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Review – nose – throat manifestations of autoimmune rheumatic diseases E.D. Papadimitraki1, D.E. Kyrmizakis2, I. Kritikos1, D.T. Boumpas1,3

Department of 1Rheumatology, Clinical ABSTRACT Introduction and , 2Department of Ear-nose-throat (ENT) manifestations E a r-nose-throat (ENT) manifestations , and 3Department of of connective tissue disorders represent of rheumatologic disorders represent a Internal , University Hospital, a diagnostic challenge for clinicians as diagnostic challenge for the rheumatol- , University of Crete, Heraklion, Greece. they often constitute the initial sign of ogist, the otorhinolaryngologist, and an otherwise asymptomatic autoim - the general practicioner. Not uncom- Eva D. Papadimitraki, MD; Dionysios E. Kyrmizakis, MD, DDS; Iraklis Kritikos, mune disease. More o v e r, in patients monly ENT symptoms represent the MD; and Dimitrios T. Boumpas, MD, with known autoimmune rheumatic dis - initial sign of an otherwise asympto- FACP. eases, ENT manifestations can be over - matic or even undiagnosed autoim- Please address correspondence to: looked. mune disorder which often calls for Dimitrios T Boumpas, MD, FAC P , Hearing disturbances may be seen in prompt and aggressive immunosup- Medical School, University of Crete, patients with systemic lupus ery t h e - pressive treatment. Moreover, ENT 1 Voutes Street, Herakleion, Greece. matosus, We g e n e r’s granulomatosis, symptoms may be overlooked by the E-mail: [email protected] relapsing polychondritis, polyart e r i t i s patient or the internist who are usually Received on November 18, 2003; accepted nodosa, Cogan’s syndrome, Sjögre n ’s preoccupied with the main manifesta- in revised form on March 30, 2004. s y n d rome, and less frequently in tions of the disease. Herein we review Clin Exp Rheumatol 2004; 22: 485-494. Churg-Strauss syndrome and Adaman - the most frequent ENT manifestations © Copyright CLINICALAND EXPERIMEN- t i a d e s - B e h ç e t ’s disease. Nose and of connective tissue disorders with TAL 2004. paranasal sinuses are variably affected emphasis on what we consider to be during the course of Wegener’s gran - helpful diagnostic clues that could Key words: Autoimmune disorders, ulomatosis, Churg-Strauss syndro m e , facilitate early diagnosis and treatment. hearing loss, parasinusitis, voice relapsing polychondritis and sarcoido - hoarseness, oral ulcers, . sis. Recurrent mucosal ulcerations are Hearing-audiovestibular common in systemic lupus erythemato - disturbances sus and A d a m a n t i a d e s - B e h ç e t ’s dis - Immune-mediated inner ear disease ease. Xerostomia is a common feature (IMIED) of primary and secondary Sjögre n ’s Ear damage has been occasionally re- syndrome; salivary gland enlargement ported to complicate the course of vari- may be also seen in these patients, as ous rheumatologic disorders. Immune well as in patients with sarcoidosis. mediated inner ear disease (IMIED) The cricoarytenoid can be involv - produces immune mediated sensori- ed during the course of rh e u m a t o i d neural hearing loss while other mani- a rthritis, and festations such as vertigo, and ; osteoarthritic changes have also an occasional sense of auricular full- been described. Motility disorders of ness complete the clinical spectrum of the upper and/or the lower portions of the disorder. Patients may complain of the esophagus have been reported in diminished hearing acuity or decreased patients with dermatomyositis/polymy - sound discrimination. IMIED typically ositis, systemic sclerosis and systemic evolves subacutely or with a time . course that ranges from a few days to Trigeminal nerve dysfunction may oc - several months. This helps the clinician cur in patients with Sjögre n ’s syn - to distinguish between IMIED and drome, systemic sclerosis, systemic lu - M e n i e r e ’s syndrome, which usually pus erythematosus and mixed connec - follows a more prolonged time course. tive tissue disease. Peripheral facial In addition, IMIED is at least to some nerve palsy has been described to com - extent bilateral (although the two sides plicate the course of Sjögre n ’s syn - can be affected asymmetrically or even drome and sarcoidosis. asynchronously with the interval be-

