MD, Ph.D Mario Vaccaro
email: mario.vaccaro@unime.itlinking

PhD Francesco Borgia

PhD Olga Barbuzza

PhD Sebastiano Gangemi

MD Biagio Guarneri

Linking powered by eXtyles DERMATOMYOSITIS AND CUTANEOUS METASTASES FROM BREAST CANCER: SIMULTANEOUS DEVELOPMENT AND PARALLEL COURSE

come

INTRODUCTION

Dermatomyositis (DM) is a rare disorder of the connective tissue, clinically characterized by weakness of proximal muscles and peculiar cutaneous involvement. DM can be exclusively or predominantly cutaneous, or also affect various organs: lungs, heart, joints, gastrointestinal system. Peaks of incidence occur in children and middle-aged adults: in the latter, DM is frequently a paraneoplastic syndrome, and its course is closely correlated with that of the underlying malignancy [START_REF] Parodi | Dermatomyositis in 132 patients with different clinical subtypes: cutaneous signs, constitutional symptoms and circulating antibodies[END_REF][START_REF] Callen | Dermatomyositis (2006)[END_REF].

We report a typical case of DM occurring in a patient affected by extensive cutaneous recurrence of breast cancer and skin metastases, with simultaneous onset and parallel course of the diseases. To the best of our knowledge this association has not been previously reported.

CASE REPORT

A 74-years-old woman was diagnosed in November 2005 with stage IIIC infiltrating ductal carcinoma of her right breast. She underwent partial mastectomy and was treated postoperatively with four cycles of docetaxel, followed by locoregional radiotherapy. This led to clinical remission, with no residual lesions visible in computed tomography scan; serum level of Cancer Antigen-15.3 was 19,7 U/ml. She was therefore put on therapy with anastrozole.

In December 2006, she was referred to our outpatients' service because of erythematous lesions recently appeared on the upper part of her body, associated to progressively worsening general asthenia. Clinical examination showed heliotrope rush with periorbital oedema, as well as erythematous and poikilodermatous macules with slight scales, Neurologic evaluation showed diffuse hyposthenia, with major involvement of proximal muscles; a myogenic pattern in the deltoid muscle was observed on electromyography. Laboratory exams revealed increased levels of antinuclear antibodies (titer 1:160), SSA-Ro antibodies (3000 IU/ml), creatin phosphokinase (300 U/L), erythrocyte sedimentation rate (49 mm/h). Nailfold capillaroscopy showed rarefaction of capillaries, with loss of the normal distribution pattern; moreover, some megacapillaries were present. Muscle biopsy revealed a predominantly perimysial and perivascular lymphocytic infiltrate, obliteration of multiple blood vessels, some areas of muscle infarction. Skin biopsy showed atrophic epidermis, vacuolar degeneration of the basal layer, dermal oedema, caused by mucin, and mild perivascular infiltration of lymphocytes.

On the above basis, we diagnosed DM, and the patient was treated with oral prednisone 1 mg/kg/day, with adequate tapering, and immunoglobulins (2 g/kg). Hormonal treatment was stopped and antiblastic therapy with gemcitabine and Linking powered by eXtyles liposomal doxorubicin (5 cycles) was started; the therapy was well tolerated and achieved a moderate improvement of the loco-regional relapse of the tumor and a parallel improvement of the cutaneous and muscular involvement.

DISCUSSION

Dermatomyositis is well known as a paraneoplastic syndrome, although an exact estimation of its association with internal malignancies is not possible, because of the heterogeneity of literature data [START_REF] Callen | Relation between dermatomyositis and polymyositis and cancer[END_REF][START_REF] Ponyi | Cancerassociated myositis: clinical features and prognostic signs (2005)[END_REF][START_REF] Levine | Cancer and myositis: new insights into an old association[END_REF][6]. Several Scandinavian researchers, however, have evaluated the frequency of malignancy in subjects affected by DM and in the general population, and have observed that the slight increase in cancer frequency in DM patients is not highly significant, and could be explained by a more aggressive cancer search [START_REF] Hill | Frequency of specific cancer types in dermatomyositis and polymyositis: a populationbased study[END_REF]. Various types of malignancies have been found in association with DM: the most common are carcinomas of the lung, breast, ovary, stomach, but many others have been reported in literature; their rate of incidence in patients with DM is similar to that observed in the general population [START_REF] Callen | Relation between dermatomyositis and polymyositis and cancer[END_REF][START_REF] Ponyi | Cancerassociated myositis: clinical features and prognostic signs (2005)[END_REF][START_REF] Levine | Cancer and myositis: new insights into an old association[END_REF][6].

The pathogenic link between DM and tumors is still conjectural. DM has to be considered as an autoimmune disease in which both genetic and coincidental factors (such as neoplastic antigens, hormones or hormone precursors, fetal proteins, antibodies, cytokines) seem to play a determinant pathogenic role, through disregulation of the immune system and production of antibodies and cytotoxic lymphocytes against autoantigens which are similar to tumor antigens. The production of large amounts of the above biologically active substances may cause tissue damage through deposition of immune complexes and/or recognition/modification of muscular and cutaneous antigens, which can subsequently activate autoreactive T-lymphocytes [START_REF] Levine | Cancer and myositis: new insights into an old association[END_REF][START_REF] Borgia | Dermatomyositis associated with IgG myeloma[END_REF].

Many lines of evidence have suggested that tumor necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of DM [START_REF] Werth | Associations of tumor necrosis factor alpha and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis[END_REF]: this is confirmed by the good results obtained using different regimens of anti-TNF agents (etanercept, infliximab or rituximab) for the treatment of DM [START_REF] Efthimiou | Tumor necrosis factor-alpha in inflammatory myopathies: pathophysiology and therapeutic implications[END_REF][START_REF] Chung | A pilot trial of rituximab in the treatment of patients with dermatomyositis[END_REF]. It is well known that ovarian or peripherallyderived estrogens may induce production of proinflammatory cytokines (i.e.TNF-alpha) by skin or immune cells [START_REF] Carruba | Estrogen regulates cytokine production and apoptosis in PMA-differentiated, macrophage-like U937 cells[END_REF][START_REF] Sereda | Improvement in dermatomyositis rash associated with the use of antiestrogen medication[END_REF]. Recently, Sereda et al. [START_REF] Sereda | Improvement in dermatomyositis rash associated with the use of antiestrogen medication[END_REF] described the case of 2 young women with breast cancer, whose DM-associated skin manifestations significantly improved while taking antiestrogens such as docetaxel (a selective estrogen receptor modulator) and anastrazole (an aromatase inhibitor), probably because of inhibition of the TNF-alpha synthesis.

In our patient, no changes in DM-related rash were observed during antiestrogen treatment, suggesting that different immunologic and non immunologic pathways may be involved in the pathogenesis of DM. Studies with larger groups of patients and longer observation periods are necessary to better clarify the relationship between DM and malignancies, autoimmunity and hormonal status (i.e. estrogens), as well as the risks and benefits associated to therapy.

  involving cheeks, upper chest [fig.1a], and the extensor surface of both arms. Erythematous, infiltrating, indurated plaques in the axillary region, close to the site of the previous partial mastectomy [fig.1b], and multiple nodules in the back [fig.1c] and abdomen were also observed. Breast ultrasonography showed multiple lesions in the right breast; fine needle aspiration followed by cytologic examination was positive for tumoral cells, in agreement with the diagnosis of extensive cutaneous metastatic breast cancer.

Figure 1 (

 1 Figure 1 (a-c): (a) heliotrope rush with periorbital oedema and erythematous and poikilodermatous macules with slight scales involving cheeks and upper chest; (b) erythematous, infiltrating, indurated plaques and nodules in the axillary region; (c) multiple metastatic nodules on the back.


MD Theodoros P Vassilakopoulos

Professor Gerassimos A Pangalis
email: pangalis@med.uoa.gr

MD Marina P Siakantaris

MD Despina Gribabis

MD Spyridon Bouros

MD Ioannis Metaxas

MD Xanthi Yiakoumis

MD Charalambos Floudas

MD Evangelia M Dimitriadou

MD Lambrini Pantazi

MD Catherine Tsoukala

Penelope Korkolopoulou

MD Anastasios Andreopoulos

MD George Vaiopoulos

KIKUCHI'S LYMPHADENOPATHY A RELATIVELY RARE BUT IMPORTANT CAUSE OF LYMPHADENOPATHY IN GREECE, POTENTIALLY ASSOCIATED WITH THE ANTIPHOSPHOLIPID SYNDROME

Keywords: Kikuchi"s disease, Kikuchi-Fujimoto, lymphadenopathy, cervical, antiphospholipid syndrome, autoimmune disease

Kikuchi-Fujimoto disease is a form of reactive lymphadenopathy, which was firstly described in Japan, but is uncommon in the Western world. We retrospectively reviewed the medical records of 9 cases of adult or adolescent Kikuchi´s disease diagnosed in a single Haematology Unit in Athens, Greece between 1990 and 2006. The median age of the patients was 25 years (14-40) and 8/9 were females. All patients presented with cervical lymphadenopathy sparing the supraclavicular fossa; one had associated axillary lymphadenopathy, 7 had fever and 2 were asymptomatic. The median duration of lymphadenopathy before presentation was 30 days (10-45). Just palpable splenomegaly was recorded in 3 patients. The median value of the maximal lymph node diameter was 2 cm (1-5) and only 1/9 had nodes >2 cm in their largest diameter. Lymphadenopathy was tender in 2 patients; hard nodes were observed in 3. The median leukocyte count was 4.7×10 9 /l (2.2-4.9) with a normal differential in 7/9 patients. No infectious agent could be demonstrated. One patient however had clinical and laboratory evidence of primary antiphospholipid syndrome (APLS). In conclusion, Kikuchi´s disease represents a rare but important diagnostic possibility for patients presenting with lymphadenopathy in Greece and other Western countries. In this setting, autoimmune disorders, mainly lupus and APLS, should be considered and excluded by the appropriate laboratory work-up.

