Aids to management of headache disorders in primary care (2nd edition) : on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign against Headache.

The Aids to Management are a product of the Global Campaign against Headache, a worldwide programme of action conducted in official relations with the World Health Organization. Developed in partnership with the European Headache Federation, they update the first edition published 11 years ago.The common headache disorders (migraine, tension-type headache and medication-overuse headache) are major causes of ill health. They should be managed in primary care, firstly because their management is generally not difficult, and secondly because they are so common. These Aids to Management, with the European principles of management of headache disorders in primary care as the core of their content, combine educational materials with practical management aids. They are supplemented by translation protocols, to ensure that translations are unchanged in meaning from the English-language originals.The Aids to Management may be individually downloaded and, as is the case for all products of the Global Campaign against Headache, are available without restriction for non-commercial use.

European Headache Federation consensus on technical investigation for primary headache disorders.

The diagnosis of primary headache disorders is clinical and based on the diagnostic criteria of the International Headache Society (ICHD-3-beta). However several brain conditions may mimic primary headache disorders and laboratory investigation may be needed. This necessity occurs when the treating physician doubts for the primary origin of headache. Features that represent a warning for a possible underlying disorder causing the headache are new onset headache, change in previously stable headache pattern, headache that abruptly reaches the peak level, headache that changes with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre, first onset of headache ≥50 years of age, neurological symptoms or signs, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding. All national headache societies and the European Headache Alliance invited to review and comment the consensus before the final draft. The consensus recommends brain MRI for the case of migraine with aura that persists on one side or in brainstem aura. Persistent aura without infarction and migrainous infarction require brain MRI, MRA and MRV. Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all TACs. For primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required. Because there is little and no good evidence the committee constructed a consensus based on the opinion of experts, and should be treated as imperfect.

Acquired Hemophilia in an Elderly Patient with Non-Small Cell Lung Cancer: a Case Report.

Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. We report here a case of AHA that occurred in the Department of Medicina D'Urgenza in Sant'Andrea Hospital in a patient with previous diagnosis of NSLC. The aim of this article is to allow a more comprehensive knowledge of AHA that both for the rarity and the poor literature is underdiagnosed; for all these reasons, it is important that different specialists, like emergency specialists, experts in internal medicine, hematologists, and oncologists, acquire a more complete knowledge of the clinical and laboratory features of this disease, allowing an early diagnosis crucial for the evolution of the coagulopathy.

OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation.

BACKGROUND: Risk factors for suicide are at least partially heritable and functional polymorphisms of targeted genes have been suggested to be implicated in the pathogenesis of this phenomenon. However, other studies examining the association between specific gene variants and suicide revealed inconsistent findings. We aims to evaluate the possible association between MAO-A3, CYP1A2*1F and GNB3 gene variants, hopelessness and suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. METHODS: 56 women were genotyped for MAO-A3, CYP1A2*1F and GNB3 gene variants. Participants were also assessed using Beck Hopelessness Scale (BHS), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A), and the Suicidal History Self-Rating Screening Scale (SHSS). RESULTS: Patients with higher total scores on affective dysregulated temperaments are more likely to have higher BHS (11.27+/=5.54 vs. 5.73+/=3.81; t19.20 = -3.57; p < 0.01) and higher SHSS total scores (4.79+/=3.31 vs. 1.05±2.31; t17.74 = -3.90; p < 0.001) than those with lower total scores. 67% of patients in the dysregulated group has BHS total scores >= 9 indicating high levels of hopelessness. No association was found between MAO-A3, CYP1A2*1F and GNB3 gene variants and suicidal risk as assessed by BHS and SHSS. CONCLUSIONS: This study did not sustain the association between MAO-A3, CYP1A2*1F and GNB3 gene variants and increased suicidal risk in patients with chronic migraine and affective temperamental dysregulation. Further studies investigating the gene-environment interaction or focusing on other genetic risk factors involved in suicidal behaviour are needed.  

Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS).