485 REVIEW ENTmanifestations of rheumatic diseases / E.D. Papadimitraki et al. tween involvement of the two sides microscopic polyangiitis (MP). Not ocular – usually intersis- reaching one year in rare cases), which uncommonly progressive ear disease – tial keratitis – and profound SNHL is a useful diagnostic tool for the dis- either sensorineural or mixed hearing which results from recurrent episodes tinction between IMIED and acoustic loss – represents the first manifestation of inner ear disease that manifest with neuroma. An MRI investigation, how- of disease. In these cases the presence Meniere-like attacks and prominent ever, is usually essential to rule out the of high titres of anti-MPO-ANCA anti- vestibular symptoms such as vertigo, diagnosis of cerebellopontine angle le- bodies is an extremely useful diagnos- nausea, sensorineural hearing distur- sion – usually a vestibular swannoma – tic tool (8, 9). Sudden or gradual hear- bances and ataxia. Various combina- particularly in the initial stages where ing impairment has been estimated to tions of systemic vasculitic symptoms no signs of bilateral involvement are occur in nearly 50% of all patients with may coexist. Cardiac valve – particu- clinically evident. Fluctuating symp- relapsing polychondritis (RP) at some larly aortic valve – involvement is a tom patterns over a period of several point in their disease. It may take the potentially life-threatening acute com- months have also been described. A form of conductive hearing loss (attrib- plication of Cogan’s syndrome which subset of patients with disease limited uted to the expansion of the inflamma- warrants high clinical suspicion and to the inner ear have serum antibodies tory procedure to the middle ear and early intervention (13). against a 68 KD inner ear antigen (1). eustachian tube), sensorineural hearing Early detection of IMIED is of critical Both unilateral and bilateral sensori- loss (when vasculitis of the auricular importance since the timely institution neural hearing loss (SNHL) predomi- artery or its cochlear branch occurs), or of aggressive is nantly affecting the middle and high mixed hearing impairment (10). essential for non-reversible hearing frequencies have been reported in The most frequent otologic deficit in loss to be avoided. Meniere’s disease, patients with SLE and there is enough patients with Wegener granulomatosis barotrauma, noise exposure, presbya- evidence to support a strong associa- (WG) is conductive hearing loss result- cousis, viral cochleitis, ototoxic agents tion between SNHL and the presence ing from granulomatous nasopharyn- such as aminoglycosides and loop di- of high titers of anticardiolipin antibod- geal involvement, secondary eustachi- uretics, meningitis and cerebrovascular ies. Subclinical SNHL has been des- an tube dysfunction and serous otitis represent other causes of cribed in more than 22% of patients media. Serous otitis media results from SNHL. Acute or chronic otitis media, with SLE by some investigators. Acute inflammation and irritation from nasal tumors of the middle ear, tympanic audiovestibular failure has also been secretions of the orifice of the eustachi- membrane perforation and lesions of described in primary antiphospholipid an tube. It manifests with conductive the external ear such as , syndrome (APS). There are scarce bib- hearing loss without pain or signs of squamous cell carcionomas or other liographic evidence that suggest a po- acute inflammation, although it is often tumors, psoriasis and accumulation of tential association between SNHL and complicated by recurrent episodes of cerumen have been accused of causing acute aortic insufficiency, a rare mani- acute otitis media. Clinical signs in- conduction hearing loss. festation of SLE. No correlation be- clude the presence of a concave, lus- The Weber and Rinne tests examine the tween the disease status or the presence tress drum with or without superficial relative adequacy of air and con- of ANA antibodies and the appearance radial vessels and a colourless, yellow duction of sound. SNHL is to be sus- of SNHL has been confirmed. On the or mubby appearance. Some patients pected if the vibratory sound is louder other hand, administration of NSAIDs also suffer from purulent otitis media on the “good” side and conductive and antimalarial drugs, a common clin- with pain, fever, a sensation of pressure hearing loss is to be suspected if the ical practice in SLE patients, may rep- in the ear, hearing loss, tympanic hy- vibratory sound is louder on the “bad” resent a confounding factor since both peraemia and bulging – in the acute side during the Weber test. A positive categories of medication have been phase – or discharge, and painless hear- Rinne test is normal and a negative associated with SNHL (2-5). SNHL of ing loss and central perforations of the Rinne test – occurring when sound is at the middle and high frequencies and tympanic membrane in the chronic least equally loud or louder when the the clinical finding of a patulous eus- forms. SNHLis much less frequent and fork is placed on bone as compared to tachian tube have been described in when it occurs it is typically accompa- when it is held next to the ear – is con- patients with systemic sclerosis (SSc). nied by tinnitus without vertigo. Mixed sistent with conductive loss, particular- Mixed type hearing loss has been patterns are often seen and the toxic ly if the Weber test lateralizes to the reported much less frequently (6). action of inflammatory products from same side (Fig. 1). A tympanogram and SNHL in the course of Sjögren’s syn- the middle ear or direct granulomatous an MRI investigation should be used to drome (SS) is partially attributed to the involvement of the inner ear are con- confirm clinical findings and exclude presence of high titers of anticardi- sidered to be predisposing factors (1). other diagnoses. olipin antibodies (7). C h u rg Strauss syndrome (CSS) and When aggressive treatment is adminis- Myeloperoxidase (MPO) associated Adamantiades-Behçet’s disease (ABD) tered in time, auditory function can be vasculitis has been implicated in the have been rarely associated with audio- preserved or recovered. A three-month pathogenesis of hearing loss in patients vestibular deficits (11, 12). regimen of prednisone which can be with polyarteritis nodosa (PN) and Cogan’s syndrome is characterized by progressively tapered by the end of the

