IL-1 inhibitors versus other immunosuppressants in Schnitzler Syndrome: An Updated Review

Authors: Mohddiya Masmoum¹*, Raneem Masmoum¹, Jabr Asmew²

Affiliations

1. Alfaisal University, College of Medicine, Riyadh, Saudi Arabia

2. University of Benghazi, Faculty of Medicine, Benghazi, Libya

Doi: 10.5281/zenodo.14055667

JERMS

Published: Nov/2024.

Volume: 1(1):16-26

*corresponding author

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Abstract

Schnitzler Syndrome is a rare, late-onset acquired autoinflammatory disorder characterized by chronic urticarial rash, monoclonal gammopathy, and systemic inflammation. The syndrome shares clinical and biological features with other autoinflammatory conditions such as NLRP3-associated periodic syndromes also known as Cryopyrin associated periodic syndrome (CAPS), and adult-onset Still's disease (AOSD). The central role of interleukin-1β (IL-1β) in the pathogenesis of Schnitzler Syndrome is underscored by the dramatic efficacy of IL-1 blocking therapies. This review compares the effectiveness and safety of IL-1 inhibitors, particularly anakinra and canakinumab, against other immunosuppressive treatments for managing Schnitzler Syndrome. Anakinra, a recombinant human IL-1 receptor antagonist, which blocks both IL-1α and IL-1β is shown to provide rapid and complete control of symptoms within hours of administration. However, it necessitates daily injections, which may be deemed difficult in terms of compliance. Canakinumab, a selective anti-IL-1β monoclonal antibody which only blocks IL-1β, offers more prolonged dosing intervals and maintains clinical remission with less frequent administrations. Both Anakinra and Canakinumab may effectively improve the symptoms of inflammation but have no effect on the monoclonal component of Schnitzler Syndrome and do not reduce the risk of developing lymphoproliferative disorders, which remains a significant prognostic concern. In some patients who were non-responsive to IL-1 inhibitors, tocilizumab, an interleukin-6 (IL-6) receptor antibody, proved to be highly but often lost efficacy in most patients over time, so that its use should be limited to IL-1 inhibitor non-responders. Other immunosuppressants, such as rituximab, and corticosteroids, have shown limited efficacy but come with a higher burden of side effects.

Introduction & Background

Schnitzler syndrome is a rare acquired autoinflammatory disorder first described by Dr. Liliane Schnitzler in 1972, characterized by a combination of chronic urticarial rash with monoclonal gammopathy, typically of the IgM kappa isotype, along with systemic inflammatory symptoms such as fever, bone pain, and arthralgia [1-3]. The prevalence of the Schnitzler syndrome is not well-established due to its relative rarity and its underdiagnosis, although it seems to be an important differential diagnosis for chronic urticaria and fevers of unknown origin [4-6]. A critical role of interleukin-1β (IL-1), a proinflammatory cytokine, has been revealed in the pathogenesis of Schnitzler Syndrome, which is pivotal in the inflammatory response associated with the disease. Elevated levels of IL-1β are responsible for the typical symptoms and systemic inflammation in the patients [1-3,7]. Although a role for IL-1β is apparent, the exact mechanisms that interlink the monoclonal gammopathy with autoinflammatory features are unknown [2,3,7]. This review has been done focusing on the current therapeutic options for Schnitzler Syndrome with a focus on IL-1 inhibitors in comparison to other immunosuppressants. It reviews the current literature, clinical trials and some case reports on Schnitzler syndrome’s pathogenesis, clinical features and the efficacy, safety, and practical issues related to these treatments for this very difficult, most often underdiagnosed condition and helps to improve knowledge and care in the future. The diagnostic criteria of Schnitzler Syndrome have changed with time. Current criteria include the presence of a chronic urticarial rash and monoclonal IgM immunoglobulin, accompanied by at least two of the following: recurrent fever, objective signs of abnormal bone remodeling, elevated C-reactive protein (CRP) levels or leukocytosis, and a neutrophilic infiltrate on skin biopsy [4,8]. These criteria aid in the differentiation of Schnitzler Syndrome from other similar conditions that have some overlapping clinical features, such as cryopyrin-associated periodic syndromes (CAPS), a systemic autoinflammatory disease characterized by interleukin 1β-mediated inflammation involving skin, joints, central nervous system, and eyes, and adult-onset Still's disease (AOSD), which is also a systemic autoinflammatory disease characterized by fevers, arthralgia, and a salmon-colored rash [1,4].The introduction of IL-1 blocking therapies has radically changed the treatment of Schnitzler Syndrome. Anakinra is a recombinant human IL-1 receptor antagonist that has been very effective in controlling inflammation caused by Schnitzler Syndrome and often rapidly resolves the symptoms [1,4,9,10]. On the other hand, anakinra needs daily injections, which can become a heavy burden for the patient [9,10]. Canakinumab is a fully human monoclonal antibody to IL-1β with the advantage of less frequent administrations; clinical remission is maintained with subcutaneous injections every eight weeks [11-13]. Although IL-1 inhibitors are very effective in managing the inflammation, they do not impact the monoclonal component of the disease and do not lower the risk of lymphoproliferative disorders such as Waldenström macroglobulinemia that develops in about 15-20% of patients [1,4,6,14]. Thus, continuous monitoring and comprehensive assessment focusing on both, the inflammatory and hematological components of the syndrome are required for effective management and improved patient outcomes. Other immunosuppressive treatments have been tried besides IL-1 inhibitors, some with some varying success. One such IL-6 receptor antagonist is tocilizumab, used in a few patients and proved highly effective, especially those where IL-1 blockade failed to elicit any response, however, the long-term efficacy is still not certain making IL-1 inhibitors the mainstay first line therapy [14,15]. B-cell depleting antibody rituximab and conventional corticosteroids, though tried with limited efficacy, are associated with significant side effects [15,16]. Thus, IL-1 targeted therapies remain the mainstay of treatment in Schnitzler Syndrome.