INTRODUCTION

Kikuchi-Fujimoto disease is an uncommon form of reactive lymphadenopathy, which was firstly described in Japan in 1972 [START_REF] Fujimoto | Cervical subacute necrotizing lymphadenitis. A new clinicopathological entity[END_REF][START_REF] Kikuchi | Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes[END_REF]. Since then it has been recognized in many other countries worldwide as a self-limited syndrome characterized by lymphadenopathy [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] Charalabopoulos | Kikuchi-Fujimoto disease in Greece. A study of four cases and review of the literature[END_REF][START_REF] Norris | Kikuchi-Fujimoto disease: A benign cause of fever and lymphadenopathy[END_REF][START_REF] Papadimitriou | Histiocytic necrotizing lymphadenitis without granulocytic infiltration[END_REF]. It usually affects young females presenting with localized -predominantly cervical-lymphadenopathy, which is frequently associated with fever. The diagnosis is based on the histologic findings. The histologic picture is characterized by karyorrhectic foci, usually with coagulative necrosis without neutrophilic infiltration, and the presence of histiocytes and immunoblasts [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF]. It may resemble to that observed in systemic lupus erythematosus (SLE), but may also be misdiagnosed as malignant lymphoma [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] Dorfman | Kikuchi"s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis[END_REF]. An association between Kikuchi´s lymphadenopathy and SLE or other autoimmune condition has been reported in some cases. In this study we present our experience with this rare disorder in a single center in Greece.

PATIENTS AND METHODS

We report 9 cases of Kikuchi´s disease diagnosed in the Haematology Unit, First Department of Internal Medicine, Athens University from 1990 to 2006 in adult or adolescent patients. Four of these cases were part of a series of 516 consecutive patients with lymphadenopathy, which has been previously published [START_REF] Pangalis | Clinical approach to lymphadenopathy[END_REF]. During the same period there was also an additional case of SLE, who reported a history of Kikuchi"s disease 7 years prior to her presentation. The clinical and laboratory features of this case were not available and were not included in this analysis. Demographic, clinical, and laboratory data were extracted from the medical records of the patients. The diagnosis was based on lymph node histological examination in all cases. All patients underwent laboratory testing with complete blood count and differential, chest X-rays, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Toxoplasma gondii serology. Most patients were also tested for erythrocyte sedimentation rate (ESR), biochemical profile, serum protein electrophoresis and the presence of rheumatoid factor, antinuclear and anti-ds DNA antibodies as well as serum complement levels.

Other tests were performed in less than half of the patients. Computed tomography and bone marrow biopsy were not routinely performed. Clinically significant anemia was defined as hemoglobin levels <115 g/l, while clinically significant thrombocytopenia as platelet counts <100x10 9 /l. Leucopenia was defined as white blood cell count < 4x10 9 /l and neutropenia as an absolute neutrophil count of less than 1.8x10 9 /l, while lymphocytopenia was defined as an absolute lymphocyte count of less than 1.5x10 9 /l.

RESULTS

Clinical, Laboratory and Histologic Findings

The demographic, clinical and laboratory data of the patients are summarized in tables 1-3. Seven patients were native Greeks, one was Phillipinian and one Kenyan. Both non-Greek patients were living in Greece for more than 10 years. The median age of the patients was 25 years (14-40) and 8/9 of them (89%) were females. All patients presented with cervical lymphadenopathy, 7 patients had fever (78%; in one case low grade only), while 2 were asymptomatic and presented with incidentally discovered lymphadenopathy.

The median duration of lymphadenopathy before presentation was 30 days (range 10-45). Splenomegaly was recorded in 3 patients (33%), but the spleen was just palpable below the left costal margin in all 3 cases. One patient had palpable mild hepatomegaly, confirmed by ultrasonography. Each one of fatigue, sorethroat, sweats, arthralgias and headache was reported by 2 patients, while a rash was recorded in a single case. Cervical lymphadenopathy was observed in all 9 patients, being unilateral in 5 (left 2; right 3) and bilateral in 4 cases. The submandibular lymph nodes were involved in 3 cases. Supraclavicular nodes were not enlarged in any case.

Eight patients had lymphadenopathy restricted to the cervical areas, while a single patient had bilateral axillary lymph nodes up to 1x1 cm, which resolved later. The median value of the maximal lymph node diameter 2 cm (range 1-5 cm), but only one out of the 9 patients had lymph nodes greater than 2 cm in their maximal diameter. Lymphadenopathy was tender in 2 (out of 7) patients.

Hard lymph nodes were observed in 3 (out of 8) patients.

According to the clinical prediction rule published by our group [START_REF] Vassilakopoulos | Application of a prediction rule to select which patients presenting with lymphadenopathy should undergo a lymph node biopsy[END_REF], only a single patient was considered to be in need of lymph node biopsy. This was due to the large size (5cm) and the hard texture of the neck mass in patient #3. However, all patients finally underwent a lymph node biopsy. This decision was based on empirical clinical judgment, in order to reach the diagnosis of Kikuchi"s disease, due to prolonged non-remitting lymphadenopathy,. Briefly the histologic findings of the 9 cases were as follows: Lymph node architecture was completely effaced in 3 and partially preserved in 6 cases.

Necrosis was present in all cases (patchy in 7 and confluent in 2), associated with apoptotic cells and nuclear karyorrhectic debris. Aggregates of histiocytes were observed in all cases (numerous in 7/9) as well as activated T-lymphocytes (numerous in 4/9) and plasmacytoid monocytes. Neutrophils and eosinophils were not observed in any case.

The median leukocyte count was 4.7×10 9 /l (2.2 -4.9); all patients had low or low-normal leukocyte counts. Leucopenia or low-normal leukocyte counts with normal differential were recorded in 7 patients. The remaining two patients presented with inversion in differential leukocyte counts. The median neutrophil count was 1.7×10 9 /l (1.1-3.2); 5/9 patients (56%) had neutropenia.

The median lymphocyte count was 1.6×10 9 /l (0.8-2.9); 4/9 (44%) patients had lymphocytopenia. Clinically significant anemia was observed in 3 patients (33%). No case of clinically significant thrombocytopenia was observed. The median ESR was 51.5 mm/h (5-65), and ESR was ≥30 mm/h in 6/8 patients (75%). Serum lactate dehydrogenase (LDH) levels were elevated in 4/6 (67%) patients and elevated aminotransferase levels were recorded in 2/6 (33%) patients. However, in patient #9 the clinical course was complicated by significant transaminasemia (5-10x), which led to a non-diagnostic liver biopsy, despite the normal initial transaminase levels. Polyclonal hypergammaglobulinemia was observed in 4/8 patients (50%). The hematologic and biochemical findings in this series of patients with Kikuchi"s disease are summarized in table 2. Baseline chest X-rays did not reveal abnormal findings in any case, although patient #9 developed severe pneumonia and pleuritis due to Pseudomonas aeruginosa during her hospitalization, which resolved with the appropriate antimicrobial treatment.

Serum tests for current infection by Epstein-Barr virus (VCA-EBV) and cytomegalovirus were performed in all patients, and were consistently negative (table 3). Among 9 patients, 8 had no evidence of current toxoplasmic infection and one had a stable IgM titer of 1/150 with negative IgG. This was considered as a false positive result. Other serological tests for various infectious agents, including herpes simplex and Yersinia enterocolitica, were negative, when performed (table 3).

Serological workup for autoimmune disorders is also summarized in table 3.

Two patients tested positive for antinuclear antibodies at titers 1/80 speckle and 1/160 diffuse. The former patient (#8) had a borderline anti-dsDNA result and a positive IgM anticardiolipin (41.3, 57.3, and 41 vs. normal limit <12.5 MPLU/ml, in serial measurements over 14 months) and β 2 -GPI assay (39.4 vs normal limit <15), while the initially normal IgG anticardiolipin increased later on (9.9 and 38 vs. normal limit <15 GPLU/ml). Lupus anticoagulant was negative. This patient had also marked polyclonal hypergammaglobulinemia.

During the evaluation of febrile lymphadenopathy she also developed thrombosis of the superior vena cava, while she had reported a history of 2 consecutive spontaneous abortions. A subsequent work-up for thrombophilia was negative. Thus a diagnosis of primary antiphospholipid syndrome (APLS) was established [START_REF] Levine | The antiphospholipid syndrome[END_REF], since she did not fulfill the diagnostic criteria for SLE. At 1-year follow-up visit she is afebrile, with persistent serologic abnormalities, but no evidence of SLE. In the second patient (#9) antinuclear antibodies disappeared after the resolution of Kikuchi"s lymphadenopathy, while she did not fulfill the diagnostic criteria for SLE at any timepoint.

Follow up

In all patients lymphadenopathy resolved without specific treatment. None of the patients developed SLE during the initial observation phase, usually of 6-12 month duration. Long term follow-up beyond this phase was available for 4 patients (excluding the recent patient #9), all of whom were in excellent clinical condition at a median of 8.5 years after the diagnosis (range 2.5-15).

Cases of recurrent Kikuchi´s disease or comorbid conditions have not been observed, with the exception of the synchronous antiphospholipid syndrome in patient #8, and the Pseudomonas pneumonia which complicated the clinical course of patient #9.