486 ENT manifestations of rheumatic diseases / E.D. Papadimitraki et al. REVIEW

or extra-vascular granulomas and in- flammatory lesions rich in eosinophils are the main histopathological features of nasal mucosa in CSS. Peripheral eosinophilia, eosinophilic infiltration of other tissues such as the gastroin- testinal tract and , and systemic vasculitic symptoms (malaise, fever, anorexia), pulmonary infiltrates, , heart, nervous system and renal disease are all late manifestations of the dis- ease. Anti-neutrophil cytoplasmic anti- bodies (ANCA), eosiniphilia and hy- p e rgammaglobulinaemia are helpful diagnostic tools for the clinician to dis- tinguish between a simple atopic pre- disposition and the presence of active vasculitis (Fig. 2c) (16, 17).

Wegener’s granulomatosis Nasal obstruction caused by diff u s e crusting and abundant purulent secre- tions and bloody nasal discharge or epistaxis suggest active WG. On the other hand, necrosis of the septal carti- lage anteceded by vessel destruction of the anterior portion of nasal septum (locus Kiessebachii) may lead to septal perforation, which together with deformity caused by massive destruction of the nasal tissue charac- Fig. 1. Algorithm for the evaluation of suspected audiovestibular impairment in patients with systemic terize late, although not necessarily autoimmune disorders. active disease. Smell disturbances may occur due to extensive mucosal in- fourth week usually controls disease. If Nose and paranasal sinuses volvement, while chronic carriage of significant improvement has not oc- Churg-Strauss vasculitis Staphylococcus aureus partially re- curred by the end of the second week or Allergic rhinitis is frequently present in sponsive to antibiotics is typical of if a relapse occurs during the tapering patients with Chürg-Strauss (CSS) vas- Wegener disease (18). of , cyclophosphamide culitis. Typical symptoms include sea- Paranasal sinus involvement is of may be added to the steroid treatment. sonal or perennial itching nose, sneez- major importance in WG. During the If auditory function has not been ing, and obstructed airflow, which are acute phase – where a biphasic course restored by the end of the 12th week accompanied by a thin and colorless of relapsing symptoms of rhinitis auditory damage is considered irrever- discharge and in more severe cases by together with extreme malaise, high sible and treatment stops. Methotrexate facial pressure, pain, periorbital edema fevers, abundant purulent secretions, has been proposed as an alternative, and cyanosis (15). Nasal examination headaches and sensitive paranasal sin- although less effective, therapeutic reveals a pale bluish mucosa with tur- uses follow an initial subsidal of acute agent, preferably when the diagnosis of binate edema; nasal polyposis and sub- rhinitis – one cannot distinguish be- IMIED has not been securely estab- sequent smell disturbances may further tween ordinary infection and active lished and other diagnoses such as complicate the disease. Recurrent sinu- vasculitis, not even by CT or MRI in- M e n i e r e ’s syndrome have not been sitis is a common finding but neither vestigations. Post-nasal secretion, ruled out (1). However, a recent ran- rhinitis nor sinusitis seem to share the chronic cough, nasal congestion and domized trial including 67 patients destructive pattern seen in WG and RP. concentration disturbances are all sug- with rapidly progressive bilateral Nasal eosinophilia together with a pos- gestive of chronic sinusitis. A friable SNHL has shown that methotrexate is itive history for asthma – usually pro- nasal mucosa with nasal polyps and/or of no benefit in maintaining the hearing minent during the initial phase and pre- diffuse submucosal nodularity are the improvement achieved with prednisone sent in all patients with fully developed most frequent clinical signs. therapy (14). disease – support the diagnosis. Intra- Persistent, recurrent or worsening

487 REVIEW ENTmanifestations of rheumatic diseases / E.D. Papadimitraki et al.

(a) (b)

(c) (d)

Fig. 2. Computed tomography of the nose and paranasal sinuses of a 62-year female with Wegener granulomatosis. (a) Axial view: bilateral nasal fossa mass with minimal erosion of the anterior nasal septum; (b) coronal view: non-specific bilateral antral mucosal thickening; (c) cytoplasmic antineutrophil cyto- plasmic antibodies (C-ANCA) by indirect immunofluoresence with normal neutrophils, from the same patient. Heavy cytoplasmic staining is evident. Orig- inal magnification 20x and 40 x respectively (Courtesy of D. Drigiannakis).

