Involving patients who attempt suicide in suicide prevention: a focus groups study.

The aim of this study is to gain insight into the individual experiences of patients who attempt suicide in order to better understand the reasons for and emotions behind a suicide attempt, thus also gaining insight, through the patients' own input, into the risk and protective factors which might influence possible repeat attempts and the attitude towards the assistance they receive. Two focus groups were conducted involving 17 participants, all hospitalized at the time of research for attempting suicide. The patients proved themselves competent, even expert in indicating reasons for, risk factors of and prevention strategies for suicide. The main findings suggest that the relational factor represents a key point both as a trigger for the suicide attempt and for promoting the communication of the intent or for preventing a repeat suicide attempt, as interpersonal relationships and an empathic environment were, in essence, what was perceived as therapeutic and protective and enabled the expression of thoughts and self-understanding. Accordingly psychotherapy, non-specific relationship 'monitoring' after discharge and tutored self-help groups have been suggested. Feasibility and implementing methods as well as the role of the nurse for such interventions were discussed.

Results of a phase I study in patients suffering from secondary-progressive multiple sclerosis demonstrating the safety of the amino acid copolymer PI-2301 and a possible induction of an anti-inflammatory cytokine response.

PI-2301 is an immunomodulator that could be an alternative therapy for MS. A placebo-controlled, multiple-ascending dose, double-blind study was performed in patients with secondary-progressive MS. Treatment was given subcutaneously once weekly for 8 weeks, followed by a 4-week open-label treatment period with active drug. The most common adverse event was transient injection site reactions. Non-significant trend for increases in serum levels of IL-3, IL-13, and CCL22 over time were suggestive of a beneficial T(H)2 immune response in subjects dosed with PI-2301 at 3 and 10 mg. MRI data indicated a non-significant trend for a reduction of lesion numbers in subjects treated with 1 and 3 mg PI-2301.

Multicenter randomised trial on home-based telemanagement to prevent hospital readmission of patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) remains a common cause of disability, death and hospital admission. Several investigations support the usefulness of programs of disease management for improving clinical outcomes. However, the effect of home-based telemanagement programs on the rate of hospital readmission is still unclear and the cost-effectiveness ratio of such programs is unknown. The aim of the study was to determine whether a home-based telemanagement (HBT) programme in CHF patients decreased hospital readmissions and hospital costs in comparison with the usual care (UC) follow-up programme over a one-year period. METHODS AND RESULTS: Four hundred-sixty CHF patients (pts), aged 57+/-10 years were randomised to two management strategies: 230 pts to HBT programme and 230 pts to UC programme. The HBT pts received a portable device, transferring, by telephone, a one-lead trace to a receiving station where a nurse was available for interactive teleconsultation. The UC pts were referred to their primary care physicians and cardiologists. The primary objective of the study was one-year hospital readmission for cardiovascular reasons. During one-year follow-up 55 pts (24%) in HBT group and 83 pts (36%) in UC group had at least one readmission (RR=0.56; 95% CI: 0.38-0.82; p=0.01). After adjusting for clinical and demographic characteristics, the HBT group had a significantly lower risk of readmission compared with the UC group (HR=0.50, 95% CI: 0.34-0.73; p=0.01). The intervention was associated with a 36% decrease in the total number of hospital readmissions (HBT group: 91 readmissions; UC group: 142 readmissions) and a 31% decrease in the total number of episodes of hemodynamic instability (101 in HBT group vs 147 in UC group). The rate of hearth failure-related readmission was 19% (43 pts) in HBT group and 32% (73 pts) in UC group (RR=0.49, 95% [CI]: 0.31-0.76; p=0.0001). No significant difference was found on cardiovascular mortality between groups. Mean cost for hospital readmission was significantly lower in HBT group (euro 843+/-1733) than in UC group (euro 1298+/-2322), (-35%, p<0.01). CONCLUSIONS: This study suggests that one-year HBT programme reduce hospital readmissions and costs in CHF patients.

Cardiac event recording yields more diagnoses than 24-hour Holter monitoring in patients with palpitations.

Palpitation is a common symptom that sometimes results from a substantial cardiac arrhythmia. We compared the diagnostic yield of trans-telephonic event monitors with those of Holter monitoring in patients with intermittent palpitations. In all, 310 patients were randomly assigned to receive an event recorder or 24-hour Holter monitoring. Event recorders were used for seven days or until two recordings were obtained while symptoms occurred. The main end-point was an electrocardiogram (ECG) recorded during symptoms. The patients with palpitation recorded the one-lead ECG trace and sent it to a telemedicine call centre, where a nurse responded. There were 119 symptomatic patients in the event recorder group and 74 in the Holter group. The total costs were 6019 for event recording and 9605 for Holter monitoring. The average costs were 51 per symptomatic patient detected by event recorder monitoring and 130 per symptomatic patient detected by Holter monitoring. More patients therefore received a clear diagnosis, and more quickly, when using event recording than with Holter monitoring. For this reason, event recorders are preferable to Holter monitors for patients with palpitations.