Migraine is a disabling neurological disease that affects 14.7 % of Europeans. Studies evaluating the economic impact of migraine are complex to conduct adequately and with time become outdated as healthcare systems evolve. This study sought to quantify and compare direct medical costs of chronic migraine (CM) and episodic migraine (EM) in five European countries. Cross-sectional data collected via a web-based survey were screened for migraine and classified as CM (≥15 headache days/month) or EM (<15 headache days/month), and included sociodemographics, resource use data and medication use. Unit cost data, gathered using publicly available sources, were analyzed for each type of service, stratified by migraine status. Univariate and multivariate log-normal regression models were used to examine the relationship between various factors and their impact on total healthcare costs. This economic analysis included data from respondents with migraine in the UK, France, Germany, Italy, and Spain. CM participants had higher level of disability and more prevalent psychiatric disorders compared to EM. CM participants had more provider visits, emergency department/hospital visits, and diagnostic tests; the medical costs were three times higher for CM than EM. Per patient annual costs were highest in the UK and Spain and lower in France and Germany. CM was associated with higher medical resource use and total costs compared to EM in all study countries, suggesting that treatments that reduce headache frequency could decrease the clinical and economic burden of migraine in Europe. Comparing patterns of care and outcomes among countries may facilitate the development of more cost-effective care, and bring greater recognition to patients affected by migraine.

The evaluation of the intracavitary effusions by a bedside ultrasound examination.

OBJECTIVE: This study aims to evaluate the bedside use of the pocket-sized ultrasound (US) device for the detection of the intracavitary effusions. METHODS: We randomly enrolled 40 patients admitted to S. Andrea Hospital of Rome. Every patient received a clinical and biochemical evaluation and a bedside US examination to detect and estimate the intracavitary (pleural, pericardial and intra-abdominal) effusions; the US measurements have been compared to the computed tomography (CT) scans (as gold standard). RESULTS: The patients presented a high prevalence of effusions: right pleural 16/40 = 40% (esteemed volume 236.3±500.7 ml, mean±standard deviation m±SD), left pleural 8/40 = 20% (127.0±377.4 ml), pericardial 12/40 = 30% (47.5±72.8 ml) and intra-abdominal effusions 5/40 = 12.5% of cases (110.9±600.6 ml). Linear regression analysis showed a significant correlation between US and CT measurements: pleural r = 0.973 p <  1×10-38, pericardial r = 0.927 p <  1×10-39, intra-abdominal space r = 0.921 p <  1×10-59. The accuracy of the bedside US at the pleural, pericardial and abdominal level was respectively 98%, 93% and 96% (Cohen's kappa coefficient 0.966, 0.841 and 0.833). CONCLUSIONS: The present study showed a high prevalence of the intracavitary effusions and a high accuracy of the bedside US. The bedside US by a pocket-sized device is promising tool for its advantages of reproducibility and non-invasiveness of the device.

Chronic migraine: current concepts and ongoing treatments.

Migraine is an episodic painful disorder occasionally developing into a chronic form. Such disorder represents one of the most common neurological diseases in clinical practice. Chronicization is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine's natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks. Medication Overuse Headache (MOH) has been defined as a headache present on > or = 15 days/month, with regular overuse for > 3 months of one or more drugs used for acute and/or symptomatic headache management. Subtypes of MOH attributed to different medications were delineated. Misuse of ergots, triptans, opioids or combination analgesics on > or = 10 days/month was required to make the diagnosis of MOH, while > or = 15 days/month were needed for simple analgesic-overuse headache. CM's low prevalence produces an extremely high disability grade. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH. In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the washout period. At the moment we have not a total agreement whether prophylactic treatment should be started before, during, or after discontinuation of the overuse drug. Both drugs have been approved for CM treatment in view of their well-defined resistance to previous prophylaxis drugs. Recently, the PREEMPT clinical program has confirmed onabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM.

Rimegepant for the treatment of migraine.

Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist developed with a novel quick-dissolve oral tablet formulation for the acute treatment of migraine by Biohaven Pharmaceuticals, under license from Bristol Myers Squibb. The completed phase II and III trials showed its efficacy in terms of pain freedom, pain relief, release of migraine symptoms and lifestyle recovery, with an effect sustained up to 48 h. Significant clinical efficacy has been reported with a rimegepant single dose. Rimegepant was well tolerated and the few adverse events were mild or moderate and did not cause trial discontinuation. It received Food and Drug Administration (FDA) approval on February 27, 2020, for the acute treatment of migraine headache. Three clinical trials are currently ongoing to evaluate: i) the long-term safety as migraine acute treatment; ii) the efficacy and safety as a preventive treatment for migraine; and iii) the efficacy and safety for refractory trigeminal neuralgia. Future studies should be designed also to evaluate potential drug-drug interactions.

