Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles

2021 ◽  
pp. annrheumdis-2021-220578
Author(s):  
Vivian E Saper ◽  
Michael J Ombrello ◽  
Adriana H Tremoulet ◽  
Gonzalo Montero-Martin ◽  
Sampath Prahalad ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Hla Typing ◽  
Delayed Hypersensitivity ◽  
Still’S Disease ◽  
Hla Association ◽  
Childhood Arthritis ◽  
Still's Disease ◽  
Systemic Symptoms ◽  
Delayed Hypersensitivity Reaction ◽  
Control Study

ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.MethodsIn a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.ResultsStill’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

Urticaria as a Cutaneous Sign of Adult-Onset Still's Disease

2006 ◽  
Vol 10 (2) ◽  
pp. 99-103 ◽  
Author(s):  
Roberta F. J. Criado ◽  
Paulo Ricardo Criado ◽  
Cidia Vasconcellos ◽  
José Carlos M. Szajubok ◽  
Nilceo S. Michalany ◽  
...  
Keyword(s):  
Periodic Fever ◽  
Antibody Test ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Cutaneous Lesions ◽  
Still's Disease ◽  
Uncommon Presentation ◽  
Systemic Symptoms ◽  
Adult Onset Still's Disease

Background: The cardinal signs and symptoms of adult-onset Still's disease (AOSD) include periodic fever, arthralgia and arthritis, lymphadenopathy, hepatosplenomegaly, an evanescent rash accompanied by neutrophilic granulocytosis, and a negative rheumatoid factor and antinuclear antibody test. Objective: To alert clinicians and dermatologists to internal diseases such as AOSD when assisting patients with urticarial eruptions and systemic symptoms. Methods: A case report of a 52-year-old white woman who received conventional therapy for urticaria for 3 years, with no improvement. Following this period, a diagnosis of AOSD was performed based on the presence of systemic symptoms. Results: The inflammatory activity markers decreased by the second month of methotrexate therapy; however, the cutaneous lesions failed to disappear. Thalidomide was initiated, and total improvement of the cutaneous lesions was observed after 2 weeks. Conclusion: Urticarial rash is an uncommon presentation of AOSD, and clinicians must be alert to the possibility of a misdiagnosis in these cases.

scholarly journals Management of adult-onset Still’s disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Serena Colafrancesco ◽  
◽  
Maria Manara ◽  
Alessandra Bortoluzzi ◽  
Teodora Serban ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Delphi Process ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Biologic Treatment ◽  
Still's Disease ◽  
Late Treatment ◽  
Adult Onset Still's Disease

Abstract Background Adult-onset Still’s disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion. Methods A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still’s disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. In the third step, the voting results were analyzed, and the statements were finalized. Results Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as the first and as a subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment. Conclusions The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies.

scholarly journals Anti-Interleukin-1 Agents in Adult Onset Still's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Cecilia Giampietro ◽  
Bruno Fautrel
Keyword(s):  
Therapeutic Option ◽  
Interleukin 1 ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Highly Correlated ◽  
New Generation ◽  
Adult Onset Still's Disease ◽  
Over Time

Interleukin 1β(IL-1β) is emerging as a master mediator of adult onset Still’s disease (AOSD) pathogenesis. This pleiotropic cytokine, whose expression is under the control of the inflammasome pathway, has a wide type of effects. As a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations. The study of proinflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity. These experimental evidences and the analogy with other autoinflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1βas a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases. Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFαfailed to control symptoms. While a growing number of evidences supports the utilisation of anakinra in AOSD, a new generation of anti-IL1βantagonists is developing. Canakinumab and rilonacept, thanks to their higher affinity and longer half-life, could improve the management of this invalidating disease.

Beneficial Effect of Interleukin 1 Inhibition with Anakinra in Adult-onset Still’s Disease. An Open, Randomized, Multicenter Study

2012 ◽  
Vol 39 (10) ◽  
pp. 2008-2011 ◽  
Author(s):  
DAN NORDSTRÖM ◽  
ANN KNIGHT ◽  
REIJO LUUKKAINEN ◽  
RONALD van VOLLENHOVEN ◽  
VAPPU RANTALAIHO ◽  
...  
Keyword(s):  
Short Form ◽  
Interleukin 1 ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Open Label ◽  
Link Type ◽  
Still's Disease ◽  
Open Label Extension ◽  
Adult Onset Still's Disease

Objective.To study the efficacy of anakinra versus disease-modifying antirheumatic drugs (DMARD) in refractory adult-onset Still’s disease (AOSD).Methods.In a 24-week study, 22 patients with AOSD taking prednisolone ≥ 10 mg/day received anakinra (n = 12) or DMARD (n = 10). The primary endpoint was achievement of remission.Results.At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission. Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011). During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission.Conclusion.Anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase. (ClinicalTrials.gov Protocol Registration NCT01033656).

scholarly journals Correction to: Management of adult-onset Still’s disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Serena Colafrancesco ◽  
◽  
Maria Manara ◽  
Alessandra Bortoluzzi ◽  
Teodora Serban ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Consensus Group ◽  
Adult Onset Still's Disease

Following publication of the original article [1], it was brought to our attention that the AOSD Consensus Group was incorrectly tagged and therefore not searchable. The publishers apologize for this error.

