Relapses in giant cell arteritis: Updated review for clinical practice.

Giant cell arteritis (GCA), the most common primary vasculitis in adults, is a granulomatous systemic vasculitis usually affecting the aorta and its major branches, particularly the carotid and vertebral arteries. Although remission can be achieved in most patients with GCA using high-dose glucocorticoids (GC), relapses are frequent, occurring in >40% of GC-only treated patients, mostly during the first two years after diagnosis. Relapsing courses lead to high GC exposure, increasing the risk of treatment-related adverse effects. Although tocilizumab is an efficacious GC-sparing therapy that allows increased sustained remission and reduced cumulative GC doses, relapses are common after drug discontinuation. This narrative review examines the most relevant features of relapses in GCA, including its definition, classification, frequency, clinical, laboratory, and imaging characteristics, chronology, probable pathophysiology, and predictive factors. In addition, we discuss treatment options for relapsing patients and the effect of relapses on patient outcomes.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Maternal and fetal outcomes of pregnancy in women with primary systemic vasculitis: A single-center cohort study of 20 patients and 30 pregnancies.

OBJECTIVES: To analyze pregnancy outcomes of patients with primary systemic vasculitis followed in a third-level referral center. METHODS: Retrospective cohort study of all pregnant women with systemic vasculitis followed between 2009 and 2022 at the High-Risk Pregnancy Clinic of the Department of Systemic Autoimmune Diseases of the Hospital Clínic, Barcelona. RESULTS: Twenty women with primary vasculitis were identified, with a total of 30 pregnancies. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (n = 7) and Behçet disease (n = 4) were the most frequent types of vasculitis. All women had the diagnosis of vasculitis before pregnancy, with a median time between disease diagnosis and pregnancy of 5.8 years (range: 2 months-29 years). Most were in remission at conception (76.7 %). During pregnancy, a vasculitis flare occurred in 4 (13.3 %) patients (one each with Takayasu arteritis, eosinophilic granulomatosis with polyangiitis [EGPA], IgA vasculitis [IgAV], and Behçet disease [BD]). Four (16.7 %) of the successful pregnancies had post-partum relapses (one each with EGPA, granulomatosis with polyangiitis, IgAV, and BD). Eighty percent of pregnancies resulted in live babies. In four cases (13.3 %), medical termination of pregnancy was decided, considering the mother or baby health risk. There were two spontaneous miscarriages, and no stillbirths or neonatal deaths. Preeclampsia was the most frequent maternal complication (25 %). Newborns were preterm in 24 % and low birthweight in 20 % of cases. No maternal deaths occurred. CONCLUSIONS: This cohort study shows that vasculitis relapses during pregnancy and post-partum, together with other pregnancy complications, occur in a considerable number of patients with systemic vasculitides, although a final good pregnancy outcome can be expected in most cases. These findings emphasize the convenience of managing these special situations in expert reference centers.

Clinico-pathological phenotypes of systemic sclerosis-associated myopathy: analysis of a large multicentre cohort.

OBJECTIVE: The objective of this study was to analyse the clinico-serological and histological phenotypes of patients with SSc with associated myopathy. METHODS: From November 2002 to September 2020, 52 patients with SSc underwent a muscle biopsy for suspected myopathy. We established two subgroups according to the histological findings based on the presence of isolated fibrosis or fibrosis together with significant inflammation. These patterns were designated as fibrosing and inflammatory, respectively. Clinical data, antibody profile, electrophysiologic studies, muscle biopsy findings and data regarding treatment, mortality and survival were compared between the two groups. RESULTS: Fourteen biopsies had a fibrosing pattern, whereas 26 showed an inflammatory pattern that could be classified (according to the predominant pattern) into DM (n = 7), necrotizing myopathy (n = 4) and non-specific myositis (n = 15). Additionally, 12 muscle biopsies were reported as neurogenic atrophy (n = 2), or normal muscle or minimal changes (n = 10). Compared with the inflammatory group, SSc patients with the fibrosing pattern presented a higher prevalence of ischaemic heart disease (38.5% vs 3.8%, P = 0.011), conduction abnormalities or arrhythmias (61.5% vs 26.9%, P = 0.036), anti-topo I antibodies (42.9% vs 11.5%, P = 0.044), greater median ESR (53.5 mm/h vs 32.5 mm/h, P = 0.013), with poor response to treatment and a higher mortality (42.9% vs 3.8%, P = 0.004) and lower cumulative survival (P = 0.035). CONCLUSIONS: Patients with SSc-associated myopathy require a comprehensive approach that encompasses clinical, serological and histopathological aspects, given their outcome predictive capacity. At least two different phenotypes can be drawn, considering clinico-pathological features. Significant differences are delineated between both a fibrotic and an inflammatory phenotype.