symptoms usually lead the clinician to enlargement of the lacrimal gland can disease (23). When atypical/recurrent/ a more extensive evaluation. By that also occur. Histology reveals necrotis- persistent episodes of sinusitis occur, a time granulomatous lesions and/or dif- ing granulomatous vasculitis with more extensive evaluation including a fuse mucosal thickening together with varying degrees of chronic inflamma- chest X-ray, serum creatinine and erosion and bony destruction of the tory cells (22). A N C A measurement, urinalysis and septum and turbinates, erosion of the Upper airway abnormalities are fre- finally a biopsy of an involved site ethmoid sinuses and even complete quently present at initial presentation should be considered. bony obliteration of the maxillary, with up to 92-99% of patients develop- CD30, soluble CD26 and soluble CD23 frontal and sphenoid sinuses may be ing such symptoms during the disease are preferentially expressed in general- apparent in CT scans (Fig. 2a, b) (19). course (23). Not uncommonly, patients ized, active disease. A shift of the T cell The mastoids are also commonly in- do not have renal or pulmonary in- response from a Th1 pattern in local- volved. Granulomas can be detected as volvement in the very initial stage ized disease towards a Th0/Th2 pattern low signal intensity lesions on T1 and despite the fact that 70%-80% of them in generalized-vasculitic disease has T2 weighted sequences in MRI scan- will finally present with pulmonary been reported to occur and may explain nings of the nasal cavity or paranasal and/or renal disease. Pulmonary nod- the different clinical presentations ob- sinuses. Intraorbital WG involvement ules and infiltrates may be asympto- served in the same patient or among is usually accompanied by paranasal matic and renal disease may progress to different individuals (24,25). Localized sinus disease and a hypointense signal advanced uremia without overt clinical We g e n e r’s granulomatosis (LW G ) on a T2 weighted MRI image is helpful manifestations. ANCAmay be negative without pulmonary or renal involve- in suggesting the diagnosis (20, 21). in a significant percentage of cases, ment but ANCA-positive and with a Nasolacrimal duct obstruction and particularly in the absence of severe compatible histology has been recog-

488 ENT manifestations of rheumatic diseases / E.D. Papadimitraki et al. REVIEW nized as a distinct subtype of disease characterized by the sudden onset of ly but not invariably painless oral ulcers, (26). This further highlights the pre- pain and swelling, redness and warmth characteristically localized on the soft dilection of WG for the head and neck involving the cartilageous portion of and hard (in rare cases these may region, denoting the frequent referral of the external ear with sparing of the lob- be found anywhere on the buccal mu- such patients to an ENT d e p a r t m e n t ule (Fig.3). Severe relapsing polychon- cosa or the tongue), which occasionally and the crucial role of heightened clini- dritis with laryngo-tracheal involve- develop a central depression, expand cal suspicion and serologic confirma- ment has been associated with ear- and perforate, represent a common clin- tion for early diagnosis and treatment. piercing; it has been speculated that the ical finding. Nasal and genital mucosa commercially used steel studs may may also be involved (31). Relapsing polychondritis become immunogenic after conjuga- Recurrent painful oral ulceration (more Nasal stiffness with rhinorhea, crusting tion with protein carriers during the than 3 attacks annually) represents an and epistaxis can also be seen in pa- period that they are left in the wounded important early manifestation of ABD. tients with relapsing polychondritis. (28). Repeated attacks give Typically extensive and multiple, they Later, when sustained or recurrent car- rise to a soft and floppy appearance of are surrounded by erythema and range tilage