DISCUSSION

Although Kikuchi´s lymphadenopathy was originally described in Japan 35 years ago, it has been reported worldwide during the last 15 years [START_REF] Fujimoto | Cervical subacute necrotizing lymphadenitis. A new clinicopathological entity[END_REF][START_REF] Kikuchi | Lymphadenitis showing focal reticulum cell hyperplasia with nuclear debris and phagocytes[END_REF][START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] Charalabopoulos | Kikuchi-Fujimoto disease in Greece. A study of four cases and review of the literature[END_REF][START_REF] Norris | Kikuchi-Fujimoto disease: A benign cause of fever and lymphadenopathy[END_REF][START_REF] Papadimitriou | Histiocytic necrotizing lymphadenitis without granulocytic infiltration[END_REF]. The true incidence of Kikuchi´s lymphadenopathy in unselected series of adult patients presenting with lymphadenopathy is not known. Figures up to [START_REF] Norris | Kikuchi-Fujimoto disease: A benign cause of fever and lymphadenopathy[END_REF].7% of all lymph node biopsies have been reported in Asia, reflecting the increased local incidence of the disease, but actually refer to highly selected populations of patients with clinically significant lymphadenopathy requiring a lymph node biopsy [START_REF] Kuo | Kikuchi's disease (histiocytic necrotizing lymphadenitis). A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy[END_REF]. Published experience with Kikuchi"s disease in Greece is limited [START_REF] Charalabopoulos | Kikuchi-Fujimoto disease in Greece. A study of four cases and review of the literature[END_REF]. Among 9 patients presented here, 4 had been part of a series of 516 consecutive, unselected, patients, who presented with lympadenopathy in a single Haematology Unit [START_REF] Pangalis | Clinical approach to lymphadenopathy[END_REF]. On the basis of these data, the estimated frequency of Kikuchi´s disease was 0.8% among patients presenting with lymphadenopathy in a teaching hospital in Greece. However the self-limited course of the disease may lead to underestimation of its true incidence, since, in an unknown fraction of patients, the disease may resolve prior to the final decision to perform a lymph node biopsy.

The etiology of Kikuchi´s lymphadenopathy remains unknown. Several infectious agents have been proposed as potential causes of the disease but clear evidence is lacking. On the basis of serologic findings Kikuchi´s lymphadenopathy has been associated with Toxoplasma gondii, Yersinia enterocolitica, HTLV-1, and hepatitis C virus, while EBV and human herpesvirus-6 and 8 (HHV-6 and HHV-8) have been detected by polymerase chain reaction or in situ hybridization [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] Papadopoulou | Kikuchi-Fujimoto"s disease in a male with HCV infection[END_REF]. Rubella, brucellosis and parvovirus B19 have also been associated with Kikuchi"s disease [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] Charalabopoulos | Brucella melitensis infection stimulates an immune response leading to Kikuchi-Fujimoto disease[END_REF].

However all these associations are either rare or have not been confirmed by alternative laboratory methods. In the present series there was no serologic evidence for the implication of infectious agents in the pathogenesis of the disease, as shown in table 3. It must be stressed out that the reported Pseudomonas pneumonia was not considered as the cause of Kikuchi"s disease in patient #9. We rather believe that it was a complication of the disease, which was already present for almost 45 days.

In a review of 108 predominantly American cases of Kikuchi´s lymphadenopathy [START_REF] Dorfman | Kikuchi"s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis[END_REF] the median age was 30 years, almost 95% of the patients were younger than 40 years, and the male to female ratio was 1:4.

Fever complicated the clinical picture in 39% of the patients, weight loss and sweats in 10-15% of the patients, but other symptoms, except of local ones, were recorded with frequencies of less than 5%. The mean duration of the symptoms was 3 months (range 1-24). In 81% of the patients lymphadenopathy was localized, in 14% it was limited to two sides, and was more generalized in only 6% of the patients.

In another report of 58 patients from Taiwan [START_REF] Yu | Clinical manifestations of Kikuchi's disease in southern Taiwan[END_REF] the mean age was 25 years and the male to female ratio was 1:1.76. Fever complicated the clinical picture in 43% of the patients, sore throat was recorded in 21%, but weight loss and night sweats were very rare (3% and 2% of the patients respectively). The median duration of symptoms was 4 weeks. All patients had cervical lymphadenopathy (usually posterior and 21% bilateral) and only 5% had axillary lymphadenopathy. Thus approximately 95% of the patients had 1 or 2 involved nodal sites. Small nodes, <2 cm, were recorded in 75% of the patients (range 0.5-9 cm) and tenderness in 50%, while splenomegaly was very rare (3%).

Our data confirm that patients suffering from this self-limited condition are mainly young females, presenting with predominantly cervical lymhadenopathy sparing the supraclavicular fossa. The disease is frequently febrile. Leucopenia or low-normal leukocyte counts with normal differential are the rule. Although not diagnostic, this combination of the demographic, clinical and laboratory features should raise the suspicion of Kikuchi´s disease in patients with unexplained lymphadenopathy. The marked predilection to the involvement of cervical lymph nodes and the young age of the patients is clear [START_REF] Dorfman | Kikuchi"s histiocytic necrotizing lymphadenitis: an analysis of 108 cases with emphasis on differential diagnosis[END_REF][START_REF] Yu | Clinical manifestations of Kikuchi's disease in southern Taiwan[END_REF]; however female predominance may be less prominent in Asia than in Europe or USA [START_REF] Yu | Clinical manifestations of Kikuchi's disease in southern Taiwan[END_REF].

The diagnosis of Kikuchi´s disease is based on the histologic findings.

Histological examination reveals partial maintenance of the lymph node architecture, with the presence of reactive germinal centers in residual follicles. There are patchy areas of irregularly shaped necrosis, which is occasionally confluent. The necrosis consists of eosinophilic fibrinoid deposits including nuclear fragments and is surrounded by large accumulations of histiocytes, phagocytosing the aforementioned cellular debris. These areas of histiocytic aggregates also include small lymphocytes, activated large T lymphocytes, scarce plasma cells and nests of plasmacytoid monocytes. The consistent absence of neutrophils and eosinophils, as in our cases, is a distinctive feature of Kikuchi"s disease. Reliable cytological diagnosis has been reported in half of the patients in one study, but it cannot substitute lymph node biopsy [START_REF] Viguer | Fine-needle aspiration cytology of Kikuchi´s lymphadenitis: A report of ten cases[END_REF]. All of our patients actually underwent a lymph node biopsy. Based on the clinical prediction rule published by our group [START_REF] Vassilakopoulos | Application of a prediction rule to select which patients presenting with lymphadenopathy should undergo a lymph node biopsy[END_REF], only 1 patient fulfilled the criteria to undergo a lymph node biopsy, while in the remaining patients the decision was made on the basis of clinical judgment, due to the presence of ""suspicious"", persistent, unexplained lymphadenopathy. This clinical prediction rule was developed in order to facilitate the differentiation between serious and non-serious lymphadenopathy. In this sense failure to classify patients with Kikuchi"s disease in the group of patients predicted to be in need of biopsy is consistent with the benign, "non-serious" nature of the disease. between the two entities are given in table 4. The presence of fever with low nodal "disease burden" and the whole clinical picture may help to avoid such misinterpretations.

Another clinical problem is the reported association with SLE [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF][START_REF] El-Ramahi | Kikuchi disease and its association with systemic lupus erythematosus[END_REF][START_REF] Hu | Lupus lymphadenitis simulating Kikuchi´s lymphadenitis in patients with systemic lupus erythematosus: A clinicopathological analysis of six cases and review of the literature[END_REF][START_REF] Tumiati | Kikuchi´s disease in systemic lupus erythematosus: an independent or dependent event?[END_REF][START_REF] Vila | Therapeutic response and longterm follow-up in a systemic lupus erythematosus patient presenting with Kikuchi´s disease[END_REF]. Several authors have reported the association between Kikuchi"s disease and SLE. In a review of 35 cases SLE developed after the diagnosis of Kikuchi"s disease in 14 and concomitantly with the disease in 14, while

Kikuchi"s developed after SLE in 7 patients [START_REF] Santana | Kikuchi-Fujimoto´s disease associated with systemic lupus erythematosus: case report and review of the literature[END_REF]. Thus SLE should carefully be excluded both serologically and histologically in every patient with Kikuchi´s disease. SLE-associated lymphadenopathy can be histologically differentiated from Kikuchi"s disease on the basis of the presence of hematoxylin bodies, neutrophils, vasculitic lesions, the Azzopardi phenomenon and the abundance of plasma cells (see table 4). However these clear features may not always be present, leading to diagnostic problems. Whether SLE really complicates the course of a small minority of patients with Kikuchi´s lymphadenopathy or these cases actually represent examples of misdiagnosis at the initial presentation of SLE with lymphadenopathy is unclear [START_REF] Bosch | Enigmatic Kikuchi-Fujimoto disease. A comprehensive review[END_REF]. However, although the clinical findings usually resolve rapidly, prolonged follow-up is needed after a diagnosis of Kikuchi´s lymphadenopathy has been established, in order to detect rare cases, who might develop SLE.

In our series SLE did not develop in any patient after the diagnosis of Kikuchi´s disease. It must be pointed out that during the study period, one patient presented with SLE and reported an episode of Kikuchi"s lymphadenopathy 7 years prior to the diagnosis. This patient was not included in the stydy because there was no histologic verification available to confirm that the patient had indeed Kikuchi"s disease and not lupus lymphadenitis.

However 2/7 patients tested had positive antinuclear antibodies and 1/3 tested had antithyroid antibodies, suggesting a relation of Kikuchi"s disease with autoimmunity, which is more clearly shown in previously reported studies.

