Chronic Atypical Neutrophilic Dermatosis Research Articles

Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS

ObjectivesPatients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid...

Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS).

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

Annular Neutrophilic Dermatoses.

Neutrophilic dermatoses (NDs) are a group of diseases characterized by sterile neutrophilic infiltrations. Many of the NDs usually present with infiltrated erythematous plaques, nodules, urticarial plaques, or pustules. Lesions may show variability, and atypical presentations may develop among the NDs. Annular lesions have been reported in many NDs and may lead to diagnostic problems. Clinical features and histopathologic findings such as localization of the neutrophilic infiltrate, existence of other cell types, and absence of true vasculitis may be helpful to distinguish NDs. Some of these NDs are associated with infections, inflammatory diseases, and malignancies. In most NDs, systemic steroids and dapsone are very effective and usually first choices. Colchicine, antimicrobials, such as doxycycline, tetracycline, and sulphapyridine, and other immunosuppressants, such a cyclosporine, methotrexate, and mycophenolate mofetil have been used successfully in treating many NDs. TNF-α inhibitors have also been used successfully in many NDs. JAK kinase inhibitors are effective in CANDLE syndrome, anakinra in neutrophilic urticarial dermatosis, and intravenous immunoglobulin in resistant pyoderma gangrenosum. We discuss the diagnosis and management of the NDs that may present with annular lesions.

Clinical analysis of 49 cases of non-inflammasome related conditions

Objective: To summarize the clinical characteristics and provide clues for early identification of non-inflammasome related conditions. Methods: The clinical manifestations, laboratory tests, genetic testing and follow-up of 49 children with non-inflammasome related conditions in Peking Union Medical College Hospital from January 2006 to February 2022 were retrospectively analyzed. Results: A total of 49 children, 29 of them were boys and 20 were girls. The age of onset was 0.8 (0.3, 1.6) years, the age at diagnosis was 5.7 (2.8, 8.8) years, and the time from onset to diagnosis was 3.6 (1.9, 6.3) years. Combined with genetic testing results, 49 children with non-inflammasome related conditions were found, including 34 cases (69%) of Blau syndrome, 4 cases (8%) of tumour necrosis factor receptor-associated periodic syndrome, 4 cases (8%) of haploinsufficiency of A20, 2 cases (4%) of Majeed syndrome, 2 cases (4%) of pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome and 3 cases (6%) of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. There were 22 cases (45%) with a positive family history. The clinical manifestations included 37 cases (76%) cases with rash, 38 cases (78%) with joint involvement, 33 cases (67%) with eye involvement, 17 cases (35%) with recurrent fever. In addition, 11 cases (22%) were complicated with digestive system involvement. Thirty cases (61%) presented as elevated inflammatory indexes (erythrocyte sedimentation rate and (or) C-reactive protein), positive autoantibodies were noticed in 3 cases (6%). The patients were treated with glucocorticoid in 23 cases (47%), immunosuppressive agents in 43 cases (88%) and biologic agents in 37 cases (76%). During the follow-up of 5.8 (2.9, 8.9) years, 3 cases (6%) died. Conclusions: The symptoms of non-inflammasome related conditions include recurrent fever, rash, joint and ocular involvement with increased inflammatory indexes and negative autoantibodies. Up to now, glucocorticoids, immunosuppressants and biologic agents are the most popular medications for the non-inflammasome related conditions.

Human induced pluripotent stem cells generated from Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome patients with a homozygous mutation in the PSMB8 gene (NIHTVBi016-A, NIHTVBi017-A, NIHTVBi018-A)

We have successfully generated induced pluripotent stem cells (iPSC) from dermal fibroblasts and peripheral blood mononuclear cells from patients with a homozygous missense mutation in the gene encoding PSMB8. Biallelic loss of function mutations in this gene are responsible for the PSMB8 deficiency termed Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). The iPSC carrying the homozygous PSMB8 gene mutation (c.224C > T, T75M) are phenotypically normal and have the capacity to differentiate toward the three germ layers. These iPSC have great potential to study the role of PMSB8 in the regulation of immune responses and other cellular pathways.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies: CANDLE/PRAAS, SAVI, and AGS.

Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long-term monitoring of patients with these rare diseases. Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.

Biological Treatments and Target Therapies for Pediatric Respiratory Medicine: Not Only Asthma.

