Bruno Tumiati

Hearing Loss in the Sjogren Syndrome

Ear involvement in autoimmune diseases is not unusual. Sensorineural hearing loss is commonly reported as the first otologic manifestation of Wegener granulomatosis [1], polyarteritis nodosa [2], systemic lupus erythematosus [3], and rheumatoid arthritis [4, 5]. Furthermore, although a high prevalence of cranial neuropathies resulting from the Sjogren syndrome is generally recognized, symptoms and signs of eighth-nerve disorder have not been specifically sought [6]. The lack of published data on the connection between the Sjogren syndrome and auditory function prompted us to study whether such a relation exists and, if it does, to determine its pathogenesis. Methods Patients The initial study sample consisted of 31 women with a mean age of 52 years. These were all of the patients with the Sjogren syndrome who were consecutively seen at Reggio Emilia Hospital (a secondary referral center) in Reggio Emilia, Italy, from April 1993 to May 1995. Patients were classified as having primary Sjogren syndrome by the criteria established by Vitali and colleagues [7]. All patients had objective keratoconjunctivitis sicca, xerostomia, and biopsy specimens from the minor salivary gland that were class 3 or higher [8]. No patient met the criteria for any other connective tissue disease. Forty-five female blood donors volunteered to serve as controls and were matched with the patients for age. No control had a history of or symptoms compatible with such autoimmune diseases as xerophthalmia, xerostomia, or the Raynaud phenomenon. Inclusion criteria for both groups were intact tympanic membranes without visible scarring; no previous use of ototoxic drugs; and no history of otorrhea, otologic surgery, exposure to occupational or recreational noise, and skull trauma or infection of the upper respiratory tract at least 1 month before the study began. Thirty patients with the Sjogren syndrome and 40 controls met these criteria. All patients gave written informed consent. Audiologic Evaluation Otologic evaluation, including pneumatic examination with a hand-held micro-otoscope, was done by the same otolaryngologist in all patients. Audiologic tests, including the assessment of pure tone air and bone conduction thresholds, were conducted in a soundproof chamber with an Amplaid 455 audiometer (Ampliphon, Milan, Italy), calibrated according to the criteria of the American National Standards Institute. Pure tone thresholds at 125, 250, 500, 1000, 2000, 4000, and 8000 Hz were calculated for each ear. Hearing was classified as subnormal if the patients audiogram was more than 20 dB below the accepted normal reading for the patients age group at more than one test frequency in one or both ears. Patients with sensorineural hearing loss were further assessed by use of such supraliminal tests as the Fowler balance test, the Short Increment Sensitivity Index, and the Rosenberg threshold tone decay test. As measured by the tone decay test, decay greater than 15 dB within 1 minute was considered pathologic. Scores on speech reception threshold and speech discrimination tests were then evaluated. Middle-ear pressure was measured, and tympanometric graphs were plotted by using a Grason-Stadler GS33/1 acoustic impedance meter (Grason-Stadler, Inc., Littleton, Massachusetts) at a probe tone frequency of 220 Hz; Jerger and Jergers differentiation of tympanograms [9] was used to analyze the study data. The ipsilateral and contralateral stapedius reflexes were tested using pure tones (500 to 4000 Hz). Patients with bilateral, symmetrical sensorineural hearing loss and cochlear involvement did not have further testing. Patients with unilateral deafness and supraliminal test results that suggested retrocochlear disease were evaluated for brainstem auditory evoked potentials; a positive result on this test was followed by magnetic resonance imaging. Immunologic Evaluation We tested patients for autoantibodies, including antinuclear antibodies, by using kidney and Hep-2 substrate. The presence of antibodies to Ro (SS-A), antibodies to La (SS-B), and IgG and IgM anticardiolipin antibodies was determined by using enzyme-linked immunosorbent assay [10]. Rheumatoid factor was detected in serum samples by using a rheumatoid arthritis latex test. Statistical Analysis Statistical analyses were done by using SAS software, version 6.0 (SAS Institute, Cary, North Carolina). The Fisher exact test was used to compare percentages, and 95% CIs were calculated. All P values were two tailed; a P value less than 0.05 was considered statistically significant. Results The demographic and clinical data of the 30 study patients with the Sjogren syndrome are summarized in Table 1. Antinuclear antibodies at a titer of 1:320 or greater were present in all 30 patients. Twenty-seven of 30 patients had antibodies to RO, and 20 of 30 had antibodies to La. Results of rheumatoid factor testing were positive in 28 of 30 patients. Three patients had a history of skin lesions for which biopsy had been