SLE is the prototype of autoimmune diseases, and its treatment concept influences the whole idea of autoimmune disease treatment. (T2T/SLE), which is more or less the same as the idea of “the need to introduce the concept of target therapy in lupus erythematosus” proposed by the author in the Chinese Medical Journal more than 3 years ago [1]. This year, T2T/SLE was proposed in a high profile in Europe, suggesting that the treatment concept and strategy of SLE are being updated, and the treat to target (T2T) concept has gradually become the consensus of SLE treatment. For clinical disciplines involved in SLE, including major internal medicine, dermatology, rheumatology and immunology, and renal specialties, they need to pay attention to this new concept.
I. Formation of the T2T/SLE concept
In view of the experience in the treatment of chronic diseases such as cardiovascular disease and diabetes, the concept of T2T has been gradually expanded to other specialties of medicine and other diseases.T2T is a treatment strategy that gives clinical treatment a clear direction and goal, that is, once the disease is diagnosed, it should be induced toward the goal of complete remission, and even if complete remission cannot be achieved, it should be controlled at a low level of activity as much as possible in order to prevent or reduce the harm of the disease to the organism.
SLE is a chronic, incurable disease. Evidence-based follow-up studies have shown that failure to achieve complete remission with initial treatment, persistent disease activity, and recurrent disease episodes are indications of poor prognosis for SLE. Given that the current treatment modalities for SLE recommended by various guidelines only leave most SLE patients in a state of chronic activity, recurrent disease fluctuations, and alternating activity and remission, the long-term prognosis is not ideal.
To improve the long-term prognosis of SLE, the idea that the goal of induction therapy must be directed toward disease remission and long-term maintenance in remission has gradually emerged. The Journal first proposed the concept of T2T/SLE in March 2011, and more than 1 year later, in May 2012, a group of European SLE experts met in Zurich, Switzerland, to discuss the need and feasibility of introducing the T2T treatment concept for SLE and to establish a T2T/SLE working group. The discussion was published in the 2012 supplement to Clin Exp Rheumatol, the first English journal to introduce the concept of T2T/SLE [2]. After 2 more years of research, the T2T/SLE working group submitted a recommendation for T2T/SLE to the Annual European Congress of Rheumatology, and it was published in Ann Rheum Dis in June 2014.
II. Shortcomings of the traditional treatment model for SLE
The traditional treatment concept of SLE is a staged treatment, i.e. induction therapy and maintenance therapy. Currently, the 2 classical treatment models for the treatment of moderate to severe SLE internationally are the US NIH protocol and the European protocol. The US NIH protocol is: 1 intravenous cyclophosphamide (IV-CTX) 1,0 g/m2 body surface area once a month for 6 months as induction therapy, then once every 3 months as maintenance therapy. The European protocol is: IV-CTX 500 mg once every half month, followed by switching to azathioprine maintenance therapy after 6 consecutive doses (3 months).
According to the author’s experience, after 6 months of treatment according to the US NIH protocol or after 3 months according to the European protocol, most Chinese SLE does not achieve disease remission, and it may not be appropriate to enter maintenance therapy at this time. The current status of SLE treatment in Western countries is not ideal either, as the T2T/SLE Working Group noted that at least 60%-85% of SLE patients are currently in “alternating relapse/remission” or persistent chronic activity. They also cited a follow-up of 1613 SLE cases, which showed that only 38 patients (2.4%) had achieved sustained remission for 5 consecutive years; another follow-up in 2010 showed that only a very small number of SLE patients could achieve inactive status within 1 year with current treatment, and the majority remained in a state of persistent disease activity or exacerbation. Failure to achieve control of lupus nephritis within 6 months is an indication of poor prognosis. It is these “unsatisfactory” conditions that have stimulated SLE specialists to seek new treatment concepts and models.
Over the years, in the treatment of SLE, on the one hand, these classical US NIH and European protocols have been promoted and their standardized treatment has been emphasized; on the other hand, it has been emphasized that the treatment of SLE is an art and requires individualized treatment based on evidence-based medicine.
