[Off-label biological therapies in patients with large vessel vasculitis and/or polymyalgia rheumatica : Safety and efficacy analysis of a nationwide German registry (GRAID2)]. / Off-label-Biologikatherapie bei Patienten mit Großgefäßvaskulitiden und/oder Polymyalgia rheumatica : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the safety and clinical outcome of biological therapies in patients with large vessel vasculitis (LVV) or polymyalgia rheumatica (PMR) refractory to standard of care therapy in a real-life setting in Germany. METHODS: GRAID 2 (German Registry in Autoimmune Diseases 2) is a retrospective, noninterventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy treated with an initial off-label biological between August 2006 and December 2013. The retrospective documentation comprised case history, diagnosis, course of disease including safety and overall efficacy. RESULTS: Data from 14 patients were collected, 11 with LVV (78.6%) and 3 with isolated PMR (21.4%). Ten patients were treated with tocilizumab (71.4%), while 3 patients received infliximab infusions (21.4%) and 1 patient was treated with rituximab (7.1%). All clinical as well as laboratory efficacy parameters improved substantially. After the first application, tolerability of biologicals was assessed as "very good"/"good" by the physicians in 92.3% of the patients. Altogether, 8 adverse events (AEs) occurred in 4 patients including 3 infections (1 urogenital infection, 2 diverticulitis) representing a rate of 23.6 infections per 100 patient-years. One of these infections (diverticulitis under infliximab treatment) was rated as serious AE, requiring ICU treatment representing a rate of serious AEs of 7.9 per 100 patient-years. No deaths occurred during the observation period. CONCLUSION: With known limitations of a retrospective database, the results of this survey confirm data of smaller case series and proof-of-concept studies and suggest a substantial response to biological therapies in patients with otherwise refractory LVV or PMR with no new safety signals.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis.

OBJECTIVE: To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests. METHODS: Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain. RESULTS: 23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP. CONCLUSION: Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction.

Assessment of autonomic function in a cohort of patients with ANCA-associated vasculitis.

OBJECTIVE: To assess symptoms and objective parameters of autonomic dysfunction (AD) in patients with ANCA-associated vasculitides. METHODS: Symptoms and objective parameters of AD were assessed in patients with ANCA-associated vasculitis and in age-matched healthy controls. Autonomic symptoms were explored by COMPASS31, a validated questionnaire addressing symptoms of six autonomic domains (orthostatic, vasomotor, secretomotor, gastrointestinal, pupillomotor, and bladder dysfunction). Objective autonomic parameters consisted of expiratory/inspiratory (E/I) ratio during the deep breathing test (DBT), blood pressure response to cold pressor test (CPT), and skin conductance changes during mental arithmetic. RESULTS: 27 patients and 27 healthy controls have been enrolled. 27 patients and 27 controls completed COMPASS31. 21 patients and 18 controls underwent objective autonomic testing. Vasculitis patients had significantly higher COMPASS31 total scores than controls (median 10.4 vs 3.0; p = 0.005). In the sub-domain analysis, significant differences were seen in the vasomotor and the bladder domain (p = 0.004; p < 0.001, respectively). No correlation was found between COMPASS31 score and disease duration, number of affected organs, or Birmingham vasculitis activity score (BVAS). There was no significant difference in any of the objective autonomic parameters between patients and controls. In a subgroup analysis, no difference in objective autonomic parameters was found between patients with active disease (n = 12) and patients in remission (n = 7). CONCLUSION: Patients with ANCA-associated vasculitides commonly have symptoms of autonomic dysfunction that are independent of disease duration and disease severity. However, at least in this single-centre observation, there was no evidence of impaired autonomic regulation in three autonomic function tests in vasculitis patients.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography.

OBJECTIVE: To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). METHODS: CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. RESULTS: In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. CONCLUSIONS: Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence 'inflammation-FD-new bone formation' was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

Gustatory and olfactory function in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity. METHOD: Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment. RESULTS: Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease. CONCLUSIONS: Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID).

OBJECTIVE: The objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. METHODS: The GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. RESULTS: Data from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.6 ± 7.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. CONCLUSION: With the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE.

[Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. / Biomarker in der Rheumatologie. Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually.

[New biologics and orally available compounds. What is still in the pipeline?]. / Neue Biologika und oral verfügbare neue Medikamente. Was ist noch in der Pipeline?

Biologics have revolutionized the treatment of inflammatory joint disease in the last decade. By precisely targeting and inhibiting inflammatory cytokines as well as the blockade of cells centrally integrated in the immune system, inhibition of inflammation has become possible which had been unthinkable before. The medical need to improve our current approach with biologics even more is based on three observations: (1) even though the clinical effect of a given biologic is evident in the majority of patients, not all show a satisfactory response, (2) the blockade of important mediators of the immune system bears the risk of infection and potentially malignant events and (3) all current biologics need to be administered parenterally. The present review describes several innovative biologics and low molecular weight compounds which are currently being investigated in clinical trials in patients suffering from inflammatory rheumatic conditions. Some of them may become a part of our growing armamentarium to treat these diseases which still represent a major burden to the patients and society.

