The one-year infection risk among patients diagnosed with giant cell arteritis: use of antibiotics and hospitalisations.

OBJECTIVES: Patients with giant cell arteritis (GCA) primarily have their infections managed by primary care providers and hospitalisation is rarely necessary. Existing studies in GCA focus on infection-related hospitalisations only, whereas the use of antibiotic prescriptions is largely unknown. This study aims to examine the one-year overall infection risk among patients with GCA. METHODS: This nationwide observational cohort study included patients aged ≥50 years with a first-time GCA diagnosis in the Danish National Patient Registry (1996-2022). Patients with GCA were matched 1:10 by sex and date of birth with general population individuals and followed from date of diagnosis. Overall infections were defined as redeemed antibiotic prescriptions or infection-related hospitalisations. Utilising a pseudo-observation approach, we assessed 1-year cumulative incidence proportions (CIP), risk differences (RD), and relative risks (RR) of infections. RESULTS: The study included 17 773 incident patients with GCA and 177 730 reference individuals. Patients with GCA had a 1-year CIP of 52.4% (95% CI: 51.7-53.2) for overall infections and 17.6% (95% CI: 17.1-18.2) for infection-related hospitalisations. Compared with the reference cohort, patients with GCA had a RR of 1.40 (95% CI: 1.38-1.42) for overall infections and 2.71 (95% CI: 2.61-2.82) for infection-related hospitalisations. Additionally, higher cumulative glucocorticoid doses, advanced age (≥70 years), and higher comorbidity were associated with an increased risk of infections among patients with GCA. CONCLUSIONS: The use of antibiotic prescriptions and infection-related hospitalisations in the first year after a GCA diagnosis is high compared with the background population. The cumulative glucocorticoid dose is associated with the infection risk.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [ß (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [ß (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [ß (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]. CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses.

Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

The utility of transbronchial lung biopsies to guide the treatment decision in patients with rheumatic inflammatory diseases: a retrospective cross-sectional study.

The role of transbronchial lung biopsies (TBB) in the diagnostic workup of systemic inflammatory rheumatic disease-associated interstitial lung disease (SIRD-ILD) is unclear and TBB is not generally recommended. The study objective was to examine the utility of TBB to guide treatment in a population of patients with SIRD-ILD. All patients from the Department of Rheumatology, Rigshospitalet, Denmark, who had TBB performed, from 2002 to 2016 were identified. Patient demographics as well as smoking status, previous lung disease, pulmonary function test, SIRD-diagnosis, imaging results and immunomodulatory therapy pre- and post-bronchoscopy were obtained. Histology findings were used to dichotomize patients into a high-inflammatory group or a low-inflammatory group. The high-inflammation group primarily consisted of non-specific interstitial pneumonia, organizing pneumonia, lymphocytic infiltrating pneumonia and granulomatous inflammation whereas the low inflammation group primarily consisted of histological findings of usual interstitial pneumonitis and biopsies describing fibrosis and/or sparse unspecific inflammation. Therapeutic consequence was defined as intensification of therapy. Differences in treatment intensification were calculated using a binominal logistic regression model. Ninety-six patients had TBB performed. Biopsies from 55 patients were categorized as high inflammatory and 41 as low inflammatory, respectively. In the high-inflammatory group, 38 (69%) had their therapy intensified compared to 6 (14%) in the low-inflammatory group (Odds ratio 8.0, 95% confidence limits 3.2-20.0, P < 0.001). No procedure-related complications were registered. TBB findings can guide treatment strategy in SIRD-ILD patients with suspected activity in the pulmonary disease. TBB appears safe and could be considered as part of the diagnostic workup.

Mortality and cardiovascular morbidity among patients diagnosed with Takayasu's arteritis: a Danish nationwide cohort study.