Both the US NIH and European protocols have some problems. First of all, SLE is a highly heterogeneous group of diseases. The heterogeneity is reflected in the fact that the disease involves different tissues and organs with different degrees of inflammatory activity, resulting in differences in the severity of the disease, as well as in the differences in physical status, threat of infection, sensitivity and tolerance to drugs, and so on. Therefore, the same treatment regimen should not be dogmatically chosen for treating different individuals with SLE, nor should they be uniformly transferred to maintenance therapy at a certain time cut-off point (6 months for the US NIH regimen and 3 months for the European regimen) at the same time. Rather, the intensity of induction therapy and the mode of step-down therapy should be determined on a patient-by-patient basis.
Although the US NIH regimen and the European regimen have been validated by rigorous multicenter randomized controlled trials, the level of evidence as evidence-based medicine is high and their internal validity cannot be questioned. However, the study sample set is mainly type IV lupus nephritis and does not include the entire SLE population. We should be clear about another concept of evidence-based medicine, “external validity”. When we extrapolate the evidence from type IV lupus nephritis to other types of lupus nephritis or other SLE, the external validity is not high. As noted by the T2T/SLE Working Group’s overall treatment principles, this disease is complex and diverse. Therefore, the US NIH protocol and the European protocol are not applicable to all types of SLE.
In the history of SLE treatment, the traditional staged therapy was an important milestone that increased the 5-year survival rate of SLE from less than 50% to approximately 90%. Today, we are no longer satisfied with this 5-year survival rate of approximately 90%; we are seeking to provide SLE patients with long-term remission and long-term high quality-of-life survival. Therefore, a T2T/SLE treatment concept needs to be introduced.
III. General rules and recommendations for T2T/SLE
The research on T2T/SLE is just beginning and there are still many elements that need to be improved. In June this year, the T2T/SLE working group initially proposed 4 general principles and 11 recommendations. The following is an interpretation of the general rules and recommendations proposed by the T2T/SLE working group, combined with the author’s own clinical experience.
1. General principles of T2T/SLE
The T2T/SLE Working Group proposed four general principles for T2T/SLE through detailed discussion, circulation and voting. These general principles emphasize first and foremost patient autonomy, the centrality of patient decision-making, and the need for specialists with experience in treating SLE to communicate fully with patients about mutual concerns when selecting treatment options, and to make each treatment decision on an individualized and balanced basis. The group discussed the need for a “hierarchy of treatment goals”. While some elements are self-evident, such as that saving a patient’s life is more important than reducing hormone doses, it is not yet possible to make conclusive recommendations on how to stratify treatment goals, and this is a clinical topic that needs to be studied next.
Given the complexity and diversity of SLE, the general rules of T2T/SLE also emphasize the need for multidisciplinary cooperation, requiring not only the cooperation of physicians from different specialties, but in some cases, medical and paramedical departments and other related specialties to work together as a team to treat the disease. t2t has relatively fixed treatment protocols for chronic diseases such as diabetes, hypertension, and gout. Because of the high heterogeneity of SLE, the immediate and long-term risks of therapeutic agents, and the differences in tolerance of different treatment regimens among individuals, T2T/SLE emphasizes regular monitoring and review, and treatment regimens must be evaluated and adjusted at reasonable intervals. The emphasis here is on “reasonable” time intervals.
2. Recommendations for T2T/SLE
The 11 recommendations for T2T/SLE are actually a series of treatment goals. The first goal is to achieve remission of the disease, including overall disease and organ involvement, and if remission cannot be achieved, to control the disease to the lowest possible level of activity. SLE is a disease that is prone to alternating relapsing-remitting, and relapses, especially severe ones, are equally damaging to patients. SLE is prone to relapsing-remitting disease. Therefore, for SLE in remission, prevention of relapses is also an important treatment goal for SLE. Regular review and long-term follow-up are necessary to control mild or subclinical recurrence of the disease by adjusting the treatment in a timely manner.
Recommendation 3 suggests that “escalation of therapy based solely on lupus serology (stable or not, or persistently active) is not recommended for patients without clinical symptoms.” While escalating therapy for asymptomatic SLE with abnormal serology may reduce the risk of disease relapse, the side effects associated with increased medication need to be weighed. This relies on the physician’s experience and judgment to adjust treatment only for patients at risk of relapse.