[Quality of a multidisciplinary orthopaedic-rheumatological consultation]. / Qualität einer interdisziplinären Sprechstunde in der Rheumaorthopädie.

AIM: An interdisciplinary approach plays an important role in orthopaedic rheumatology. The aim of this study was to test the quality of an interdisciplinary consultation, which analyzed a pool of orthopaedic patients in terms of rheumatological disease. METHOD: Orthopaedic patients (n=100) were transferred to a multidisciplinary team of experts in a two-stage selection process. Patient data were examined with regard to diagnosis and therapy. A patient interview analyzed the course of disease and effects of the consultation. Patients were questioned on the development of pain, diagnostics and therapy as well as their general satisfaction. RESULTS: Rheumatological disease was diagnosed in 42% of patients, while specific anti-rheumatic therapy was started in 41%. An improvement in symptoms as a result of treatment was seen in 63% of cases. Patient examinations revealed an above-average level of satisfaction in 63% of patients. CONCLUSION: Interdisciplinary consultation led to improved and faster diagnosis and therapy of rheumatological diseases, which was positively evaluated by the pool of patients treated.

Information and participation in decision-making about treatment: a qualitative study of the perceptions and preferences of patients with rheumatoid arthritis.

OBJECTIVES: To elicit the perceptions and preferences of patients with rheumatoid arthritis regarding information and participation in treatment decision-making. To analyse the patients' narratives on the background of the ethical discourse on various approaches to treatment decision-making. DESIGN: In-depth interviews with themes identified using principles of grounded theory. PARTICIPANTS: 22 patients with long-standing rheumatoid arthritis. MAIN OUTCOME MEASURES: Qualitative data on patients' perceptions and preferences regarding information and participation in decision-making about treatment. RESULTS: Decision-making about treatment has been described by the patients as a process consisting of different stages with shifting loci of control and responsibility. Patients initially received one treatment recommendation and were not aware of alternative treatment options. Those participants in this study who wanted information about negative effects of a treatment cited "interest in one's own health" and the potential "use of information" as reasons for their preference. The physicians' expert knowledge and clinical experience regarding the effects of medication were cited as arguments by patients for a treatment recommendation. CONCLUSIONS: The patients' accounts of decision-making about treatment differ from models of physician-patient relationship that have been put forward in ethical discourse. These differences may be relevant with respect to the starting point of an ethical analysis of treatment decision-making. Patients' accounts with respect to a lack of information on treatment alternatives point to ethically relevant challenges regarding treatment decision-making in clinical practice.

Evaluation of a Novel Semi-Automated Ultrasound System for the Detection of Synovitis: A Prospective Study involving 45 Patients with Rheumatoid Arthritis.

Background: Arthrosonography has proven to be more sensitive and reliable for the detection of synovitis than clinical examination, but a comprehensive examination of small joints is time-consuming. The automated breast volume scanner (ABVS) has been developed to allow automatic and reproducible series of consecutive B-mode pictures of the female breast. Objectives: To analyze the comparability of ABVS and conventional manual ultrasonography (mUS) for the detection of synovitis in hands and feet of patients with rheumatoid arthritis (RA). Methods: 45 patients with early and established active rheumatoid arthritis were recruited for this trial. All subjects were assessed clinically and by manual (Esaote MyLab70) and automated ultrasound (ACUSON S2000™ ABVS). The wrists, the metacarpophalangeal and proximal interphalangeal joints of the hands and the metatarsophalangeal joints of the feet were examined. Results: A total of 2 340 joint aspects were examined with both methods. ABVS detected 291 grade 1, 124 grade 2, 100 grade 3 cases of synovitis (515 in total) compared to 267, 180 and 145 cases of synovitis (592 in total) with mUS. 242 erosions and 52 cases of tenosynovitis were found by ABVS compared to 244 erosions and 99 cases of tenosynovitis found by mUS. Kappa coefficients for the agreement between both methods ranged from 0.51 in PIP joints to 0.71 in MCP joints. The correlations with clinical parameters as well as interrater agreements were comparable for both ultrasound methods. Conclusion: Based on the results, ABVS seems to be a promising technology for the comprehensive and time-saving assessment of synovitis in RA.

Increased spontaneous in vitro apoptosis in double negative T cells of humans with a fas/apo-1 mutation.

We describe a 17 year old patient suffering from Canale-Smith syndrome (CSS) including chronic lymphadenopathy, splenomegaly, hypergammaglobulinemia and recurrent Coombs positive hemolytic crises. The parents are not consanguine, all other family members including two brothers are healthy. Peripheral blood mononuclear cells of the patient showed an increased rate of CD3 positive, CD4/CD8 double negative T-lymphocytes. In vitro assays showed these cells to have an increased rate of spontaneous apoptosis. Though expression of Fas/Apo-1 (CD95) and Fas-ligand (FasL) was detected on RNA- and protein level we found Fas/Apo-1 mediated apoptosis being significantly reduced. Sequencing of the fas/apo-1 gene proved the patient RT and his father to carry a point mutation at position 804 located in exon 9 (death domain) leading to an amino acid substitution. For developing of CSS, a fas/apo-1 mutation seems to be necessary but not sufficient. An additional independent mechanism must be involved in the pathogenesis of human lpr<-phenotype.

