miositi - uniroma1.it pm...brillante a un profondo rosso porpora. questo colore viene osservato...
TRANSCRIPT
MIOSITI
CORSO DI LAUREA IN MEDICINA E CHIRURGIA C
Prof. Fabrizio Conti
The inflammatory myopathies, collectively named myositis, share the clinical features of slowly progressive, symmetric muscle weakness, and fatigue. Another common feature is the presence of mononuclear inflammatory cell infiltrates in muscle tissue.
Chronic, idiopathic, inflammatory myopathies can occur as isolated inflammatory muscle disorders or be associated with another defined connective tissue disease such as Sjögren’s syndrome, systemic sclerosis, mixed connective tissue disease, SLE or RA.
Inflammatory myopathies can be subclassified into three major groups: 1. polymyositis (PM), 2. dermatomyositis (DM) 3. inclusion body myositis (IBM).
CLASSIFICATION
EPIDEMIOLOGY – RARE DISEASES
Incidence rate of idiopathic inflammatory myositis is 2-7 per 1
million inhabitants.
Polymyositis and dermatomyositis are more frequent in
women than in men (women:men, 3:1).
The peak of incidence is in fifty to sixty years old people
although polymyositis or dermatomyositis may start at any age.
The ratio between polymyositis and dermatomyositis correlates
directly with UV-light irradiation.
ETIOLOGY
Polymyositis and dermatomyositis are considered to be autoimmune diseases. Genetic factors In Caucasians the strongest association is to HLA DRB1*0301 and DQA1*0501, whereas in Asians the strongest associations are to HLAB7. Associations between myositis and non-HLA genes such as for proinflammatory cytokines (-308TNFA genotype).
ETIOLOGY
Environmental factors Infections. Some acute and self limiting forms of myositis have been reported with coxsackie, echo and influenza viral infections, mainly in children, but their role in chronic myositis is uncertain. UV-light exposure. DM (anti-Mi-2) Malignancies Patients with DM have an increased risk of having a malignancy. This increased risk is both at the time of DM diagnosis but also after more than 10 years. For polymyositis the association with malignancies is uncertain.
CLINICA – Impegno muscolare in PM/DM
Impegno muscolatura scheletrica: debolezza muscolare prossimale e simmetrica a carico dei muscoli del cingolo scapolare e pelvico, prossimali degli arti, muscoli del collo Forme aggressive: muscoli faringei, esofagei e respiratori I muscoli dell’occhio non sono mai interessati
Deficit muscolare: salire le scale alzarsi dalla sedia e dal letto accovacciarsi incrociare le gambe deambulare sollevare il capo dal cuscino deglutire voce nasale disfagia
Dolore spontaneo o provocato a carico delle masse muscolari
CLINICA – Impegno muscolare in PM/DM
In PM/DM dysphagia is not rare, usually the upper type. The basic disorder is the cricopharyngeal muscle oedema caused by inflammation. The cricopharyngeus muscle is a sphincter with circular fibers, which in normal conditions is in a tonic state. Only during swallowing is this tonic state inhibited for a very short time. Disruption of the relaxation phase is referred to as achalasia. Inflammation and oedema during myositis may inhibit relaxation and cause weakness of this muscle with resulting dysphagia. Detection of cricopharyngeal achalasia in myositis is important: 1) there is a danger of aspiration of oesophageal contents into the airways , 2) cricopharyngeal myotomy may lead to a rapid improvement of the patient’s condition.
CLINICA – Impegno muscolare in PM/DM
The cutaneous manifestations of DM may be mild or severe and may in some cases dominate the clinical symptoms. The skin rash may proceed the muscle symptoms by months or even years and in some patients the skin manifestations may be the only clinical sign of DM, often named amyopathic dermatomyositis or dermatomyositis sine myositis. The cutaneous manifestations may fail to respond to immunosuppressive treatment despite improvement of muscle symptoms. Thus it is possible that different molecular pathways or disease mechanisms cause the skin rash and the muscle inflammation.
CLINICA – Impegno cutaneo
Gottron‘s changes (the most specific skin manifestation) are erythematous to violaceous papules and plaques (Gottron’s papules), or macules (Gottron’s sign), over extensor surfaces of joints, generally in a symmetric distribution.
