1, Topic scoping - what are the comorbidities that the guideline attempts to address?
To properly refine the scope of the CPG around multimorbidity in SLE, the CPG developers will adopt a clear strategy. As part of the CPG, both the primary conditions of SLE, as well as related coexisting conditions or specific combinations of those conditions will be addressed. It is expected that the CPG will attempt to address comorbidities including thyroid disease, depression and anxiety, obesity, dyslipidaemia, hypertension, osteoporosis, cardiovascular diseases, allergic disorders, gastrointestinal diseases, infections, neurologic diseases, cerebrovascular diseases, kidney diseases, respiratory diseases, diabetes mellitus, malignancy, skin diseases, and hematologic disorders. According to a recent study, 51.0% of 399 SLE patients with multiple comorbidities had at least three physical disorders and 33.1% had at least two mental disorders(6). This is a large percentage showing multimorbidity across both categories. The CPG will categorize comorbid disorders by organs and domains. For example, SLE with coexisting conditions such as hypertension, dyslipidemia, and obesity can be classified as a metabolic disorder. Clinical evidence and epidemiological data will be examined during the scoping phase to determine the important coexisting conditions. The scoping phase will begin with preliminary literature searches.
2, Establishing guideline development group - who will be included in the guideline panel to provide expertise?
The synthesis and evaluation of evidence will become more complex if the scope is expanded beyond a single condition. Therefore, to address SLE with multimorbidity rather than one single condition, the CPG workgroup will need to incorporate a broader range of expertise(7). CPG workgroup for SLE with comorbidities will consist of clinicians, researchers, guideline methodologists, and experts in TCM, immunology, rheumatology, nephrology, cardiology, metabolic disease, osteology, dermatology, radiology, and evidence-based medicine. Four main groups including a steering group led by the responsible technical officer, a guideline development group made up of external experts, an external review group, and a systematic review team will be established. The steering group is primarily responsible for identifying the topic and key questions to be included in the guideline, drafting recommendations and the final guideline, as well as providing administrative support. The guideline development group aims to finalize the scope and key questions, formulate evidence-based recommendations, conduct the Grading of Recommendations Assessment, and approve the final guideline document. The external review group assists in identifying any errors or missing data and provides feedback on clarity, setting-specific issues, and implementation implications. While systematic reviews are fundamental parts of CPG development, it is the responsibility of the systematic review group to conduct systematic searches for relevant evidence, assess the quality of eligible studies, and summarize the findings. A conflict of interest in the workgroup could seriously undermine the objectiveness and independence of guidelines(14). Any conflict of interest will need to be declared and managed appropriately by the workgroup.
3, Formulating key clinical questions – what key clinical questions should be answered to formulate recommendations?
The formation of key clinical questions governs a systematic search of the evidence. “PICO” elements including population, intervention, comparator and outcome will be considered when forming a clinical question. It seeks to answer who will be affected (population), what action is being considered (intervention), what other options are available (comparator), and what the recommendation is trying to accomplish (outcome). In particular, the outcome is an important consideration when forming a recommendation for solving a complicated issue. The presence of comorbidities in SLE usually increases the number of potentially relevant outcomes. For example, one of the important outcomes for the management of SLE co-existing with musculoskeletal symptoms may include the progression of hypertension. It is because nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and indomethacin, which are commonly used by SLE patients co-existing with musculoskeletal symptoms, serositis, and headaches, cause significant rises in blood pressure(15, 16). The CPG will focus on integrative treatments of TCM and CM, thus key questions will relate to the effectiveness and safety of these treatments. After forming key clinical questions, they will be answered to formulate the recommendation. The following questions are examples aimed to be answered:
(1) In SLE patients, what integrative medicine of TCM and CM, compared with routine treatments shows effectiveness for managing different comorbidities?
(2) In which comorbidities of SLE do CM and TCM show the most benefit in the process of management?
(3) In SLE patients, which comorbidities of SLE should be treated by TCM/CM alone to achieve effectiveness?
Clinical practitioners' perspectives about treatment for SLE with comorbidities will be gathered through a questionnaire. The goal is to identify the most important clinical questions by conducting two rounds of the Delphi survey. The survey plans to involve 15 immunologists and 15 TCM practitioners with a minimum of five years' clinical experience managing SLE. Following the first round of the survey, all participants will rate the items that failed to reach a consensus. The key questions will be ranked based on their importance.
4, Selecting and rating outcomes – how to make judgements regarding the values and preferences of patients to determine the importance of outcomes?