Response to mepolizumab according to disease manifestations in patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a relapsing disease with frequent glucocorticoid dependence. Mepolizumab has been demonstrated to reduce flares and spare glucocorticoids (GC). However, EGPA is a heterogeneous condition and the effects of mepolizumab on specific disease manifestations has not been completely delimitated. OBJECTIVES: To analyse the impact of mepolizumab on manifestations derived from small-vessel vasculitis, ENT (ear, nose and throat) symptoms, asthma, eosinophilic tissue infiltration and anti-neutrophil cytoplasmic antibody (ANCA) status in a single-centre cohort of EGPA patients. METHODS: Medical charts of EGPA patients treated with mepolizumab were retrospectively reviewed by the authors to describe demographics, clinical characteristics, steroid dose at the initiation of mepolizumab and during follow-up, flares, disease activity, damage accrual and laboratory results. RESULTS AND CONCLUSIONS: Among 56 patients with EGPA regularly controlled at our department, 11 patients were treated with mepolizumab because of corticodependence and unsatisfactory disease control. The mean time of treatment was 38 months (range: 3-66 months). Patients with persistent symptoms improved their asthma control, but 3 of them persisted with recurrent ENT symptoms in spite of treatment with mepolizumab. None of the patients developed vasculitic manifestations (cutaneous, neurological, gastrointestinal, renal) during treatment. All patients achieved a Birmingham Vasculitis Activity Score (BVAS) of 0 points at 12 months or earlier. In general, patients reduced the number of flares, which tended to be milder, and all related to asthma or ENT manifestations. The improvement in disease activity allowed notable glucocorticoid tapering.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome.

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Impact of remdesivir according to the pre-admission symptom duration in patients with COVID-19.

BACKGROUND: The use of remdesivir has demonstrated a significant reduction in the time to recovery in patients with COVID-19. However, the impact on mortality is still controversial. Therefore, it is necessary to evaluate whether there is a specific subgroup of patients in whom an active antiviral therapy also reduces the mortality. METHODS: Patients admitted for >48 h in our hospital for a SARS-CoV-2 confirmed or suspected infection from February 2020 to February 2021 were retrospectively analysed. The primary outcome of the study was mortality at 30 days. Univariate and multivariate analyses were performed to identify predictors of mortality. RESULTS: In total, 2607 patients (438 receiving remdesivir and 2169 not) were included with a median (IQR) age of 65 (54-77) years and 58% were male. Four hundred and seventy-six were admitted to the ICU (18.3%) and 264 required invasive mechanical ventilation (10.1%). The global 30 day mortality rate was 10.7%. Pre-admission symptom duration of 4-6 days and ≤3 days was associated with a 1.5- and 2.5-fold increase in the mortality rate, respectively, in comparison with >6 days and treatment with remdesivir was independently associated with a lower mortality rate (OR = 0.382, 95% CI = 0.218-0.671). The analysis showed that the major difference was among patients with shorter pre-admission symptom duration (<6 days). CONCLUSIONS: Patients with ≤3 days and 4-6 days from symptom onset to admission are associated with a 2.5- and 1.5-fold higher risk of death, respectively. Remdesivir was associated with 62% reduced odds of death versus standard-of-care and its survival benefit increased with shorter duration of symptoms.

Prevalence of cardiovascular risk factors, the use of statins and of aspirin in Takayasu Arteritis.

