Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative

The PRO-KIND initiative started in January 2015 aiming to standardize the diagnosis and management of children with rheumatic diseases nationally. All members of the GKJR were invited to participate in the process. A priori, a unified formal PRO-KIND framework and multi-step process for the development of consensus-based protocols was established. The PRO-KIND working group for the rare hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS was established in February 2015. The speaker (JKD) and the coordinator (EL) were selected. The approach of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group included 1) evidence synthesis including published recommendations and context adaptation, 2) statement development 3) iterative consensus building and final approval of statements and 4) diagnostic algorithm and treat-to-target CTP development (see Fig. 1).

Members of the PRO-KIND working group have previously led (JKD) or participated (SMB) in the Europe-wide SHARE initiative and developed evidence-based recommendations for the diagnosis and management of autoinflammatory diseases [19]. These had synthesized the published evidence until June 2013. Therefore, the PRO-KIND working group anchored the PRO-KIND statements in the SHARE recommendations and reviewed the relevant evidence of studies published July 2013 until January 2018. The SHARE recommendations were modified based on new evidence and cultural context and adjusted, where appropriate. Evidence levels and strength of recommendations were adapted accordingly. The Oxford Centre for Evidence-based Medicine levels of evidence and grades of recommendation were utilized to support the evidence for each statement [24]. Modified recommendations were drafted and iteratively discussed, adjusted and vetted in regular telephone conferences. All members of the PRO-KIND working group were asked to participate in seven teleconferences/face-to-face meetings and two online surveys. The first web-based survey was limited to the PRO-KIND working group members and aimed to finalize the PRO-KIND statements. In parallel, the progress of the PRO-KIND working group was presented and discussed at the annual GKJR Scientific Meetings 2016–2018. Subsequently, all GKJR members were invited to complete a web-based survey. Consensus was considered achieved, when at least 80% of responders supported a statement.

The approved statements were integrated into three disease specific CTPs. The PRO-KIND CAPS/TRAPS/ MKD/HIDS expert working group adjusted these in iterative reviews. The final documents were submitted to the GKJR Board for approval.

The working group commenced its formal work in October 2015 and included 12 experienced German and Austrian paediatric rheumatologists; all experts¹ in the field of autoinflammatory diseases. All members committed to completing the comprehensive evidence synthesis and iterative statement and CTP development.

The updated literature search followed the previously described SHARE search and selection strategy [19] and yielded an additional 25 publications for the timeframe including 19 for CAPS, 4 for TRAPS and 6 for MKD/HIDS; some manuscripts focused on more than one disease. The synthesised literature and current clinical practice of the working group members were reviewed. The 2015 SHARE recommendations for the management of autoinflammatory diseases were adjusted based on new evidence and context. This resulted in 38 drafted statements, of which two were removed due to the lack of consensus. These had focussed on glucocorticoid therapy and stem cell transplantation. A total of 36 statements reached an agreement above 80%; these were nine overarching principles and 27 disease-specific statements including 7 for CAPS, 11 TRAPS and 9 MKD/HIDS (see Additional file 1: Table S1 and Additional file 2: Table S2).

The management of patients with AID requires an interdisciplinary team of generalists and subspecialists including paediatricians, rheumatologists and other specialists including but not limited to ophthalmologists, otolaryngologists, nephrologists and genetic counsellors, as well as physiotherapists, occupational therapists and psychosocial specialists [25]. The impact of AID on individual patients varies widely; close monitoring of disease activity in the individual patient is therefore needed. Treatment aims are early control of diseases activity, prevention of disease and treatment related damage and optimal health-related quality of life (HRQoL). Validated instruments including the patient-reported AIDAI [26] and global assessment scales for physicians and patients/parents [27] should be utilized to determine disease activity and impact in addition to regular assessments and inflammatory markers (see Additional file 1: Table S1). Measures of HRQoL and disease damage should be integrated into care [28, 29].

For each disease, specific diagnostic and monitoring statements were developed incorporating the distinct challenges of each condition. The risk of macrophage activation syndrome in MKD/HIDS was based on new evidence [30]. Additional suggestions were made for particularly severe disease. Most importantly, high-level evidence from a randomized controlled trial for the effectiveness of IL-1 inhibition for TRAPS and MKD/HIDS was integrated [27].

The diagnosis of a rare hereditary AID should be considered in patients that experience the following symptoms: recurrent fever, headaches, musculoskeletal complaints, abdominal pain, rash, eye involvement, lymphadenopathy, fatigue and especially increased irritability in children and emotional lability in adults [31] (see Fig. 2). In the presence of these symptoms inflammatory markers including CRP and/or SAA should be determined. The linkage of AID specific clinical symptoms and raised inflammatory markers provides strong evidence of an AID.

In addition typical clinical symptoms for CAPS include urticaria-like rash, cold/stress triggered episodes, sensorineural hearing loss, chronic aseptic meningitis and skeletal abnormalities such as epiphyseal overgrowth and frontal bossing [11]. TRAPS patients may present with prolonged fever episodes of ≥5 days, migratory rash, periorbital edema, myalgia and may have a positive family history [11]. The typical phenotype in MKD/HIDS includes a disease onset at < 1 year of age, gastrointestinal symptoms, painful lymph nodes, aphthous stomatitis, maculopapular rash and disease flares associated with variable triggers such as infections and vaccinations [11]. The differential diagnosis of AIDs has to be thoroughly explored and includes neoplasms, infections, autoimmune conditions and other inborn errors of immunity. Molecular genetic testing should be considered in all patients. Genetic counselling for patients and their families is often required [32]. AID phenotype and genotype can differ substantially, not all genetic variants are pathogenic [31]. The current state of the pathogenicity of a genetic variant can be determined using the infevers database [33]. The presence of a pathogenic variant supports the clinical diagnosis. Potential disease-related damage includes inner ear deafness, vision loss, cognitive impairment, growth retardation, bone and/or joint deformities, osteoporosis, AA Amyloidosis and renal failure.

