Giant cell arteritis: incidence and phenotypic distribution in Western Norway 2013-2020.

Objectives: There is an increasing awareness of the spectrum of phenotypes in giant cell arteritis (GCA). However, there is sparse evidence concerning the phenotypic distribution which may be influenced by both genetic background and the environment. We established a cohort of all GCA-patients in the Bergen Health Area (Western Norway), to describe the phenotypic distribution and whether phenotypes differ with regards to incidence and clinical features. Methods: This is a retrospective cohort study including all GCA-patients in the Bergen Health Area from 2013-2020. Data were collected by reviewing patient records, and patients considered clinically likely GCA were included if they fulfilled at least one set of classification criteria. Temporal artery biopsy (TAB) and imaging results were used to classify the patients according to phenotype. The phenotype "cranial GCA" was used for patients with a positive TAB or halo sign on temporal artery ultrasound. "Non-cranial GCA" was used for patients with positive findings on FDG-PET/CT, MRI-, or CT angiography, or wall thickening indicative of vasculitis on ultrasound of axillary arteries. Patients with features of both these phenotypes were labeled "mixed." Patients that could not be classified due to negative or absent examination results were labeled "unclassifiable". Results: 257 patients were included. The overall incidence of GCA was 20.7 per 100,000 persons aged 50 years or older. Overall, the cranial phenotype was dominant, although more than half of the patients under 60 years of age had the non-cranial phenotype. The diagnostic delay was twice as long for patients of non-cranial and mixed phenotype compared to those of cranial phenotype. Headache was the most common clinical feature (78% of patients). Characteristic clinic features occurred less frequently in patients of non-cranial phenotype compared to cranial phenotype. Conclusion: The overall incidence for GCA was comparable to earlier reports from this region. The cranial phenotype dominated although the non-cranial phenotype was more common in patients under 60 years of age. The diagnostic delay was longer in patients with the non-cranial versus cranial phenotype, indicating a need for examination of non-cranial arteries when suspecting GCA.

Trends in the occurrence of ischaemic heart disease over time in rheumatoid arthritis: 1821 patients from 1972 to 2017.

OBJECTIVE: To evaluate trends of acute myocardial infarction (AMI) and ischaemic heart disease (IHD) in rheumatoid arthritis (RA) patients compared with the general population over time. METHOD: We performed a retrospective cohort study of 1821 RA patients diagnosed from 1972 to 2013. Aggregated counts of the total population of the same county (Hordaland, Norway) and period were used for comparison. Information on AMI and IHD events was obtained from hospital patient administrative systems or cardiovascular registries. We estimated incidence rates and excess of events [standardized event ratio (SER) with 95% confidence interval (CI)] compared with the general population by Poisson regression. RESULTS: There was an average annual decline of 1.6% in age- and gender-adjusted AMI incidence rates from 1972 to 2017 (p < 0.035). The difference in events (excess events) in RA patients compared with the general population declined on average by 1.3% per year for AMI and by 2.3% for IHD from 1972 to 2014. There were no significant excess AMI (SER 1.05, 95% CI 0.82-1.35) or IHD events (SER 1.02, 95% CI 0.89-1.16) for RA patients diagnosed after 1998 compared with the general population. CONCLUSION: Incidence rates and excess events of AMI and IHD in RA patients declined from 1972 to 2017. There were no excess AMI or IHD events in RA patients diagnosed after 1998 compared with the general population.

Major differences in medical and surgical treatment of psoriatic arthritis and rheumatoid arthritis: a comparison of two historic cohorts.

OBJECTIVES: Substantial changes in the handling of patients with inflammatory arthritis have occurred during the past half century. Polyarticular psoriatic arthritis (PsA) has been treated with the same synthetic disease-modifying anti-rheumatic drugs (DMARDs) as rheumatoid arthritis (RA), but for PsA there is less documentation regarding their effect. For biologic DMARDs, evidence of effect is more convincing. We have previously investigated the risk of orthopaedic surgery in patients with RA and PsA to see whether the change in treatment over time has improved the long-term outcome of inflammatory arthritis. For RA, patients diagnosed from 1999 onwards had a lower risk of surgery than patients diagnosed in earlier years. For PsA, the risk of surgery did not change similarly. We wished to compare RA patients to PsA patients with regard to medical and surgical treatment. METHOD: We compared a historic cohort of 1010 RA patients diagnosed in 1972-2009 to a historic cohort of 590 PsA patients diagnosed in 1954-2011. RESULTS: PsA patients received significantly less medical treatment both in the first year of disease and during the disease course. Risk of surgery during the disease course was lower for PsA than for RA (20% vs 31%). The risk of surgery in RA patients diagnosed from 1999 onwards was similar to that of PsA patients. CONCLUSIONS: PsA patients received less intensive treatment than RA patients. Their prognosis, regarding orthopaedic surgery, was also less severe. Contrary to RA, the change in treatment did not have beneficial effects regarding the risk of orthopaedic surgery.