Given that some clinicians treating SLE are accustomed to stopping immunosuppression after remission from induction therapy and using only hormonal maintenance therapy, the T2T/SLE Working Group emphasizes that in lupus nephritis, induction therapy with immunosuppression needs to be followed by continued maintenance therapy with the appropriate intensity of immunosuppression for more than 3 years. In fact, not only for lupus nephritis, but also for the treatment of other severe SLE, the author believes that the principle of immunosuppressive treatment with induction and maintenance therapy needs to be followed. For example, after induction therapy with cyclophosphamide, it is necessary to switch to azathioprine or methotrexate as follow-up therapy.
The need for lifelong hormone use for the treatment of SLE is a matter of ongoing controversy. This time, the T2T/SLE working group has made hormone discontinuation one of the goals of the maintenance treatment phase of SLE, clearly proposing complete discontinuation of hormones whenever possible. Because the hazards of long-term hormone maintenance therapy have been widely concerned by scholars, and because small doses of hormones mainly play an anti-inflammatory role, it is not justified to continue using hormones for maintenance therapy if the disease has achieved complete remission and there is no active inflammation in the body.
Experts within the T2T/SLE working group are not in agreement about the use of antimalarials. Some experts believe that antimalarials should be used throughout in all SLE patients unless contraindicated, while others disagree with this view. The latter believes that antimalarials are not completely risk-free and that “contraindications” need to be taken into account when selecting them. The T2T/SLE Working Group also noted that some countries still use atipine for the cutaneous manifestations of SLE. Therefore, it is recommended that “the use of antimalarials should be considered with caution”.
In summary, T2T/SLE is a new concept in the treatment of SLE. The goal of this concept is to achieve remission of the disease as much as possible, with an emphasis on systemic remission of symptoms and remission of the affected organs, and the lowest possible disease activity if remission is not achieved despite efforts. In highly heterogeneous SLE, achieving treatment goals requires clinicians to abandon dogmatic thinking and individualize the selection and adjustment of appropriate therapeutic measures and appropriate follow-up intervals under close monitoring to achieve a better prognosis and higher quality of life for SLE patients.
The general principles and recommendations proposed by the T2T/SLE Working Group:
1. The management of SLE should be based on joint decision-making between patients and physicians.
2. Treatment of SLE should be aimed at ensuring long-term patient survival, preventing organ damage, and improving health-related quality of life by controlling the degree of disease activity and minimizing complications and drug toxicity.
3, To recognize the complexity and diversity of the clinical manifestations of the disease, attention must be paid to multidisciplinary participation in the management of SLE.
4. Patients with SLE require long-term regular disease monitoring, assessment and/or adjustment of treatment regimens.
Recommendations.
1. The goal of treatment for SLE is to achieve remission of systemic symptoms and organ damage, or if remission is not achieved, the lowest possible disease activity (as judged by a validated lupus activity index and/or organ-specific indicators).
2. Prevention of relapses (especially severe relapses) is a realistic and feasible goal and the aim of treatment.
3. Escalation of therapy based solely on lupus serologic indices (stable or not, or persistent activity) is not recommended for patients without clinical symptoms.
4. Because damage due to disease, treatment and comorbidities can lead to subsequent cumulative damage and death, prevention of damage should be an important therapeutic goal in SLE.
5. In addition to controlling disease activity and preventing damage, attention should also be paid to factors that negatively affect health-related quality of life (HRQOL), such as fatigue, pain, and depression.
6. Early identification and treatment of kidney damage in lupus nephritis is highly recommended.
7. For lupus nephritis, it is recommended that immunosuppressive therapy be maintained for at least 3 years after induction therapy, with the intention of obtaining better outcomes.
8. The goal of maintenance therapy for lupus is to reduce hormones to the minimum dose needed to control disease activity, and hormones should be completely discontinued if possible.
9. Prevention and treatment of conditions associated with antiphospholipid syndrome should be a treatment goal for SLE, and treatment recommendations are the same as for primary antiphospholipid syndrome.
10.The use of antimalarial drugs should be carefully considered regardless of whether other treatments are used.
11, In addition to immunomodulatory therapy, relevant adjuvant therapy should be considered to control comorbidities in patients with SLE.