Initiation of HAART in drug-naive HIV type 1 patients prevents viral breakthrough for a median period of 35.5 months in 60% of the patients.

The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.

Positive influence of the Delta32CCR5 allele on response to highly active antiretroviral therapy (HAART) in HIV-1 infected patients.

The heterozygous 32 base pair deletion of the chemokine receptor 5 (Delta32CCR5) has been associated with a more benign course of HIV-1-infection. To study the influence of Delta32CCR5 on the response to antiviral therapy we analyzed the presence of Delta32CCR5 by PCR in PBMC from 107 randomly selected HIV-1-infected patients treated with HAART for at least three months. 24 of 107 patients were heterozygous for Delta32CCR5 (22.4%). Before initiation of HAART Delta32CCR5 heterozygous patients (d/w) did not differ from homozygous CCR5 wild-type patients (w/w) regarding viral load and CD4 counts. After a median treatment time on HAART of 17.5 months (d/w, range 6-31 months, p = n.s.) or 19 months (w/w, range 3-33 months) all 24 patients (100%) with the Delta32CCR5 mutation, but only 58/83 patients (69.9%) with wild-type CCR5 showed a suppression of HIV-1-viremia below 500 copies/ml (p = 0.0020). Furthermore, 20/24 (83.3%) of the Delta32CCR5 heterozygous patients achieved CD4 counts above 200/microliter, but only 57/83 (68.7%) of the patients homozygous for CCR5 wild-type (p = 0.011). Our data indicate that the presence of heterozygous Delta32CCR5 is associated with a better response to HAART suggesting that therapeutic strategies targeting CCR5 could be of value for a sustained suppression of HIV-1 by HAART.

Automatic face classification of Cushing's syndrome in women - a novel screening approach.

OBJECTIVE: Cushing's syndrome causes considerable harm to the body if left untreated, yet often remains undiagnosed for prolonged periods of time. In this study we aimed to test whether face classification software might help in discriminating patients with Cushing's syndrome from healthy controls. DESIGN: Diagnostic study. PATIENTS: Using a regular digital camera, we took frontal and profile pictures of 20 female patients with Cushing's syndrome and 40 sex- and age-matched controls. MEASUREMENTS: Semi-automatic analysis of the pictures was performed by comparing texture and geometry within a grid of nodes placed on the pictures. The leave-one-out cross-validation method was employed to classify subjects by the software. RESULTS: The software correctly classified 85.0% of patients and 95.0% of controls, resulting in a total classification accuracy of 91.7%. CONCLUSIONS: In this preliminary analysis we found a good classification accuracy of Cushing's syndrome by face classification software. Testing accuracy is comparable to that of currently employed screening tests.

Differential role for IL-2 and IL-15 in the inhibition of apoptosis in short-term activated human lymphocytes.

Interleukin (IL)-15 is a newly described cytokine with properties similar to IL-2. Even though it does not share sequence homology with IL-2, both cytokines bind to the same receptor with the noted exception of a cytokine specific alpha-chain. In this study the authors compared IL-2 and IL-15 to determine their ability to rescue short term activated lymphocytes (phytohaemagglutinin stimulation of peripheral blood mononuclear cells for 6 days, followed by expansion in medium containing IL-2 for 2 days) from apoptotic cell death. The authors found that both IL-2 and IL-15 can inhibit induction of apoptosis in this experimental model with similar time and dose kinetics. On mRNA or protein levels induction of pro- and anti-apoptotic gene products like fasL, bcl-2, or bax with minor effects on fas/Apo-1 or bcl-XL was observed under culture conditions with both IL-2 and IL-15. Next, it was found that phytohaemagglutinin (PHA) blasts were less responsive (in terms of cellular proliferation and prevention from apoptosis) to IL-2 if signals through the alpha-chain were blocked, with no effect on beta-chain specific monoclonal antibodies (MoAb). By contrast, IL-15 was less effective in induction of cellular proliferation and prevention of apoptosis if IL-2R beta-chain specific MoAb were added to cell cultures. Testing intracellular signalling induced by IL-2 or IL-15, the authors found identical changes in tyrosine phosphorylation patterns in PHA blasts cultured in medium or under IL-2 or IL-15 stimulation. By contrast, they found consistent differences if PHA stimulated peripheral blood mononuclear cells (PBMC) were expanded in medium containing IL-15 (instead of IL-2). These IL-15 expanded PHA blasts showed a significantly increased percentage of apoptosis after growth factor withdrawal. Furthermore, IL-2 was more efficient than IL-15 in rescuing IL-15 expanded PHA blasts from apoptosis. In IL-15 expanded PHA blasts expression of IL-2R alpha-chain was lower than that in IL-2 expanded PHA blasts. A model presenting a differential role for IL-2 and IL-15 in inhibition of apoptosis in vivo is discussed.