Increasing incidence and prevalence of ANCA-associated vasculitis in Northern Norway.

OBJECTIVE: ANCA-associated vasculitides (AAV) have increased in prevalence since the 1980s. We aimed to investigate the incidence and prevalence of AAV during a 15-year period from 1999 to 2013 in Northern Norway, looking for variations during this period. METHODS: Patient records were retrieved from The Northern Norwegian Vasculitis Registry; in addition we searched all regional hospital databases. Patients diagnosed with AAV from 1999 through to 2013 were included. For prevalence data, patients residing in the area, but with AAV diagnosis prior to 1999, were also included. The diagnosis of AAV was based on the European Medicines Agency algorithm. RESULTS: We identified 140 cases; 88 were classified as granulomatosis with polyangiitis (GPA), 37 as microscopic polyangiitis (MPA) and 15 as eosinophilic granulomatosis with polyangiitis (EGPA). Adult (age ≥15 years) annual incidence rates per million were as follows: for GPA 15.6 (95% CI: 12.5, 19.2), MPA 6.5 (95% CI: 4.6, 9.0), EGPA 2.7 (95% CI: 1.5, 4.5) and overall AAV 24.7 (95% CI: 20.8, 29.2). Incidences of MPA and overall AAV showed an increasing trend (P < 0.05). Adult point prevalence rates per million in 2013 were 261 (95% CI: 213, 316) for GPA, 58.2 (95% CI: 36.9, 87.3) for MPA, 32.9 (95% CI: 17.5, 56.3) for EGPA and 351 (95% CI: 296, 416) for overall AAV. CONCLUSION: The incidence rate of GPA and the prevalence rates of GPA and EGPA are currently the highest reported. MPA increased significantly from a prior low incidence. The overall AAV annual incidence and prevalence are still increasing.

Staphylococcus Aureus carriage and long-term Rituximab treatment for Granulomatosis with polyangiitis.

Objective. Chronic nasal carriage of Staphylococcus aureus (SA) increases the risk of relapse while Rituximab (RTX) is an effective agent for inducing and maintaining remission in patients with Granulomatosis with polyangiitis (GPA). We investigated whether B cell depletion and hypogammaglobulinemia that occur during RTX treatment increase the risk of chronic SA nasal carriage and subsequent disease flares, in GPA patients on long-term RTX maintenance therapy. Methods. Retrospective cohort study from a disease registry involving 29 GPA patients receiving RTX maintenance (median RTX dose of 9 g) during a median period of 49 months. Nasal swabs were collected prior and during RTX for a median of 3 and 9 swabs respectively. Persistent SA nasal carriage was defined with the presence of SA in more than 75% of nasal swabs. Results. SA nasal carriage did not change during RTX (p = 0.297). However, the rate of positive nasal swabs in GPA patients with transient SA nasal carriage during RTX maintenance increased from 0 prior RTX to 0.42 during RTX (p = 0.017). Persistent SA nasal carriage did not increase the risk of relapses (p = 0.844), of hypogammaglobulinemia (p = 0.122) and of severe infections (p = 0.144), but reduced the risk of chronic infections (p = 0.044). Change in SA carriage status during RTX did not influence the risk of relapses (p = 0.756), hypogammaglobulinamia (p = 0.474) and infections, either severe (p = 0.913) or chronic (p = 0.121). Conclusion. Long-term RTX maintenance therapy in GPA patients did not significantly influence SA nasal carriage status. Persistent SA carriage during long-term RTX treatment did not seem to increase the risk of relapses, but seemed to decrease the risk of hypogammaglobulinemia associated chronic infections.

Serum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis.