inflammation has developed, sep- the external ear. The levels of anti-type in size from a few millimeters to 2 cen- tal perforation and/or saddle nose de- II collagen (anti-CII) antibodies and timeters (minor form <1 cm, major formity may occur. As in WG, olfaction urinary type II collagen neoepitope form >1 cm). The cheek, tongue, palate can also be compromised. Nasal chon- (uTIINE) seem to parallel the severity and oropharynx are commonly involv- dritis is present in 29% of patients with of the disease and uTIINE has been ed sites. Aphthous ulcers of ABD are RP at the onset while 53% of them will shown to reflect an enhanced T H 1 remarkably persistent and their exis- eventually develop such a lesion (27). immune response which is associated tence indicates active disease. As they Auricular chondritis, non-erosive, asym- with uncontrolled disease (29). often appear prior to other manifesta- metric, migratory , ocular A CT scan to evaluate laryngotracheal tions of ABD (genital ulceration, inflammation, respiratory tract chon- involvement is of extreme importance uveitis, skin lesions, , and large dritis with hoarseness and subsequent and a thorough cardiologic evaluation vessel involvement such as deep ve- infections, cohclear or vestibular dys- to detect valvular lesions and aortic nous thrombosis and arterial aneury- function, and cardiac manifestations aneurysms is also considered neces- sms), the differential diagnosis from often coexist. It is of note that upper sary. simple aphthous , herpes sim- and lower airway involvement is some- plex virus infection, inflammatory bo- times asymptomatic and unrecognized Other diseases wel disease, HIVinfection and hemato- until recurrent secondary infection has Nasal obstruction, rhinorhea, crusting, logic disorders that cause similar le- occurred. necrotising sinus and palatal destruc- sions could be difficult and a biopsy is The most common presenting symp- tion have been reported to occur in pa- then required. However, six or more tom is auricular chondritis, which is tients with sarcoidosis, sometimes prior ulcers of variable size, surrounding ery- to other manifestations such bilateral thema and a predilection for the non- hilar lymphadenopathy, pulmonary, he- keratinized mucosa of the soft palate patic, skin and nervous system involve- and oropharynx should raise the suspi- ment (30). Nasal septal perforation cion of ABD (Table I) (32, 33). manifesting with obstruction, epistaxis, Deep, painful mucosal ulcers of the post-nasal discharge, whistling and tongue, cheeks, palate and gingiva to- crusting may be seen in patients with gether with “strawberry gingival hy- SLE or primary antiphospholipid syn- perplasia” have been described in rare drome and is attributed to local ische- cases to complicate WG (17). Relaps- mia or inflammation (31). ing polychondritis, Granulomatous and non-granuloma- and mixed connective tissue disease tous infections such as tuberculous and (MCTD) can also manifest with oral fungal rhinosinusitis respectively, and ulcerations (27,34). Topical or system- T-cell (Stewart’s granulo- ic corticosteroids, colchicine and even mas), leprosy, viral , carcinoma biologic agents such as etanercept have and sarcoma, have to be included in the been proposed for the management of Fig. 3. Chondritis affecting the cartilageous por- differential diagnosis of chronic para- severe recurrent aphthous ulcers (35- tion of the right ear of a 48-year-old patient who nasal sinus disease. 37). presented with an earache, asymmetric pol- yarthritis, tracheitis and an aortic aneurysm. The inflammatory process spares the lobule, a char- Oral, pharyngeal, laryngeal and Xerostomia acteristic feature helping in distinguishing esophageal diseases Xerostomia is an invariable character- between relapsing chondritis and cellulitis of the Oral ulcers istic of sicca syndrome, which is com- ear. In systemic lupus erythematosus, usual- mon in patients with primary or sec-