Peptidylarginine deiminase 4 (PAD4) activity in early rheumatoid arthritis.

Objectives: Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes catalysing the conversion of arginine residues to citrulline, which may constitute a risk factor in rheumatoid arthritis (RA) pathogenesis. We investigated PAD activation by serum (PADAct) in early RA, and the associations between PAD activation and disease characteristics, treatment response, and progression of radiographic damage.Method: Sera from disease-modifying anti-rheumatic drug (DMARD)-naïve early RA patients (n = 225), classified according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria, and healthy controls (n = 63) were analysed for PAD4 activating capacity at 0, 3, 12, and 24 months using a high-performance liquid chromatography fluorometric method. Associations for PADAct were evaluated by Mann-Whitney U and chi-squared tests. Changes in PADAct levels were compared using the Wilcoxon signed-rank test.Results: PADAct positivity occurred in 42% (n = 95) of the patients and was more prevalent in anti-citrullinated protein antibody (ACPA)-positive vs ACPA-negative patients (47% vs 20%, p = 0.002), but not in rheumatoid factor (RF)-positive vs RF-negative patients (44% vs 38%, p = 0.49). PADAct-positive were younger than PADAct-negative patients [mean ± sd 48.7 ± 13.5 vs 53.2 ± 13.7 years, p = 0.011]. Median [25th, 75th percentile] PADAct levels were higher in patients than in controls (8768 [7491, 11 393] vs 7046 [6347, 7906], p < 0.0001) and decreased after initiation of DMARD treatment, but were not associated with treatment response or progression of radiographic damage after 2 years of follow-up.Conclusion: Serum capacity to activate PAD4 was associated with ACPA and RF positivity and earlier disease onset in early RA patients, and decreased after initiation of DMARD treatment, indicating that anti-PAD treatment could potentially be beneficial in RA.

Survival and death causes of patients with giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

BACKGROUND: Our objective was to determine the survival and causes of death in a large and well-characterized cohort of patients with giant cell arteritis (GCA). METHODS: This is a hospital-based, retrospective, observational cohort study including patients diagnosed with GCA in Western Norway during 1972-2012. Patients were identified through computerized hospital records using the International Classification of Diseases (ICD)-coding system. Medical records were reviewed. Patients were randomly assigned population controls matched on age, sex, and geography from the Central Population Registry of Norway (CPRN). Date and cause of death were obtained from the Norwegian Cause of Death Registry (NCoDR). The survival was analyzed using Kaplan-Meier methods with the Gehan-Breslow test and the causes of death using cumulative incidence and Cox models for competing risks. RESULTS: We identified 881 cases with a clinical diagnosis of GCA of which 792 fulfilled the American College of Rheumatology (ACR) 1990 classification criteria. Among those fulfilling the ACR criteria, 528 were also biopsy-verified. Cases were matched with 2577 population controls. A total of 490 (56%) GCA patients and 1517 (59%) controls died during the study period. We found no difference in the overall survival of GCA patients compared to controls, p = 0.413. The most frequent underlying causes of death in both groups were diseases of the circulatory system followed by cancer. GCA patients had increased risk of dying of circulatory disease (HR 1.31, 95% CI 1.13-1.51, p < 0.001) but lower risk of dying of cancer (HR 0.56, 95% CI 0.42-0.73, p < 0.001) compared to population controls. CONCLUSIONS: We found no difference in the overall survival of GCA patients compared to matched controls, but there were differences in the distribution of underlying death causes.

Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial.

BACKGROUND AND OBJECTIVES: The 52-week, randomized, double-blind, noninferiority, government-funded NOR-SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT-P13 was not inferior to continued treatment with infliximab originator. The NOR-SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT-P13 throughout the 78-week study period (maintenance group) versus patients switched to CT-P13 at week 52 (switch group). The primary outcome was disease worsening during follow-up based on disease-specific composite measures. METHODS: Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. RESULTS: Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per-protocol set). Adjusted risk difference was 5.9% (95% CI -1.1 to 12.9). Frequency of adverse events, anti-drug antibodies, changes in generic disease variables and disease-specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. CONCLUSION: The NOR-SWITCH extension showed no difference in safety and efficacy between patients who maintained CT-P13 and patients who switched from originator infliximab to CT-P13, supporting that switching from originator infliximab to CT-P13 is safe and efficacious.