OBJECTIVE: Rituximab (RTX) is a B cell depleting agent used to induce and maintain remission in patients with granulomatosis with polyangiitis (GPA). As the development of hypogammaglobulinaemia in GPA patients on long-term RTX has not been addressed, the aim of this study was to investigate changes in immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term RTX maintenance therapy in GPA. METHODS: We used a single-centre cohort study of 29 GPA patients who received a median total cumulative dose of CYC of 17 g and were treated with 2 g RTX followed by re-treatment with either 2 g once annually, 1 g biannually or a combination of both. Ig levels were measured before each RTX re-treatment and hypogammaglobulinaemia was defined as levels of total immunoglobulin <6 g/l. RESULTS: During a median follow-up of 4 years, patients received a cumulative dose of 9 g RTX. While serum Ig levels decreased during RTX maintenance, the largest decrease occurred after the first infusion. Baseline Ig levels and the CYC cumulative dose predicted Ig levels, whereas the RTX cumulative dose did not. Eight patients (28%) discontinued RTX due to hypogammaglobulinaemia. Male gender [hazard ratio (HR) = 8.7, P = 0.044], kidney involvement (HR = 6.5, P = 0.083) and the 1 g biannual regimen (HR = 8.0, P = 0.024) increased the risk to discontinue RTX due to hypogammaglobulinaemia, whereas orbital-subglottic involvement (HR = 0.23, P = 0.080) decreased it. CONCLUSION: Hypogammaglobulinaemia occurred in one-quarter of GPA patients during RTX maintenance, independent of the RTX cumulative dose. Male gender, kidney involvement and the 1 g biannual RTX regimen constitute risk factors for severe hypogammaglobulinaemia necessitating withdrawal of RTX.

Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre.

OBJECTIVE: Rituximab (RTX) is an anti-CD20 antibody used successfully in granulomatosis with polyangiitis (GPA) for induction and maintenance of remission. Our study aims to evaluate the long-term efficacy and safety of chronic pre-emptive RTX therapy in GPA. METHODS: Retrospective study of 35 GPA patients treated with RTX between April 2004 and September 2011 for active disease and maintenance. RTX was initiated as two 1 g infusions 2 weeks apart and thereafter 2 g of RTX was readministered annually. Patients were followed for 47 (2-88) months. They received a median RTX dose of 8 g (2-13) over 5 (1-10) rounds. RESULTS: All patients had a clinical response, but nine relapses were recorded (flare rate of 6.6/100 patient-years). At last visit, 13 patients (37%) had discontinued RTX mainly due to hypogammaglobulinaemia (57%). Nine patients (26%) had severe infections (infection rate of 6.6/100 patient-years) and 10 patients (29%) had chronic infections. Risks factors for severe infections are a high cumulative dose of CYC, low CD4 cell count and a significant drop in total immunoglobulins after the first RTX round. Risks factors for chronic infections are low IgG level during RTX maintenance and possibly the cumulative RTX dose. CONCLUSION: Long-term pre-emptive RTX maintenance was efficacious in reducing the risk for relapse but was discontinued in one-third of the patients. The patients' net state of immunodeficiency under RTX changes over time as low immunoglobulin serum levels increased the risk for infections.

Successful treatment with bortezomib in type-1 cryoglobulinemic vasculitis patient after rituximab failure: a case report and literature review.

Type-1 cryoglobulinemic vasculitis (CV) and mixed CV differ in their pathophysiology, clinical expression and treatment response. We report one patient with type-1 cryoglobulinemic vasculitis and skin ulcers that had remained active despite treatment with a variety of immunomodulating drugs including rituximab. The patient had a past medical history of non-Hodgkin lymphoma 10 years after CV onset for which she went into complete remission. The patient developed subsequent hematological anomalies in the serum and in the bone marrow without a definite diagnosis of myeloma. The patient finally went into clinical remission of her cryoglobulinemic vasculitis after treatment with bortezomib and dexamethasone. But she did not achieve an immunological remission and still had positive cryoglobulinemia and serum kappa-type free light chains. This suggests that bortezomib, a proteasome inhibitor that inhibits angiogenesis and production of paraproteins, is a promising treatment in type-1 cryoglobulinemic vasculitis.

The economic burden of TNFα inhibitors and other biologic treatments in Norway.

