Search Results
From 3708 articles regarding use of anti-IL-1-related drugs in dermatological diseases, after filtering duplicates and selecting studies according to title, abstract, and keywords, 77 studies met the criteria for full-text review. Of these, 21 [DIRA (n = 13) and DITRA (n = 8)] fulfilled the inclusion criteria. After reviewing citations of references for these studies, three new articles [DIRA (n = 2) and DITRA (n = 1)] were obtained. Finally, 24 studies, including 15 describing DIRA (n = 15) and 9 describing DITRA (n = 9), were included in the scoping review. A reference list of all included and excluded articles with reasons for exclusion is presented in Fig. S1 in Supplementary Information.
Evidence for Mapping the Studies of IL-1-Based Treatment in Patients with DIRA/DITRA
DIRA
Fifteen studies, published between 2009 and 2017 as full papers (n = 11) or congress abstracts (n = 4), followed mainly an observational design (13 case reports, 1 case series), and only one was an intervention study. Only three studies (20%) had an a priori protocol that was included in a public registry. Twelve (63.1%) were elaborated as multicentric studies involving up to nine different institutions. The average numbers of authors and affiliations per article were 11 (range 3–45) and 5 (range 2–14), respectively, and different medical specialties were involved [pediatrics (n = 11), genetics (n = 11), rheumatology (n = 7), allergy–immunology (n = 6), and dermatology (n = 5)], although authors from academia (n = 4) and the pharmaceutical industry (n = 1) were also included. Most studies were performed in the USA [8], with the National Institutes of Health (NIH, Bethesda, MD, USA) and associated centers of institutions participating in more studies (n = 10; Table S1 in Supplementary Information). Other countries that also participated were Brazil (n = 3), Turkey (n = 2), Germany (n = 1), and Puerto Rico (n = 1). The studies were published in journals from disciplines such as rheumatology (n = 5), general medicine (n = 4), dermatology (n = 3), immunology (n = 2), and radiology (n = 1).
In seven (46.7%) and ten (66.7%) studies, disclosures related to the source of funding (five, public sources; one, public and pharmaceutical sources; and one without funding) or authors’ conflicts of interest (CoIs) were declared, respectively. AMGEN (five authors), Novartis (two authors), and Lilly (two authors) were the pharmaceutical companies most frequently cited in CoIs by the authors.
DITRA
Nine studies related to use of anti-IL-1 drugs in DITRA were found. All were observational case report studies. No a priori design or registration was reported for any of these studies. Five of nine (55.5%) were multicenter studies (range 1–5). No centers participated in more than one study. Two were performed in Spain and France, and one each was performed in The Netherlands, USA, Italy, Denmark, and Germany. Articles were published between 2011 and 2018. Six papers were published in dermatology journals, two in rheumatology journals, and one in a pediatrics journal. Three were full papers, three were letters, and three were abstracts from conferences. The average numbers of authors and affiliations per article were 7.2 (range 4–15) and 3.22 (range 1–7), respectively. The most frequent specialties were dermatology in eight papers and genetics and pediatrics in five papers. One study [16] declared funds from Strasbourg High Throughput Next Generation Sequencing facility (GENOMAX) and INSERM UMR_S 1109. Four did not report funding or did not provide funding information. In two of the studies, the authors declared CoIs (Novartis and Sobi for three and two authors, respectively; these companies were the most frequently declared in CoIs). Three and four papers declared no CoIs or did not provide such information, respectively.
Evidence for Analysis of Epidemiology of IL-1-Based Agents in Treatment of Patients with DIRA/DITRA
DIRA
Individual data were obtained from 19 patients who had been treated with anakinra (n = 17) and canakinumab (n = 2). Eight of 19 (42.10%) patients were female. Of these 19 patients, 3 each were from Brazil and Puerto Rico, 2 each were from Turkey, Lebanon, and The Netherlands; and 1 each was from India, Canada, and Germany. Data from three patients could not be obtained. Seven of 11 (63.63%) patients were full-term infants, and 4 of 11 (36.36%) were preterm newborns. Data for eight patients were missing. Pustular dermatitis and localized swelling were observed in 12 and 6 patients, representing the most frequent symptom of onset of the disease. During disease evolution, patients presented with pustular skin rash (severe in 6 of 19 cases), multiple bone involvement (ribs being the most frequent site, in 17 of 19), fever (in 8 of 16), lung involvement (in 7 of 19), venous thrombosis (in 5 of 19), and elevation of acute-phase reactants (in 19 of 19). With respect to age at disease presentation, data were obtained from 18 patients. The median age was 14 days (range 0–365 days). Median age at diagnosis was 24 months (range 1.5–180 months). The median delay in diagnosis was 19.5 months (range 0.5–179.5 months). Seventeen of 18 (94.4%) patients had received previous treatment. Of these, 13 were treated with corticosteroids, 12 with antibiotics, 4 with NSAIDs, 3 with antifungals, 3 with acitretin, and 1 each with methotrexate, cyclosporine, intravenous immunoglobulins, azathioprine, thalidomide, and etanercept.