We present a description of pediatric pneumology biological medications and other target therapies. The article aims at introducing the importance of a molecular approach to improve treatments. The first item treated was T2-High asthma and its current biological treatment and prescribing indications to propose a flow-chart to guide the clinical choice. Molecular rationales of such treatments are used to introduce a more general description of the biological and molecular approach to target therapies application. We introduce a general interpretation approach to neutrophilic asthma using the molecular plausibility one in order to propose possible future treatments mainly targeting interleukin-1 (IL-1), IL-17, IL-12, and IL-23. Indeed, cytokines can be excellent targets for several biological treatments. Downregulation of specific cytokines can be crucial in treating autoinflammatory and rheumatological diseases with a pulmonary involvement. Such conditions, although rare, should be early recognized as they can involve significant improvement with a properly targeted therapy. We face these conditions in a cherry-picking fashion picturing SAVI (STING-associated vasculopathy with onset in infancy), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), and COPA (coat proteins alpha syndrome) syndrome pulmonary involvement. Such examples are functional to introduce molecular-based approach for patients with rare conditions. Molecular plausibility can be highly valuable in treating patients with not-approved but possibly highly effective therapies. Due to the rarity of these conditions, we stress the concept of basket trials using the example of cytokinin-directed immunosuppressive treatment. Lastly, we provide an example of augmentative therapy using the alpha1 antitrypsin deficiency as a model. In summary, the article presents a collection of the most recent achievements and some possible future developments of target therapies for pediatric pulmonary conditions.

Efficacy and Safety of Janus Kinase Inhibitors in Type I Interferon-Mediated Monogenic Autoinflammatory Disorders: A Scoping Review

ImportanceType I interferon (IFN)-mediated monogenic autoinflammatory disorders (interferonopathies) are childhood-onset rare multisystemic diseases with limited treatment options. The Janus kinase (JAK) inhibitors are promising potential therapeutic candidates for immune-mediated chronic inflammatory skin diseases.ObjectiveTo review the use of JAK inhibitors to improve decision-making when treating interferonopathies with cutaneous manifestations.Evidence ReviewThe MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched for studies that used JAK protein inhibitors to treat IFN-related monogenic diseases with cutaneous manifestations in humans. The search results are reported using the scoping review approach.FindingsSeventeen open-label studies assessing the efficacy of ruxolitinib, baricitinib, or tofacitinib reported variable responses in patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and related syndromes, stimulator of IFN genes [STING]-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCh-L), gain-of-function mutations of STAT1 (GOF-STAT1), or Aicardi-Goutiéres syndrome. JAK inhibitors improved clinical and analytical parameters and decreased flare numbers, plasma inflammatory markers, and expression of IFN-stimulated genes. BK viremia and upper respiratory infections were the most frequent and severe adverse events. Significant heterogeneity in efficacy assessment methods and poor reporting of safety events were detected.Conclusions and RelevanceEvidence of the use of JAK inhibitors in patients with interpheronopathies is scarce and of low methodological quality. Future clinical trials should use validated scales and report drug safety in a more accurate way.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00517-9.

Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features

BackgroundMonogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown.ObjectivesWe investigated allergic, immunological and clinical phenotypes in FMF...

Rare health conditions 39: Krabbe disease; chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (‘CANDLE’); Batten disease; and working with young children

The purpose of this series is to highlight a range of rare health conditions: those that affect no more and usually fewer than 1 person in every 2000. Many healthcare assistants (HCAs) and nurses will encounter some of these conditions, given the high number of these conditions. This 39th article will briefly explore three of these conditions—Krabbe disease, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE), and Batten disease—and also discuss working with young children and their families.

Insights into CANDLE Syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a recently described chronic autoinflammatory disease, pathophysiologically related to intracellular proteasome/immunoproteasome dysfunction. This review chronicles the recognition of CANDLE syndrome, the developments in the understanding of the pathomechanism, genetic background, and the emerging therapeutic strategies of this condition.

A novel mouse model of proteasome associated autoinflammatory syndromes

Abstract Proteasome associated autoinflammatory syndromes (PRAAS) represent a rare class of early-onset autoinflammatory diseases, including chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome). CANDLE is an inherited autosomal recessive disease associated with recurrent fevers, skin lesions, lipodystrophy and other comorbidities. Point mutations in the proteasome subunit beta type-8 (psmb8) gene, which encodes the beta-5i (ß5i) catalytic subunit of the 20S immunoproteasome, have been linked to CANDLE. The immunoproteasome is induced in cells in response to interferon (IFN) signaling. In cells lacking functional immunoproteasomes, oxidant-damaged proteins aggregate and likely create a feed-forward loop resulting in greater cytokine-mediated stress. We have developed a novel mouse model via targeted mutation within the psmb8 gene, which harbors a specific point mutation (224C>T) present in CANDLE patients. Our data shows that this mutation leads to marked differences in the expression of the immunoproteasome subunit ß5i within these mice. Thus, this mouse model is likely to exhibit changes in the immunoproteasome consistent with human disease upon interferon signaling. As mice with the targeted mutation do not directly yield a CANDLE-like phenotype at rest, it suggests that induction of disease-associated morbidity requires additional drivers. To test this, we are investigating interferons as initiators of disease pathogenesis. Future research will entail subjecting these mice to viral infection in order to identify if such triggers can initiate PRAAS-like symptoms in CANDLE patients. These mice may prove to an essential tool in understanding such disorders.