In this context, one of the 9 patients reported here actually had primary APLS, which was diagnosed concomitantly with Kikuchi"s lymphadenopathy. This patient did not fulfill the diagnostic criteria for SLE. There are 3 recent additional case reports linking Kikuchi"s lymphadenopathy with the APLS, either primary or secondary to SLE [START_REF] Chen | Systemic lupus erythematosus with simultaneous onset of Kikuchi-Fujimoto's disease complicated with antiphospholipid antibody syndrome: a case report and review of the literature[END_REF][START_REF] De Larranaga | Catastrophic antiphospholipid syndrome and Kikuchi-Fujimoto disease: the first case reported[END_REF][START_REF] Papaioannou | Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) associated with antiphospholipid syndrome: case report and literature review[END_REF]. Thus the APLS should also be looked for in patients with Kikuchi"s lymphadenopathy, since it may coexist with Kikuchi"s disease.

In * Only a single case with hemoglobin levels < 10 g/dl (9.8g/dl) ** 126×10 9 /l ‡ above the upper normal limit of the laboratory

From the clinical point

  of view, Kikuchi´s lymphadenopathy raises problems of differential diagnosis, because of its subacute presentation with a picture reminiscent of Hodgkin´s or non-Hodgkin´s lymphoma, dominated by limited, usually cervical lymphadenopathy in febrile patients with elevated ESR. However the absence of supraclavicular lymphadenopathy and mediastinal enlargement, the frequently small size of enlarged nodes (less than or equal to 2 cm in all but one case in this study), the low or low-normal leukocyte count with normal differential and the absence of other cytopenias or thrombocytosis may facilitate the clinical distinction between lymphoma and Kikuchi´s disease in most cases. Extensive diagnostic work-up with computed tomography, bone marrow biopsy or other tests beyond that needed for the clarification of the cause of lymphadenopathy is not justified for the vast majority of cases of Kikuchi´s disease. At the histologic level the presence of T-immunoblasts, occasionally bearing atypical morphologic features, in Kikuchi"s disease may result to confusion with aggressive non-Hodgkin´s lymphomas, mainly of the T-cell phenotype. CD8+ cells predominate in Kikuchi"s disease, while the majority of the T-cell lymphomas are CD4+ rather CD8+. Clues for the differential diagnosis

Table 2 :

 2 Summary of non specific laboratory findings in 9 patients with Kikuchi´s lymphadenopathy (leukocyte counts and differential are reported in table[START_REF] Fujimoto | Cervical subacute necrotizing lymphadenitis. A new clinicopathological entity[END_REF]

	Laboratory test				Tested (#)	Abnormal
						(#)	(%)
	Blood Counts
	Hemoglobin<115 g/l	9	3 *	33
	Platelets <140×10	9 /l	9	1 **	11
	ESR ≥30mm (1	st hour)	8	5	63
	↑ γ-globulins (polyclonal)	8	4	50
	Serum LDH (elevated)	‡	6	4	67
	ALT/AST (elevated)	‡		6	2	33
	Alkaline phosphatase (ALP) /γ-	6	0	0
	glutamyltranspeptidase (γGT)
	(elevated)	‡

Table 3 :

 3 Summary of work-up for infectious and autommune diseases in 8 patients with Kikuchi´s lymphadenopathy Abnormal results were considered those, which were indicative of current infection ** This was a false-positive result, as described in the body of the text § HHV-6, Parvo-B19, Q-fever, RSV, Adenoviruses, Mycoplasma, Leishmania donovani, HBV, HCV, Mumps, Measles, AMA, Scl-70, pANCA, c ANCA were performed in 1 or 2 cases each and were negative

	Infectious Disease		Tested	Abnormal	Autoimmune Disease	Tested	Abnormal
	Serological Work up	*. §	(#)	(#)	Work up §	(#)	(#)
	EBV-VCA		9	0	Antinuclear antibodies	7	2 ¶
	CMV		9	0	Anti-ds DNA	7	1 ¶
	Toxoplasma gondii		9	1 **	Rheumatoid factor	7	0
	Herpes Simplex		5	0	Serum complement (C 3 , C 4 )	5	0
	Yersinia Enterocollitica	4	0	ENA	4	0
	Wright test		3	0	Antimicrosomal/Antithyroglo	3	1
					bulin antibodies
					Anticardiolipin IgM	2	1
					IgG	2	1
	¶ 1/80 speckled and 1/160 diffuse, anti-dsDNA 7.5 (max 7.0)
	*

Table 4 :

 4 A summary of the differential diagnosis of Kikuchi"s disease from non-Hodgkin T-cell lymphomas and Systemic Lupus Erythematosus. encrustation of blood vessel walls with nuclear material due to fibrinoid necrosis

		T-Non Hodgkin's Lymphoma	Kikuchi's Disease	Systemic Lupus Erythematosus
	Clinical-Laboratory features
	Site of lymphadenopathy	Any peripheral and/or internal site	Mainly cervical	Peripheral and/or internal
	Size of lymph nodes	Varible, usually large and increasing	Variable, usually small, up to 2 cm	Variable, usually small, up to 2-3 cm
	Systemic symptoms	Fever, night sweats, weight loss (B-	Fever almost always, night sweats,	Fever common, other systemic
		symptoms) are common	flu-like symptoms	features of SLE present
	Haematological findings	Very	variable	(leukocytosis,	Leukopenia or low-normal counts	Leukopenia,	lymphocytopenia,
		thrombocytosis or cytopenias)		thrombocytopenia common
	ANA or other autoantibodies	Rare (low titers)		Uncommon or low titers	Almost always in high titers
	Histological features
	Necrosis	Coagulative necrosis (when present)	Usually prominent with karyorrhectic	Common, with karyorrhectic debris
					debris
	Nodal architecture	Usually complete effacement	Usually partial effacement	Usually partial effacement
	Polymorphous histiocytic infiltrates	Rare (CD68+, MPO -)		Prominent (CD68+, MPO +)	Prominent (CD68+, MPO +)
	Neutrophils	Present			Absent	Present but rare
	Plasmacytoid monocytes	Rare or Absent		Common	Common
	Plasma cells	Scarce			Scarce	Numerous
	Immunoblasts	Yes			Variable, may be atypical, T-	Variable
					phenotype
	Hematoxylin bodies	Absent			Absent	Present
	Azzopardi phenomenon	Absent			Absent	Present
	Vasculitic lesions	Absent			Absent	Present
	Immunophenotypic features	CD4+ >>CD8+ or CD4+CD8+ cells	CD8+ cell predominance	CD8+ cell predominance
		(abnormal T-cell phenotype)
	Clonal T-cell receptor rearrangements Yes			No	No

*


María Teresa Saldaña

Ana Navarro

Concepción Pérez

Xavier Masramón

Javier Rejas

Dr María Teresa-Saldaña

Patient-Reported-Outcomes in subjects with painful lumbar or cervical radiculopathy treated with Pregabalin: Evidence from medical practice in Primary Care settings

Keywords: Radiculopathy, pregabalin, primary health care, epidemiologic studies, outcomes research, clinical practice

Introduction

Spinal pain is the most common form of chronic pain [START_REF] Verhaak | Prevalence of chronic benign pain disorder among adults: a review of the literature[END_REF], with prevalences of back pain in the general population of 15-45% [START_REF] Lawrence | Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States[END_REF][START_REF] Bressler | The prevalence of low back pain in the elderly. A systematic review of the literature[END_REF][START_REF] Elliott | The epidemiology of chronic pain in the community[END_REF], and of 13-22% in the case of cervical pain [START_REF] Van Der Donk | The association of neck pain with radiological abnormalities of the cervical spine and personality traits in a general population[END_REF][START_REF] Cote | The Saskatchewan Health and Back Pain Survey. The prevalence of neck pain and related disability in Saskatchewan adults[END_REF][START_REF] Webb | Prevalence and predictors of intense, chronic, and disabling neck and back pain in the UK general population[END_REF]. A neuropathic mechanism is implied in the genesis of this type of pain in 10-19% of all patients with back pain [START_REF] Carey | Acute severe low back pain. A population-based study of prevalence and care-seeking[END_REF][START_REF] Loney | The prevalence of low back pain in adults: a methodological review of the literature[END_REF][START_REF] Berger | Clinical characteristics and economic costs of patients with painful neuropathic disorders[END_REF], resulting in impaired quality of life, and increased utilization of health care resources and economical cost [START_REF] Berger | Clinical characteristics and economic costs of patients with painful neuropathic disorders[END_REF][START_REF] Mcdermott | The burden of neuropathic pain: results from a cross-sectional survey[END_REF][START_REF] Lachaine | Painful neuropathic disorders: an analysis of the Regie de l'Assurance Maladie du Quebec database[END_REF]. As in other types of chronic pain, patients with back pain not only suffer important comorbidities in the form of other painful disorders [START_REF] Berger | Clinical characteristics and economic costs of patients with painful neuropathic disorders[END_REF][START_REF] Mcdermott | The burden of neuropathic pain: results from a cross-sectional survey[END_REF][START_REF] Lachaine | Painful neuropathic disorders: an analysis of the Regie de l'Assurance Maladie du Quebec database[END_REF], but frequently also present with prominent sleep disturbances [START_REF] Smith | How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature[END_REF], as well as anxiety and mood disorders [START_REF] Rush | Depression and chronic low back pain: establishing priorities in treatment[END_REF][START_REF] Mcwilliams | Depression and anxiety associated with three pain conditions: results from a nationally representative sample[END_REF].