Review

Pathogenesis of Schnitzler Syndrome

Schnitzler Syndrome is an acquired autoinflammatory disease characterized by a combination of chronic urticarial rash and monoclonal gammopathy, predominantly of the IgM kappa isotype. The disorder presents with clinical and biological similarities to other autoinflammatory diseases, like NLRP3-associated autoinflammatory disorders and adult-onset Still's disease [1,2,17]. The pathogenesis of Schnitzler Syndrome is significantly influenced by interleukin-1β, a cytokine centrally involved in the drive of inflammation in this condition [1,3]. Elevated levels of IL-1β present with such typical symptoms of Schnitzler Syndrome as recurrent fever, arthralgia, bone pain, and high acute-phase reactants. This link is further supported by the spectacular effectiveness of IL-1 blocking therapies in controlling the symptoms of Schnitzler Syndrome [1-3]. However, the exact mechanisms linking the monoclonal gammopathy to the autoinflammatory features are still not clear and additional studies are required to clarify these links [2,3,7].

Clinical Features and Diagnosis

The diagnosis of Schnitzler Syndrome requires a combination of clinical and laboratory findings. This is commonly done by the use of the Strasbourg diagnostic criteria, which describe a chronic urticarial rash and monoclonal IgM gammopathy combined with at least two minor criteria: recurrent fever, abnormal bone remodeling, elevated CRP or leukocytosis, and a neutrophilic infiltrate on skin biopsy [4,8]. In cases where the monoclonal component is IgG, if three minor criteria are present, the diagnosis can be regarded as definite and probable if two are present [8]. Most commonly, it presents with a chronic urticarial rash associated with many systemic symptoms that include fever, arthralgia, bone pain, lymphadenopathy, fatigue, loss of weight, and splenomegaly [1,2,4,6]. Laboratory results are usually high in inflammatory markers, such as C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR), in addition to leukocytosis [4,8]. Imaging examinations may show abnormal bone remodeling, especially in the long bones [8]. It is therefore incumbent upon clinicians to consider Schnitzler Syndrome in the differential diagnosis of such patients due to increased risk of lymphoproliferative disease so that the diagnosis and treatment processes are both effective and prompt [6].

IL-1 Inhibitors in the Treatment of Schnitzler Syndrome

IL-1 inhibitors revolutionized the treatment of Schnitzler Syndrome by targeting the key cytokine driving its inflammatory response [4]. Anakinra is a recombinant human IL-1 receptor antagonist, which has been found to be very effective in controlling the symptoms of the Schnitzler Syndrome. The patients experienced prompt and complete resolution of symptoms within hours of the administration; hence, anakinra is a very potent treatment option [1,4,9,10,18,19]. The burden, however, of the need for daily subcutaneous injections of anakinra sometimes has huge impacts on patients' quality of life and adherence to treatment regimens [9,10]. Canakinumab, a fully human monoclonal antibody targeting IL-1β, offers an advantage with its longer dosing intervals, maintaining clinical remission with subcutaneous injections every eight weeks. Clinical trials have shown that canakinumab induces complete and sustained clinical responses, with significant reductions in inflammatory markers and improvements in quality of life and was not associated with a loss of its therapeutic effect over time [11-14,20]. In a placebo-controlled study in 20 patients with active Schnitzler Syndrome, a significantly higher percentage of complete clinical responses was obtained with canakinumab versus placebo, with maintained positive effects on markers of inflammation and quality-of-life assessments during the period of 16 weeks [12]. Another study showed that monthly injections of canakinumab maintained clinical remission, significantly reduced CRP levels, and had a favorable safety profile [13]. In some cases, where anakinra was not tolerated or had minimal therapeutic effects, switching to canakinumab showed complete control of symptoms, resumed the therapy and was more tolerated [21]. Though highly effective, canakinumab is not approved in the Schnitzler Syndrome indication; such recognition by regulatory bodies is still to be built at the end of in-depth research [15]. Anakinra and canakinumab were also highly efficacious in treating other autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), rheumatoid arthritis (RA), systemic juvenile idiopathic arthritis (sJIA) and Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome [9,11,22-24]. Further studies should compare the efficacy, failure rate, long term outcomes and combination or alternation between anakinra and canakinumab [25]. Furthermore, two additional IL-1 blockers, gevokizumab and bermekimab, are currently in clinical trials and showed promising results. However, there is no systematic review on randomized clinical trials on the safety and efficacy of these biologics in treating immune-mediated diseases such as Schnitzler syndrome [11].