489 REVIEW ENTmanifestations of rheumatic diseases / E.D. Papadimitraki et al. ondary SS. Patients complain of oral Table I. Oral ulcers in systemic lupus erythematosus and Adamantiades-Behçet disease. dryness when eating, intolerance of spicy food, the need to drink liquids Systemic lupus erythematosus Adamantiadis-Behçet’s disease when swallowing dry food, and the Few Multiple inability to speak for long periods of time. Dental caries and Small (£ 1 cm) Variable size are serious complications, occurring in Palate (usually) Cheek, tongue, palate, oropharynx approximately 65% and 50% of pa- Painless (usually) Painful tients, respectively. Dysphagia may al- Central depression, perforation Surrounded by erythema, persistent so develop. Reduced salivary pooling, tooth caries and gingival margins are unilateral salivary gland enlargement, a inflammation that affects the pharynx, common clinical findings. Mouth dry- neoplasm such , trachea and bronchi, thus producing an ness can also be found in uncontrolled or other primary sali- irritating dry cough in patients with SS. diabetes mellitus, amyloidosis, sar- vary gland tumor should also be ruled Gastroesophageal reflux disease, asth- coidosis, HIV infection, and in patients out. Other potential causes of bilateral ma, chronic post-nasal drip, chronic receiving , anticholiner- salivary gland enlargement include vir- bronchitis, bronchectasis and the ad- gics, or diuretics. Patients who have al infections, amyloidosis, lymphoepi- ministration of ACE-inhibitors have to u n d e rgone radiotherapy present with thelial cysts (HIV-related or not), tuber- be considered in the evaluation of mouth dryness or other more serious culosis, leprosy, alcoholism or cirrho- chronic cough. ENT complaints; a careful history to sis, hyperlipidaemia and the coexis- exclude these agents is required. tence of other clinical parameters Cricoarytenoid arthritis and Other manifestations of SS include ker- should be estimated before attributing subglottic stenosis atoconjuctivitis sicca, vaginal dryness, salivary gland enlargement to SS. The cricoarytenoid joint can be poten- symmetric polyarthritis, hypothy- Heerfordt syndrome is defined as a tially affected during the course of var- roidism, non-productive cough and combination of bilateral parotid en- ious inflammatory . Rheu- pulmonary fibrosis, skin dryness or largement, anterior uveitis, fever and matoid arthritis (RA) is complicated by leukocytoclastic vasculitis and hyper- facial palsy, and is found in patients cricoarytenoid arthritis in 30% of cas- gammaglobulinaemia. The presence of with sarcoidosis. However, isolated es. Sore throat, hoarseness and inspira- antinuclear antibodies (ANA), anti- painless, usually unilateral salivary tory stridor are the most common clini- SSA/Ro, anti SSB/La antibodies and gland enlargement has also been cal manifestations. Airway obstruction rheumatoid factor (RF) support the described as a common clinical finding requiring immediate tracheostomy has diagnosis, which can be confirmed by in these patients (43). been described (46). Laryngoscopy biopsy. Secondary SS is associated reveals redness and oedema, reduced with a variety of connective tissue dis- Sore throat (pharyngitis) vocal cord motility, unilateral or bilat- orders such as , Sore throat and recurrent episodes of eral vocal adduction, incomplete clo- systemic lupus erythematosus, sclero- pharyngitis that prove remarkably re- sure of the posterior commisure (which derma and polymyositis (38, 39). sistant to ordinary therapeutic regimens favors aspiration) and arytenoid carti- have been reported as an important lage asymmetry. Occasionally a signifi- Salivary gland enlargement early clinical manifestation of adult on- cantly narrowed glottic fissure may Salivary gland enlargement is another set Still’s disease (ASD). Sore throat also be noticed. Erosion-luxation of the common manifestation of SS. T h e was present in approximately 92% of cricoarytenoid joint and surrounding parotids and/or submandibular glands patients who fulfilled the diagnostic soft tissue swelling can be demonstrat- are unilaterally or more often bilateral- criteria for ASD in a large study (44). ed on high resolution (HR) CT scan ly affected. Glands are firm, non-tender In a review of 369 cases of ASD in the (47). and usually diffusely enlarged on phys- English literature, 69% of patients pre- Upper airway obstruction due to laryn- ical examination (lymphoepithelial sented with persistent sore throat as geal involvement is a rare but well doc- sieladenitis) (38, 40). Patients with SS one of the initial clinical manifestations umented complication of SLE, which have an increased risk of developing (45). or arthritis, salmon usually occurs in association with other salivary gland or extra-salivary lym- rash, high fevers and palpable lym- symptoms and signs that indicate phoma, and more often marginal zone/ phadenopathy may or may not coexist active disease. Bilateral cord immobili- MALT . Persistent enlarge- in those early stages but should be ty can be noticed. Interestingly, SLE ment of the parotid glands, low C4 lev- anticipated to appear within the next cricoarytenoid arthritis is highly re- els and palpable purpura suggest the few months in patients with ASD. sponsive to steroid treatment which is potential evolution to lymphoma and usually inadequate for the cricoary- should be taken into consideration dur- Trachiitis tenoid arthritis of RA(48). ing the evaluation of parotid gland Persistent mucosal dryness and defec- Ankylosing spondylarthritis (AS) can enlargement (41, 42). In the analysis of tive secretions account for the subacute also affect the cricoarytenoid joint.