Mani: lesioni sono bianco-rossastre, lucenti, leggermente desquamate e atrofiche.
Heliotrope rash, periorbital edema. This is a typical rash on the upper and lower eyelids, often together with edema of the soft tissue around eyes.
Dermatomiosite: rash eliotropo L’eliotropo è una pianta del genere Heliotropium. Il colore dell’eliotropo varia da un viola brillante a un profondo rosso porpora. Questo colore viene osservato nell’area periorbitale dei pazienti con dermatomiosite
Rash a “scialle”
Red or violaceous erythemas may also be located over the shoulders, neck and chest
Rash in dermatomyositis involves frequently face and chest in the shape of V. Depigmentation on the chest occurs after some time during the course of illness.
Typical rash on the lateral part of the thigh (holster sign).
Mechanic’s hands: hyperkeratosis with frequent fissuring along the lateral and palmar aspects of the fingers.
Periungual erythema, nail-fold telangiectasies and cuticular overgrowth
Dermatomiosite: coinvolgimento periunguale (capillaroscopia della plica ungueale)
normale sclerosi sistemica
dermatomiosite infantile dermatomiosite
Subcutaneous calcifications are more common in juvenile dermatomyositis than in adults. However, they can be seen also in adult PM/DM. Calcinosis predominantly occurs on sites that are subject to friction such as the dorsal side of the elbows and may be localized to the skin, subcutaneous fat, fascia and muscle. It is a difficult condition to treat.
Dermatomiosite: calcinosi, coscia (radiografia) Ampia calcificazione in diversi piani: tessuto sottocutaneo, fascia e muscolo.
Skin rash may be precipitated by UV light exposure. There are no specific histopathological skin features for dermatomyositis as most features found are also seen in patients with SLE, thus skin biopsy is rarely helpful to distinguish between these two disorders.
CLINICA – Impegno cutaneo
CLINICA – Impegno polmonare
Dyspnea and cough are common symptoms in patients with PM/DM and interstitial lung disease (ILD) was found in 60-70 % at time of diagnosis. ILD may even be asymptomatic and detected by high resolution computerized tomography (HRCT) and pulmonary function tests. ILD in myositis is not different from idiopathic ILD and is often slowly progressive but occasionally an acute onset life threatening form. Pulmonary complications are a major factor causing morbidity and mortality in myositis.
A clinically distinct subset of myositis in patients with autoantibodies directed against synthetases. The most frequent of these autoantibodies is anti-Jo1 directed against histidyl-tRNA synthetase, present in approximately 20% of patients with PM/DM. Other anti-tRNA synthetase (anti-PL-7, anti-PL-12, anti-KS, anti-OJ, anti-EJ, anti-Zo) have been found in myositis patients. Characteristic clinical features: • myositis, • interstitial lung disease, • Raynaud’s phenomenon, • non-erosive symmetric polyarthritis in small joints, • mechanic’s hands.
CLINICA – Sindrome anti-sintetasi
CLINICA – artrite
Arthralgia and arthritis which is usually non-erosive are common in myositis patients. The arthritis mainly affects small joints in the hands and feet. In particular, arthritis is common in patients with anti-Jo1 and other anti-synthetase. The arthritis is rarely a major clinical problem.
CLINICA – miocardio
Cardiovascular disease is a major risk factor for death among myositis patients. The most frequently reported clinically overt manifestations are congestive heart failure, and conduction abnormalities.
Miosite a corpi inclusi
Identified as a subset of myositis in the 1960s.
Insidious onset of muscle weakness over months to years.
Distal and asymmetric muscle weakness, particularly of the muscles of the forearm and hand resulting in finger flexor weakness.
The prevalence is estimated to 4-9:1,000,000
Males affected more than females
Age of onset usually greater than 50
Myopathic and neuropathic changes on EMG
Autoantibodies are present in 30%
IBM may be associated with another inflammatory connective tissue disease
Mononuclear cell infiltrates and vacuoles containing amyloid on
muscle biopsy
Responds poorly to corticosteroids and immunosuppressants.
Patogenesi
Fisiologia del muscolo
Il muscolo scheletrico costituisce il 40% del peso corporeo ed è costituito da cellule multinucleate la cui lunghezza varia da pochi millimetri a circa 30 cm. Ogni fibra è circondata da un sottile strato di tessuto connettivo, l'endomisio e più fibre formano un fascio che è circondato da un altro strato di tessuto connettivo, il perimisio. Una caratteristica delle fibre muscolari differenziate è l'assenza di espressione delle molecole di istocompatibilità (MHC) di I classe.