OBJECTIVE: Costly biologic therapies have improved function and quality of life for patients suffering from rheumatic and inflammatory bowel diseases. In this survey, we aimed to document and analyze the costs. METHODS: In 2008, the total costs of tumor necrosis factor alpha inhibitors and other biologic agents in Norway were registered prospectively. In addition to costs, the pattern of use in the four Norwegian health regions was analyzed. The expenses were calculated in Norwegian krone and converted into Euros. RESULTS: The pattern of use was similar in all four regions, indicating that national guidelines are followed. Whereas the cost was similar in the southeast, western, and central regions, the expenses per thousand inhabitants were 1.56 times higher in the northern region. This indicates that patients in the northern region experienced a lower threshold for access to these drugs. The gap in costs between trusts within northern Norway was about to be closed. The Departments of Rheumatology and Gastroenterology had the highest consumption rates. CONCLUSION: The total cost of biologic agents was significant. Northern Norway had among the highest consumption rates worldwide. This can partly be explained. Further exploration calls for a national registry for the use of these drugs.

Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth.

OBJECTIVE: To examine possible associations between chronic inflammatory arthritides and pregnancy outcomes with separate analyses of first and subsequent births before and after diagnosis. METHODS: Linkage of data from a registry of patients with chronic inflammatory arthritides and the Medical Birth Registry of Norway enabled a comparison of pregnancy outcomes in women with chronic inflammatory arthritides and pregnancy outcomes in reference subjects. Outcomes of first birth and subsequent births before and after diagnosis were analyzed separately. Associations between chronic inflammatory arthritides and the women's health during pregnancy and delivery as well as perinatal outcomes were assessed in logistic regression analyses with adjustments for maternal age at delivery and gestational age. RESULTS: We analyzed 128 first births and 151 subsequent births after diagnosis and 286 first births and 262 subsequent births before diagnosis in patients and compared them with first and subsequent births in reference subjects. Firstborn children of women diagnosed as having chronic inflammatory arthritides were more often preterm (odds ratio [OR] 1.85 [95% confidence interval (95% CI) 1.09-3.13]) and small for gestational age (OR 1.60 [95% CI 1.00-2.56]). They also had lower mean birth weight (P=0.01) and higher perinatal mortality (OR 3.26 [95% CI 1.04-10.24]). Birth by caesarean section (all classifications) was more frequent in patients than in reference subjects, and elective caesarean section was 2-fold more frequent in patients, both in first birth (OR 2.60 [95% CI 1.43-4.75]) and in subsequent births (OR 2.18 [95% CI 1.33-3.58]). No excess risks of clinical importance were observed prior to diagnosis of chronic inflammatory arthritides. CONCLUSION: Excess risks were related to first birth in women diagnosed as having chronic inflammatory arthritides, including a higher rate of perinatal mortality. A higher caesarean section rate was related to all patient deliveries. Mainly, pregnancy outcomes before diagnosis did not differ from those in reference subjects.

Fertility in women with chronic inflammatory arthritides.

OBJECTIVE: To compare fertility rates in women with RA, other chronic arthritides (OCAs) and JIA with reference women from the general population. METHODS: Each woman from a Norwegian patient registry was matched by year of birth with 100 reference women randomly selected from the National Population Registry. Data linkage of patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring in patients and references until October 2007, and indirectly also nulliparous (childless) women. Groups were compared with Mann-Whitney U-test for continuous variables and chi-squared tests for categorical variables. Poisson regression analysis was applied to calculate relative fertility rates in the diagnostic groups vs references. RESULTS: Among 631 patients 849 children were registered in MBRN. Of these, 289 children (34.0%) were born after time of diagnosis vs 44.3% in references. Altogether, 206 of 631 patients (32.6%) were nulliparous vs 26.4% in references (P < 0.001). Among RA patients, 28.4% (96 of 338) were nulliparous vs 24.5% in references (P = 0.09), 30.7% (67 of 218) in OCA patients vs 24.5% in references (P = 0.03) and 57.3% (43 of 75) in JIA patients vs 40.9% in references (P = 0.004). Adjusted relative fertility rates in RA, OCA and JIA after diagnosis were 0.88, 0.84 and 0.84, respectively, compared with references. CONCLUSION: A higher proportion of women with chronic inflammatory arthritides were nulliparous compared with references, and relative fertility rates were reduced in all patient groups.