Rilonacept is another IL-1 inhibitor investigated as an option for treatment in Schnitzler Syndrome and consists of a fusion protein containing the IL-1 receptor. It showed the efficacy for some patients, thus offering an alternative in case of intolerance to anakinra or canakinumab. However, generally, it is less effective compared to other IL-1 inhibitors and thus not considered a first-line kind of treatment options [15,16]. A study involving eight patients treated with rilonacept reported significant reductions in daily health assessment scores and physician's global assessment scores, accompanied by decrease in CRP and serum amyloid A (SAA) levels [16]. Long-term efficacy and complete remission have been established with IL-1 inhibitors [16,21,26]. A multicenter French nationwide study of 42 patients with Schnitzler Syndrome, 29 of whom received treatment with IL-1 receptor antagonists reported dramatic responses to all patients receiving IL-1 inhibitors with no loss of efficacy with a median follow-up of 36 months [11]. Anakinra was found to be effective with a good tolerance profile but some patients had severe infections [11]. These long-term data put forth a case for the importance of IL-1 inhibitors in sustaining disease control and improving patient outcomes.

Other Immunosuppressive treatments versus IL-1 inhibitors

While IL-1 inhibitors are considered the most effective treatment options of Schnitzler Syndrome, other immunosuppressive treatments have been investigated with some degrees of success. Tocilizumab, an IL-6 receptor antagonist, has been used in patients when there is no response to IL-1 blockade. Tocilizumab can reduce clinical symptoms and lower inflammatory markers, but it can be less effective over time, making it not reliable for long term management [15]. Where IL-1 inhibitors have failed, tocilizumab potentially provides a second line of defense, though its use must be carefully monitored due to the potential for loss of efficacy and side effects.

Rituximab is a B-cell depleting antibody that has been used in only limited numbers of Schnitzler Syndrome patients. It has shown partial benefit to some with a decrease in paraproteinemia and inflammation, though the use is still not widespread because patient variability and related possible adverse effects remain. There is one case report of a patient who did not present a beneficial effect from rituximab after the effective elimination of B cells and a reduction in paraprotein levels. In contrast, anakinra induced complete remission within days in this patient, thus underscoring the fact that IL-1 inhibitors are much more effective than rituximab in the treatment of Schnitzler Syndrome [27,28]. Thus, this variability of response underlines the necessity of tailoring therapeutic concepts to the individual patient's profile.

Traditional corticosteroids are occasionally effective but cannot be generally recommended due to their severe side effects and the high dosage necessary to control symptoms [16]. High-dose corticosteroids may lead to osteoporosis, hypertension, diabetes, and an increased risk of infections and can therefore not be continued in the long term. Other biologic agents tried, including anti-tumor necrosis factor (anti-TNF) therapies, have shown no consistent benefit. Thalidomide and colchicine also have limited success, having been tried in other inflammatory disorders. Thalidomide was withdrawn in some patients who developed polyneuropathy and colchicine was only partially effective in some patients. Overall, rituximab, anti-TNF, interferon-α, corticosteroids and thalidomide were effective in only about 20% of cases, followed by colchicine and pefloxacine compared with 83% of patients who went into complete remission and 17% into partial remission with IL-1 inhibitors [16,29].