done; leukocytoclastic vasculitis had subsequently been diagnosed in these patients. Biopsy was done in 4 patients who presented with palpable purpura, and the presence of vasculitis was confirmed. Table 1. Clinical and Laboratory Variables in Patients with the Sjogren Syndrome The results of audiologic assessment showed that patients with the Sjogren syndrome had a higher prevalence of sensorineural hearing impairment than did their normal counterparts (Table 2). Fourteen of the 30 patients with the syndrome had sensorineural hearing loss (46% [95% CI, 28% to 66%]); this condition was bilateral in 10 patients and unilateral in 4 patients. Nine of 14 patients were asymptomatic and had hearing loss that was detectable only on audiologic testing. Hearing loss in the remaining 5 patients was clinically significant: Four patients had moderate hearing loss (35 to 54 dB) and 1 had severe hearing loss (55 to 74 dB), classified on the basis of average pure tone score for speech frequencies of 500, 1000, and 2000 Hz. Table 2. Incidence of Hearing Loss in Patients with the Sjogren Syndrome and in Controls In contrast, only one control (2.5% [CI, 0.06% to 13%]) had sensorineural hearing loss (P < 0.001). One patient with the Sjogren syndrome and one control showed mild bilateral conductive hearing loss. The audiometric configuration for 12 patients with the Sjogren syndrome who had sensorineural hearing loss sloped at a high frequency (2000 to 8000 Hz); the configuration for the remaining 2 patients was essentially flat. The one control with sensorineural hearing loss had a flat audiometric configuration. In two patients with serious unilateral deafness, results of supraliminal tests and speech audiometry showed discrimination scores consistent with retrocochlear disease. We therefore did brainstem auditory evoked potentials and cerebral magnetic resonance imaging. The results of these tests were negative for pontocerebellar diseases. Middle-ear pressure was normal in all patients and all controls. No significant differences in mean compliance value were found between the patients with the Sjogren syndrome and the controls. In the Sjogren syndrome group, no significant statistical relation was found between sensorineural hearing loss and patient age, erythrocyte sedimentation rate, or previous treatment with steroids. The Raynaud phenomenon was present in seven patients with sensorineural hearing loss (50%) and five normoacusic patients (31%); this difference was not statistically significant. No relation between impaired hearing acuity and the presence of vasculitis was seen: Vasculitis was mainly restricted to the skin and was present in three patients with sensorineural hearing loss and four normoacusic patients with the Sjogren syndrome. No statistically significant difference was found in disease duration between patients with abnormal hearing and those with normal hearing. Furthermore, no correlation was found between hearing loss and antinuclear antibody and C3 and C4 levels. Nine of the 14 patients with the Sjogren syndrome who had sensorineural hearing loss (64% [CI, 36% to 86%]) had anticardiolipin antibodies compared with 3 patients (18% [CI, 4% to 45%]) in the normal hearing group (P = 0.02). Of these 9 patients, 3 were positive for IgG anticardiolipin antibodies, 2 were positive for IgM antibodies, and 4 were positive for IgG and IgM antibodies. Two patients with hearing loss and 1 patient without hearing loss had a false-positive result on the VDRL test. Of the 30 patients with the Sjogren syndrome, 90% had antibodies to RO and 66% had antibodies to La. Antibodies to RO were present in all patients with the Sjogren syndrome who had sensorineural hearing loss. Discussion Our results accord with those of previous investigators who showed a high prevalence of sensorineural hearing loss in patients with autoimmune diseases. Involvement of the middle ear is commonly described in patients with Wegener granulomatosis, with an incidence of 35% to 47% [1]. Some studies of patients with rheumatoid arthritis have shown a prevalence of inner-ear disease ranging from 26% to 48%. This incidence does not correlate with age; sex; duration of disease; or previous therapy with salicylates, steroids, or other drugs [4, 5]. In a controlled study of patients with systemic lupus erythematosus [3], 57% of patients had sensorineural hearing loss that was not correlated with the severity of the underlying disease or the presence of vasculitis. A high prevalence of cranial neuropathies is an accepted consequence of the Sjogren syndrome. In addition, symptoms and signs of eighth-nerve disorder have been reported in some cases [6]. It appears, however, that most physicians who regularly treat patients with the Sjogren syndrome do not routinely ask them about hearing or balance or test them for audiologically detectable hearing loss. This suggests that the association between the Sjogren syndrome and sensorineura

Kikuchi's disease in systemic lupus erythematosus: an independent or dependent event?