OBJECTIVES: To assess the long-term mortality and risk of cardiovascular events (CVE) among Danish patients with Takayasu's arteritis (TAK). METHODS: Administrative registers with nationwide coverage were used to identify patients diagnosed with TAK in Denmark during 1994-2014 and construct an age- and gender-matched cohort of population-controls. CVE were identified by means of hospital discharge diagnoses and categorised as major or minor, based on severity. Cox regression analyses were used to calculate hazard ratios (HRs) for death and first-time hospitalisations for CVE as a measure of relative risk. RESULTS: 79 patients with TAK were identified, corresponding to an incidence rate of 0.7 (95% confidence interval (CI): 0.6-0.9)/million/year. Median duration of follow-up in the TAK cohort was 6.4 (IQR: 3.7-11) years. Mortality was significantly higher among the TAK patients than among the population controls during the first 3 years of follow-up [HR for death: 8.0 (95% CI: 3.0-21)], but not after >3 years [HR for death: 0.5 (95% CI: 0.1-3.5)]. Risk of CVE was significantly increased among TAK patients after ≤3 years [HR for major CVE: 12 (95% CI: 3.8-37), HR for minor CVE: 19 (95% CI: 7.5-50)] as well as after >3 years [HR for major CVE: 7.6 (95% CI: 2.8-21), HR for minor CVE: 3.0 (95% CI: 1.01-9.0)]. CONCLUSIONS: Compared to the general population, patients with TAK experience markedly increased mortality during early follow-up periods. The long-term risk of CVE is high among patients affected by the disease.

Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays.

OBJECTIVE: This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs). METHODS: Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays. RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945). CONCLUSIONS: Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.

A multicentre study to improve clinical interpretation of proteinase-3 and myeloperoxidase anti-neutrophil cytoplasmic antibodies.

Objective: The objective of this multicentre study was to improve the clinical interpretation of PR3- and MPO-ANCAs as an adjunct for the diagnosis of ANCA-associated vasculitis (AAV) by defining thresholds and test result intervals based on predefined specificities and by calculating test result interval-specific likelihood ratios (LRs). Methods: Eight different PR3- and MPO-ANCA immunoassays from seven companies were evaluated using 251 diagnostic samples from AAV patients and 924 diseased controls. Results: Thresholds for antibody levels were determined based on predefined specificities (95, 97.5, 99 and 100%) and used to delimit test result intervals. Test result interval-specific LRs were determined. For all assays, the LR for AAV increased with increasing antibody level. For all but one immunoassay, high antibodies levels (associated with LR >55) were found in a substantial fraction (>65%) of patients. The area under the curve (AUC) of receiver operating characteristics analysis of a diagnostic approach in which positive results were confirmed by IIF or another immunoassay was not substantially higher than the AUC of performing immunoassay only. The highest AUC was found when immunoassay was combined with another immunoassay or with IIF. Conclusion: To diagnose AAV based on PR3- and MPO-ANCA, it is useful to define thresholds for antibody levels and to assign test result interval-specific LRs. Higher antibody levels are associated with a higher likelihood for disease. Such information improves clinical interpretation.

Impact of pre-existing co-morbidities on mortality in granulomatosis with polyangiitis: a cohort study.

OBJECTIVE: To assess the impact of pre-existing co-morbidities on mortality among patients affected by granulomatosis with polyangiitis (GPA). METHODS: By means of the Danish National Hospital Register, we identified a cohort of patients hospitalized for GPA during 1994-2010 (n = 308). The burden of pre-existing co-morbidities among the patients was quantified according to the Charlson Comorbidity Index (CCI). Each patient was matched with five age- and gender-matched population controls with no pre-existing co-morbidities captured by the CCI (CCI score = 0). The study subjects were followed throughout 2010. Cox regression analyses were used to calculate mortality rate ratios (MRRs). RESULTS: The median duration of follow-up in the GPA cohort was 5.8 years (interquartile range 2.3-10.0). Compared with their matched population controls, the MRR for patients presenting with a CCI score of 0 (n = 246) was 3.9 (95% CI 2.0, 7.5) during years 0-2 and 1.4 (95% CI 0.9, 2.0) from the second year of follow-up onwards. The corresponding MRRs were 13.3 (95% CI 5.8, 31) and 1.9 (95% CI 1.1, 3.6) for patients with a CCI score ⩾1 (n = 62). In a direct comparison, GPA patients with a CCI score ⩾1 were found to have significantly higher mortality than GPA patients with a CCI score of 0 during years 0-2 [adjusted MRR 3.4 (95% CI 1.6, 7.0)] but not after >2 years of follow-up [adjusted MRR 1.3 (95% CI 0.7, 2.6)]. CONCLUSION: During early follow-up periods, the mortality among GPA patients with pre-existing co-morbidities is markedly higher than that among GPA patients with no pre-existing illnesses. Our analyses identify an increased CCI score for pre-existing co-morbidities as an important risk factor for a fatal outcome in GPA.

Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Mortality in patients with giant cell arteritis.