The aim of this study was to assess the prevalence of cardiovascular risk factors in TAK, to describe the use of aspirin and statins and the risk factors associated with vascular ischemic complications and relapses. We conducted a retrospective study on TAK patients diagnosed between 2010 and 2018. Demographic, clinical, laboratory data and treatments were evaluated at diagnosis and during the follow-up. We included fifty-two TAK patients with median age 37.5 years [range 16-53] and 43 (83%) women. At diagnosis, cardiovascular risk factors were present in 32 (62%) patients: hypertension (n = 20, 38%), hyperlipidemia (n = 8, 15%), tobacco use (n = 16, 31%). During the median 4-year follow-up [range 0.1-17 years], 17 (33%) patients had at least one ischemic event and 15 (29%) patients needed endovascular procedure. Whereas TAK patients with cardiovascular risk factors were more frequently on statins and anti-hypertensive drugs, they have higher rates of cumulative ischemic complications (5 (24%) versus 21 (67%); p = 0.004), but similar rates of aspirin-treated patients. Patients who have developed vascular ischemic events were more frequently smokers (53% versus 20%; p = 0.03). The vascular complication-free survival was not significantly different in TAK patients with or without statins or aspirin at diagnosis. During the follow-up, 27 (52%) patients had at least one relapse, and the relapse-free survival was not significantly different in patients treated with statins or aspirin. Cardiovascular risk factors in TAK have to be strictly controlled since these risk factors could be associated with increased risk of ischemic complications.

HLA association with the susceptibility to anti-synthetase syndrome.

OBJECTIVE: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). METHODS: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. RESULTS: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P=1.56E-09, odds ratio-OR [95% confidence interval-CI]=2.54 [1.84-3.50] and 21.4% versus 5.5%, P=18.95E-18, OR [95% CI]=4.73 [3.18-7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P=0.0003, OR [95% CI]=0.48 [0.31-0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P=0.001, OR [95% CI]=2.54 [1.39-4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. CONCLUSIONS: Our results support the association of the HLA complex with the susceptibility to ASSD.

Simultaneous presentation of granulomatosis with polyangiitis (GPA) and immunoglobulin G4-related disease (IgG4-RD). Leaving an open question: widening the spectrum of a single disease or real overlap?

Because of a similar organ involvement and histopathological features, IgG4-related disease (IgG4-RD) may mimic some forms of granulomatosis with polyangiitis (GPA). However, several cases of clear coexistence or overlap of both diseases have been reported. We describe a case of a 47-year-old man presenting with a renal mass and a nasal crusting showing histopathological features of IgG4-RD in both territories. Cytoplasmic/proteinase 3 (PR3) antineutrophil cytoplasmic antibodies (ANCA) were positive and the patient subsequently developed kidney failure and nephritic syndrome that led to a renal biopsy re-evaluation revealing changes compatible with segmental necrotising glomerulonephritis and GPA. Remission induction therapy with prednisone and rituximab was started and clinical and laboratory parameters returned to normal. After administering a maintenance regimen based in rituximab 500 mg every six month the patient remained asymptomatic during 4 years of follow-up and free of prednisone the last 18 months. Although coexistence or overlap of GPA and IgG4-RD may be established in some clinical scenarios, the possibility of widening the spectrum of a single disease is also postulated.

Quick diagnosis units: predictors of time to diagnosis and costs.

Financial crisis has forced health systems to seek alternatives to hospitalization-based healthcare. Quick diagnosis units (QDUs) are cost-effective compared to hospitalization, but the determinants of QDU costs have not been studied.We aimed at assessing the predictors of costs of a district hospital QDU (Hospital Plató, Barcelona) between 2009 and 2016.This study was a retrospective longitudinal single center study of 404 consecutive outpatients referred to the QDU of Hospital Plató. The referral reason was dichotomized into suggestive of malignancy vs other. The final diagnosis was dichotomized into organic vs nonorganic and malignancy vs nonmalignancy. All individual resource costs were obtained from the finance department to conduct a micro-costing analysis of the study period.Mean age was 62 ±â€Š20 years (women = 56%), and median time-to-diagnosis, 12 days. Total and partial costs were greater in cases with final diagnosis of organic vs nonorganic disorder, as it was in those with symptoms suggestive or a final diagnosis of cancer vs noncancer. Of all subcosts, imaging showed the stronger correlation with total cost. Time-to-diagnosis and imaging costs were significant predictors of total cost above the median in binary logistic regression, with imaging costs also being a significant predictor in multiple linear regression (with total cost as quantitative outcome).Predictors of QDU costs are partly nonmodifiable (i.e., cancer suspicion, actually one of the goals of QDUs). Yet, improved primary-care-to-hospital referral circuits reducing time to diagnosis as well as optimized imaging protocols might further increase the QDU cost-effectiveness process. Prospective studies (ideally with direct comparison to conventional hospitalization costs) are needed to explore this possibility.