Expression of interferon-regulated genes in juvenile dermatomyositis versus Mendelian autoinflammatory interferonopathies

BackgroundJuvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI.MethodsA peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics.ResultsIRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients’ IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (rs = 0.33–0.47) and more strongly with skin activity (rs = 0.58–0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S.ConclusionsOur findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

M263 CANDLE SYNDROME IN A CHILD WITHOUT PSMB8, PSMB4, PSMB9 OR PSMA3 MUTATIONS

CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperatures) syndrome is an autosomal recessive autoinflammatory interferonopathy associated with loss-of-function mutations in proteasome genes. This results in over-production of type I interferons (IFN) and inflammation. Here, we present a case without an identifiable CANDLE gene mutations.

Oral manifestations of primary immunodeficiencies

To understand the current state of the issue of dental manifestations of primary immunodeficiencies, foreign literature on the problem has been analyzed. The article describes the dental manifestations of many primary immunodeficiencies, which can be both secondary and major symptoms. The article presents the data on the following syndromes: severe combined immunodeficiency, hyper IgE, Wiskott – Aldrich, DiGeorge, deficiency of STIM1 and ORAI1, NEMO deficiency and IκBα deficiency, common variable immunodeficiency, X-linked agammaglobulinemia, hyper IgM, selective IgA deficiency, autoimmune lymphoproliferative syndrome, autoimmune polyendocrine syndrome type 1, Chediak – Higashi syndrome, CD70 deficiency, severe congenital neutropenia syndromes, leukocyte adhesion deficiency, localized aggressive periodontitis, Papillon – Lefevre syndrome, chronic mucocutaneous candidiasis, Marshall syndrome, hyper IgD syndrome, Aicardi – Goutières syndrome type 7, cherubism syndrome, CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), chronic recurrent multifocal osteomyelitis, periodontal Ehlers – Danlos syndrome, and C1 inhibitor deficiency. The role of secretory immunoglobulins of salivary fluid is described.

Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.

Nakajo–Nishimura syndrome (NNS) is a rare hereditary autoinflammatory disorder with lipodystrophy. This disease is caused by a homozygous mutation of PSMB8 gene, which encodes immunoproteasome subunit β5i. Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers. NNS was considered to be endemic to the Kansai area of Japan, but patients with similar phenotypes and the mutation of PSMB8 gene were reported in other countries, and named Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy (JMP) syndrome. These syndromes are now called proteasome-associated autoinflammatory syndromes (PRAASs), and their main pathophysiological mechanism seems to be interferonopathy. In this review, the history, characteristics, and the pathophysiological mechanism of PRAASs will be discussed, focusing mainly on NNS.

Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome

BackgroundCANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib.Case presentationWe report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease.ConclusionsCANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.

Proteomic profiling of autoinflammatory diseases, NOMID and CANDLE before and after treatment with interleukin-1 or with interferon blockade

Abstract Systemic Autoinflammatory diseases (SAIDs) present with chronic sterile inflammation. NLRP3 mutation cause the IL-1 mediated SAID Neonatal-Onset Multisystem Inflammatory Disease (NOMID), that presents early in life with fever, rash, neutrophilic meningitis, hearing loss and eye inflammation. Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy and Elevated Temperature (CANDLE) caused by additive loss-of-function mutations in proteasome genes including PSMB8, leads to chronic type 1 interferon signaling, characterized by early-onset fever, neutrophilic panniculitis, lipodystrophy, cytopenias, myositis and lymphocytic meningitis. IL-1 blocking treatments are approved for NOMID, and JAK-inhibitors show efficacy in CANDLE treatment. We used proteomic analysis to compare differentially-regulated proteins in active NOMID and CANDLE compared to healthy children before and after treatment to identify inflammatory pathways that distinguish NOMID and CANDLE and are uniquely responsive to either IL-1 or IFN signaling blockade. Serum samples from active NOMID (n=12) and CANDLE (n=7) before and after treatment and healthy controls (n=7) were subjected to proteomic profiling using SomaLogic platform (n=1129 proteins). Enriched pathways were identified in REACTOME and KEGG. Cytoscape was used for network extraction and visualization. Differentially expressed proteins in NOMID vs CANDLE suggested endothelial cell function, coagulation and complement cascades and inflammation related pathways dysregulation. Distinct protein markers (i.e. cytokine and chemokines) are consisted the different immune dysregulation in NOMID and CANDLE; and uniquely respond to either IL-1 or IFN signaling blockade.

Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) is a rare autoinflammatory interferonopathy caused by additive loss-of-function mutations in proteasome genes. Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.