490 ENT manifestations of rheumatic diseases / E.D. Papadimitraki et al. REVIEW

Unilateral and very rarely bilateral vo- geal cancer represent some of the etio- and are responsible for cal cord fixation with maintenance of logic factors of hoarseness and dyspho- oropharyngeal dysphagia in systemic the adducted cord position appear to be nia that have to be excluded. Severe sclerosis (SSc) (55). Vi d e o e s o p h a g o- late manifestations of uncontrolled dis- subglottic stenosis (SGS) causing sev- scopy is the most useful diagnostic tool ease (49). ere acute dyspnea and requiring trache- for the evaluation of oropharyngeal Gouty laryngeal arthritis presenting ostomy has been described in patients dysphagia. with hoarseness, dysphonia and dys- with WG. In this set of patients SGS Primary Sjögren’s syndrome has been phagia can accompany multiple joint often occurs independently of the dis- described to affect the contractility of involvement or appear as a single gout ease activity and the type of therapy the upper third of the esophagus (as manifestation (50). Tophi of the laryn- and seems to be unresponsive to sys- evidenced by manometric studies), thus geal soft tissue or vocal cords causing temic immunosuppressive treatment inducing symptoms of esophagolaryn- similar symptoms have rarely been re- (53). geal reflux and dysphagia (Table II) ported (51). (56). Degenerative ulcerations in the crico- Oropharyngeal dysphagia arytenoid joint resembling osteoarthri- In patients with dermatomyositis (DM) Esophageal dysphagia tis (OA) may also occur. These struc- or polymyositis (PM), cricopharyngeal Connective tissue disorders can also tural changes are comparable to OA of achalasia due to impaired cricopharyn- affect the distal third or the entire eso- the limbs and may lead to impaired ary- geal muscle activity may cause oropha- phagus, causing secondary gastro-pha- tenoid cartilage movements (and thus ryngeal dysphagia manifesting as diffi- ryngeal-esophageal reflux disease impaired vocal quality and reduced vo- culty in swallowing liquids more than (GPERD) or other esophageal motility cal activity). In one study 50% of the solids, dysarthria and dysphonia. The disorders. GPERD has been implicated laryngeal in patients over 40 posterior cricoarytenoid muscle is the as an important causative factor of years of age exhibited such degenera- only muscle keeping the vocal cords in many serious ENT and other manifes- tive changes (52). adduction so that when impaired, the tations such as chronic throat clearing, Acute laryngitis, gastroesophageal re- vocal cords come together. Thus if the dry cough, sore throat, asthma, globus flux disease, chronic post-nasal drip, posterior cricoarytenoid muscle is pharyngeus, dysphagia, cricoarytenoid smoking, alcohol use and chronic vocal involved, airway obstruction can occur. arthritis, subglottic stenosis following strain (all potential causes of chronic Oropharyngeal dysphagia may be fur- mechanical ventilation, contact ulcers laryngitis), spasmodic dysphonia, hy- ther complicated by aspiration of the and granulomas or even cancer of the pothyroidism, vocal cord polyps and esophageal contents into the airways larynx (57). Other commonly described nodules, laryngeal palsy (post-thyreoi- (54). manifestations of GPERD include dectomy or due to other causes), laryn- Narrowing of the oral aperture, rigidity heartburn, regurgitations and hypersali- geal conversion disorders and laryn- and thinning of the soft palate, larynx vation. Interestingly, ENT complaints may be present in the absence of heart- burn – the hallmark of GPERD – in up Table II. Esophageal involvement and secondary ENT manifestations in autoimmune dis- to 60% of cases. Laryngoscopic evalu- orders* ation reveals diffuse erythema and edema of the posterior portion of the Esophageal disorder Symptoms Evaluation Commonly larynx, granulomas and/or ulcerations associated disorders of the vocal cords and histologically Oropharyngeal dysphagia Prominent difficulty Videoesophagoscopy DM, PM, SS, SSc demonstrable esophagitis may or may swallowing liquids, be not be present. dysarthria, dysphonia, Involvement of both the upper and aspiration lower portion of the esophagus occurs Esophageal dysphagia Equal difficulty Barium swallow, SSc, SLE equally in the diffuse and limited sub- swallowing liquids endoscopy, manometric types of SSc but is rare in patients with and solids studies localized scleroderma. Raynaud’s phe- nomenon affecting the vessels of the GPERD ± heartburn, 24 hr ph-metry, SSc, DM, PM, SLE hypersalivation, endoscopy for esophagus concurrently with Ray- regurgitations, complications n a u d ’s hands, latent neurogenic dys- dry cough, sore throat, function resulting in muscle atrophy and, chronic throat clearing, less importantly, infiltration/replace- secondary cervical dysphagia ment of smooth muscle fibers with col- lagen have all been implicated in the ENT: ear nose throat; DM: dermatomyositis; PM: polymyositis; SS: Sjögren’s syndrome; SSc: sys- pathogenesis of esophageal dysmotility temic sclerosis; SLE: systemic lupus erythematosus; GPERD: gastro-pharyngeal-oesophageal reflux (58, 59). Esophageal dysphagia of SSc disease. typically takes the form of intermittent,