Effect of home-based telecardiology on chronic heart failure: costs and outcomes.

Chronic heart failure (CHF) remains a common cause of disability. We have investigated the use of home-based telecardiology (HBT) in CHF patients. Four hundred and twenty-six patients were enrolled in the study: 230 in the HBT group and 196 in the usual-care group. HBT consisted of trans-telephonic follow-up and electrocardiogram (ECG) monitoring, followed by visits from the paramedical and medical team. A one-lead ECG recording was transmitted to a receiving station, where a nurse was available for reporting and interactive teleconsultation. The patient could call the centre when assistance was required (tele-assistance), while the team could call the patient for scheduled appointments (telemonitoring). The one-year clinical outcomes showed that there was a significant reduction in rehospitalizations in the HBT group compared with the usual-care group (24% versus 34%, respectively). There was an increase in quality of life in the HBT group (mean Minnesota Living Questionnaire scores 29 and 23.5, respectively). The total costs were lower in the HBT group (107,494 and 140,874, respectively). The results suggest that a telecardiology service can detect and prevent clinical instability, reduce rehospitalization and lower the cost of managing CHF patients.

Telecardiology: one-lead electrocardiogram monitoring and nurse triage in chronic heart failure.

We investigated a home-based intervention based on telecardiology in patients with chronic heart failure (CHF). Two hundred and thirty CHF patients, aged 59 years (SD 9), in stable condition and with optimized therapy were enrolled. The programme consisted of trans-telephonic follow-up and electrocardiogram (ECG) monitoring followed by visits from a paramedical and medical team. The patient could call the centre when required (tele-assistance), while the team could call the patient at prescheduled times (telemonitoring). During the first 12 months, there were 3767 calls (873 ad hoc and 2894 scheduled calls). There were 648 events, including 126 episodes of asymptomatic hypotension and 168 episodes which were not due to cardiological symptoms. No actions were taken by the nurse after 2417 calls (64%). A change in therapy was suggested after 418 calls, hospital admission in 62 patients, further investigations for 243 patients and a consultation with the general practitioner in 41 patients. A total of 2303 one-lead ECG recordings were received (10 per patient); 126 recordings (6%) were diagnosed as pathological in comparison with the baseline one. The one-lead ECG recording was used for titration of beta-blockers in 79 patients (mean dosage 38 mg vs 42 mg, P<0.01). Home telenursing could be an important application of telemedicine and single-lead ECG recording seems to offer additional benefit in comparison with telephone follow-up alone.

HLA haplotypes and susceptibility to rheumatoid arthritis. More than class II genes.

Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Complete characterization of the DQB1 first exon polymorphism.

Here we report an additional source of variation resulting from genetic polymorphism in HLA-DQbeta1 genes, namely, allelic diversity in the first exon of the HLA-DQB1 locus, which encodes the leader peptide sequence. Six different variants, including a novel polymorphic site, were detected among the DBQ1 haplotypes.

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region.

BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.

Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors.

OBJECTIVES: (a) To describe the clinical characteristics of acute sarcoid arthritis and the diagnostic value of its presenting clinical features; (b) to evaluate whether disease onset is seasonal; and (c) to evaluate whether smoking behaviour or the presence of HLA class II alleles is a risk factor for the disease. METHODS: 579 consecutive patients with recent onset arthritis who had been newly referred to a rheumatology outpatient clinic were included in a prospective cohort study. The presenting clinical features, the smoking behaviour, and the results of HLA-DQ and HLA-DR DNA typing of 55 patients with sarcoid arthritis, 524 patients with other arthritides of recent onset, and samples of the normal population were compared. RESULTS: In all cases the disease showed a self limiting arthritis and overall good prognosis. The diagnostic ability of a combination of four clinical features--symmetrical ankle arthritis, symptoms of less than two months, age below 40 years, and erythema nodosum--was exceptionally high. When test positivity is defined as the presence of at least three of four criteria the set rendered a sensitivity of 93%, a specificity of 99%, a positive predictive value of 75%, and a negative predictive value of 99.7%. The disease clustered in the months March-July. The disease was negatively associated with smoking (odds ratio (OR) 0.09; 95% confidence interval (95% CI) 0.02 to 0.37) and positively associated with the presence of the DQ2 (DQB1*0201)-DR3 (DRB1*0301) haplotype (OR 12.33; 95% CI 5.97 to 25.48). CONCLUSION: The disease entity acute sarcoid arthritis has highly diagnostic clinical features. The seasonal clustering, the protective effect of smoking, and the association with specific HLA class II antigens support the hypothesis that it results from exposure of susceptible hosts to environmental agents through the lungs.