Tocilizumab in Adult-onset Still’s Disease: the Israeli Experience

2014 ◽  
Vol 41 (2) ◽  
pp. 244-247 ◽  
Author(s):  
Ori Elkayam ◽  
Nizar Jiries ◽  
Zvi Dranitzki ◽  
Shay Kivity ◽  
Merav Lidar ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Treatment Algorithm ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Disease Modifying Drugs ◽  
Still's Disease ◽  
Randomized Controlled Studies ◽  
Israeli Experience ◽  
Adult Onset Still's Disease

Objective.To describe the Israeli experience of treating adult-onset Still’s disease (AOSD) with tocilizumab (TCZ).Methods.Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of followup.Results.Nine male and 6 female patients, aged 33 ± 12 years, mean disease duration 9 years (range: 1–25) were identified. They had used a mean of 3.6 disease-modifying drugs, including 10 patients with tumor necrosis factor blockers. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients). All patients completed at least 6 months of treatment. The mean followup period was 15.7 ± 9 months. At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain. Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dl, respectively. After 6 months of treatment and at the end of followup, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of followup.Conclusion.TCZ 8 mg/kg was extremely efficacious in treating adult patients with refractory Still’s disease. Both TCZ and interleukin 1 blockade should be considered in the treatment algorithm of AOSD. Randomized controlled studies are needed to validate these findings.

scholarly journals COVID Arm: Delayed Hypersensitivity Reactions to SARS-CoV-2 Vaccines Misdiagnosed as Cellulitis

2021 ◽  
Vol 12 ◽  
pp. 215013272110244
Author(s):  
Aleksandra L. Lindgren ◽  
Andrea Hui Austin ◽  
Kathleen M. Welsh
Keyword(s):  
Delayed Hypersensitivity ◽  
Common Finding ◽  
Topical Steroids ◽  
Hypersensitivity Reactions ◽  
The Novel ◽  
Vaccination Site ◽  
Vaccine Site ◽  
Systemic Symptoms ◽  
Delayed Hypersensitivity Reaction ◽  
Distinguishing Features

The term “COVID arm” has been coined to describe a harmless delayed hypersensitivity reaction occurring approximately a week after administration of the novel SARS-CoV-2 mRNA vaccine. It appears as a red, warm, pruritic, indurated, or swollen area in the vicinity of the vaccine site. These reactions, especially if accompanied by systemic symptoms, have been mistaken for cellulitis. We report 3 cases of COVID arm, 2 of which were mistaken for cellulitis. Distinguishing features of COVID arm from cellulitis include pruritus as a common finding, occurrence approximately a week after vaccination, a lack of progression of symptoms, rapid response to topical steroids, and/or spontaneous resolution usually over 4 to 5 days. Practice Points: • Patients receiving SARS-CoV-2 vaccines may experience delayed hypersensitivity reactions characterized by erythema, swelling, and itching occurring near the vaccination site (COVID arm), approximately a week after vaccination. • Clinicians can distinguish SARS-CoV-2 vaccine reactions from cellulitis by the time of onset (approximately a week vs 5 days), by the lack of progression of symptoms, and resolution over 4 to 5 days. • Severe cases of COVID arm may be treated with topical steroids.

scholarly journals Macrophage Activation Syndrome Associated with Adult-Onset Still’s Disease Successfully Treated with Anakinra

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Aswini Kumar ◽  
Hiroshi Kato
Keyword(s):  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Interleukin 1 ◽  
Pulse Therapy ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Onset Still's Disease ◽  
Activation Syndrome

Macrophage activation syndrome (MAS) is a potentially fatal complication of Adult-Onset Still’s disease (Still’s disease). Whereas an increasing body of evidence supports interleukin-1 (IL-1) blockade as a promising treatment for Still’s disease, whether it is therapeutic for MAS associated with Still’s disease remains unclear. We report a 34-year-old Caucasian man with one-decade history of TNF-blockade-responsive seronegative arthritis who presented with abrupt onset of fever, serositis, bicytopenia, splenomegaly, hepatitis, and disseminated intravascular coagulation. Striking hyperferritinemia was noted without evidence of infection, malignancy, or hemophagocytosis on bone marrow biopsy. NK cells were undetectable in the peripheral blood, whereas soluble IL-2 receptor was elevated. His multiorgan disease resolved in association with methylprednisolone pulse therapy, Anakinra, and a tapering course of prednisone. This case reinforces the notion that Still’s disease is inherently poised to manifest MAS as one of the clinical phenotypes by shedding light on the role of IL-1 underlying both Still’s disease and related MAS.

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