Patogenesi
The inflammation in myositis affects striated muscle but not smooth muscle. Occasionally heart muscle could be involved. The cellular infiltrates of skeletal muscle are characterized mainly by T lymphocytes and macrophages. In DM perivascular and perimysial location dominated by CD4+ T cells and macrophages. In PM in the endomysium. Other typical changes are degenerating, necrotic fibers, and regenerating muscle fibers.
Dermatomiosite: miosite acuta (fotomicroscopia)
Infiltrato di linfociti e istiociti. Le alterazioni muscolari nella polimiositie sono identiche a quelle riscontrate nella dermatomiosite. (ematossilina-eosina, media potenza)
Dermatomiosite: miosite acuta (fotomicroscopia)
Diffuso infiltrato interstiziale mononucleato, degenerazione di una grossa fibra muscolare. (ematossilina-eosina, alta potenza)
Dermatomiosite: miosite cronica (fotomicroscopia)
In questa sezione di un paziente con DM ci sono diffuse alterazioni della muscolatura scheletrica con atrofia di alcune fibre muscolari. Del tessuto fibroso neoformato ha rimpiazzato alcuni fasci muscolari. E’ presente una lieve reazione infiammatoria mononucleata. (ematossilina-eosina, media potenza)
Patogenesi
The histopathology of IBM resembles polymyositis with endomysial infiltrates with a predominance of CD8+ T cells. In addition, characteristic findings are rimmed vacuoles and intracellular amyloid deposits or 15 – 18 nm tubofilamentous inclusions found on electron microscopy. Early in the course of IBM only the inflammatory infiltrates may be evident and the histopathology may be indistinguishable from polymyositis. If a polymyositis patient responds poorly to immunosuppressive treatment it is wise to consider the IBM diagnosis and repeat the muscle biopsy.
Muscle biopsy section from a patient with inclusion body myositis. A. hematoxylin and eosin staining, degenerating and regenerating fibres, infiltrates of mononuclear inflammatory cells. B. rimmed vacuoles
A B
Patogenesi
Another feature of inflamed muscle tissue, in all subsets of myositis, is expression of MHC class I in muscle fibers, which normally do not express these antigens. MHC class I antigen expression is present on muscle fibers in a majority of myositis patients both on regenerating and degenerating fibers and, importantly, on otherwise normally looking muscle fibers. Sometimes only a few fibers are positive, in other cases almost all fibers express MHC class I antigen. In vitro studies demonstrated that proinflammatory cytokines or chemokines may induce MHC class I and class II on cultured muscle cells.
MHC-class-I-positive-fibers
Patogenesi
The most frequently reported cytokines in all the three subsets of idiopathic inflammatory myopathies are proinflammatory cytokines; IL-1α, IL-1β and TNF-α.
Diagnosi
EMG is part of the diagnostic procedures, a pathologic EMG with changes compatible with myopathy is a support for myositis, but the changes are non-specific. Conversely a normal EMG does not preclude myositis as the changes may be focal. Muscle biopsy is important for several reasons: 1) to confirm inflammatory changes and muscle fiber changes
characteristic of an inflammatory myopathy, 2) to distinguish between polymyositis and IBM, 3) to exclude other myopathies such as dystrophies and metabolic
myopathies. Notably a positive muscle biopsy is required for a definitive
diagnosis of polymyositis.
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
Myositis-specific antibodies
ANTIBODY DISEASE ASSOCIATION PREVALENCE
Anti-tRNA synthetases
(Jo-1)
(anti-PL-7, anti-PL-12,
anti-KS, anti-OJ,
anti-EJ, anti-Zo)
Raynaud´s phenomenon,
interstitial lung disease,
“mechanic’s hands”
20%
Anti-SRP (signal
recognition protein)
African-American women,
poor prognosis
Rare
Anti-Mi-2
Older women, “shawl
sign,” good prognosis
<20%
Anti-CADM-140 Amyopathic myositis,
interstitial lung disease
20%
Miositi ed Autoanticorpi
Utilità per la diagnosi e caratterizzazione di subset di malattia
Miosite specifici antisintetasi (Jo-1) (10-38%) anti-SRP
anti-Mi-2
anti-CADM-140
Miosite associati PM/Scl
(10-56%) RNP
SSA
Magnetic resonance imaging. Inflammation causes edema, which is seen on images that suppress the signal from fat (STIR or T2 weighted image with fat suppression) as white matter.
