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. But it’s 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. Interestingly, 15%-20% of SchS patients develop a clinical overt lymphoproliferative disorders, and the MyD88 L256P variant present in 30% of SchS patients. 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, but with the exception of somatic mosaicism occasionally seen in the myeloid lineage . 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 neuropathy4. Hepatomegaly can be found in 9% SchS patients. In 1999, a case of SchS with nodular regenerative hyperplasia of the liver was reported. 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. Meanwhile, IL-1 receptor antagonist modulated liver inflammation and fibrosis in mice. On the other hand, although there has 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). 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. In addition, IL-1 blockade managed systemic autoinflammation with intractable epilepsy. In our study, patient 1 was accompanied with hepatic cirrhosis and epilepsy of unknown reason, for which we carefully excluded infections, autoimmune diseases, and alcoholic liver disease. 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. As of now, this was the first case report of SchS associated with concomitant liver and neural damage.
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[19–21]. A fully humanized IL-1β-specific antibody named canakinumab is also effective to treat SchS[22–24]. Anti-IL-6 treatment such as tocilizumab can be effective and is considered an alternative therapy in patients with SchS when anti-IL-1 therapy is unresponsive or unavailable[26, 3]. 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 SchS25. 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. Clinical and experimental studies have demonstrated its immunosuppressive and anti-inflammatory effects[28, 29]. It should be noted that TwHF was effective in patients with chronic urticaria. In addition, it could alleviate inflammation in mice models of cardiomyopathy and ulcerative colitis through inhibiting expression of NLRP3 inflammasome[31–33]. In our study, the second patient had a good response to TwHF treatment. Taken these data together, we suggest that TwHF is useful in SchS patients. However, due to the sample limitation of our study, more clinical trials are required.