Despite the introduction of new treatments, the management of patients with neuropathic pain remains a challenge [START_REF] Finnerup | Algorithm for neuropathic pain treatment: an evidence based proposal[END_REF]. In clinical practice, patients with neuropathic pain including those with spinal pain, often receive suboptimal treatment. In this context, the most widely used pharmacological treatments in these patients are nonsteroidal antiinflammatory drugs [START_REF] Berger | Clinical characteristics and economic costs of patients with painful neuropathic disorders[END_REF][START_REF] Mcdermott | The burden of neuropathic pain: results from a cross-sectional survey[END_REF][START_REF] Lachaine | Painful neuropathic disorders: an analysis of the Regie de l'Assurance Maladie du Quebec database[END_REF], which are scantly effective in the management of pain with a neuropathic component such as the one found in radiculopathies [START_REF] Harden | Unmet needs in the management of neuropathic pain[END_REF]. Such suboptimal treatment of neuropathic pain contributes substantially to the patient disease burden [START_REF] Tolle | Painful diabetic neuropathy: a cross-sectional survey of health state impairment and treatment patterns[END_REF][START_REF] Tolle | Patient burden of trigeminal neuralgia: results from a cross-sectional survey of health state impairment and treatment patterns in six European countries[END_REF][START_REF] Van Seventer | A cross-sectional survey of health state impairment and treatment patterns in patients with postherpetic neuralgia[END_REF]. Although a number of therapies are available for neuropathic pain, including antidepressants, tramadol, opioids and different antiepileptic drugs, the results of a recent systematic review suggest that, in view of their balance between efficacy and tolerability, gabapentin and pregabalin (PGB) can be regarded as first line treatments for peripheral pain with a neuropathic component [START_REF] Finnerup | Algorithm for neuropathic pain treatment: an evidence based proposal[END_REF]. In addition, these antiepileptic drugs, together with antidepressants, offer the advantage of acting not only on pain but also on the associated symptoms of depression [START_REF] Finnerup | Algorithm for neuropathic pain treatment: an evidence based proposal[END_REF]. The presence of psychological disorders in these subjects may exacerbate pain intensity and disability. Therefore, treatment with anticonvulsive drugs or antidepressants could optimize treatment effectiveness and reduce the occurrence of adverse events [START_REF] Argoff | The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach[END_REF].

Pregabalin (PGB) is a structural analog of gamma-aminobutyric acid (GABA) that selectively binds the alpha 2 -delta (α 2 -δ) subunit, of voltage-dependent calcium channels, and which possesses analgesic, anxiolytic and antiepileptic properties [START_REF] Tassone | Pregabalin: A novel gammaaminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders[END_REF]. In placebo controlled clinical trials, PGB has demonstrated efficacy in ameliorating pain relief and in improving the affective component of pain and sleep disturbances in patients with peripheral diabetic neuropathy [START_REF] Rosenstock | Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebocontrolled trial[END_REF][START_REF] Lesser | Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial[END_REF][START_REF] Richter | Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial[END_REF][START_REF] Freynhagen | Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible-and fixed-dose regimens[END_REF], postherpetic neuralgia [START_REF] Dworkin | Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial[END_REF][START_REF] Sabatowski | 1008-045 Study Group (2004) Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial[END_REF][START_REF] Van Seventer | Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial[END_REF], and spinal cord injury , a model of central neuropathic pain [START_REF] Siddall | Pregabalin in central neuropathic pain associated with spinal cord injury: a placebocontrolled trial[END_REF]. However, there is no information on the effect of PGB in patients with cervical or lumbosacral radiculopathy under routine clinical practice ("real world" conditions); these patients representing up to two-thirds of all cases of neuropathic pain in same studies [START_REF] Berger | Clinical characteristics and economic costs of patients with painful neuropathic disorders[END_REF].

The present work was conducted to show evidence from the clinical practice of the effect of PGB upon different Patient-Reported-Outcomes (PROs), representative of the multidimensional nature of these disorders, in a large group of subjects with painful cervical or lumbosacral radiculopathy treated in the primary care setting under conditions of routine clinical practice.

Methods

Study design

This work presents the results of a secondary analysis of a multicentre, observational (naturalistic) and prospective 12-week study, whose objective was to assess the cost of refractory painful radiculopathy of cervical, or lumbosacral origin in Primary Care Settings under real life conditions: the LIRA study [START_REF] Saldaña | Health, non-health resources utilization and costs of treating refractory painful Radiculopathy in Primary Care Settings (PCS) under routine medical practice in Spain[END_REF]. The study was carried out between September 2005 and April 2006, and involved the participation of 381 primary care physicians randomly selected by quotas according to regional population density in Spain. This was a noninterventional study, and the analgesic treatment administered to the patients was determined by the clinical judgment of the supervising physician. The physician could substitute previous treatment with some other drug, or add a new drug to the existing treatment. In accordance to the Spanish recommendations, the study was approved by the Ethics Committee of Hospital de la Princesa (Madrid), and it was conducted in agreement with the principles contained in the Declaration of Helsinki for studies in humans.

The objective of this secondary analysis was to compare the effect of two patterns of PGB treatment, add-on and monotherapy (PGB add-on and PGB monotherapy groups), when compared with a treatment pattern not including PGB (non-PGB group) on pain alleviation and associated symptoms involving depression, anxiety, sleep, disability and quality of life.

Study population

The original study included patients of both genders aged 18 years or older. The subjects were refractory to previous analgesia and suffered chronic pain with a duration of over 6 months. Refractory was defined as no pain reduction after treatment with at least one course of an analgesic in monotherapy. The pain was secondary to cervical radiculopathy, defined as neck pain irradiating towards the arms, or to lumbosacral radiculopathy, defined as lumbar or sacral pain irradiating to the calves or feet and exhibiting a distribution consistent with involvement of nerve root L5 or S1, respectively. In addition, the patients were required to present a score of ≥ 4 in the DN4 neuropathic pain diagnostic questionnaire (see below), have a sufficient cultural and educational level to complete health questionnaires written in Spanish, and give their informed consent. This secondary analysis only included those patients who met the aforementioned selection criteria, and who had not received treatment with PGB prior to the start of the study.

The study sample size was defined for the primary endpoint of the LIRA study, i.e., the determination of cost and its evolution after 12 weeks of follow-up, under conditions of routine clinical practice in the PCS. Therefore, no sample size predetermination was made for the secondary analysis presented in this work.

Clinical evaluations and measurement instruments

The patients were followed-up for 12 weeks, and were evaluated twice: at baseline and at end of study. At the baseline visit, the clinicians administered the DN4 neuropathic pain diagnostic questionnaire, the selection criteria were checked, and patient sociodemographic data were collected, along with information on the duration of the disease and its treatment, and the use of health care and non-health care resource utilization in the 12 weeks prior to patient inclusion, as reflected in the patient case history. On both the baseline visit and after the 12 weeks of follow-up, the patients were required to complete the Short-Form McGill Pain Questionnaire (SF-MPQ), the Sheehan Disability Inventory (SDI), the Medical Outcomes Study Sleep Scale (MOS), the Hospital Anxiety and Depression Scale (HADS), and the EQ-5D. In addition, the patients kept a diary, with weekly recordings of pain intensity [visual analog scale (VAS) of the SF-MPQ] and health status (health status VAS of the EQ-5D).

The DN4 (Douleur Neuropathique 4 questions) neuropathic pain diagnostic questionnaire consists of 10 items that describe different pain characteristics, and allows discrimination of neuropathic pain from non-neuropathic pain. If the patient exhibits a score of at least 4 out of 10 possible points (range 0-10), the patient is considered to have neuropathic pain, with a sensitivity of 83% and a specificity of 90% [START_REF] Bouhassira | Development and validation of the Neuropathic Pain Symptom Inventory[END_REF][START_REF] Bouhassira | Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)[END_REF][START_REF] Perez | Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component[END_REF].

The main component of the Short-Form McGill Pain Questionnaire (SF-MPQ) comprises 15 descriptors (11 sensory and 4 affective descriptors) that are scored on a scale of 0=no pain to 3=severe pain [START_REF] Melzack | The short-form McGill Pain Questionnaire[END_REF]. The sum of the different intensities in turn yields three pain scores: sensory, affective and total. The second part of the SF-MPQ consists of a 100-mm VAS for scoring the intensity of the pain experienced by the patient in the previous week. The third part of the instrument is a measure of the intensity of pain at the time of the evaluation, and involves a 6-point scale from 0=no pain to 5=unbearable pain.

The Sheehan Disability Inventory (SDI) is a simple and frequently used instrument that evaluates patient functional alteration in three domains: work, social life/leisure, and family life/home responsibilities [START_REF] Sheehan | The measurement of disability[END_REF]. Each domain is scored on an 11-point scale from 0=no impairment to 10=extremely impaired. The instrument contains two additional items that explore perceived stress and social support. The former is likewise scored on an 11-point scale, while perceived social support is scored on an 11-point scale expressed as percentages from 0%=no support to 100%=ideal support. The SDI yields three scores: the disability score consisting of the sum of the scores of the first three items, ranging from 0-30; the fourth item (perceived stress) score, ranging from 0-10; and the fifth item (social support) score, which, unlike the previous four scores, must be inverted.

The Medical Outcomes Study Sleep Scale (MOS) is a self-administered questionnaire that explores key aspects of sleep [START_REF] Hays | Sleep measures[END_REF]. It consists of 12 items distributed into 6 subscales or domains: sleep disturbance, snoring, waking up with shortness of breath or headache, the adequacy of sleep, daytime somnolence, and amount of sleep. In addition, the MOS-sleep provides a summarizing index of sleep problems based on the scores of 9 of its itemsthe higher the score is, the worse the sleep, except when referring to the dimensions amount of sleep and adequacy of sleep, which are interpreted in the opposite manner. The scale has shown good psychometric properties in patients with neuropathic pain [START_REF] Rejas | Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain[END_REF].