Copyright © 1972-2004 American College of Rheumatology Slide Collection. All rights reserved.
Polymyositis: differential diagnosis
Hypothyroidism
Drug-induced myopathies
Corticosteroids, colchicine, HMG-CoA reductase inhibitors, zidovudine,
hydroxychloroquine, alcohol
Infections
Viral, toxoplasmosis, trichinosis, bacterial pyomyositis
Connective tissue disorders
SLE, scleroderma, MCTD
Systemic vasculitis
PAN, Wegener’s granulomatosis
Diagnostic criteria for diagnosis of PM/DM by Bohan and Peter, 1975
Terapia
Treatment with glucocorticoids made a substantial improvement in survival and in reduced disability. High initial doses of glucocorticoids are recommended. IBM is usually non-responsive. Addition of immunosuppressive drugs to glucocorticoids is indicated in a majority of patients: MTX, AZA, CyA, Cy, IgG IV.
1. Physician´s overall assessment of disease activity on a visual analogue scale (VAS)
2. Patient/parent overall assessment of disease activity (VAS) 3. Functional assessment (Health assessment questionnaire) 4. Muscle strength testing (Manual muscle test (MMT)) 5. Serum levels of at least 2 of 4 muscle enzymes (CK, LD, AST, ALT) Extramuscular score (MYOSITIS DISEASE ACTIVITY ASSESSMENT VISUAL ANALOGUE SCALES (MYOACT) or the MYOSITIS INTENTION TO TREAT ACTIVITY INDEX (MITAX)) in which disease activity in seven organ systems, including muscles is scored (general symptoms, skin, joints, G-I tract, pulmonary, heart and muscles.)
Valutazione attività di malattia
SINDROME DI SJÖGREN
CORSO DI LAUREA IN MEDICINA E CHIRURGIA C
Prof. Fabrizio Conti
Malattia multisistemica
Lazy gland syndrome
Esocrinopatia autoimmune
Epitelite autoimmune
SINDROME DI SJÖGREN
… a relatively common autoimmune disease characterized by dysfunction and destruction of exocrine glands associated with lymphocytic infiltrates …
(Moutsopoulos H.M.)
AUTOIMMUNE FEATURES IN SJÖGREN’S SYNDROME
Ipergammaglobulinemia Anticorpi anti-nucleari (90% dei casi)
Anti-Ro (60/90%), anti-La (30-60%)
C4 basso Fattore reumatoide (40-50%)
Altri autoAb (anti-fodrina, anti-R muscarinico M3)
Crioglobuline (20%)
Infiltrato linfocitario ghiandolare Overlap con altre malattie autoimmuni Familiarità per malattie autoimmuni
Henrik Samuel Conrad Sjögren, Swedish ophthalmologist,
1899-1986.
Sindrome di Sjögren Primaria
entità clinica isolata
Sindrome di Sjögren Secondaria
associata ad altre malattie del connettivo ben definite:
- Artrite Reumatoide
- Lupus Eritematoso Sistemico
- Sclerosi Sistemica
- Polimiosite
- altre
Infiltrati mononucleati rotondeggianti inizialmente periduttali, i cosiddetti foci, i quali successivamente si associano a fenomeni di perdita della componente acinare e a fibrosi e a ridotta capacità secretiva.
LINFOCITI B
LINFOCITI T
CELLULE EPITELIALI
CELLULE FOLLICOLARI DENDRITICHE
CELLULE MIOEPITELIALI
MASTOCITI
CELLULE ENDOTELIALI
Patogenesi
ACH ACH
AUTOAB
IL-1 TNF-alfa
CELLULA ACINARE
LINFOCITI
NERVO COLINERGICO
ACH
RECETTORE MUSCARINICO M3
Cosa determina lo stato di persistente attivazione delle cellule epiteliali?