One study [17] presented aggregate data from six patients who had been treated with rinolacept. These patients received pretreatment with anakinra and were included among the 19 previously exposed patients described above.
DITRA
Individual data were obtained from nine patients. All had been treated with anakinra, and one had also received canakinumab. Three of eight (37.5%) were female. One patient had missing data. Two patients were from Morocco, and one patient each was from Tunisia and Denmark. The origins of the remaining patients were not reported. Onset disease was localized in four patients (two for the diaper and scalp, two for the elbow and perineum) and generalized in four patients. During disease evolution, the disease worsened, presenting with erythroderma or pustules in all patients for whom data were available. The process was accompanied by fever in four of six (66.6%) patients and elevation of acute inflammation reactants in five of six (83.3%) patients. The ages at onset and disease diagnosis varied from neonate to adulthood (14 days to 47 years and 3 months to 54 years, respectively). The delay in diagnosis ranged from 2 months to 17 years. All patients previously received other treatments, including corticosteroids in seven patients, acitretin and ciclosporin in six patients each, methotrexate in four patients, cyclosporine in three patients, and adalimumab and infliximab in two patients each.
Evidence of Different Genotypic Variations in Patients with DIRA/DITRA Treated with IL-1 Inhibitors
DIRA
Nine different mutations in IL1RN, showing a homozygous genotype in all cases, were described among patients with DIRA treated with anti-IL-1 drugs in the included studies. A genomic 175-kb deletion on chromosome 2 was observed in patients #6, #7, #11, #13, and #15; two nonsense mutations were detected in patients #2, #3, and #10 (c.229G → T) and patients #4 and #5 (c.160C → T); a 15-bp frame deletion (c. 213_227delAGATGTGGTACCCAT resulting in p.Asp72_Ile76del) was observed in patients #8 and #9; 2-bp (c.156_157delCA) and 22-kbFootnote 1 frameshift deletions were identified in patients #1 and #18, respectively; and an intronic variant of unknown clinical significance in the IL1R1 gene (position c.840, 6 bp upstream of the exon 9 splice-acceptor site), which could potentially interfere with transcript splicing machinery, was found in patient #14. Additionally, the p.R26X IL1RN mutation was observed in patient #16, c.396delC nucleotide deletion was observed in patient #17, and both p.Ile74_Pro78del and p.Gln48Thr IL1RN mutations were observed in patient #19. No mutation analysis was performed in patient #12.
DITRA
Thee different homozygous and heterozygous mutations in IL36RN were described among patients with DITRA treated with anti-IL-1 drugs in the included studies. IL36RN c.80T > C (p.Leu27Pro) was the most frequent homozygous mutation, present in patients #1, #4, and #8. Patient #8 also presented a microduplication including the NSD1 gene (5q35.2-q35.3). Homozygous mutation at c.115 + 6T > C in patient #3 was also reported. Patient #6 was diagnosed with an homozygous mutation for IL36RN, but the position was not reported. Regarding heterozygous mutations, patients #2, #6, and #8 were identified as carriers of IL36RN c338C > T (pSer113Leu) at exon 5, in patients #2, #6, #8, and #9. Patients #8 and #9 also presented a heterozygous mutation in IL36RN c.142C > T (p.Arg48Trp) and NLRP3 c.2107C > A (p.Gln703Lys) at exon 3, respectively.