Manifestaciones clínicas y anticuerpos asociados y específicos de miositis en 15 pacientes chilenos con dermatomiositis: serie clínica en un centro universitario / Clinical manifestations and antibody profile in 15 patients with dermatomyositis

Background: Certain associated and specific myositis antibodies are related to certain clinical phenotypes of dermatomyositis (DM), disease severity and the presence of cancer. Aim: To describe the clinical profile of Chilean patients with DM and their associated and specific myositis antibodies. Material and Methods: Review of medical records of 15 patients with DM aged 31 to 72 years. Their clinical characteristics, laboratory tests and complementary tests were reviewed. In serum samples from each patient the presence of 16 specific antibodies was analyzed by immunoblot technique (Myositis Profile Euroline Blot test kit). Results: Fourteen (93.3%) patients had skin manifestations, five (33.3%) had pulmonary involvement, two (13.3%) had an associated cancer and nine (60%) had specific antibodies associated with myositis. Conclusions: These patients with DM had a clinical profile similar to what has been described elsewhere. The profile of myositis specific antibodies was different from reports in other populations.

Impact of a systematic evaluation of connective tissue disease on diagnosis approach in patients with interstitial lung diseases.

To date, there is no clear agreement regarding which is the best method to detect a connective tissue disease (CTD) during the initial diagnosis of interstitial lung diseases (ILD). The aim of our study was to explore the impact of a systematic diagnostic strategy to detect CTD-associated ILD (CTD-ILD) in clinical practice, and to clarify the significance of interstitial pneumonia with autoimmune features (IPAF) diagnosis in ILD patients.Consecutive patients evaluated in an ILD Diagnostic Program were divided in 3 groups: IPAF, CTD-ILD, and other ILD forms. Clinical characteristics, exhaustive serologic testing, high resolution computed tomography (HRCT) images, lung biopsy specimens, and follow-up were prospectively collected and analyzed.Among 139 patients with ILD, CTD was present in 21 (15.1%), 24 (17.3%) fulfilled IPAF criteria, and 94 (67.6%) were classified as other ILD forms. Specific systemic autoimmune symptoms such as Raynaud phenomenon (19%), inflammatory arthropathy (66.7%), and skin manifestations (38.1%) were more frequent in CTD-ILD patients than in the other groups (all P < .001). Among autoantibodies, antinuclear antibody was the most frequently found in IPAF (42%), and CTD-ILD (40%) (P = .04). Nonspecific interstitial pneumonia, detected by HRCT scan, was the most frequently seen pattern in patients with IPAF (63.5%), or CTD-ILD (57.1%) (P < .001). In multivariate analysis, a suggestive radiological pattern by HRCT scan (odds ratio [OR] 15.1, 95% confidence interval [CI] 4.7-48.3, P < .001) was the strongest independent predictor of CTD-ILD or IPAF, followed by the presence of clinical features (OR 14.6, 95% CI 4.3-49.5, P < .001), and serological features (OR 12.4, 95% CI 3.5-44.0, P < .001).This systematic diagnostic strategy was useful in discriminating an underlying CTD in patients with ILD. The defined criteria for IPAF are fulfilled by a considerable proportion of patients referred for ILD.

Emerging PD-1 and PD-1L inhibitors-associated myopathy with a characteristic histopathological pattern.