Rifaximin alters gut microbiota profile, but does not affect systemic inflammation - a randomized controlled trial in common variable immunodeficiency.

Common variable immunodeficiency (CVID) patients have reduced gut microbial diversity compared to healthy controls. The reduced diversity is associated with gut leakage, increased systemic inflammation and ten "key" bacteria that capture the gut dysbiosis (dysbiosis index) in CVID. Rifaximin is a broad-spectrum non-absorbable antibiotic known to reduce gut leakage (lipopolysaccharides, LPS) in liver disease. In this study, we explored as a 'proof of concept' that altering gut microbial composition could reduce systemic inflammation, using CVID as a disease model. Forty adult CVID patients were randomized, (1:1) to twice-daily oral rifaximin 550 mg versus no treatment for 2 weeks in an open-label, single-centre study. Primary endpoints were reduction in plasma/serum levels of soluble (s) CD14, sCD25, sCD163, neopterin, CRP, TNF, LPS and selected cytokines measured at 0, 2 and 8 weeks. Secondary endpoint was changes in intra-individual bacterial diversity in stool samples. Rifaximin-use did not significantly change any of the inflammation or gut leakage markers, but decreased gut microbial diversity compared with no treatment (p = 0.002). Importantly, the gut bacteria in the CVID dysbiosis index were not changed by rifaximin. The results suggest that modulating gut microbiota by rifaximin is not the chosen intervention to affect systemic inflammation, at least not in CVID.

Correction to: Incidence of giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

Following publication of the original article [1], the authors reported an error.

Predictors for orthopaedic surgery in patients with rheumatoid arthritis: results from a retrospective cohort study of 1010 patients diagnosed from 1972 to 2009 and followed up until 2015.

OBJECTIVES: To investigate how patient characteristics, time of diagnosis, and treatment affect the need for orthopaedic surgery in patients with rheumatoid arthritis (RA). METHOD: We reviewed the medical history of 1544 patients diagnosed with RA at Haukeland University Hospital in Bergen, Norway, from 1972 to 2009, of whom 1010 (mean age 57 years, 69% women) were included in the present study. Relevant orthopaedic procedures were obtained from the Norwegian Arthoplasty Register and the hospital's administrative patient records. In total, 693 procedures (joint synovectomies 22%, arthrodeses 21%, prostheses 41%, and forefoot procedures 12%) were performed in 315 patients. Survival analyses were completed to evaluate the impact of different factors such as age, gender, radiographic changes, and year of diagnosis, on the risk of undergoing surgery. RESULTS: Patients diagnosed in 1972-1985 and 1986-1998 had a relative risk of undergoing surgery of 2.4 and 2.2 (p < 0.001), respectively, compared to patients diagnosed in 1999-2009. Radiographic changes at diagnosis and female gender were also significant risk factors. Anti-rheumatic medication was significantly different in the three time periods. CONCLUSION: Patients with a diagnosis in the early years had a greatly increased risk of having orthopaedic surgery performed. This is probably due to the year of diagnosis being a proxy for the type and intensity of medical treatment.

Incidence of giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons older than 50 years. The highest incidence rates of the disease have been reported in Scandinavian countries. Our objective was to determine the epidemiology of GCA in an expected high-incidence region during a 41-year period. METHODS: This is a hospital-based, retrospective, cohort study. Patients diagnosed with GCA in Bergen health area during 1972-2012 were identified through computerized hospital records (n = 1341). Clinical information was extracted from patients' medical journals, which were reviewed by a standardized method. We excluded patients if data were unavailable (n = 253), if the reviewing rheumatologist found GCA to be an implausible diagnosis (n = 207) or if the American College of Rheumatology (ACR) 1990 classification criteria for GCA were not fulfilled (n = 89). Descriptive methods were used to characterize the sample. Incidence was analyzed by graphical methods and Poisson regression. RESULTS: A total of 792 patients were included. The average annual cumulative incidence of GCA was 16.7 (95% CI 15.5-18.0) per 100,000 of the population ≥ 50 years old. The corresponding incidence for biopsy-verified GCA was 11.2 (95% CI 10.2-12.3). The annual cumulative incidence increased with time in the period 1972-1992 (relative risk (RR) 1.1, p < 0.001) but not in 1993-2012 (RR 1.0, p = 0.543). The incidence was higher in women compared to men (average annual incidence 37.7 (95% CI 35.8-39.6) vs. 14.3 (95% CI 13.2-15.5), p < 0.001) with women having a twofold to threefold higher incidence rate throughout the study period. Average annual incidence increased with age until the 7th decade of life in both sexes throughout the study period (2.8 (95% CI 2.3-3.3) for age <60, 15.5 (95% CI 14.4-16.8) for age 60-69, 34.5 (95% CI 32.8-36.4) for age 70-79 and 26.8 (95% CI 25.3-28.4) for age ≥80 years, p < 0.001 for all age adjustments). CONCLUSIONS: Our study confirms an incidence of GCA comparable to previous reports on Scandinavian populations. Our results show increasing incidence from 1972 through 1992, after which the incidence has levelled out.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.