Extremely Severe Case of COVID-19 Pneumonia Recovered Despite Bad Prognostic Indicators: a Didactic Report.

COVID-19 is a highly infectious respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Starting from Wuhan (China) where it was firstly reported, it rapidly spread to the rest of the world, causing a pandemic with more than 300,000 deaths to date. We report an extremely severe case of coronavirus pneumonia in an over 80-year-old patient with hypertension, coronary heart disease, chronic heart failure, and chronic obstructive pulmonary disease. Despite a clearly poor anamnestic and clinical prognostic forecast, she was successfully discharged thanks to a careful evaluation of the case and of the complications that have arisen. Although a higher vulnerability of geriatric patients has been observed, the literature on elderly COVID-19 patients has remained very scarce, especially in those over 80. The article aims to explore factors that may allow the successful outcome and provides important elements to better understand this disease.

COVID-19: is it just a lung disease? A case-based review.

Due to its extreme virulence, COVID-19 virus has rapidly spread, developing a severe pandemic. SARS-COV-2 mostly affected the respiratory tract, causing a severe acute lung failure. Although the infection of airways, COVID-19 can be associated with chronic and systemic damages still not so much known. The purpose of this research is to collect recent evidence in literature about systemic diseases caused by COVID-19. The format of the present article has features of a systematic case-based review (level of evidence), and it is structured as a case series report (patients of our COVID-19 Medicine Ward have been selected as cases). Data for this review have been selected systematically, taking evidence only from indexed journals and databases: PubMed, Scopus, MEDLINE, and Cochrane systems. Papers chosen included systematic reviews, case series, clinical cases, meta-analysis studies, and RCTs. We start collecting studies since 2003. The main keywords used were "COVID-19" "OR" "SARS" "OR" "SARS - COV 2" "AND" "systemic disease" / "nephropathy" / "cardiac pathology" / "central nervous system." Clinical cases belong to our COVID-19 Medicine Ward. One of the most severe COVID-19 clinical presentations includes cardiovascular problems, like myocarditis, pericarditis, and acute hearth failure. Cytokine release syndrome caused by COVID-19 develops severe acute kidney failure. It is still unknown the way coronavirus damages the liver, brain, and reproductive system. Considering the majority of the new studies about this pathology, it issues that COVID-19 is considered to be a multi-organ disease.

Underdiagnosis and undertreatment of migraine in Italy: a survey of patients attending for the first time 10 headache centres.

The aim of this study was to asses the clinical features, pattern of healthcare and drug utilization of migraine patients attending 10 Italian headache centres (HC). Migraine is underdiagnosed and undertreated everywhere throughout the world, despite its considerable burden. Migraine sufferers often deal with their problem alone using self-prescribing drugs, whereas triptans are used by a small proportion of patients. All patients attending for the first time 10 Italian HCs over a 3-month period were screened for migraine. Migraine patients underwent a structured direct interview about previous migraine diagnosis, comorbidity, headache treatments and their side-effects and healthcare utilization for migraine. Patient satisfaction with their usual therapy for the migraine attack was evaluated with the Migraine-Assessment of Current Therapy (ACT) questionnaire. The quality of life of migraine patients was assessed by mean of Short Form (SF)-12 and Migraine-Specific Quality of life (MSQ) version 2.1 questionnaires. Of the 2675 patients who attended HCs for the first time during the study period, 71% received a diagnosis of migraine and the first 953 subjects completed the study out of 1025 patients enrolled. Only 26.8% of migraine patients had a previous diagnosis of migraine; 62.4% of them visited their general practitioner (GP) in the last year, 38.2% saw a specialist for headache, 23% attended an Emergency Department and 4.5% were admitted to hospital for migraine; 82.8% of patients used non-specific drugs for migraine attacks, whereas 17.2% used triptans and only 4.8% used a preventive migraine medication. Triptans were used by 46.4% of patients with a previous diagnosis of migraine. About 80% of migraine patients took over-the-counter medications. The Migraine-ACT revealed that 60% of patients needed a change in their treatment of migraine attacks, 85% of whom took non-specific drugs. Both the MSQ version 2.1 and the SF-12 questionnaires indicated a poor quality of life of most patients. Migraine represents the prevalent headache diagnosis in Italian HCs. Migraine is still underdiagnosed in Italy and migraine patients receive a suboptimal medical approach in our country, despite the healthcare utilization of migraine subjects being noteworthy. A cooperative network involving GPs, neurologists and headache specialists is strongly desirable in order to improve long-term migraine management in Italy.