Evidence for Efficacy and Safety of IL-1-Based Agents in Treatment of DIRA/DITRA
DIRA
We obtained individual data for 17 patients treated with anakinra and 2 patients treated with canakinumab. Length of therapy varied between 2 weeks and 4.5 years for anakinra and was up to 12 months for canakinumab. The initial dosage of anakinra ranged from 1 to 5 mg/kg/day, with 1 mg/kg/day being the dosage most frequently used, in 9 of 13 patients (69.2%) for whom data were available. The dosage was increased in eight patients up to 2.5–3 mg/kg/day or until achieving clinical and analytical response. Two patients required dosage reduction, one due to achieving therapeutic response and the other due to development of generalized urticaria. In two other patients, the initial dosage was maintained. In 11 patients treated with anakinra, concomitant use of corticosteroids was reported; in nine of these cases, the drugs were finally withdrawn, and in two cases, dosage reduction was performed. All patients achieved immediate (day–hours) clinical responses, and all but one patient also showed an analytical response. The patient who did not show complete response to anakinra was homozygous for a deletion of approximately 175 kb on chromosome 2q, which harbored six genes from a cluster of IL-1-related genes, i.e., IL1RN and genes encoding IL-1 family members 9 (IL1F9), 6 (IL1F6), 8 (IL1F8), 5 (IL1F5), and 10 (IL1F10) [1].
In the short term (< 12 weeks), 15 (88.2%) patients showed good clinical response. In two cases, response was not reported. Ninety percent of patients for whom data were available in the medium/long term (> 24 weeks) (n = 10) showed good response. The nonresponder in this group showed a clinical phenotype of chronic recurrent multifocal osteomyelitis and finally responded to azathioprine, corticosteroids, and intravenous immunoglobulins [18].
In the two patients treated with canakinumab, one showed good immediate, short-term, and medium/long-term response, and the other required dosage increase to achieve good response in the short term. No medium/long-term data were available for this patient.
With respect to drug safety, anakinra was associated with some adverse events, including transient injection-site reactions (n = 3) and anaphylactic reactions (n = 2). An episode of vomiting and diarrhea was reported in a patient treated with high dosage of canakinumab. Finally, subsequent discontinuation of anakinra in nine patients was reported following a flare-up of their disease.
Aggregated data from six patients with DIRA treated with rinolacept were reported in an intervention study with follow-up visits at 3, 12, and 24 months. These patients had previously received anakinra, and their data were among those published individually, corresponding to patients #8, #9, #10, #13, and #15. The sixth patient corresponded to one of those included in the article by Aksentijevich et al. (Table S1 of Supplementary Information). All patients were treated with an initial bolus of 4.4 mg/kg/dose rilonacept and were discharged on 2.2 mg/kg/week. All except one patient required rilonacept dosage escalation to 4.4 mg/kg/week due to partial clinical response. All patients remained in clinical and analytical remission. Rilonacept was well tolerated, no serious adverse events were reported, and none of the patients met protocol adverse event criteria for rilonacept dosage reduction or permanent discontinuation. The most common events were upper respiratory infection (100%), otitis media (66.7%), and rash (66.7%). Finally, clinical responses to rilonacept were comparable to those observed with anakinra, although there was a clear preference by relatives and patients for staying on weekly versus daily injections [17].
DITRA
Efficacy and safety data were available for nine patients with DITRA. All patients were treated with anakinra at 2–5 mg/kg/day or 100 mg/day, and one patient was also treated with canakinumab 3 mg/kg every 8 weeks. Duration of anakinra treatment ranged from 3 days to 12 months. With regard to efficacy, 77.8% of patients who received anakinra experienced good initial (hours–days) clinical response. Of these, 33.3% maintained the response in the short term (<12 weeks). In the medium/long term (> 24 weeks), 22.2% of patients continued the treatment. One patient, in whom anakinra had previously failed, received treatment with canakinumab, and this treatment did not prove effective at the initial time or in the short- or long-term analyses [16].
With respect to the safety of anakinra, one case of systemic infection was reported, another one of renal and hepatic laboratory abnormalities, rising white blood cell count, and deteriorating clinical status with progressive pustulation and, finally, pain at the injection site without erythema. No adverse events were reported in the patient who had been treated with canakinumab.
In five of eight patients in whom anti-IL-1 drugs failed, the final therapeutic regimens were etanercept and acitretin [19], adalimumab and methotrexate [20], secukinumab [21], ustekinumab [22], and infliximab [23].