The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.

Reduction in orthopaedic surgery in patients with rheumatoid arthritis: a Norwegian register-based study.

OBJECTIVES: The disease course of patients with rheumatoid arthritis (RA) has become milder in recent years. In this study we investigated the incidence of orthopaedic surgery in patients with RA. METHOD: From the Norwegian Arthroplasty Register we selected joint replacement procedures conducted during the years 1994-2012 (n = 11 337), and from the Norwegian Patient Register we obtained data on synovectomies (n = 4782) and arthrodeses (n = 6022) during 1997-2012. Using Poisson regression we analysed the time trends in the incidence of procedures performed. RESULTS: There was a significant decrease in the incidence of arthroplasty surgery (coefficient of -0.050 per year) and synovectomies (coefficient of -0.10) and a declining trend of arthrodeses in patients with RA in the study periods. The greatest reduction was found in procedures involving the wrist and hand. CONCLUSIONS: We found a decrease in orthopaedic surgery in patients with RA that continued into the biologic era and throughout the study period. The general increasing trend in the use of synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs) thus coincides with less joint destruction and an improved long-term prognosis of patients with RA.

Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9.

Patients with common variable immunodeficiency (CVID) have reduced numbers and frequencies of dendritic cells (DCs) in blood, and there is also evidence for defective activation through Toll-like receptors (TLRs). Collectively, these observations may point to a primary defect in the generation of functional DCs. Here, we measured frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) in peripheral blood of 26 CVID patients and 16 healthy controls. The results show that the patients have reduced absolute counts of both subsets. However, the decreased numbers in peripheral blood were not reflected in reduced frequencies of CD34(+) pDC progenitors in the bone marrow. Moreover, studies at the single cell level showed that DCs from CVID patients and healthy controls produced similar amounts of interferon-α or interleukin-12 and expressed similar levels of activation markers in response to human cytomegalovirus and ligands for TLR-7 and TLR-9. The study represents the most thorough functional characterization to date, and the first to assess bone marrow progenitor output, of naturally occurring DCs in CVID. In conclusion, it seems unlikely that CVID is secondary to insufficient production of naturally occurring DCs or a defect in their signalling through TLR-7 or TLR-9.

Bacterial findings in infected hip joint replacements in patients with rheumatoid arthritis and osteoarthritis: a study of 318 revisions for infection reported to the norwegian arthroplasty register.

High rates of Staphylococcus aureus are reported in prosthetic joint infection (PJI) in rheumatoid arthritis (RA). RA patients are considered to have a high risk of infection with bacteria of potentially oral or dental origin. One thousand four hundred forty-three revisions for infection were reported to the Norwegian Arthroplasty Register (NAR) from 1987 to 2007. For this study 269 infection episodes in 255 OA patients served as control group. In the NAR we identified 49 infection episodes in 37 RA patients from 1987 to 2009. The RA patients were, on average, 10 years younger than the OA patients and there were more females (70% versus 54%). We found no differences in the bacterial findings in RA and OA. A tendency towards a higher frequency of Staphylococcus aureus (18% versus 11%) causing PJI was found in the RA patients compared to OA. There were no bacteria of potential odontogenic origin found in the RA patients, while we found 4% in OA. The bacteria identified in revisions for infection in THRs in patients with RA did not significantly differ from those in OA. Bacteria of oral or dental origin were not found in infected hip joint replacements in RA.

Chemokines and common variable immunodeficiency; possible contribution of CCL19, CCL21 and CCR7 to immune dysregulation.