SummaryThe authors describe necrotizing histiocytic lymphadenitis (Kikuchis disease) in association with systemic lupus erythematosus (SLE). To our knowledge this is the first case report where SLE preceded Kikuchis disease. Whether Kikuchis disease is an independent event or directly connected with SLE is discussed.

PTPN22 R620W polymorphism in the ANCA-associated vasculitides

OBJECTIVES PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations. METHODS PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegeners) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls. RESULTS The frequency of the minor allele (620W) was significantly higher in GPA patients than in controls [P = 0.005, χ(2 )= 7.858, odds ratio (OR) = 1.91], while no statistically significant association was found with MPA or CSS. Among GPA patients, the 620W allele was particularly enriched in ANCA-positive patients as compared with controls (P = 0.00012, χ(2 )= 14.73, OR = 2.31); a particularly marked association was also found with ENT involvement (P = 0.0071, χ(2 )= 7.258, OR = 1.98), lung involvement (P = 0.0060, χ(2 )= 7.541, OR = 2.07) and skin manifestations of all kinds (P = 0.000047, χ(2 )= 16.567, OR = 3.73). CONCLUSION The PTPN22 620W allele confers susceptibility to the development of GPA (but not of MPA or CSS), and particularly of its ANCA-positive subset.

Increased plasma levels of platelet-derived growth factor (PDGF-BB + PDGF-AB) in patients with never-treated mild essential hypertension

Platelet-derived growth factor (PDGF) could play a role in both vascular hypertrophy and atherosclerotic disease associated with hypertension. To assess whether plasma PDGF level is increased in mild essential hypertension, we measured plasma PDGF concentration in 25 never-treated patients with uncomplicated mild essential hypertension and in 22 normotensive healthy subjects. To evaluate the contribution of platelets to plasma PDGF in the two groups, we also measured plasma beta-thromboglobulin (BTG). Measurement of PDGF was carried out through an enzyme-linked immunoadsorbent assay, which detects two PDGF dimers, namely PDGF-BB and PDGF-AB. Both plasma PDGF and BTG were higher in the hypertensive than in the normotensive subjects. The ratio of PDGF to BTG was similar in the two groups. Plasma PDGF was weakly correlated with plasma BTG in the normotensive subjects, whereas this relationship was lost in the hypertensive patients. Our results suggest that the increase in plasma PDGF (PDGF-AB + PDGF-BB) in never-treated essential hypertension is mainly due to platelet activation. The increased circulating level of PDGF could play a role in the vascular structural changes associated with hypertension.

Cogan's syndrome: A new possible complication of antiphospholipid antibodies?

SummaryA 55-year-old woman with a six-year history of Sjögrens syndrome (SS) and the positivity of IgG and IgM antiphospholipid antibodies (aPL) developed a sudden onset of sensorineural hearing loss associated with vertigo. This suggested the presence of an atypical Cogans syndrome (CS), which might be a focal, neurological complication of aPL.

Heart Rate Variability in Patients with Sjögren’s Syndrome

Abstract: Heart rate variability (HRV) gives information about sympathetic–parasympathetic autonomic balance. Our purpose was to determine whether HRV is abnormal in patients with Sjögren’s syndrome. In 16 patients with Sjögren’s syndrome and 30 matched controls, a short time analysis of HRV was performed for both the frequency and the time domain. In the time domain, patients tended to display a slower heart rate, greater R-R variability and higher standard deviation of the mean (SDNN) than did healthy subjects, but the differences were not statistically significant. In the frequency domain the spectral measures of HRV showed a slight reduction of LF and an increase of HF; as a result, the ratio between high and low frequencies, representative of sympathovagal modulation, was significantly reduced. Our data suggest an increase in the parasympathetic control of heart rate in patients with Sjögren’s syndrome. This predominance in vagal tone could exert a protective and antiarrhythmic role in patients with primary Sjögren’s syndrome, and may be relevant with reference to the lower incidence of sudden death in this disorder compared to other major autoimmune diseases.