Early and aggressive treatment of rheumatoid arthritis patients affects the association of HLA class II antigens with progression of joint damage.

OBJECTIVE: The presence of certain HLA class II antigens is strongly associated with the progression of joint destruction in rheumatoid arthritis (RA). Such antigens may be more effective than other class II antigens in inducing the formation of autoreactive T cells after presentation of (auto)antigens. We investigated whether early and aggressive treatment with disease-modifying antirheumatic drugs could modify this relationship. METHODS: We analyzed data from 2 studies of patients with early RA treated according to different strategies. The first study consisted of 2 cohorts, one (n = 109; median disease duration before treatment 4 months) was treated according to the pyramid strategy (initial nonsteroidal antiinflammatory drugs, followed by chloroquine [CQ] or sulfasalazine [SSZ] when necessary), and the other (n = 97; median disease duration before treatment 2 weeks) was immediately treated with CQ or SSZ. The second study comprised 155 patients (median disease duration 4 months) from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial, in which patients were randomly assigned to combination treatment with step-down prednisolone, methotrexate (MTX), and SSZ (n = 76) or with SSZ alone (n = 79). Prednisolone and MTX dosages were tapered and stopped after 28 and 40 weeks, respectively. The extent of joint damage was measured by the modified Sharp method. RESULTS: In the pyramid treatment cohort, the median increase in Sharp score after 2 years was 12 in patients positive for the shared epitope (SE) and 1 in SE- patients. In the immediate treatment cohort, the median increase was 3 in SE+ patients and 2 in SE- patients. In the SSZ group of the COBRA study, the median increase in Sharp score after 1 year was 11 in DR4+ patients and 3 in DR4- patients. In the combination treatment group, the median increase was 4 in DR4+ patients and 2 in DR4- patients. Significance was confirmed by multiple regression using log-transformed scores. CONCLUSION: Early and aggressive antirheumatic drug treatment affects the association of HLA class II alleles with progression of joint damage in RA.

Influence of HLA polymorphism on persistent remission in rheumatoid arthritis.

BACKGROUND: Several studies have reported an association between the presence of the shared epitope (SE) and susceptibility to rheumatoid arthritis (RA). Recent studies have shown that certain HLA-DRB1 alleles in combination with predisposing DQB1 and DQA1 alleles may protect against the development of RA. This model is known as the rheumatoid arthritis protection (RAP) hypothesis. OBJECTIVE: To determine the distribution of HLA-DRB1 and DQB1/DQA1 alleles in a cohort of patients with RA in remission and to determine the association between these HLA alleles and the persistence of remission. PATIENTS AND METHODS: HLA-DRB1 and DQB1 typings were performed in 167 patients with RA in remission, defined according to the American College of Rheumatology criteria. The disease course, as defined by the persistence of remission during a follow up of two years, was compared between subgroups. According to the RAP hypothesis patients were divided into three subgroups: patients carrying predisposing DQ alleles, patients carrying predisposing alleles in combination with protective alleles (DQ(RA+)/DERAA phenotype), and patients lacking the predisposing alleles. According to the SE hypothesis, patients were divided into three subgroups based on whether they were carrying two, one, or no predisposing alleles (SE alleles). RESULTS: Predisposing DQ alleles along with a DERAA-bearing allele were present in 14 (8%) of the 167 patients. At least one SE allele was present in 116 (69%) patients; 34 of them (20%) were carrying two copies. The disease course was not significantly different between the subgroups according to the SE and RAP hypothesis, respectively. CONCLUSION: The frequency of DQ(RA+)/DERAA combinations and of SE alleles in patients with RA clinically in remission was similar to that found in other RA populations. Persistent remission of RA was not associated with any particular HLA subtypes, indicating that HLA typing is not useful for predicting persistent clinical remission.

[Potential cost reductions for the National Health Service through a telecardiology service dedicated to general practice physicians]. / Riduzione potenziale dei costi per il Servizio Sanitario Nazionale mediante un servizio di telecardiologia dedicato ai medici di medicina generale.