Fremanezumab for the prevention of chronic and episodic migraine.

On September 15, 2018, the U.S. Food and Drug Administration (FDA) approved subcutaneous fremanezumab, a calcitonin gene-related peptide (CGRP) monoclonal antibody, for the treatment of episodic and chronic migraine in adults, with two recommended dosages: 225 mg monthly or 675 mg every 3 months. On March 28, 2019, the European Commission granted fremanezumab Marketing Authorization in the E.U. for the same indication. In this monograph we review data on the pharmacokinetics, metabolism and safety of fremanezumab as reported in the scientific literature from phase I to phase III studies. Fremanezumab demonstrated a very low incidence of adverse events. Primary and secondary endpoints in randomized, controlled trials on the efficacy of fremanezumab were achieved. Fremanezumab was demonstrated to be able to reduce the number of migraine days, headache hours and number of days with use of acute treatment agents. No data on drug-drug interactions with fremanezumab are available. However, it is worth mentioning that fremanezumab showed a very low incidence of development of adverse drug antibodies compared with other CGRP antibodies.

Chronic daily headache and medication overuse headache: clinical read-outs and rehabilitation procedures.

The impact of headache on the person and society represents a public health issue. Recently a study evaluated 51% of headache's prevalence in Europe, of which 14% is affected by migraine. Besides, 4% of adult population is affected by chronic forms, which constitute therefore an even more relevant problem in terms of health and social policies. The International Classification of Headache Disorders, II version (ICHD-II) recognises 24 types of chronic headache and states primary episodic headaches as chronic when attacks appear for more than 15 days per month, for at least three months. Headache given by drugs overuse, defined by ICDH-II in 2004 (and revised in 2005) as Medication Overuse Headache (MOH), is associated with overuse of a combination of analgesics, barbiturates, opioids, ergot alkaloids, aspirin, AINS, caffeine and triptans. Patients affected by MOH present a reduced work performance and a significant alteration in the quality of life. Furthermore, some psychological and behavioural states seem particularly important in promoting and sustaining drug abuse. The management and rehabilitation of patients affected by CDH, abusing symptomatic drugs, consists in the withdrawal and/or gradual reduction of their assumption, because of tolerance and addiction possibilities.

[Chronic daily headache: management and rehabilitation]. / Cefalea cronica quotidiana: gestione e riabilitazione.

In 2001, WHO evidenced headache among the first twenty disability agents in the world. The International Classification of Headache Disorders, II version (ICHD-II) recognises 24 types of chronic headache and states primary headaches as chronic when attacks appear for more than 15 days per month, for at least three months. Migraine given by drugs overuse, defined by ICDH-II in 2004 (and revised in 2005) as MOH, represents a common and debilitating disorder, which can be defined as generation, perpetuation and persistence of intense chronic migraine caused by the frequent and excessive use of (symptomatic) drugs, giving an immediate relief. MOH is associated with overuse of a combination of analgesics, barbiturates, opiods, Ergot alkaloids, aspirin, FANS, caffeine and triptans. Furthermore, some psychological and behavioural states seem particularly important in promoting and sustaining drugs abuse. The management and rehabilitation of patients affected by CDH, over-using symptomatic drugs, consists in the suspension and gradual reduction of their assumption, because of tolerance and addiction possibilities. Therapeutic success, defined as total absence of headache or frequency reduction over 50% in a period of time from 1 to 6 months, stands around 72-74%.

Cervical 10 kHz spinal cord stimulation in the management of chronic, medically refractory migraine: A prospective, open-label, exploratory study.