OBJECTIVE: The aim of this study was to examine whether GCA is associated with increased mortality. METHODS: We conducted a nationwide population-based cohort study including all individuals who between 1993 and 2011 were registered in the Danish National Hospital Register and the Danish Pathology Register with a biopsy-proven diagnosis of GCA (n = 1787). Through the Danish Civil Registration System we identified a comparison cohort of 33 953 persons from the background population, individually matched on age and sex. Data on causes of death were obtained from the Danish Registry of Causes of Death. We used Poisson regression to determine mortality rate ratios as estimates of relative risk of death and specific causes of death. RESULTS: Compared with the general population, the relative risk (RR) of death in patients diagnosed with GCA was 1.17 (95% CI 1.01, 1.36) and 1.22 (95% CI 1.05, 1.41) 0-2 years and >10 years after diagnosis, respectively, whereas we observed no increased mortality during the follow-up period of 2-10 years [RR 0.96 (95% CI 0.88, 1.05)]. The increased mortality during the first 2 years of follow-up was mainly due to diseases of the circulatory system, including aortic aneurisms. CONCLUSION: GCA is associated with slightly increased early and late mortality.

Prolonged risk of specific malignancies following cyclophosphamide therapy among patients with granulomatosis with polyangiitis.

OBJECTIVE: The long-term cancer risk for patients treated for granulomatosis with polyangiitis (GPA) is not well characterized. We assessed the risk of early and late-occurring cancers among 293 patients diagnosed with GPA from 1973 to 1999 and followed throughout 2010. METHODS: Cancer incidence in the cohort was determined by linkage with the Danish Cancer Registry and compared with that in the general population by calculation of standardized incidence ratios (SIRs). RESULTS: The median duration of follow-up was 9.7 years (range 0-36). Seventy-three cancers occurred, of which 30 were non-melanoma skin cancers (NMSCs) and 11 were bladder carcinomas. A high occurrence of NMSC was observed from the second year of follow-up onwards, with a SIR of 7.0 (95% CI 2.3, 16) for cases diagnosed ≥20 years after GPA. The incidence of bladder cancer increased after 5-9, 10-14 and 15-19 years of follow-up, with SIR estimates for these latency periods of 5.3 (95% CI 1.1, 15), 14.4 (95% CI 5.3, 31) and 10.5 (95% CI 1.2, 38), respectively. The incidence of myeloid leukaemia was significantly increased during years 5-9 [SIR 23.9 (95% CI 2.7, 86)]. Increased incidence of NMSC, bladder cancer and myeloid leukaemia was observed among patients exposed to cumulative CYC doses >36 g, while the only malignancy type observed in excess among those treated with lower CYC doses was NMSC. The cancer risk among CYC-naive patients was not significantly increased. CONCLUSION: GPA patients experience a greater than expected number of specific malignancies following conventional therapies. Our analyses demonstrate a substantially increased risk of very late-occurring NMSC and bladder cancer in this patient group.

Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and synovial hyperplasia leading to progressive joint destruction. Fibroblast-like synoviocytes (FLS) are central components of the aggressive, tumour-like synovial structure termed pannus, which invades the joint space and cartilage. A distinct natural killer (NK) cell subset expressing the inhibitory CD94/NKG2A receptor is present in RA synovial fluid. Little is known about possible cellular interactions between RA-FLS and NK cells. We used cultured RA-FLS and the human NK cell line Nishi, of which the latter expresses an NK receptor repertoire similar to that of NK cells in RA synovial fluid, as an in vitro model system of RA-FLS/NK cell cross-talk. We show that RA-FLS express numerous ligands for both activating and inhibitory NK cell receptors, and stimulate degranulation of Nishi cells. We found that NKG2D, DNAM-1, NKp46 and NKp44 are the key activating receptors involved in Nishi cell degranulation towards RA-FLS. Moreover, blockade of the interaction between CD94/NKG2A and its ligand HLA-E expressed on RA-FLS further enhanced Nishi cell degranulation in co-culture with RA-FLS. Using cultured RA-FLS and the human NK cell line Nishi as an in vitro model system of RA-FLS/NK cell cross-talk, our results suggest that cell-mediated cytotoxicity of RA-FLS may be one mechanism by which NK cells influence local joint inflammation in RA.

Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis.