B-lymphocyte activating factor levels are increased in patients with Wegener's granulomatosis and inversely correlated with ANCA titer.

Circulating autoantibodies against neutrophils (ANCA) are a distinctive finding in patients with Wegener's granulomatosis (WG). B-lymphocyte activating factor (BAFF) promotes autoantibody production by increasing B cell survival and proliferation. We investigated serum BAFF levels (s-BAFF) in a WG patient cohort in relation to ANCA titers and disease activity. Baseline data were obtained in twenty-two WG patients (55% female, age 44 years, disease duration 1 year). S-BAFF was determined by capture ELISA and associations between s-BAFF, clinical (Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI) and Disease Extent Index (DEI)) and biochemical (C-reactive protein (CRP), IgG and ANCA) disease measures were analysed in a cross sectional as well as longitudinal analysis. S-BAFF was increased in WG patients compared to healthy controls (1.8 vs. 0.55 ng/ml, p < 0.01). S-BAFF was higher in ANCA negative than ANCA-positive WG sera (2.16 vs. 1.29 ng/ml, p < 0.01), correlated independently and inversely with ANCA levels (Rs -0.48, p < 0.01) but did not correlate with CRP, BVAS, DEI or VDI scores. Individual s-BAFF profiles were stable over time in 68% of patients. The finding of a negative correlation between ANCA levels and s-BAFF that is independent of steroid treatment indicates that BAFF does not directly drive ANCA production in WG.

Effectiveness and retention rates of methotrexate in psoriatic arthritis in comparison with methotrexate-treated patients with rheumatoid arthritis.

OBJECTIVE: To examine the effectiveness and 2-year retention rates of methotrexate (MTX) in MTX naïve patients with psoriatic arthritis (PsA). METHODS: Data on 430 patients with PsA participating in an ongoing longitudinal observational multicentre study in Norway were analysed. 1218 MTX naïve patients with rheumatoid arthritis (RA) from the same study served as a reference population. Assessments included measures of disease activity (28 joint counts, acute phase reactants), health status and utility scores. Six-month effectiveness data were compared both by crude analyses and with adjustments for age, sex and the respective baseline values. Two-year drug survival was compared by Kaplan-Meier and Cox regression analyses. RESULTS: After 6 months of MTX treatment, both patients with PsA and those with RA improved in most disease activity measures and patient reported outcomes. In the adjusted analysis, patients with PsA tended to have less improvement, but changes were in the same range as in patients with RA. Two-year retention rates of MTX therapy in patients with PsA and RA were 65% and 66%, respectively, with only minor differences in reported reasons for discontinuation. Lower age, longer disease duration and higher Modified Health Assessment Questionnaire (MHAQ) score and patient global assessment were independent predictors of MTX termination within the first 2 years of treatment. CONCLUSION: In this real-life study, MTX treatment was associated with improvement in disease activity and health-related quality of life in patients with PsA after 6 months of treatment. Retention rates of MTX were similar in PsA and RA.

The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study.

OBJECTIVE: To compare the 1-year retention rates of anti-tumor necrosis factor alpha (anti-TNFalpha) medications in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) with complementary analyses of the effect on health status. METHODS: Our analyses comprised 847, 172, and 249 anti-TNFalpha treatment courses in patients with RA, PsA, and AS, respectively. Crude drug survival was compared and hazard ratios (HRs) for treatment termination were calculated with adjustments for age, sex, investigator's global assessment, and concomitant methotrexate (MTX). Adjusted changes in health-related quality of life (HRQOL) were compared among the groups. RESULTS: Unadjusted 1-year retention rates were 65.4%, 77.3%, and 77.5% in the RA, PsA, and AS groups, respectively. The adjusted HRs for treatment termination were 0.76 (95% confidence interval [95% CI] 0.53-1.07) for PsA versus RA and 0.66 (95% CI 0.47-0.92) for AS versus RA. High baseline disease activity and female sex were significantly associated with premature treatment termination, whereas concomitant MTX was associated with better drug survival. However, the impact of MTX was apparent for RA and PsA, but not for AS in stratified analyses. The improvements in HRQOL were superior in patients with PsA and AS compared with RA. CONCLUSION: Our results suggest that survival of anti-TNFalpha treatment is superior in AS and PsA patients compared with RA patients. Larger improvements in HRQOL in patients with spondylarthritides may contribute to the differences in drug survival. Concomitant MTX was associated with better retention rates in RA and PsA patients, but not AS patients.

Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies.

BACKGROUND: The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures. AIM: To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification. METHODS: A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener's granulomatosis, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener's granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener's granulomatosis were included to distinguish Wegener's granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise. RESULTS: A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted kappa = 0.886). CONCLUSION: The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.

Fatigue in patients with lupus is not associated with disturbances in cerebral blood flow as detected by SPECT.

OBJECTIVES: Fatigue is a common complaint in patients with systemic lupus erythematosus (SLE). We investigated whether focal or general disturbances of cerebral blood flow (CBF), as assessed by SPECT, were associated with the presence of fatigue in an unselected group of SLE patients. METHODS: Fifty-six patients were included. Mean age was 47.5 years (+/-12.7), mean disease duration 14.7 years (+/-8.9), and disease activity measured by SLE disease activity index (SLEDAI) was 5.7 (+/-5.4). Fatigue was assessed by the Fatigue Severity Scale (FSS) and CBF by Tc-99m-hexamethyl propylamine oxime (HMPAO)-SPECT. The images were read and processed quantitatively by a computer program using the primary visual cortex as reference region and > 15% CBF deviation as definition of abnormality. RESULTS: The mean FSS score was 4.6 (+/-1.8). SPECT revealed focal CBF disturbances in 17 patients (30.4 %). Generalized symmetrical CBF reductions were present in 32 patients (57.1 %). There were no significant associations between CBF disturbances in any region of the brain and the degree of fatigue. CONCLUSIONS: Fatigue in SLE patients is not related to focal or general CBF disturbances. Therefore, factors that do not influence blood flow seem responsible for the fatigue phenomenon.

Fatigue in patients with systemic lupus erythematosus: the psychosocial aspects.

OBJECTIVE: Studies to prove a relationship between fatigue and immunological, inflammatory, or other disease characteristics of systemic lupus erythematosus (SLE) have shown no consistent findings. To further elucidate the basis for fatigue in SLE, we examined the affective states, personality traits, and mental health status in an unselected group of patients with SLE. METHODS: Fifty-seven Caucasian patients with SLE were examined. Fatigue was measured by the Fatigue Severity Scale. Personality traits and psychological function were evaluated by the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), the affective states by Beck Depression Inventory, and mental health status by the General Health Questionnaire version 30 (GHQ-30). RESULTS: Fatigue was closely associated with high scores on subscales Depression (D-2) and Hysteria (Hy-3) on MMPI-2 (R2 = 0.31; p = 0.0002), as well as with high scores on BDI (R2 = 0.22; p = 0.0006) and GHQ (R2 = 0.33; p < 0.0001). CONCLUSION: Fatigue does not seem to be caused by any easily recognizable single or multiple factor(s) of an inflammatory or immunological state. Our results point to fatigue being a multifaceted phenomenon where several psychosocial factors are strongly related, and indicate that fatigue is part of a complex response to chronic disease.

Baseline features and initial treatment as predictors of remission and relapse in Wegener's granulomatosis.

