 years and fever for 4 years. He developed urticarial rash on the face, limbs, and trunk ( Fig. 1a and b) when he was 55 years old. A skin biopsy showed fibrinoid changes of blood vessels, perivascular infiltration of lymphocytes, histiocytes, and eosinophils, as well as some nuclear dusts, consistent with urticarial vasculitis (Fig. 1c). He had hearing loss, and bilateral sensorineural deafness was diagnosed at the age of 56. He also had intermittent edema of lower limbs since then. He noticed episodes of high fever, headache, fatigue, lymphadenopathy, and epilepsy since the age of 62. The episodes occurred every 1-2 weeks, lasted for several hours, and symptoms recovered in between the episodes. The analysis of cerebrospinal fluid was normal. Brain MRI showed chronic ischemic changes and senile atrophy of the brain. Electroencephalogram was unremarkable. Lymph node biopsy showed reactive hyperplasia. There was no report of family history for periodic fever syndrome. He did not drink and denied history of drug use.
The patient was diagnosed as definite SchS because he fulfilled two obligate criteria (chronic urticarial and c Skin biopsy from the right leg of patient 1 showed fibrinoid changes of blood vessels, perivascular infiltration of lymphocytes, histiocytes, and eosinophils, as well as some nuclear dusts, consistent with urticarial vasculitis. Black arrow: eosinophil infiltration monoclonal IgM) and two minor criteria (recurrent fever and leukocytosis/elevated CRP). He was treated with antihistamines with no response. He received methylprednisolone 16 mg per day and methotrexate 12.5 mg per week with a complete response. However, his symptoms relapsed after methylprednisolone tapered to 12 mg per day. Due to unavailability of IL-1 antagonist agents in China, he was treated with tocilizumab 8 mg/kg per month. After 3 months, he was completely symptom-free with only mild fatigue. We assessed serum tests which showed WBC was 9.6 × 10 9 /L, ESR 15 mm/h, and CRP 0.7 mg/L. Liver function showed that AST and ALP were declined to 21 U/L and 72 U/L, respectively. Currently, the patient is treated with tocilizumab 8 mg/kg per month, methylprednisolone 6 mg per day, and methotrexate 12.5 mg per week.

Patient 2
A 49-year-old Chinese Han woman presented with recurrent fever, urticarial rash, and arthralgia for 1 year. She had noted the disease attacked every several weeks, with each flare lasting 2 days to 2 months. The clinical features were characterized by high fever, arthralgia with bilateral elbows and knees involved, myalgia, and superficial lymphadenopathy. Recurrent urticarial rash was observed during the disease course. Non-steroidal anti-inflammatory drugs (NSAIDs) were effective to alleviate fever and arthralgia. There was no family history of periodic fever syndrome. Leukocytosis, elevated ESR, and CRP were associated with the attacks, and they normalized in between the disease episodes. Serum IgM κ chain was positive. Serological markers were negative for systemic autoimmune disorders and infection. A skin biopsy showed infiltration of lymphocytes and neutrophils around the blood vessels in the dermis. MyD88 L265P mutation was identified by whole exome sequencing.
As the patient met two obligate criteria (chronic urticarial and monoclonal IgM) and three minor criteria (recurrent fever, a neutrophilic dermal infiltrate on skin biopsy, and leukocytosis/elevated CRP), she was diagnosed as definite SchS. Since she refused biologic agents due to a financial difficulty and she was concerned about the adverse effects of steroids and other immunosuppressants, she preferred to take traditional Chinese medicine. She received tripterygium wilfordii Hook F (TwHF) 20 mg, three times daily, with a good response. At a 3-month follow-up, she was symptomfree, with levels of ESR and CRP decreased to normal (10 mm/h, 2 mg/L, respectively).

Systemic literature review
A total of 355 cases of SchS patients were identified through the PubMed search [3,4,6,7]. The clinical manifestation of these patients and our patients are summarized in Table 1. The largest retrospective study including 281 patients with SchS was published in 2014 which contained phenotype of all SchS patients by that time [4]. Patients had disease onset around 50 years old, with a higher ratio of male to female. Among these 357 SchS patients, the common clinical features were urticarial rash (357/357, 100%), monoclonal IgM gammopathy (314/357, 88%), fever (271/357, 76%), join and/or bone pain (203/357, 57%), and enlarged lymph nodes (102/357, 29%) ( Table 1). In regard to the genotype, it had ESR erythrocyte sedimentation rate, CRP C-reactive protein, ND no data, NA not applicable * Normal range was not mentioned in this reference (CRP was 18-257 mg/L) been confirmed that MyD88 L256P mutation was detected in a third of SchS and was the most common genetic factor found among SchS patients to date. Meanwhile, no activating NLRP3 mutations were presented in SchS patients except occasional myeloid-lineage-restricted mosaicism [8,9]. Anti-IL-1 receptor and IL-1β antibodies are preferred treatments of SchS, which are highly effective in 90% patients. Anti-IL-6 agent tocilizumab also worked in five patients who had no response to anakinra [4].