VIRUS
HERPES
RETROVIRUS
EBV
CMV
HHV6
HHV8
HTLV1
HRV5
ENTEROVIRUS: COXSACKIE
HLA (DR2, DR3, DQA10501, C4A null, DQw1/w2)
TAP2
GSTM1
Altri geni che regolano apoptosi
Background genetico
L’importanza della genetica
questi geni di suscettibilità sembrano associarsi più con la produzione di specifici autoanticorpi, in particolare gli anti-Ro, che con la malattia.
• Prevalenza 0,09-3,52 %
• Incidenza 3,9-5,3 casi/anno/100.000
- etnia
- età pazienti
- criteri classificativi adottati
- tests utilizzati
EPIDEMIOLOGIA
• F/M 9-14: 1
35-45 anni ma casi pediatrici e senili
SINDROME DI SJÖGREN: CRITERI CLASSIFICATIVI CEE
1. SINTOMI OCULARI
Definizione: risposta positiva ad almeno una delle seguenti tre domande
a) Sente una sensazione quotidiana di secchezza a livello oculare da almeno tre mesi ?
b) Ha l’impressione ricorrente di avere la sabbia negli occhi ?
c) Usa lacrime artificiali più di tre volte al giorno ?
2. SINTOMI ORALI
Definizione: risposta positiva ad almeno una delle seguenti tre domande
a) Ha una sensazione di secchezza orale da almeno tre mesi ?
b) Ha avuto una tumefazione ricorrente o persistente delle gh. salivari in età adulta ?
c) Beve frequentemente liquidi per aiutare la deglutizione ?
3. SEGNI OCULARI
Definizione: un test positivo dei due seguenti:
a) Schirmer b) Rosa Bengala
5. COINVOLGIMENTO GHIANDOLE SALIVARI
Definizione: un test positivo dei tre seguenti
a) Scintigrafia salivare
b) Scialografia
c) Secrezione salivare senza stimolo
4. ISTOPATOLOGIA
Definizione: almeno un focus (50 linfociti) su una superficie di 4 mm2 di tessuto di gh. salivari minori
6. AUTOANTICORPI
Definizione: presenza di almeno uno dei seguenti autoanticorpi
Anti-Ro o anti-La o entrambi
4 criteri su 6 tra cui o la biopsia o gli autoAb
Minor salivary gland biopsy in a patient with SS: presence of dense lymphocytic aggregates, associated with acinar rarefaction and widening of salivary ducts
CRITERI DI ESCLUSIONE
Precedente irradiazione testa e/o collo Infezione da virus C dell’epatite Infezione da HIV Linfoma pre-esistente Sarcoidosi GVDH Uso di anti-colinergici
Polmoni
Pan-
creas GE Reni Epato-
biliari Linfoma
maligno
Pseudo-linfoma
Linfoma
benigno
Organi interni
Superficie
Linfocita-
B
Manifestazioni
Esocrine
TG
Pelle
F-E
L-T
Naso
Occhio
Bocca
Pelle
Articolazioni
Sierose
SNC
SNP
Fenomeno di
Raynaud Citopenia
Ematologica
Astenia
Febbre
Tiroidite
Vasculiti
Infiammatorie
Vasculite
Vasospastica
Patologie indotte
da mediatori
Patologie
autoimmunitarie
Manifestazioni
non esocrine
L-T: Laringe-Trachea, F-E: Faringe-Esofago, TG: Tratto Genitale, GE:Gastro Enterico, SNC: Sistema Nervoso Centrale, SNP: Sistema Nervoso Periferico.
400 pazienti: 373 F, 27 M (F:M 14;1) età media 58.7 aa (range 16-87)
Xerostomia 98% Xeroftalmia 93%
Xerosi cute 31% Secch. genitale 19% Tumef. parot. 18%
MANIFESTAZIONI GHIANDOLARI
MANIFEST. EXTRA-GHIANDOLARI
Artralgie/artrite 37% F. Raynaud 16% Vasculite cute 12% Tiroidite 15% Polmoni 9% SNP 7% Febbre 6% Linfoproliferat. 2% Rene 6% SNC 1% Pancreatite 1%
• Solo sindrome sicca 35% • Sindrome sicca + manifestazioni extraghiandolari 65%
Ann Rheum Dis 2005;
64:347–354.