The Hospital Anxiety and Depression Scale (HADS) is also a self-administered instrument composed of 14 items, of which 7 explore symptoms of depression and 7 assess anxiety [START_REF] Zigmond | The hospital anxiety and depression scale[END_REF]. Each item is scored from 0 to 3, where 0=no symptom and 3=most severe or frequent symptom. The two scores are obtained by adding the 7 items of each subscale -one relating to depression and the other to anxiety (HADS-D and HADS-A) -each score ranging from 0 to 21 points.

The EQ-5D questionnaire evaluates patient-perceived health [START_REF] Euroqol | EuroQol -A new Facility for the Measurement of Health-Related Quality of Life[END_REF]. It offers a generic measure of health based on 5 items that explore the degree of alteration in 5 dimensions: mobility, personal care, daily life activities, pain/discomfort, and anxiety/depression. The scores of the 5 items can be used to calculate a utility index that varies from -0.6 to 1.0, where the highest scores correspond to better patient health. The instrument also includes a 20-cm visual analog scale (EQ-5D VAS) ranging from 0=worst imaginable health status to 100=best imaginable health status.

As the original study was designed as an observational epidemiological research, forced adverse events reporting (i.e.: type of adverse event, seriousness, etc.) could not be implemented except to document the reason for discontinuation before the end of study visit.

Statistical analysis

For the statistical analysis of this secondary evaluation, and according to the treatment prescribed from the baseline visit as established by clinical judgment, the patients were divided into three groups: patients that substituted or added another drug other than PGB to previous treatment (Non-PGB group); patients that substituted previous treatment with PGB as monotherapy (PGB monotherapy group); and patients that received PGB added onto the existing therapeutic regimen (PGB add-on group).

The baseline characteristics of the patients are reported as the mean and standard deviation for quantitative variables, while qualitative variables are represented as absolute and relative frequencies. Normality distribution assumptions were verified using the Kolmogorov-Smirnov test. Analysis of variance (ANOVA), the Kruskal-Wallis test and the chi-square test were used to assess the baseline homogeneity of the variables in the three study groups.

The proportion of patients with a reduction of at least 50% in pain intensity as rated by the SF-MPQ pain VAS was calculated and defined as responders. The cumulative number of days without pain or with mild pain was calculated (< 40 mm on the VAS of the SF-MPQ). In addition, the changes in the above mentioned scales and subscales versus baseline were used as assessment variables. The comparison between groups of the changes in quantitative variables versus baseline was carried out by analysis of covariance (ANCOVA), adjusting for the baseline score on each corresponding scale and the number of previous drugs. In turn, the changes in ordinal qualitative variables versus baseline were evaluated by means of a logistic regression model, adjusting for the baseline score and the number of previous drugs. These analyses were made in application to the included patients that completed the 12 weeks of follow-up, and for whom changes in the baseline variables could be calculated. The statistical significance of the comparisons between treatments groups was adjusted by means of the Tukey multiple comparisons method. All statistical tests were two-sided, and statistical significance was considered for p<0.05.

With the purpose of evaluating the clinical significance of the changes in the different measurements, a calculation was made of the effect size obtained, based on the difference between the means of a given measurement before and after treatment, divided by the corresponding standard deviation measured before treatment [START_REF] Kazis | Effect sizes for interpreting changes in health status[END_REF]. Interpretation of the effect size was based on the established criterion which considers an effect size of 0.20 -<0.50 as small; a size of ≥ 0.50 and < 0.80 as moderate; and a size of ≥ 0.80 as large [START_REF] Kazis | Effect sizes for interpreting changes in health status[END_REF].

Based on the weekly patient scores corresponding to the VAS of the EQ-5D, calculations were made of the gains in QALYs (quality-adjusted life years) after 12 weeks of follow-up. The direct VAS score divided by 100 was used as an estimator of utility value (in metric terms 0 -1, where 0=death and 1=perfect health), from which the gain in QALYs was calculated. Trapezoidal approximation was used for this calculation, employing the baseline and weekly utility values as reference values [START_REF] Brooks | EuroQoL: the current state of play[END_REF].

Results

Patient distribution

A total of 1,879 patients were included in the LIRA study, of which 1,351 had not been previously exposed to PGB and met the inclusion / exclusion criteria for this secondary analysis. The analysis was finally performed in 1,304 patients (96.5%) that completed the 12 weeks of the study. Figure 1 reports these data, along with the causes of patient losses to followup. Radiculopathy was of lumbar origin in 86.9% of cases, and of cervical origin in 13.1% (without significant differences in this distribution according to treatment group).

Baseline demographic and clinical characteristics

The recruited population was of middle age, with a female predominance, and over half of the subjects were without working activity (Table 1). On average, patients had painful radiculopathy for two years and were treated with at least one curse of an analgesic. The most frequent previous treatments were analgesics, particularly nonsteroidal antiinflammatory drugs (NSAIDs) and paracetamol, which were used by at least 60% and almost 50% of the subjects, respectively. Frequency of previous drug use was numerically different between groups.

However, except for vitamin use (more frequently used by PGB add-on group, p<0.001), differences in the others type of drug were hardly statistical significant (Table 1). The three treatment groups were similar in terms of demographics characteristics, with the exception of fewer previous treatments in the PGB monotherapy group versus the other two groups (Table 1). The patients in the PGB add-on group generally presented with poorer clinical conditions, with increased pain intensity, worst social and working activity, and poorer quality of life (Table 2). Although of questionable clinical relevance, anxiety levels were significantly greater in the PGB add-on group than in the other two groups (Table 2). There were no differences with regard to sleep disturbances.

Drug therapy during study

Most of the patients in the non-PGB group (67%) received two or more drugs for pain treatment [mean (SD): 2.2 (1.4)], the most frequent being paracetamol (37%, mean dose+standard deviation: 2.144±1.010 mg/day), metamizol (21%, 1,087±455), tramadol (19%, 157±60 mg/day), ibuprofen (17%, 1.094±451 mg/day), diclofenac (16%, 88±49), gabapentin (13%, 989±594 mg/day), tetrazepam (8%, 65+24 mg/day), diazepam (6%, 6+3 mg/day), fentanil (6%, 59+23 mg/day), codeine (6%, 59+23 mg/day) and amitriptyline (5%, 38+28 mg/day). In the PGB monotherapy group, the mean dose was 187±106 mg/day. The most frequently used drugs in the PGB add-on group (mean dose: 191±107 mg/day) were paracetamol (42%, 2.146±1.077 mg/day), ibuprofen (21%, 1.218±555 mg/day), tramadol (20%, 163±81 mg/day), diclofenac (13%, 126±52), metamizol (11%, 1.517±863 mg/day), tetrazepam (7%, 80+42 mg/day), diazepam (6%, mean dose 7+4 mg/day), amitriptyline (5%, 28+20 mg/day) and fentanil (3%, mean dose 48+23 mg/day). The mean number of drugs during the study in this group was 2.8 (1.1).

Patient-Reported-Outcomes (PROs) Pain reduction

The three groups showed significant and clinically relevant reductions in pain severity after 12 weeks of follow-up (Table 3). Pain reduction proved significantly greater in the groups administered PGB, with changes of 56% and 51%, respectively, for PGB as monotherapy and add-on treatment, versus 36% in the patients who did not receive PGB (p<0.0001, Table 3). The differences in pain reduction were significant from the fourth week, and maintained until the end of the study (Figure 2)resulting in an increased cumulative number of days with no/mild pain (<40 mm on the VAS of the SF-MPQ) in the groups administered PGB versus the patients without PGB (p<0.0001, Table 3). At the end of the study, 63% and 56% of the patients administered PGB as monotherapy and on an add-on basis, respectively, showed a 50% reduction in pain intensity (responders), versus 33% in the non-PGB group (p<0.0001, Table 3).

Other Patient-Reported-Outcomes measurements

Improvements in comorbid conditions including sleep disturbances, depression and anxiety were significantly superior in the patients administered PGB, with clinically relevant improvement (large effect size), while the changes in the non-PGB group were only moderate (Tables 4 and5). The effect upon sleep showed a similar pattern for the 6 dimensions of the MOS-sleep scale, though none of the treatment groups showed relevant changes in the dimensions "snoring" or "waking up with shortness of breath or headache" (table 5). On the other hand, with the exception of "sleep disturbance", which exhibited a moderate effect size, the changes in the non-PGB group for all the MOS-Sleep dimensions were small. In contrast, the PGB-treated groups showed large changes for "sleep disturbance" and "adequacy of sleep", with moderate changes for "amount of sleep" and "daytime somnolence" (Table 5).

All treatment groups showed relevant improvement in the impact of painful radiculopathy on patient perceived stress and social and working activities as measured by the SDI (Table 4). Once again, these changes were significantly greater in the two groups that received PGB. General patient health according to the EQ-5D VAS also improved significantly more in the PGB-treated groups, and the clinical impact was likewise greater as measured by the effect size (Table 4), in turn giving rise to a greater gain in QALYs in the groups exposed to PGB (Table 4). These differences were seen to be significant from week 5 of the study, and maintained until week 12 (Figure 3). In general terms, the benefit observed in each of the 5 dimensions of the EQ-5D was significantly greater in the groups treated with PGB, particularly among those patients that received the drug as monotherapy (Table 4).