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 are associated with modulation of inflammatory responses. CVID patients have decreased proportions of CCR7(+) T cells in peripheral blood and we hypothesized a further dysregulation of CCL19/CCL21/CCR7 in CVID. Serum levels of CCL19 and CCL21 were compared in CVID patients and controls. T cell expression of CCR7 was related to clinical characteristics in CVID patients. Spleens extirpated from CVID patients were analysed for expression of CCL19, CCL21 and CCR7. Peripheral blood mononuclear cells (PBMC) from CVID patients and controls were analysed for cytokine response on stimulation with CCL19 and CCL21. The main findings were: (i) CVID patients have raised serum levels of CCL19 and CCL21 independently of features of chronic inflammation; (ii) CCL19 and CCR7 have similar expression in spleens from CVID patients and controls, while CCL21 is variably down-regulated in spleens from patients; (iii) T cell expression of CCR7 is particularly low in patients characterized by chronic inflammation in vivo; and (iv) PBMC from CVID patients had attenuated cytokine response to stimulation with CCL19 and CCL21. CVID patients have raised circulatory levels of CCL19 and CCL21, and an attenuated cytokine response to stimulation with these chemokines. Because CCR7, CCL19 and CCL21 are key mediators balancing immunity and tolerance in the immune system, the abnormalities of these mediators might contribute to the profound immune dysregulation seen in CVID.

Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus-infected patients with ongoing viral replication.

CCL19 and CCL21 and their receptor CCR7 are expressed constitutively within lymphoid organs, regulating lymphocyte homing. Recent studies suggest that these chemokines may have inflammatory properties. We hypothesized a role of CCL19/CCL21 in human immunodeficiency virus (HIV) infection by promoting inflammation. We examined the expression of CCL19 and CCL21 in mononuclear cells from peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) in HIV-infected patients before and during highly active anti-retroviral therapy (HAART). We also examined the ability of CCL19/CCL21 to promote inflammatory responses in these patients. PBMC from untreated HIV-infected patients (n = 29) released enhanced levels of CCL19 spontaneously compared with cells from controls (n = 20), particularly in those with symptomatic disease (n = 15, P < 0.01 versus controls). During HAART (n = 9), there was a decrease in the spontaneous CCL19 release and an increase in the phytohaemagglutinin-stimulated CCL19 release in both PBMC (P < 0.01) and BMMC (P < 0.05). In patients with enhanced HIV replication there was an increased proportion of inflammatory CD8(+)CCR7(-)CD45RA(-) T cells in peripheral blood [P < 0.01 and P < 0.05 versus controls, untreated (n = 9) and treatment failure (n = 8), respectively]. In vitro, CCL19/CCL21 promoted an inflammatory response in PBMC when accompanied by high viral load, irrespective of HAART. The HIV-tat protein significantly boosted the inflammatory effect of CCL19/CCL21 in PBMC. These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV-infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART.

CXCL16 in HIV infection - a link between inflammation and viral replication.

BACKGROUND: While some chemokines are thought to be protective in HIV-infected individuals by their ability to block HIV entry into T cells and macrophages, chemokines could also have harmful effects in HIV infection through their ability to promote inflammation. Here, we examined the regulation and the effects of CXCL16, a newly discovered chemokine of the CXC family, in HIV-infected patients. MATERIALS AND METHODS: We examined serum levels of CXCL16 in clinically well-defined subgroups of HIV-infected individuals both before (n = 62) and during HAART (n = 40) as well as in age- and sex-matched healthy controls (n = 30). We also examined the effects of CXCL16 on inflammatory and anti-inflammatory cytokines and HIV replication in peripheral blood mononuclear cells (PBMC). RESULTS: Our main and novel findings were: (i) HIV-infected patients had significant raised CXCL16 levels according to disease severity and progression. (ii) During HAART, the immunological improvement was accompanied by a modest increase in CXCL16 level. (iii) While soluble CXCL16 promoted an anti-inflammatory response in PBMC from those on successful HAART, it induced an inflammatory response and enhanced HIV replication in PBMC from those with high viral load irrespectively of ongoing HAART. (iv) Recombinant HIV-tat protein significantly increased CXCL16 release in THP-1 macrophages. CONCLUSIONS: Our findings suggest a complex interaction between CXCL16 and HIV, promoting both inflammatory and anti-inflammatory effects as well as HIV replication, partly dependent on accompanying HIV replication.