OBJECTIVE: To describe the course of disease activity and determine predictors of remission and relapse in a population based cohort of patients with Wegener's granulomatosis (WG). METHODS: Retrospective cohort study of 56 patients (median age 50 yrs) followed for 42.5 months. Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS-1) and permanent organ damage by Vasculitis Damage Index (VDI). Induction therapy consisted of prednisolone (Pred) 0.5-1 mg/kg and cyclophosphamide (CYC) daily orally 2 mg/kg (19 patients) or intravenous pulses 15 mg/kg every 2nd week (32 patients). Baseline clinical and laboratory features and cumulative treatment during the first 6 months were recorded. Multiple Cox and logistic regression analyses were used to find risk factors for remission and relapse. RESULTS: All patients surviving > 1 month achieved either complete (85%) or partial remission (15%). Higher baseline BVAS-1 increased the likelihood of achieving complete remission [BVAS-1 > 23, relative hazard (RH) 2.94, 95% confidence interval (CI) 1.48-5.85]. Relapse occurred in 31 patients (60%) after a median period of 18 months. The risk of relapse was increased in patients having received < 10 g CYC during the first 6 months (RH 2.83, 95% CI 1.33-6.02), in patients having received Pred > 20 mg/day for < 2.75 months (RH 2.41, 95% CI 1.12-5.21), and in patients with initial heart involvement (RH 2.87, 95% CI 1.09-7.58). A higher Pred dose during the first 6 months was associated with severe infections. Therapy resistance (no complete remission) was associated with baseline organ damage (VDI increase by 1, OR 1.53, 95% CI 1.03-2.27). CONCLUSION: Initial high disease activity increased and the presence of baseline organ damage reduced the likelihood for complete remission in WG. Relapse was associated with less intensive initial treatment in terms of lower CYC doses and shorter time taking Pred > 20 mg/day.

Small nerve fiber involvement in systemic lupus erythematosus: a controlled study.

OBJECTIVE: To determine if patients with systemic lupus erythematosus (SLE) may have a peripheral neuropathy involving unmyelinated and small, myelinated nerve fibers, by immunostaining epidermal nerve fibers (ENF) in skin biopsy samples for the panaxonal marker, protein gene product 9.5 (PGP 9.5). METHODS: Fifteen consecutive and nonselected SLE patients and 15 age- and sex-matched controls were included in the study. The age of the patients ranged from 25 years to 65 years, with a mean +/- SD age of 47.3 +/- 10.2 years and a disease duration of 2-28 years (mean +/- SD 14.8 +/- 8.6 years). Two 3-mm skin biopsy samples were obtained with a punch needle approximately 10 cm superior to the lateral malleolus of the right leg and immunostained with 0.1% rabbit polyclonal antibodies to human PGP 9.5. The number of ENF per millimeter was counted and recorded as the mean +/- SD of counts in six 50-microm sections, 3 from each of the 2 biopsy samples. RESULTS: The mean number of ENF per mm in patients with SLE was 8.0 +/- 1.5 (range 5.0-9.9), while the matched controls had 12.2 +/- 3.8 ENF per mm (range 6.8-18.6) (P = 0.0006). CONCLUSION: This study indicates that a small fiber involvement in patients with SLE may be responsible for the prevalent neuropathic symptoms and impaired warm sense that is observed in such patients.

Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics.

OBJECTIVE: To determine if fatigue in patients with systemic lupus erythematosus (SLE) is associated with levels of serum cytokines, antiphospholipid antibodies (aPL), or other disease features. METHODS: In a cross sectional study 57 Caucasian patients with SLE were subjected to clinical neurological examination and cerebral magnetic resonance imaging (MRI). Fatigue was evaluated by Fatigue Severity Scale (FSS) and disease activity by SLE Disease Activity Index (SLEDAI). Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 2 (IL-2), IL-6, IL-10, transforming growth factor-beta (TGF-beta), interferon-alpha (IFN-alpha), anticardiolipin antibody (aCL) IgG and IgM, as well as anti-beta2-glycoprotein I antibody (anti-beta2-GPI) IgG and IgM were analyzed by ELISA. RESULTS: Four of 5 patients with SLE had fatigue (FSS score > or = 3). There were no associations between fatigue and any sociodemographic variables, medication for SLE, disease activity, cerebral infarcts, serum cytokines, aCL or beta2-GPI antibodies, or any routine hematological, biochemical, or immunological tests. CONCLUSION: Fatigue is a common phenomenon in patients with SLE. There is no association to disease activity or other markers of disease or inflammation. Fatigue is a complex phenomenon, and cytokine involvement in brain tissue not reflected by cytokine serum concentrations in this study cannot be excluded. Alternatively, psychosocial factors may well be the dominant predictor of fatigue in patients with SLE.