Treatment strategies for patients with CAPS, TRAPS and MKD/HIDS were derived from the consensus statements. Key principles of these treat-to-target strategies included 1) anchoring individual strategies in disease activity, estimated risk and anticipated trajectories, 2) selecting validated monitoring instruments, 3) defining treatment targets and intervals and 4) providing evidence-based therapies and strategies for adjustment.

After establishing the specific diagnosis, the individual genotype, phenotype and disease activity should be determined. Patients with specific pathogenic mutations should be considered high-risk such as the increased risk of amyloidosis in TRAPS patients with cysteine mutations [30, 31, 34]. Similarly, patients with severe clinical phenotypes, those with frequent inflammatory episodes or those with organ damage at initial presentation are at high risk for adverse outcome. Disease activity and damage should be determined using validated tools. The AIDAI [26] captures disease activity over time including patient-reported frequency and severity of inflammatory clinical symptoms. In addition, inflammatory markers and the physician and patient/parent global assessments (PGA, PPGA) should be determined serially. The ADDI score [29] measures disease-related organ damage.

Complete remission is the key treatment target and defined as absence of clinical symptoms (AIDAI score < 9 [26], PGA and PPGA of 0/10) cm and normal inflammatory markers [27]. If not achievable, minimal disease activity should alternatively be considered. Monitoring intervals of 1–3 months were felt to be appropriate, when patients have active disease; well-controlled disease could be monitored at longer intervals of up to every 6 month.

Overall, treat-to-target strategies guided by multidisciplinary teams have been shown to be highly effective and associated with higher rates of complete remission in patients with CAPS [17]. On demand strategies are considered in some patients with very mild disease and seasonal disease manifestations [35, 36]. IL-1 inhibition has been shown to effectively control inflammation in patients with CAPS, TRAPS and MKD/HIDS [27, 37, 38]. In patients with moderate or severe disease activity, IL-1 inhibition improves or even prevents organ damage [39‐41]. Dose adjustments may frequently be required, particularly in children and in patients with severe disease subtypes [17]. Alternatives to IL-1 inhibitions such as TNF-inhibition in TRAPS [42] and IL-6 inhibition in MKD/HIDS [43, 44] need to be further explored. Symptomatic therapies with non-steroidal anti-inflammatory drugs (NSAIDS) or corticosteroids may be effective in some patients.

CAPS is a well characterized disease covering a spectrum from mild to severe disease course. Risk factors, disease trajectories and assessment tools for monitoring of disease activity are well studied and validated [10, 45]. The efficacy of IL-1 inhibition was confirmed in randomized clinical trials and high-quality observational studies [41, 46], which led to the approval of canakinumab and anakinra (see Table 1). More recently, 10-year safety data of IL-1 inhibition has become available for CAPS [47]. The effectiveness of treat-to-target studies with individual dose adjustments bares the promise of excellent control of disease activity [17]. Standardized monitoring of disease activity and subsequent dose or strategy adjustments are developed (Fig. 3a). Specific patient groups such as those with a severe phenotype will likely require higher doses to achieve remission [17]. NSAIDs or corticosteroids should be used as add-on therapy in CAPS for symptomatic therapy only [39].

The disease spectrum in TRAPS is equally broad, however less distinct than CAPS. Genetic variants and other risk factors are important [34]. Several treatment options for TRAPS patients are supported by evidence: IL-1 inhibition with canakinumab is effective and currently the only approved treatment for TRAPS [27] (Table 1). Therapy with other IL-1 inhibitors [36] or the TNF-α decoy receptor etanercept [42] resulted in significant improvement of symptoms and laboratory parameters. In TRAPS, targeting an alternative inflammatory pathway in non- or partial responders may be an important opportunity. Treatment with NSAIDs resulted in symptom relief in 75% of patients with TRAPS, but rarely resulted in effective cessation of inflammation [39]. Corticosteroids may also have an immediate, possibly short-term effect on inflammation in the majority of patients [39]. In TRAPS, treatment decisions should be guided by the initial and subsequent phenotypes, disease activity and risk estimation, standardized monitoring and treatment adjustments are critical to achieve remission (Fig. 3b).

MKD/HIDS encompasses a wide spectrum of clinical phenotypes from mild to severe and results in diverse symptoms [8]. The effectiveness of interleukin-1 inhibitors in patients with MKD/HIDS was demonstrated and resulted in the approval of canakinumab [27] (Table 1). Additionally, an on-demand approach for anakinra was proposed, which significantly shortened relapses in MKD/HIDS [35]. In individual cases, response to treatment with TNF-α or IL-6 inhibitors has been reported [30, 43]. In severe cases and poor quality of life, allogeneic haematopoietic stem cell transplantation (HSCT) may be considered [48]. The administration of NSAIDs and corticosteroids was shown to improve symptoms [39]. Treatment of patients with MKD/HIDS should follow a treat-to-target approach to find individual treatment strategy, medication and doses (Fig. 3c).