Discussion

Few randomized clinical trials have been run in patients presenting with pain with a neuropathic component secondary to radiculopathy, and particularly in general in chronic pain of mixed origin [START_REF] Finnerup | Algorithm for neuropathic pain treatment: an evidence based proposal[END_REF]. In addition, very few current trials address the pharmacological management of these clinical conditions. Our data appear to be the first involving PGB for the management of cervical and lumbosacral radiculopathy under conditions of routine clinical practice in the primary care setting. Our findings suggest that PGB is effective under "Real World" conditions for treating pain of this kind and also for ensuring clinically relevant improvement in the associated symptoms of anxiety, depression and sleep disturbances -with amelioration of patient disability and improvement in quality of life.

Monotherapy with PGB, or as an add-on therapy, produced a very marked decrease in pain (over 50%), with a large effect size. The proportion of responders, 63% and 56% in the monotherapy and add-on groups, respectively, was at least similar to that recorded in clinical trials of PGB among patients with diabetic neuropathy (39% and 48%) [START_REF] Rosenstock | Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebocontrolled trial[END_REF][START_REF] Lesser | Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial[END_REF][START_REF] Richter | Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial[END_REF], postherpetic neuralgia (28-50%) [START_REF] Dworkin | Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial[END_REF][START_REF] Sabatowski | 1008-045 Study Group (2004) Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial[END_REF][START_REF] Van Seventer | Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial[END_REF], and superior to the proportion observed in patients with central neuropathic pain associated with spinal cord injury (22%) [START_REF] Siddall | Pregabalin in central neuropathic pain associated with spinal cord injury: a placebocontrolled trial[END_REF]. The apparent analgesic superiority versus the subjects that did not receive PGB proved consistent across all outcome measures, with large effect sizes for the most part, and likewise superior to those seen in the non-PGB patients. These data point to the broad activity spectrum of PGB in application to pain with a neuropathic component. Although always difficult to interpret in the context of an observational study, it cannot be ruled out that this apparent superiority may be due in part to inadequate management of patients belonging to the non-PGB group. In a large percentage of cases, these latter patients were treated with NSAIDs (67%) or paracetamol (37%). While these drugs have an effect upon the somatic component of pain, they have not been shown to be effective in the management of neuropathic pain. In contrast, only 13% of the patients received gabapentin, amitriptyline in 5%, and 25% received opioids. This situation is almost analogous to that described in other countries such as the United Kingdom or Spain, likewise in the primary care setting, where NSAIDs are widely used for the treatment of mixed presentations (65%), while the use of drugs of proven clinical efficacy in the treatment of neuropathic pain, such as antiepileptic agents or tricyclic antidepressants, is more limited (10% and 3%, respectively) [START_REF] Gore | Clinical characteristics and pain management among patients with painful peripheral neuropathic disorders in general practice settings[END_REF][START_REF] Rodríguez | A Registry of the Aetiology and Costs of Neuropathic Pain in Pain Clinics: Results of the Registry of Etiologies and Costs (REC) in Neuropathic Pain Disorders Study[END_REF].

The effect of PGB on comorbid symptoms of sleep disturbances, depression and anxiety, was significantly superior in the patients administered PGB -with large effect sizes, versus the moderate changes seen in the non-PGB group. Given the frequent co-occurrence of these comorbidities in such patients [START_REF] Argoff | The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach[END_REF], the role of PGB proves particularly useful in such situations. While opiods have been shown to be effective in reducing neuropathic pain [START_REF] Finnerup | Algorithm for neuropathic pain treatment: an evidence based proposal[END_REF], their beneficial effects upon patient mood, disability and quality of life are not consistent [START_REF] Watson | Controlledrelease oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy[END_REF][START_REF] Gimbel | Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial[END_REF]. In addition, the beneficial effect of PGB on treating comorbid conditions could reduce health care resource utilization and costs. As an example, it has been reported that in patients with back pain, existing physical and mental comorbidities, led to a significant increase in health care costs [START_REF] Ritzwoller | The association of comorbidities, utilization and costs for patients identified with low back pain[END_REF]. Globally, the superior effectiveness of PGB in ameliorating pain, and its greater effect upon associated comorbidities, could explain the improvement we recorded in relation to social and working incapacitation and quality of life, compared with the patients administered other treatments.

The mean PGB dose used in our study, about 190 mg/day, lies within the effective dosing range for neuropathic pain (150-600 mg/day), and perhaps is at the lower limit when compared with the doses used in clinical trials with PGB. Most of the PGB trials mentioned above made use of a fixed-dose scheme; comparisons with our study are therefore difficult to establish. However, in a randomized clinical study of PGB versus placebo in patients with neuropathic pain associated to peripheral diabetic neuropathy or postherpetic neuropathy, in which a flexible dosing scheme was used, the mean dose was almost double what we observed in routine practice (372 mg/day) [START_REF] Freynhagen | Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible-and fixed-dose regimens[END_REF]. Whether lower doses are needed in clinical practice, or whether simple underdosing is involved, is a question which our study was unable to answer. However, underdosing seems more likely, since the prescription of doses lower than those recommended for pain, including pain of neuropathic origin, is often reported in the literature [START_REF] Van Seventer | A cross-sectional survey of health state impairment and treatment patterns in patients with postherpetic neuralgia[END_REF][START_REF] Gore | Clinical characteristics and pain management among patients with painful peripheral neuropathic disorders in general practice settings[END_REF].

Despite the lack of evidence from randomized clinical trials, it is common in clinical practice to use combinations of several drugs to treat pain with a neuropathic component [START_REF] Sindrup | Pharmacotherapy of trigeminal neuralgia[END_REF][START_REF] Dworkin | Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations[END_REF][START_REF] Gilron | Trends in opioid use for chronic neuropathic pain: a survey of patients pursuing enrollment in clinical trials[END_REF][START_REF] Gore | Burden of illness in painful diabetic peripheral neuropathy: the patients' perspectives[END_REF]. In our analysis, the PGB add-on treatment group yielded superior results compared with patients administered other treatments, and with the exception of pain, these results were moreover analogous to those obtained with PGB in monotherapy. While statistically significant, the differences observed in pain management with PGB as monotherapy compared with the PGB add-on group are of scant clinical relevance for a number of reasons: the patients in the PGB add-on group generally presented with more severe symptoms; the differences in effect size between the two PGB-treated groups were not large; and the impact upon patient disability and quality of life was similar in both groups.

Our study provides data on the effectiveness of adding PGB to existing analgesic treatment. Nevertheless, it would be worthwhile to conduct controlled clinical trials to evaluate the possibility that PGB combined with an analgesic could be superior to the drugs in monotherapy for the management of painful radiculopathy of mixed origin. There is some evidence to suggest that this may be the case. Some analgesics such as paracetamol or the NSAIDs are ineffective in application to pure neuropathic pain condition, but may be of help in the presence of a nociceptive component. On the other hand, a randomized and placebo controlled trial involving the combination of pregabalin and an NSAID has shown better performance than the drugs in monotherapy, as preoperative analgesia in vertebral fusion surgery [START_REF] Reuben | The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery[END_REF].

Our study, however, has some limitations that must be taken into account. Because of its observational nature, it is exposed to bias and confounding factors. The impact of such bias, particularly selection bias, is difficult to establish. However, at least in the PGB add-on treatment group, such bias probably acts against the drug, since these were more seriously affected patients. On the other hand, the logical open-label design may have overestimated the effect of treatment. Another limitation of our study is represented by the fact that the study did not specifically assess the effect of pharmacological intervention, hence we have no systematic evaluation of the tolerability of the treatments. However, the high proportion of patients that completed the treatment in all the groups analyzed, and the low incidence of drop-outs attributable to adverse effects, suggest that the three treatment strategies were very well tolerated. Last, it is worthy to comment on the diagnosis of radiculopathy in the study. While patients were identified using ICD-10 classification criteria for radiculopathies in conjunction with a diagnostic tool administered to assist general practitioners in categorizing the neuropathic component of pain, we cannot exclude the possibility of misdiagnosis to some extent.

Conclusions

Overall, in spite of these limitations, the results of this analysis complement the findings observed with PGB in clinical trials, then consolidating PGB as an effective therapy for the treatment of the neuropathic component of pain in subjects with cervical or lumbosacral radiculopathy in real world conditions of care. This effectiveness resulted in a reduction of the associated symptoms of pain in routine medical practice, leading to lower disability and better quality of life of patients. To conclude, our analysis suggests that in routine clinical practice, pregabalin both as monotherapy and in combination, is associated with considerable pain reduction and important improvement in associated symptoms such as sleep, affective disorders and anxiety. In addition, PGB treatment reduces associated disability and improves the health condition of patients with neuropathic pain associated with cervical or lumbosacral radiculopathy. The possible superiority of this drug over other treatments, the usefulness of pregabalin doses higher than those used in this analysis, and the potential utility of combining the drug with other treatments for the management of this type of neuropathic pain are aspects that should be further examined in the context of randomized clinical trials. 1 Total number of patients analyzed; some subjects failed to report the data relating to certain variables; *Sum of the scores of the first 3 items; † Patients responding without problems in the item.

Figure 1 .

 1 Figure 1. Patient disposition.

Figure 2 .

 2 Figure 2. Mean weekly change in pain intensity as scored by the VAS of the SF-MPQ.

Figure 3 .

 3 Figure 3. Mean weekly change in health status as scored by the VAS of the EQ-5D.

Table 1 .

 1 Demographic and clinical characteristics. Total number of patients analyzed; some subjects failed to report the data relating to certain variables;2 The patients could have received more than one previous treatment;3 Includes lidocaine, corticoids.