BOCCA
mucose aride
mancanza di saliva
saliva ispessita
fissurazioni e atrofia papille filiformi
carie in sedi atipiche
candida
tumefazione ghiandole salivari
xerostomia (bruciore, arsura, difficoltà nella
deglutizione, nell’eloquio, nella masticazione, anomalie del
gusto, problemi con la dentiera)
… patients with Sjogren's syndrome have a
significantly higher plaque index score (p < 0.005),
higher decayed/missing/filled surfaces scores (p <
0.05), increased alveolar bone loss (p < 0.05),
deeper clinical attachment level (p < 0.05), and
increased cementoenamel junction-alveolar bone crest
distance (p < 0.005).
Patients with Sjogren's syndrome are at 2.2 times
higher risk of having adult periodontitis than
healthy controls
Prevalence of periodontal disease in patients with Sjogren's
syndrome. Najara MP et al Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 1997;83:453-7.
XEROSTOMIA
Prevalenza nella popolazione generale : 14-46%
GHIANDOLARE danno da radiazioni, chirurgia, neoplasie, sarcoidosi, HCV, HIV, malattie autoimmuni, amiloidosi, GVHD. NEUROLOGICA farmaci (antidepressivi, neurolettici, parasimpaticolitici, clonidina,
betabloccanti e diuretici) , disfunzione autonomica, Alzheimer, neuropatie periferiche DISIDRATAZIONE INFEZIONI VIRALI ACUTE
PROCEDURE DIAGNOSTICHE PER LA COMPONENTE SALIVARE
Sialometria (15 min no stimolo vn 1,5 ml)
Sialography
Minor salivary gland biopsy (almeno 1 focus /4 mm2)
Scintigraphy
T1 T2
Ecografia
Nuove procedure diagnostiche per la componente orale
MR MR sialography
OCCHI
sensazione di corpo estraneo, bruciore, prurito, visione appannata, fotofobia, affaticamento, incapacità di tollerare lenti a contatto
congiuntive iperemiche detriti mucosi nel film lacrimale cheratite filamentosa ulcere corneali
FILM LACRIMALE
Lo strato più profondo, mucoso, è formato da un coacervato di mucina ed è fortemente adeso alla porzione glicoproteica sottostante. E’ costituito da un complesso di glicoproteine idratate che provengono per lo più dalle cellule mucipare caliciformi della congiuntiva ma anche dalle cellule epiteliali della cornea
Lo strato acquoso proviene per la massima parte dalla secrezione delle ghiandole lacrimali
Lo strato lipidico è’ costituito da esteri delle cere a catena lunga ed esteri di colesterolo che derivano dalle ghiandole di Meibomio
DIAGNOSTIC PROCEDURES FOR EYE INVOLVEMENT
Schirmer test I
BUT
Rosa Bengala o simili
(<5 mm in 5 minutes)
un tempo inferiore a 10” è considerato patologico
MANIFESTAZIONI ARTICOLARI
Ecografia: ispessimento membrana sinoviale
Radiologia tradizionale: riduzione lieve della rima articolare
Quadro clinico:
• Artralgie
• Artrite non erosiva
Manifestazioni dermatologiche
xerodermia
prurito
ipoidrosi
orticaria
porpora
reazioni cutanee da farmaci
fotosensibilità
Crioglobulinemia
5 % policlonale
9% monoclonale
Sjögren e linfoproliferazione
anno n.pz. linfomi (%) follow-up
Talal 1964 58 5 (8) 4
Bloch 1965 62 3 (5) 2
Kassan 1978 136 7 (5) 8,1
mcCurley 1990 138 3 (3) 12
Pavlidis 1992 120 8 (7) 7
Zuffery 1995 55 5 (9) 12
Tzioufas 1996 103 7 (7) 5
Ramos 1998 144 4 (4) 9
Skopouli 2000 261 11 (4) 3,6
LINFOMI A CELLULE B
maltomi
a cell.B monocitoidi
ad alto grado
FATTORI DI RISCHIO tumefazione parotidea
linfoadenopatia
splenomegalia
C4, anti-Ro
crioglobulinemia
porpora palpabile
MANIFESTAZIONI POLMONARI
xerotrachea
interstiziopatia
polmonite linfocitaria
iperreattività bronchiale
ipertensione polmonare
pleurite
Impegno polmonare 2-75%
Sjögren secondaria > primaria
Manifestazioni ostetriche e ginecologiche
secchezza vaginale
dispareunia
infezioni da candida
fertilità
parità
Sindrome materno fetale
da anticorpi anti-Ro/La
?