A desirable outcome is the goal of the recommendation. To produce a useful recommendation, it is essential to select the most important outcome. Each outcome will be scored from 1 to 9. There are three levels of importance for a decision: critical if the outcome is 7–9, significant if it is 4–6, and not significant if it is 1–3. Based on the average score, the relative importance of outcomes will be identified and ranked in the CPG. When multimorbidity exists, certain outcomes may lose their relative significance because competing risks are present. For example, Gergianaki found that psychiatric disorders often coexisted with the gastrointestinal disorder in SLE patients(6). In these cases, SLE patients who have psychiatric disorders such as bipolar disorder, suicidal ideation, or schizophrenia may consider improvements in outcomes from gastrointestinal disorders relatively unimportant. Similarly, in the case of SLE patients with multimorbidity, the outcome of a comorbidity which is in a serious medical emergency, such as a heart attack or stroke, will be considered of relatively high importance. Moreover, for comorbidity in SLE that is categorised as severe and incurable, palliative care for symptomatic relief may become relatively important to reduce the treatment burden(7). Therefore, considering that patients with different manifestations place different values on a given outcome, an investigation into the preferences and values of SLE patients with different comorbidities is needed. The CPG workgroup will conduct a literature review and produce recommendations based on judgements regarding values and preferences.
5, Conducting a systematic review of the evidence – how to generate a comprehensive search?
Based on the clinical questions, the systematic review team will conduct a comprehensive search of nine electronic databases, including PubMed, ISI Web of Science, EMBASE, CINAHL Plus, AMED, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang Data to source eligible studies of SLE comorbidities, by the end of October 2022. Systematic reviews, meta-analyses, network meta-analyses, and original studies such as randomized controlled trials, cohort studies, case-control studies, case series studies and epidemiological surveys, etc. will be retrieved through the above-mentioned databases. Furthermore, SLE-related guidelines will be reviewed as references from official websites, such as the Scottish Intercollegiate Guidelines Network (SIGN), the National Institute for Health and Clinical Excellence (NICE), the Asia-Pacific Alliance Against Rheumatism (APLAR) and the American College of Rheumatology (ACR).
6, Assessing Quality of Evidence – what approaches should be used to estimate the quality of evidence across all important outcomes?
For grading recommendations, GRADE (Grading of Recommendations, Assessment, Development and Evaluations) will be used(17, 18). Each outcome will be rated based on the quality of evidence, which is categorized into four levels: very low, low, moderate, and high. Several factors including study design and execution, degree of directness, precision, consistency, and publication bias can affect the quality of the evidence for outcomes. The degree of directness refers to how well the evidence from studies corresponds to the population, the intervention, the comparator, and the outcome. Evidence should be rated lower if it applies to a population different from the guideline's target population. The directness of evidence may be compromised by the burden of multimorbidity, since patients with the same comorbidities may not be included in sufficient numbers. Additionally, insufficient participants may also result in imprecision in results. Evidence-based RCTs are rated as high quality while evidence from nonrandomized trials or observational studies is rated as low quality. Complex combinations of conditions in SLE may not have been investigated using RCTs, which results in a lower quality body of evidence for outcomes from the outset. As a result of the complex nature of multimorbidity, comorbidities associated with SLE may be primarily evidenced by observational studies. The quality of evidence from observational studies may be improved by examining three factors, including dose-response gradients, plausible biases, and magnitudes of effects. Since the presence of multimorbidity complicates decision-making, it is essential to estimate the overall quality of evidence across all important outcomes(7).
7, Developing recommendations - what should be taken into consideration to develop comprehensive recommendations?
Based on the summary of domestic and oversea evidence provided by the Evidence Evaluation Group, The CPG workgroup will generate recommendations that consider the advantages and disadvantages of interventions in the Hong Kong region. Rather than assessing a single condition, the CPG workgroup will consider the complexity of multimorbidity in SLE patients. This CPG will focus on the effectiveness of the combined therapy of TCM and CM. TCM theory defines syndrome differentiation as the basis of diagnosis and the guide to treatment. TCM recommendations will be presented from the TCM's perspective of diagnosis and treatment. It is expected that recommendations will be classified based on the coexisting conditions and their severity by the CPG workgroup. The CPG workgroup will also highlight key recommendations and evaluate how coexisting conditions affect their priority. Conditions will be identified when a recommendation should not be or no longer be followed. Recommendations will be drafted by the steering group and finalized by the guideline development group. Two-round Delphi surveys will be conducted to reach an agreement through an expert consensus method.
8, Drafting and publishing the guideline document - in what format should a full guideline documentary be drafted, and where should it be published?
The full-text guideline will be drafted with sections of introduction, guideline development methods, recommendations, discussion, and limitations included. A separate document detailing the grades of recommendations and evidence quality will be prepared for guideline users to facilitate their application. The guideline will be published in relevant professional journals and on special guideline websites. A series of academic conferences will be held to promote the implementation of guidelines.