	Characteristic	Non-PGB (N=155) 1	PGB monotherapy (N=473) 1	PGB add-on (N=676) 1	p
	Sex (female), n (%)	90 (57.8)	262 (55.3)	377 (55.8) 0.879
	Age (years), mean (SD)	56.3 (13.2)	56.0 (12.7)	57.2 (12.1) 0.230
	Body mass index (kg/m 2 )	27.9 (4.2)	27.3 (3.8)	27.5 (3.8)	0.204
	Marital status (married or with couple), n (%)	120 (77.2%)	342 (72.3%) 498 (73.6%) 0.525
	Labor status, n (%)				0.149
	Active	43 (27.9)	111 (23.3)	178 (26.3)
	Housewife	26 (16.9)	70 (14.7)	114 (16.8)
	Sick leave	21 (13.6)	44 (9.1)	98 (14.5)
	Unemployed	9 (5.8)	18 (3.7)	26 (3.7)
	Retired	46 (29.9)	199 (42.1)	231 (34.1)
	Unknown	9 (5.8)	33 (7.0)	30 (4.5)
	Duration (years), mean (SD)	2.1 (3.7)	2.1 (4.1)	1.9 (3.4) 0.117
	No. previous treatments, mean (SD)	2.8 (1.7)	2.2 (1.3)	2.7 (1.4) <0.001
	Previous treatments 2 , n (%)
	NSAID	104 (67.1)	294 (62.2)	460 (68.1)	0.039
	Paracetamol	75 (48.4)	207 (43.7)	317 (46.9)	0.442
	Metamizol	41 (26.4)	96 (20.2)	134 (19.8)	0.174
	Opioids	63 (40.6)	136 (28.8)	219 (32.4)	0.022
	Antiepileptic drug	16 (10.1)	48 (10.2)	49 (7.3)	0.173
	Tricyclic antidepressants	14 (8.8)	24 (5.1)	59 (8.8)	0.049
	Benzodiazepines	21 (13.5)	78 (16.5)	137 (20.2)	0.077
	Vitamins (B6,B12)	17 (11.0)	25 (5.3)	88 (13.1)	<0.001
	Others 3	10 (6.4)	19 (4.0)	78 (11.5)	<0.001
	NSAID: nonsteroidal antiinflammatory drug; SD: standard deviation; AED: antiepileptic drug; NPP: neuropathic
	pain; PGB: pregabalin; 1

Table 2 .

 2 Baseline visit patient-reported health outcomes. Total number of patients analyzed; some subjects failed to report the data relating to certain variables; *Sum of the scores of the 3 disability items; † Patients responding without problems in the item.

	Health outcome	Non-PGB (N=155) 1	PGB monotherapy (N=473) 1	PGB add-on (N=676) 1	P
	SF-MPQ, mean (SD)
	Sensory	15.5 (5.8)	15.1 (6.0)	16.0 (6.0)	0.045
	Affective	4.8 (3.3)	4.4 (3.2)	5.0 (3.2)	0.012
	Total	20.3 (8.4)	19.5 (8.4)	21.0 (8.5)	0.016
	PPI (0-5)	2.7 (0.8)	2.7 (0.8)	2.8 (0.8)	0.014
	VAS (0-100)	71.4 (15.3)	70.4 (14.6)	72.7 (15.3)	0.032
	MOS-sleep, mean (SD)
	Summary index (0-100)	47.6 (16.9)	46.2 (17.2)	48.4 (17.2)	0.096
	Sleep disturbance (0-100)	50.6 (20.1)	48.5 (19.5)	51.96 (19.6)	0.015
	Snoring (0-100)	39.3 (30.6)	37.3 (28.6)	37.4 (28.6)	0.754
	Shortness of breath (0-100)	30.1 (25.4)	29.5 (26.6)	31.3 (26.0)	0.539
	Sleep quantity, hours	5.8 (1.5)	5.8 (1.4)	5.6 (1.3)	0.004
	Adequacy of sleep (100-0)	39.1 (23.6)	40.0 (23.1)	36.8 (23.2)	0.067
	Daytime somnolence (0-100)	40.2 (19.4)	38.1 (19.0)	37.5 (19.0)	0.230
	HADS, mean (SD)
	Depression (0-21)	10.8 (4.5)	10.0 (4.5)	10.7 (4.4)	0.014
	Anxiety (0-21)	10.5 (3.9)	9.9 (3.9)	10.6 (3.8)	0.022
	SDI, mean (SD)
	Disability (0-30)*	18.9 (6.0)	18.4 (5.8)	20.0 (5.4)	<0.001
	Perceived stress (0-100)	6.0 (2.1)	5.9 (2.1)	6.3 (1.9)	0.007
	Perceived social support, % (0-100)	58.1 (22.3)	56.0 (22.4)	57.4 (23.6)	0.503
	EQ-5D
	VAS, mean (SD) (0-100)	42.3 (17.2)	42.5 (18.2)	38.9 (17.5)	0.002
	Mobility † , n (%)	53 (34.9)	134 (28.9)	181 (27.0)	0.051
	Personal care † , n (%)	59 (38.8)	203 (43.8)	264 (39.5)	0.156
	Daily life activities † , n (%)	21 (13.8)	51 (11.1)	47 (7.0) <0.001
	Without pain, n (%)	5 (3.3)	11 (2.4)	8 (1.2)	0.002
	Without anxiety/depression, n (%)	37 (24.5)	127 (27.4)	150 (22.5)	0.010
	SD: standard deviation; VAS: visual analog scale; HADS: Hospital Anxiety Depression Scale; MOS: Medical
	Outcomes Study; PGB: pregabalin; PPI: present pain intensity; SDI: Sheehan Disability Inventory; SF-MPQ: Short
	Form McGill Pain Questionnaire. 1

Table 3 .

 3 Mean and magnitude of change (effect size) of the different pain parameters measured by the SF-MPQ according to treatment group. Short Form McGill Pain Questionnaire.1 Total number of patients analyzed; some subjects failed to report the data relating to certain variables; *Responders: patients with a reduction of at least 50% in pain intensity as scored by the VAS of the SF-MPQ.

	Health outcome	Non-PGB (N=155) 1	PGB monotherapy (N=473) 1	PGB add-on (N=676) 1	P
	SF-MPQ
	Sensory	-5.1 (5.6) [0.88]	-8.3 (6.3) [1.38]	-8.0 (5.9) [1.33]	<0.001
	Affective	-2.2 (2.7) [0.66]	-2.9 (3.0) [0.91]	-3.0 (2.9) [0.94]	<0.001
	Total	-7.4 (7.6) [0.88]	-11.2 (8.5) [1.33]	-11.0 (8.0) [1.29]	<0.001
	PPI	-0.9 (1.0) [1.13]	-1.5 (1.0) [1.88]	-1.4 (1.0) [1.75]	<0.001
	SF-MPQ Intensity (VAS)
	mm	-25.0 (22.0) [1.63]	-40.1 (23.2) [2.75]	-37.1 (24.0) [2.42]	<0.001
	%	35.6 (27.8)	56.4 (27.6)	50.7 (27.4)	<0.001
	Responders (%)*	32.9	62.8	56.3	<0.001
	Cumulative days without pain or mild pain (VAS<40 mm)	20.2 (26.9)	36.3 (29.7)	30.7 (28.9)	<0.001

Values given as mean (standard deviation)[effect size]; VAS: visual analog scale; PGB: pregabalin; PPI: present pain intensity; SF-MPQ:

Table 4 .

 4 Mean and magnitude of change (effect size) of the patient reported health outcomes at the end of the study, according to treatment group.

	Health outcome	Non-PGB (N=155) 1	PGB monotherapy (N=473) 1	PGB add-on (N=676) 1	P
	HADS
	Depression (0-21)	-2.5 (4.0) [0.55]	-3.9 (4.3) [0.87]	-3.8 (4.2) [0.86]	<0.001
	Anxiety (0-21)	-2.2 (3.4) [0.56]	-3.8 (4.0) [0.97]	-3.6 (3.6) [0.95]	<0.001
	SDI
	Disability (0-30)*	-5.7 (5.9) [0.95]	-9.2 (6.5) [1.59]	-8.9 (6.3) [1.65]	<0.001
	Perceived stress (0-100)	-1.8 (2.1) [0.86]	-3.0 (2.3) [1.43]	-2.8 (2.2) [1.47]	<0.001
	Perceived social support, % (0-100)	-1.4 (1.8) [0.06]	-2.4 (2.4) [0.11]	-1.2 (1.9) [0.05]	0.004
	EQ-5D
	VAS (0-100)	18.6 (22.3) [1.08]	29.2 (22.2) [1.60]	29.5 (21.2) [1.69]	<0.001
	Mobility † , n (%)	77 (50.7)	303 (65.3)	410 (61.1)	<0.001
	Personal care † , n (%)	90 (59.2)	360 (77.6)	487 (72.9)	<0.001
	Daily life activities † , n (%)	50 (32.9)	252 (54.7)	306 (45.7)	<0.001
	Without pain, n (%)	26 (17.1)	165 (35.7)	160 (23.9)	<0.001
	Without anxiety/depression, n (%)	74 (49.0)	302 (65.1)	388 (58.3)	0.002
	QALYs gained	0.0284 (0.0409)	0.0407 (0.0389)	0.0427 (0.0369)	<0.001

Values given as mean (standard deviation)[effect size]; VAS: visual analog scale; HADS: Hospital Anxiety Depression Scale; MOS: Medical Outcomes Study; PGB: pregabalin; SDI: Sheehan Disability Inventory; QALY: Quality-adjusted life year.

Acknowledgments

The authors thank Fernando Rico-Villademoros MD, for his assistance in the preparation of the draft of this manuscript.

This study was funded by an unrestricted grant from Pfizer Spain.

Competing interests

One of the authors of this study, Javier Rejas, is an employee of Pfizer Spain, which is the entity funding this project.

Mª Teresa Saldaña, Ana Navarro and Concepción Pérez have received honoraries from Pfizer Spain.