BACKGROUND AND OBJECTIVE: Drug-induced myopathy is among the most common causes of muscle disease. An association has recently been described between programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors and immune-related adverse events (irAE) affecting the muscle. Here, we report the clinical and pathological findings of nine unrelated patients with PD-1 and PD-L1 inhibitors-associated myopathy. METHODS: We retrospectively analyzed 317 muscle biopsies performed for diagnostic purposes from January 2017 to June 2019. Patients were attended in two tertiary centers and muscle biopsies were performed and analyzed by two myology experts. Muscle biopsies were frozen in cooled isopenthane, cryostat sectioned and stained. Immunohistochemistry studies were also performed as a routine procedure in our lab. RESULTS: We identified 9 patients receiving anti-PD-1 or PD-L1 inhibitors consulting for either muscle weakness, asthenia, myasthenic-like syndrome or other muscle related-symptoms, along with biopsy-proven inflammatory myopathy. One had concomitant myocarditis. In most of the cases muscle biopsy showed a marked phenomenon of necrosis, macrophagy and muscle regeneration with perivascular inflammatory infiltrates with a large component of macrophagic cells. A tendency to perifascicular atrophy was also noticed. The expression of MHC class I antigens predominated in the perifascicular zones. Raised muscle enzymes were detected in 7 patients. CONCLUSION: A characteristic clinic-pathological pattern, including a myasthenia gravis-like syndrome plus myositis was found in patients receiving PD-1 and PD-1 L inhibitors. A large component of macrophages resembling granulomas seems to be the pathological hallmark of the syndrome. Further information is required to understand the wide spectrum of immune-related adverse events involving the muscle during or after treatment with anti-PD-1 inhibitors, but the pathological picture seems to be characteristic.

Localised granulomatosis with polyangiitis in an older patient with rheumatoid arthritis.

New onset of granulomatosis with polyangiitis (GPA) occurring in patients previously diagnosed with rheumatoid arthritis (RA) is very uncommon. In older individuals, this condition is associated with high mortality, especially in those with renal involvement. We describe the first case of GPA in a patient older than 65 years diagnosed with RA without exposure to biologic disease-modifying anti-rheumatic drugs, presenting with pulmonary nodules due to a limited form of anti-neutrophil cytoplasmic antibody-negative GPA.

Usefulness of imaging techniques in the management of giant cell arteritis. / Utilidad de las técnicas de imagen en la valoración de la arteritis de células gigantes.

Imaging has become an essential tool in the management of patients with giant cell arteritis. Cranial involvement detected by Doppler ultrasonography is an unquestionable diagnostic finding. Imaging of the aorta and its branches with positron emission tomography, computed tomography angiography or magnetic resonance imaging may also have a role in diagnosis and in the assessment of disease activity and response to treatment, but standardisation and validation are still needed before their widespread use as an outcome measure. Aortic structural damage is associated with increased mortality in giant cell arteritis; therefore, periodic screening is recommended.

Whole-body MRI and pathological findings in adult patients with myopathies.

Magnetic resonance imaging (MRI) is considered the most sensitive and specific imaging technique for the detection of muscle diseases related to myopathies. Since 2008, the use of whole-body MRI (WBMRI) to evaluate myopathies has improved due to technical advances such as rolling table platform and parallel imaging, which enable rapid assessment of the entire musculoskeletal system with high-quality images. WBMRI protocols should include T1-weighted and short-tau inversion recovery (STIR), which provide the basic pulse sequences for studying myopathies, in order to detect fatty infiltration/muscle atrophy and muscle edema, respectively. High signal intensity in T1-weighted images shows chronic disease with fatty infiltration, whereas high signal intensity in STIR indicates an acute stage with muscle edema. Additional sequences such as diffusion-weighted imaging (DWI) can be readily incorporated into routine WBMRI study protocols. Contrast-enhanced sequences have not been done. This article reviews WBMRI as an imaging method to evaluate different myopathies (idiopathic inflammatory, dystrophic, non-dystrophic, metabolic, and channelopathies). WBMRI provides a comprehensive estimate of the total burden with a single study, seeking specific distribution patterns, including clinically silent involvement of muscle areas. Furthermore, WBMRI may help to select the "target muscle area" for biopsy during patient follow-up. It may be also be used to detect related and non-related pathological conditions, such as tumors.

Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis.

OBJECTIVE: To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model. PATIENTS AND METHODS: The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017. RESULTS: The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (P<.001), mixed microbiological infections (P=.02), and more than 1 infection (P=.01) and glucocorticoid monotherapy (P=.02). According to univariate analyses, platelets of less than 100,000/mm3 (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death. CONCLUSION: The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.