BACKGROUND: A significant minority of chronic migraine (CM) subjects fail conventional medical treatment (rCM), becoming highly disabled. Implantation of an occipital nerve stimulator is a therapeutic option for these subjects. Paresthesia-free cervical 10 kHz spinal cord stimulation (HF10 SCS) may provide an alternative. We report the results of a prospective, open-label, exploratory study assessing the long-term safety, tolerability and efficacy of cervical HF10 SCS in cohort of rCM subjects. METHODS: Included subjects were diagnosed with CM by an experienced headache specialist with the aid of an hourly headache diary. They were refractory to conventional medical treatments including onabotulinumtoxin-A injections. Medication overuse headache was not an exclusion criteria. Enrolled subjects underwent a 2- to 4-week tunnelled cervical HF10 SCS trial followed by a permanent system implant if a significant, subjective reduction in headache intensity/episodes was reported during the trial. Subjects were evaluated at baseline and 6 months after implantation with the aid of monthly diaries and headache-specific questionnaires. RESULTS: Seventeen subjects underwent a trial of cervical HF10 SCS; 14 were still implanted at 6 months (one trial failure, one trial infection, one implant site infection). Seven of the 14 subjects had >30% reduction in headache days. The average reduction in headache days was 6.9 for the overall population and 12.9 among the responders. Three subjects reported tenderness over the IPG/connection site, and one had a lead migration that required surgical revision. CONCLUSION: Paresthesia-free cervical HF10 SCS may be a safe and effective therapeutic option for chronic migraineurs refractory to conventional treatments.

Inhibition of intercellular adhesion molecule-1 (ICAM-1), soluble ICAM-1 and interleukin-4 by nitric oxide expression in migraine patients.

The mechanisms of the postulated "sterile" inflammation in migraine were studied utilizing flow cytometry (intercellular adhesion molecule 1, ICAM-1; interleukin-1 receptor, IL-1R) and enzyme-linked immunosorbent assay (soluble intercellular adhesion molecule 1, sICAM-1; interleukin-4, IL-4). Twenty patients suffering from migraine without aura, 20 healthy subjects, and 10 patients suffering from episodic tension headache were selected. All of the migraine patients were studied during a migraine crisis experimentally induced by the administration of isosorbide dinitrate (a nitric oxide donor), and 10 out the 20 were also studied during a spontaneous migraine attack. A sharp decrease in the expression of ICAM-1 (F=5.09, p<0.001 and F=2.46, p<0.05, respectively), sICAM-1 1 (F=6.21, p<0.0001 and F=3.99, p<0.007, respectively) and serum IL-4 (F=6.23, p<0.001 and F=3.64, p<0.01, respectively) were observed in experimentally induced and spontaneous migraine attacks. There was no change with respect to IL-IR 1 receptor expression values. The two control groups, tested with the same experimental procedure, showed no changes in ICAM-1 and IL-1R or in in sICAM-1 and IL-4. Our data suggest that migraine patients are more sensitive to exogenous NO than controls. In addition, our results indicate that experimental migraine crisis, induced by an NO donor, is mediated by the inhibition of IL-4 and subsequently of ICAM-1. It is likely that the described ICAM-1 downregulation inhibits during a migraine attack the critical step of transendothelial migration into the cerebral tissues of activated leukocytes, as proposed in the "sterile inflammation" hypothesis.

In vitro interactions of serotonin (5-HT) with mononuclear cells from migraine patients: alterations related to the phase of the attack.

Serotonin (5-HT) binds in a saturable and specific manner to high affinity binding sites present on the surface of human mononuclear cells. The serotonin binding to mononuclear cells has been assayed in patients with migraine, during and outside the crisis period. In these patients, unlike the episodic cluster headache patients that show a constant trend, the results are variable. This variability may depend on the fluctuation of 5-HT levels in the blood, during and after the crisis. A possible explanation for these observations is that at the beginning of the crisis the binding of 5-HT is still similar to the normal level. As the crisis goes on, there is at first an increase in 5-HT binding that saturates all the available sites and a subsequent phenomenon of desensitization, with a loss of high affinity sites. Further investigations are needed in order to assess whether or not the mononuclear cell functions are affected by the modifications of the binding of 5-HT, thought to be a regulatory molecule.

Chromosome 6p-encoded HLA-DR2 determination discriminates migraine without aura from migraine with aura.

Segregation analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA) have multifactorial inheritance, but involved genetic and environmental factors are largely unknown. A controlled study was performed to assess the HLA-driven liability to migraine and to verify if the heterogeneity between MWoA and MWA is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood donors as controls, coming from the same geographic area, were studied. Tissue typing was performed using the standard complement-dependent microlymphocytotoxicity technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for HLA Class II. Data emerging from the present study showed no altered distribution for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared to the control group. HLA Class II DR2 antigen showed a decreased frequency in MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039, RR = 0.21). These results seem to support the hypothesis of a protective role of DR2 antigen in MWA and provide additional basis for the proposed difference within MWoA and MWA.