Combination treatments that address several inflammatory pathways may present new treatment options. A combination of IL-1 inhibitors with other biologics, including IL-6 or TNF inhibitors, could have synergistic effects, improving efficacy in patients with an inadequate response to monotherapy. Moreover, therapeutic targets would be identified through screening, and therapy plans would be developed according to the patients' characteristics of the diseases. A Russian cohort study involving 17 patients with Schnitzler Syndrome reported that therapy with IL-1 inhibitors such as anakinra and canakinumab led to a complete clinical response in the majority of the patients. The study also underlined the role of differential diagnosis in ruling out other conditions, including Still's disease in adults, infectious, and lymphoproliferative diseases [28,30]. It was also illustrated that canakinumab, showed long-term safety profile and no increase in side effect was not observed with increasing cumulative doses of canakinumab over a nine-year period in patients with various pediatric rheumatic diseases, highlighting it as an effective and safe option for the treatment of Schnitzler Syndrome, thus consolidating its role as a first-line treatment [31].

Long-Term Management and Prognosis

Long-term management of Schnitzler Syndrome involves regular monitoring of disease activity and potential complications. Patients should undergo clinical evaluation, complete blood count (CBC), and CRP measurements every three months to assess disease control and detect any early signs of lymphoproliferative disorders [8]. The risk of developing lymphoproliferative diseases, such as Waldenström macroglobulinemia, remains a significant concern, occurring in about 15-20% of patients [1,4,6]. Therefore, long-term follow-up is essential to ensure timely intervention and management of complications.

Despite the effectiveness of IL-1 inhibitors in controlling inflammation and improving quality of life, they do not affect the monoclonal component of Schnitzler Syndrome. As a result, patients remain at risk for the development of lymphoproliferative disorders and systemic amyloidosis [1,4,32]. Continued research is needed to better understand the disease mechanisms and to develop therapies that can address both the inflammatory and hematologic aspects of Schnitzler Syndrome. In addition to pharmacological treatment, managing Schnitzler Syndrome requires a multidisciplinary approach involving rheumatologists, hematologists, dermatologists, and primary care physicians. This approach ensures comprehensive care, addressing both the inflammatory symptoms and potential complications. Patient education and support are also critical components of long-term management, helping patients cope with the chronic nature of the disease and adhere to their treatment regimens. A comprehensive follow-up protocol includes regular monitoring for disease activity and potential complications. Clinical evaluations, complete blood count (CBC), and C-reactive protein (CRP) measurements every three months are recommended to assess disease control and guide treatment adjustments [8]. Regular follow-up is essential to detect early signs of lymphoproliferative diseases [11,29].

Future Directions in Research and Treatment

Ongoing research into the pathogenesis and treatment of Schnitzler Syndrome is essential to improve patient outcomes. Understanding the precise mechanisms linking monoclonal gammopathy to autoinflammation could lead to the development of targeted therapies that address both aspects of the disease. Additionally, exploring the role of genetic factors and potential environmental triggers may provide insights into the variability in disease presentation and response to treatment [7,30].

The development of new IL-1 blocking agents with improved pharmacokinetic profiles is a promising area of research. Agents with longer half-lives and less frequent dosing requirements could significantly enhance patient compliance and quality of life [21]. Newer IL-1 targeting biologics, such as gevokizumab and bermekimab, are being investigated for their safety and efficacy in treating immune-mediated disorders, including Schnitzler Syndrome. These agents could offer alternative treatment options and expand the therapeutic arsenal available to clinicians [21]. Moreover, investigating combination therapies that target multiple inflammatory pathways simultaneously could offer new avenues for treatment. Combining IL-1 inhibitors with other biologics, such as IL-6 or TNF inhibitors, may provide synergistic effects and improve outcomes in patients who do not respond adequately to monotherapy. Additionally, exploring novel therapeutic targets and developing personalized treatment strategies based on patient-specific disease characteristics could further optimize management and enhance patient outcomes. Moreover, the development of diagnostic scoring system to identify patients affected with adult-onset autoinflammatory disorders is established [33]. However, the need of a scoring system that focuses on assessing the quality of life, morbidity and overall risk of lymphoproliferative disorders in patient with Schnitzler syndrome would provide potential benefits.

Conclusions

Schnitzler Syndrome is a rare autoinflammatory disorder characterized by chronic urticarial rash, monoclonal gammopathy, and systemic inflammation driven by IL-1β. IL-1 inhibitors, principally anakinra and canakinumab, transformed treatment, providing rapid and continued relief of symptoms. These treatments, however, do not affect the monoclonal component of the disease process, so patients are still at risk for lymphoproliferative disorders, for which regular monitoring is required. Other immunosuppressive therapies have variable success, but the IL-1-targeted treatments remain the mainstay of treatment. It requires a multidisciplinary approach for comprehensive management. Further research into the pathogenesis of the disease and newer avenues of therapy will improve the outcome in these patients and help both inflammatory and hematologic aspects of this syndrome.

Conflict of Interest Statement

The authors declare no conflicts of interest related to this manuscript.

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