Epidemiology of granulomatosis with polyangiitis (Wegener׳s granulomatosis) in Northern Italy: A 15-year population-based study

OBJECTIVE To investigate the epidemiology of granulomatosis with polyangiitis (GPA) over a 15-year period in a defined area of northern Italy. METHODS All patients with incident GPA diagnosed from January 1, 1995 to December 31, 2009 living in the Reggio Emilia area were identified by looking at computerized hospital discharge diagnoses, by contacting Reggio Emilia Hospital physicians and community-based specialists, and by checking the databases of the pathology and the laboratory departments and the Reggio Emilia district database for rare diseases. Patients were classified according to the European Medicines Agency (EMA) algorithm. Patients were followed up from the time of diagnosis until either their death or December 31, 2011. For each case, we identified 20 control subjects from the same geographic area matched for age and gender. RESULTS A total of 18 patients (7 men and 11 women) with GPA were identified. The overall age- and sex-adjusted incidence rate (IR) was 2.4 per million (95% CI: 1.2-3.5). The mean annual IR increased from 1.7/million/year during 1995-1999 to 3.4 during 2005-2009. The highest IR occurred in females aged 70-79 years (13.5 per million; 95% CI: 5.0-30.0) and in males aged ≥ 80 years (14.9 per million; 95% CI: 2.5-49.4). The prevalence of GPA on December 31, 2009 was 34.3 per million (95% CI: 20.3-54.2). The point prevalence per million increased from 17.8 (95% CI: 7.7-35.1) in 1999 to 34.3 (95% CI: 20.3-54.2) in 2009. Survival among individuals with GPA was significantly reduced compared to that observed in the matched control population (p < 0.001). CONCLUSION In the Italian population, GPA is very uncommon and GPA patients have reduced survival.

Necrotizing lymphadenitis in systemic lupus erythematosus Kikuchi's disease or a Kikuchi's-like disease?

Kikuchis disease or histiocytic necrotizing lymphadenitis is a recognized cause of benign lymphadenopathy, although the current clinical literature also supports a link with systemic lupus erythematosus (SLE). Eight patients represent all the cases of Kikuchis disease admitted to our hospital from 1990 to 1997. They were all young women of median age of 31 years (range 22-43 years). All patients showed cervical lymphadenopathy, and in two cases splenomegaly was present. In one patient, the diagnosis of lupus preceded the onset of Kikuchis disease by 5 months. In 4 other patients, antinuclear antibodies (ANA) were positive at titers ranging between 1:80 and 1:2560 and were associated with leukopenia ranging from 1190 to 2800 white blood cells/mm3 when the diagnosis of Kikuchis disease was made. Among these, 3 patients developed SLE after periods ranging from 6 to 25 months. The other ANA positive patient and the 2 remaining ANA negative patients did not develop any autoimmune disease after 2-A years of follow-up.The differential diagnosis between Kikuchis disease and lupus lymphadenitis cannot always be clarified histologically. We recommend that patients with necrotizing lymphadenitis, leukopenia, and ANA be closely followed. This should ensure an early diagnosis of development of an autoimmune disorder that will require treatment, rather than always considering these patients to be affected by a benign self-limited disorder like Kikuchis disease.

ENT Wegener’s granulomatosis can hide severe central nervous system involvement

The clinical manifestations of localised or early systemic forms of Wegener’s granulomatosis (WG) do not require immediate treatment to save the patient’s life and/or the function of a vital organ. The organs mainly involved are the ear, nose, throat (ENT) and lung, and the results of antineutrophil cytoplasmic antibody (ANCA) assays are frequently negative. We here describe three cases of the ANCA-negative early systemic form of WG with prevalent ENT involvement complicated by severe central nervous system (CNS) disease; in two cases, the only symptom was a mild headache. We conclude that, although apparently mild, the localised and early systemic forms of WG can hide CNS involvement and may require immediate treatment. This complication should be suspected and investigated in the case of patients with localised or early systemic disease especially in the presence of ENT involvement and negative ANCA assays.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial

Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517