491 REVIEW ENTmanifestations of rheumatic diseases / E.D. Papadimitraki et al. non-progressive dysphagia involving equally solids and liquids and being characteristically accompanied by heartburn. Reflux esophagitis, diffuse esophageal spasm (manifesting with non-cardiac chest pain and intermittent dysphagia), stricture formation, pro- gressive dysphagia concerning pre- dominantly solid foods, and an impres- sive subsidence of reflux symptoms can all alter the typical initial presenta- tion. Classic manometric findings in- clude an incompetent lower esophagic sphincter, low amplitude contractions of the distal smooth muscle portion of the esophagus and diminished peristal- sis of the upper muscle in more severe cases. 24-hour-ph-metry is suggested Fig. 4. Thickened, nodular and for both symptomatic and asympto- tender temporal artery with dim- matic GPERD patients with SSc due to inished pulses in a 64-year- o l d the high prevalence of asymptomatic patient who presented with dull headaches and scalp tenderness. disease in this population (60). Histologic analysis showed the Dermatomyositis (DM) and polymyo- presence of arteritis. sitis (PM) sometimes cause clinically significant malfunctioning of the smooth muscle of the upper gastroin- ling can be noticed during physical ex- tations. Physical examination showing testinal tract, resulting in profoundly amination. Although internal derange- thickened, tender, nodular temporal delayed gastric and esophageal empty- ment due to micro- or macro-traumatic arteries, with reduced or absent pulses ing, concerning both patients symp- loading represents the most frequent and an elevated erythrocyte sedimenta- tomatic for GPERD and asymptomatic cause of TMJS, the clinician should tion rate (ESR) (usually > 100 mm/sec) patients. Esophageal muscle dysmotili- bear in mind that the temporomandibu- in an individual who is more than 50 ty in the course of DM and PM corre- lar joint can be affected during the years of age calls for temporal artery lates well with peripheral skeletal mus- course of inflammatory arthropathies biopsy. In these cases empiric adminis- cle disease activity (61). such as RA, SS, seronegative spondy- tration of high doses of corticosteroids Hypoperistalsis or aperistalsis due to loarthropathies [ankylosing spondy- may prevent the irreversible blindness an inflammatory reaction localized to loarthritis (AS), (PA) caused by the disease (Fig. 4) (65). Jaw the esophageal muscles (predominantly and reactive arthritis], and OA(63, 64). claudication has been also described to those of the lower esophagus) or to is- Psychogenic nocturnal or jaw occur in patients with polyarteritis no- chemic vasculitic damage of the Auer- clenching and , dental ab- dosa, Churg-Strauss vasculitis and pri- bach plexus may or may not be accom- normalities and manipulations, anato- mary amyloidosis too and evaluation of panied by esophagitis in patients with mical abnormalities of the temporo- the clinical pattern together with histo- SLE, and subclinical or asymptomatic mandibular joint and even lymphopro- logic analysis of temporal artery are disease has been described in up to liferative disorders, carotodynia, stylo- needed to confirm the diagnosis (66- 72% of patients in some series (Table hyoid (Eagle’s) syndrome, trigeminal 68). II) (62). or glossopharyngeal neuralgia and parotid gland disorders, should all be Facial disease considered during the evaluation of Trigeminal nerve Temporomandibular joint syndrome TMJ symptomatology. Trigeminal neuropathy that spares the (TMJS) manifests with pain which is Prolonged chewing or talking leads to ophthalmic division of the nerve (thus usually localized around the ear or the jaw claudication in patients with cra- preserving corneal reflex) and presents pre-auricular area, may radiate to the nial giant cell arteritis (GCA). Scalp with bilateral sensory loss in the face or e a r, jaw, dentures or cervical region tenderness, headaches, amaurosis fug- muscle weakness of the mandibular and is exacerbated by protracted chew- ax or ischemic optic neuropathy and muscles has been described in patients ing. Headaches and rarely tinnitus are symptoms of polymyalgia rheumatica with SS (69). typical symptoms and crepitus during such as stiffness and pain in the shoul- Trigeminal neuropathy has also been joint maneuvers, restricted or “guard- ders and pelvic girdle muscles repre- demonstrated in patients with SSc and ed” jaw motion, and painful joint swel- sent common accompanying manifes- MCTD (a multi-systemic disorder with

492 ENT manifestations of rheumatic diseases / E.D. Papadimitraki et al. REVIEW overlapping features of SLE, SSc, and 2000; 12: 32-40. 3-11. PM). It can be differentiated from them 2. K A S TA N I O U D A K I S I, ZIAV R A N, V O U L- 19. YANG C, TA L B O T JM, HWANG P H: Bony GARI PV, EXARCHAKOS G, SKEVAS A , abnormalities of the paranasal sinuses in by the presence of high titers of anti- DROSOS AA: Ear involvement in systemic patients with Wegener’s granulomatosis. Am U1-ribonucleoprotein antibodies, rep- lupus erythematosus patients: a comparative J Rhinol 2001; 15: 121-5. resenting the most common central study. J Laryngol Otol 2002; 116: 103-7. 20. MU H L E C, REINNHOLD-KELLER E, RICH- nervous system (CNS) manifestation of 3. KO B AYA S H I S, FUJISIMOTO N, SUGIYAVA TER C et al.; MRI of the nasal cavity, the K: Systemic lupus erythamatosus with sen- paranasal sinuses and orbits in We g e n e r’s these disorders (70). sorineural hearing loss and improvement granulomatosis. Eur Radiol 1997; 7: 566-70. Trigeminal neuralgia (tic douloureux) after plasmapheresis using the double filtra- 21. PROVENZALE JM, ALLEN N B: We g e n e r’s is a different clinical entity which in- tion method. Intern Med 1992; 31: 778-81. granulomatosis. CTand MRI findings. AJNR cludes recurrent episodes of unilateral, 4. PEEVA E, BARLAND P: Sensorineural hear- Am J Neurocardiol 1996; 4: 785-92. ing loss in conjunction with aortic insuffi- 22. B O U T E S RJ, D E VR I E S - K N O P P E RT WA: paroxysmal, brief, lancinating pain that ciency in systemic lupus erythematosus. Lacrimal gland enlargement as one of the may last from several seconds to hours Scand J Rheumatol 2001; 30: 45-7. ocular manifestations of Wegener’s granulo- and radiate to the , gingiva, cheeks 5. VYSE T, LUXON LM, WALPORT MJ: Audio- matosis. Doc Opthalmol 1985; 59: 21-6. vestibular manifestations of the antiphospho- 23. HOFFMANGS: Vasculitides. Wegener granu- and jaw. Involuntary contraction of lipid syndrome. 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