Tocilizumab (TCZ), a monoclonal antibody targeting the human interleukin-6-receptor (IL-6R), is indicated for the treatment of rheumatoid arthritis (RA). We examined whether three IL6R single-nucleotide polymorphisms rs12083537, rs2228145 (formerly rs8192284), and rs4329505 with previously reported functional effects were associated with clinical response to TCZ in a retrospective study cohort consisting of 79 RA patients. Three months after initiation of TCZ therapy, changes in swollen joint count (SJC) and, subordinately, tender joint count (TJC), serum-CRP, DAS28-CRP, and EULAR-response were tested for association with the IL6R-haplotype or genotype. The major allele (A) of rs12083537 and the minor allele (C) of rs4329505 were associated with a poor SJC response (P=0.02 and 0.02, respectively). Moreover, the AAC-haplotype (for rs12083537, rs2228145, and rs4329505, respectively) was associated with a poor SJC response (P=0.00004) and, with borderline significance, EULAR-response (P=0.05). These data suggest that genetic variation in IL6R may aid in predicting TCZ therapy outcome in RA patients.

Treatment of orbital inflammation with rituximab in Wegener's granulomatosis.

OBJECTIVES: To study the efficacy of rituximab therapy for the treatment of orbital inflammation in patients with Wegener's granulomatosis (WG). METHODS: Ten WG patients with orbital inflammation were included in this case-series. None had symptoms suggestive of extra-orbital disease activity. Immunosuppressive medication (mycophenolate and prednisolone) was administered to 3 patients at the time of rituximab therapy. Three patients had previously been treated with anti-tumour-necrosis-factor-alpha antibodies, and one of these patients had also received cyclophosphamide as treatment for orbital inflammation. All patients were treated with 1000 mg of rituximab administered twice with an interval of 14 days between the infusions. Six months after therapy, a physical examination and a control computerised tomography (CT) scan was performed. RESULTS: All patients had orbital inflammation demonstrated by CT-scan before treatment (3 had bilateral and 7 unilateral orbital involvement). Orbital symptoms at study baseline included pain, pressure sensation behind the eyes, epiphora, diplopia, and affection of the visual acuity. Nine out of ten patients experienced subjective improvement. Four patients (seven eyes) with visual impairment responded to therapy, and the improvement in visual acuity was sustained throughout follow-up (median duration of follow-up: 17 months; range: 6-18 months). At the time of the control CT-scan, size-reduction of the orbital mass was observed in two patients, while the size of the orbital mass was unchanged in eight patients. CONCLUSIONS: Rituximab therapy has positive effects on symptoms, visual acuity and/or granuloma size in some WG patients with orbital inflammation. Treatment with rituximab should be considered in WG patients with this serious manifestation of the disease.

Risk of Cancer Among Sarcoidosis Patients With Biopsy-verified Nonnecrotizing Granulomatous Inflammation: Population-based Cohort Study.

OBJECTIVE: To assess the long-term risk of hematologic cancers, invasive solid tumors, and nonmelanoma skin cancer (NMSC) among sarcoidosis patients with biopsy-verified nonnecrotizing granulomatous inflammation. METHODS: We used Danish administrative registers with nationwide coverage to construct a cohort of 3892 patients with sarcoidosis and an age- and sex-matched comparison cohort of 38,920 population controls. For all patients, a biopsy demonstrating nonnecrotizing granulomatous inflammation had been obtained from the lower respiratory tract at the time of diagnosis. Study outcome was time to diagnosis of cancer. Follow-up began at time of sarcoidosis diagnosis and continued for up to 10 years. We calculated hazard ratios (HRs) as estimates of the cancer risk among the patients with sarcoidosis relative to that among the population controls and used cumulative incidence functions to calculate absolute 10-year risk estimates. RESULTS: We observed an increased long-term risk of hematologic cancers (HR during the first 2 years of follow-up: 2.71 [95% CI 1.18-6.25]; HR after > 2 years of follow-up: 2.12 [95% CI 1.29-3.47]) and NMSC (HR after > 2 years of follow-up: 1.82 [95% CI 1.43-2.32]) among the patients with sarcoidosis. An increased risk of invasive solid tumors was only observed during the first 2 years (HR 1.55, 95% CI 1.18-2.04). Compared with the population controls, the patients with sarcoidosis had an increased absolute 10-year risk of hematologic cancers (risk difference 0.56%, 95% CI 0.11-1.01%) and NMSC (risk difference 1.58%, 95% CI 0.70-2.47%). CONCLUSION: Sarcoidosis patients with biopsy-verified nonnecrotizing granulomatous inflammation have an increased long-term risk of hematologic cancers and NMSC compared with the general population.