Discussion
Due to its rarity, SchS is an exclusive diagnosis that must be distinguished from diseases with similar manifestations. The first important differential diagnosis is lymphoproliferative disorders, in which monoclonal gammopathy is one of the significant features. It is known that monoclonal gammopathy is associated with a κ light chain in more than 90% of SchS patients [4]. But it is worth mentioning that high IgM values may also occur in other diseases, for example, Waldenström macroglobulinemia (WM). WM is an IgM-secreting lymphoproliferative disorder. Moreover, MyD88 is a commonly occurring gene mutation in patients with WM [10]. Interestingly, 15-20% of SchS patients develop clinical overt lymphoproliferative disorders [11], and the MyD88 L256P variant is present in 30% of SchS patients [8]. In our report, MyD88 L265P mutation was found in one patient. In contrast to lymphoproliferative disorders, SchS has pronounced urticarial rash, yet the lymph nodes are usually reactive hyperplasia. Based on these results, SchS and lymphoproliferative disorders appear connected and likely represent a disease continuum. In our study, both patients had no evidence of lymphoproliferative disorders. Nevertheless, since SchS patients with MyD88 mutation have the high tendency to become lymphoproliferative disorders, they should be carefully followed. The second important differential diagnosis of SchS is NLRP3-autoinflammatory disease (NLRP3-AID) (formerly named as cryopyrin-associated periodic syndrome, CAPS). The clinical features of SchS closely resemble NLRP3-AID, which is caused by activating mutations in the NLRP3 (nucleotide-binding oligomerization domain leucine-rich repeats containing pyrin domain 3) gene, including recurrent urticarial rash and over release of IL-1 β. But NLRP3-AID usually occurs during pediatric ages, while SchS onset is around 50 years. Besides, patients with NLRP3-AID have prominent manifestations of central nervous system inflammation, which is absent in SchS. On the other hand, SchS conventionally presents with no germline NLPR3 mutation [8], but with the exception of somatic mosaicism occasionally seen in the myeloid lineage [9]. Additionally, monoclonal IgM in NLRP3-AID is not observed, whereas it elevates in SchS. Hence, SchS is distinct from the monogenic autoinflammatory disease NLRP3-AID.
Apart from the main manifestations of SchS, there are also some uncommon symptoms such as hepatosplenomegaly and neuropathy. Hepatomegaly can be found in 9% SchS patients [4]. In 1999, a case of SchS with nodular regenerative hyperplasia of the liver was reported [12]. Hepatic fibrosis is commonly preceded by chronic inflammation [13,14]. In the recent studies, IL-1β has been proposed as an important mediator of inflammation and tissue damage in chronic liver disease [15]. Meanwhile, IL-1 receptor antagonist modulated liver inflammation and fibrosis in mice [16]. On the other hand, although there have been no reports of neural damage in SchS, inflammatory process in this disorder may originate in the central nervous system or be acquired from systemic circulation through a breakdown in the blood-brain barrier (BBB) [17]. It has been illustrated that IL-1β was also an etiologic trigger for BBB breakdown and played a pivotal role in the activation of astrocytes [17]. In addition, IL-1 blockade managed systemic autoinflammation with intractable epilepsy [18]. In conclusion, the uncommon manifestations of SchS such as liver cirrhosis and epilepsy might be attributed to chronic inflammation mainly caused by IL-1β. In our study, patient 1 was accompanied with possible hepatic cirrhosis demonstrated by radiology, and epilepsy of unknown reason, for which we carefully excluded other etiologic factors including autoimmune diseases, heart disease, drug-induced damage, and alcoholic liver disease. It is worth mentioning that patient 1 had a concomitant occult HBV infection. Because the patient did not undergo liver biopsy, it was hard to determine the specific etiologic factor of liver cirrhosis. But taking the aforementioned concepts into consideration and the pivotal role of IL-1β overproduction in SchS, we assumed that hepatic cirrhosis and epilepsy in this patient might be related to SchS.
The availability of antagonists of the IL-1 signaling pathway has revolutionized the treatment of SchS. This is especially true for the IL-1 receptor antagonist anakinra [19][20][21]. A fully humanized IL-1β-specific antibody named canakinumab is also effective to treat SchS [22][23][24]. Anti-IL-6 treatment such as tocilizumab can be effective [25] and is considered an alternative therapy in patients with SchS when anti-IL-1 therapy is unresponsive or unavailable [3,26]. To date, patient 1 in our study was the sixth case of SchS who responded well to tocilizumab in English literature. It has been suggested that both IL-1 pathway (the common pathway) and IL-6 pathway (the alternative pathway) may play a relevant role in SchS. Other potentially therapeutic agents are promising in the treatment of SchS. Due to unavailability and high cost of IL-1 antagonist therapies in China, glucocorticoid and disease modifying anti-rheumatic drugs (DMARDs) were used to control the patients' conditions. Tripterygium wilfordii Hook F (TwHF) is a Chinese traditional herbal which has been widely used for the treatment of autoimmune diseases [27]. Clinical and experimental studies have demonstrated its immunosuppressive and antiinflammatory effects [28,29]. It should be noted that TwHF was effective in patients with chronic urticaria [30]. In addition, it could alleviate inflammation in mice models of cardiomyopathy and ulcerative colitis through inhibiting expression of NLRP3 inflammasome [31][32][33]. In our study, the second patient had a good response to TwHF treatment. However, considering that it could be an accidental phenomenon, further clinical observations and studies are necessary to evaluate the effect of TwHF in the treatment of SchS.

Conclusions
In summary, this is the first case series of SchS in the Chinese patients with illustration of phenotype and genotype in English literature. The rarity and diversity of SchS make it difficult to be recognized. Our report highlighted that anti-IL-6 agents may be alternative therapies when anti-IL-1 therapy is unresponsive or unavailable. Due to the case report, the effect of TwHF in the treatment of SchS should be further studied. Further studies are needed to explore the genotypes and treatment of SchS.