BACKGROUND: Rising health care costs resulted in increasing pressure on the health care system and stimulated new strategies for improving the efficiency of care. A telecardiology service provides a useful support to general practitioners in the management of cardiac patients and contributes to the optimization of health care costs in terms of appropriateness of hospital admission and diagnostic testing. The aim of our study was to evaluate the reduction in the number of referrals to the Emergency Department and to cardiological evaluation resulting from the employment of a telecardiology service by general practitioners. METHODS: Eight hundred and ninety-one consecutive calls arrived to the receiving station of the telecardiology service were analyzed. One hundred and fifty general practitioners received a portable electrocardiographer (Card-Guard 7100, Rehovot, Israel) transferring, by a mobile or fixed telephone, a 12-lead ECG to a receiving station, where a cardiologist was available for reporting and for interactive teleconsultation. At the onset of the phone call, a question was asked to the general practitioner: "What would you have done without the telecardiology service?". The possible answers were: "No actions"; "Referral to the Emergency Department"; "Cardiological consultancy"; "Further investigations". Then we collected the history, risk factors, symptoms and therapy of the patients; the general practitioner sent the ECG tracing by phone. RESULTS: Eight hundred and ninety-one patients were enrolled (402 males, 489 females, mean age 59 +/- 19 years); 465 (52%) patients were symptomatic; 36.4% had no evidence of previous cardiac disease, 35.1% had systemic hypertension, 10.6% had ischemic cardiac disease, 3.7% had atrial fibrillation, and 11.9% other diseases. ECG was normal in 55%. The general practitioners would have sent to the Emergency Department 106 patients (11.9%), and requested further investigations in 717 patients (80.5%). The cardiologist of the telecardiology service solved the problems of the general practitioners in 657 cases (73.7%), sent 56 patients (6.3%) to the Emergency Department, and asked for further investigations in 178 patients (20%), with a reduction of 47% of Emergency Department admission (p < 0.001) and of 95% of further investigations (p < 0.0001) respectively. The cost analysis showed a reduction, between the two modalities, varying from Itl 22,760,000 and Itl 140,060,000 for 891 calls. CONCLUSIONS: Telemedicine is a useful tool for the support of general practitioners' daily activity, with a possible cost reduction due to increased appropriateness of hospital admission and of diagnostic testing.

Human leukocyte antigen-DQ and DR polymorphisms predict rheumatoid arthritis outcome better than DR alone.

Conflicting data have been published on the value of the shared epitope (SE) hypothesis in predicting disease outcome in rheumatoid arthritis (RA). Recently we have proposed an alternative hypothesis, referred to as the RA protection (RAP) model. In this model, the HLA-DQ loci carry predisposition while HLA-DRB1 alleles encoding the motif DERAA provide protection against severe RA. In the present study, we have compared the respective values of the models in predicting both remission and erosions in early RA patients. We made use of an early arthritis clinic in which 158 RA patients and 138 patients with undifferentiated arthritis were enrolled. Patients were typed for HLA-DQ and -DR using high resolution DNA typing methods. Homozygosity for predisposing HLA-DQ alleles was associated with no remission and high erosion score. The presence of DERAA-bearing DRB1 alleles was negatively associated with erosions in otherwise predisposed individuals and increased the chance of being in remission. We found that the RAP model was significantly better than the SE model in predicting remission rate and erosion scores at one and two years in early RA patients. We conclude that HLA polymorphism does not only affect RA susceptibility, but also protects against severe disease at early stage.

Six microsatellite markers on the short arm of chromosome 6 in relation to HLA-DR3 and TNF-308A in systemic lupus erythematosus.

Differences in allelic distribution at loci surrounding the human HLA-DRB1 and tumor necrosis factor (TNF) genes have been observed in association with systemic lupus erythematosus (SLE). We investigated whether the association of HLA-DRB1*0301 (HLA-DR3) and TNF-308A with SLE could be attributed to polymorphic markers in the chromosomal region encompassed by HLA-DRB1 and HLA-C. Ninety-one consecutive Caucasian patients with SLE and 253 controls (organ donors) were typed for HLA-DRB1, microsatellites D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2 and the single nucleotide polymorphism at position -308 in the promoter of TNF. The independent contribution of alleles to disease susceptibility was estimated by cross-tabulation and multivariate logistic regression. Possession of TNF-308A was associated with susceptibility to SLE (odds ratio [95% confidence interval], 3.70 [2.24-6.11]). This remained present after stratification on possession of HLA-DR3 (pooled odds ratio, 2.53 [1.37-4.70]). Stratification revealed a possible association of possession of C1_2_5*192 with protection from SLE beyond the effects of HLA-DR3 and TNF-308A. A gene dosage effect was observed for -308A only (homozygotes, 7.75 [3.01-20.0], heterozygotes, 3.15 [1.85-5.37]). In multivariate analysis, possession of HLA-DR3, TNF-308A, and C1_2_5*192 remained independently associated with susceptibility to SLE (2.58 [1.29-5.18], 2.76 [1.43-5.31], and 0.26 [0.10-0.66], respectively). The association of possession of TNF-308A with susceptibility to SLE cannot be attributed to linkage to HLA-DR3 alone, nor to other polymorphic markers in the vicinity of the TNF gene. Further loci that are independently associated with SLE might be in the vicinity of marker C1_2_5.

Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF Registry).

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Distribution of HERV-LTR elements in the 5'-flanking region of HLA-DQB1 and association with autoimmunity.

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.

Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients.

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.