Sindrome materno-fetale da anticorpi anti-Ro/La
LES
Sjögren
Altre connettiviti
Asintomatiche
Anti-Ro/La
IgG Anti-Ro/La
IgG
placenta
Permanenti Transitori
BloccoAV
Cardiomiopatia
QT lungo (?)
Rash
Citopenie
Epatite
Manifestazioni neurologiche
Focali
Diffusi
Midollo
Disordini motori e/o sensitivi, afasia, disartria, emicrania, convulsioni, amaurosi, sindrome cerebelllare, corea
Encefalopatia acuta e subacuta, meningite asettica
Mielite trasversa, vescica neurologica, Brown-Sequard, malattia motoneurone inferiore
SNC
Disturbi psichiatrici
Depressione, isteria, ipocondria, deficit memoria, demenza, deficit attenzione
SNP Nervi cranici, polineuropatia sensitiva, polineuropatia sensitivo-motoria
Manifestazioni renali (2-26%)
Quadri clinici: acidosi tubulare renale, diabete
insipido nefrogeno, sindrome
nefrosica o nefritica
Anatomia patologica: nefrite tubulo-interstiziale
atrofia tubulare
nefrocalcinosi
glomerulonefrite (rara)
Altre manifestazioni
Astenia (57-74%)
Disturbi del sonno
“Widespread pain” (7%)
Mialgie (44%)
Fibromialgia (12-55%)
flogosi 72%
polimiosite franca 14%
IBM 22%
• Miosite
Prognosi
Tasso standardizzato di mortalità
(morti osservate/ morti attese) 1,2
Nel 20% dei casi la morte è dovuta a linfoma
Basso C4
porpora palpabile
SJÖGREN
tipo I
(20 % delle Sjögren)
tipo II
(80 % delle Sjögren)
Alto rischio
Basso rischio
GOALS OF TREATMENT IN SJÖGREN’S SYNDROME
palliation of sicca symptoms prevention of local complications
Life syle advices Local therapy
stimolation of exocrine glands Muscarinic agents
Modification of the immune response
Treatment of extraglandular manifestations
Different drugs
ALTRE CONNETTIVITI
The diagnosis of rheumatic diseases can be particularly challenging, because many clinical symptoms such as Raynaud’s phenomenon, arthritis, interstitial lung disease and small vessel vasculitis are non-specific and can be found in a variety of distinct rheumatic entities. Similar to the clinical symptoms, several serologic markers such as antinuclear antibodies (ANA), rheumatoid factor (RF), anti-Ro/SS-A- and anti-La/SS-B are not specific for a single rheumatic disease. Vice versa, other autoantibodies have a higher specificity for certain rheumatic diseases, e.g anti-CCP-antibodies for RA, anti-Sm- and anti-dsDNA for SLE, and anti-Scl70 as well as ACA for diffuse and limited systemic sclerosis.
Many patients with features of a connective tissue disease cannot be classified as having a specific connective tissue disease. For these patients, the term “undifferentiated connective tissue disease” (UCTD) has been generated. UCTD represents an heterogeneous group of patients, who do not fulfil the classification criteria for a specific disorder, but have features strongly suggestive of a connective tissue disease.
UCTD
Overlap syndromes
Up to 25 % of patients with rheumatologic diseases do not only fulfil the classification criteria for one defined disease, but for two or more rheumatologic disorders. These patients are defined as having an overlap syndrome. Overlaps between virtually all combinations of rheumatic diseases have been described.
RA SLE
MCTD
Mixed connective tissue disease (MCTD, Sharp’s syndrome) was first described in 1972 by Sharp and colleagues as a connective tissue disease with features of SLE, SSc, RA and polymyositis characterized by the presence of high titres of anti-U1-RNP autoantibodies. The clinical features of MCTD often develop over several years and are rarely all present at the initial presentation.
MCTD - PATOGENESI
MCTD is associated with HLA-DR1, HLA-DR4 and to a lesser degree with HLA-DR2 . In contrast, SLE is associated with HLA-DR2 and HLA-DR3, SSc with HLA-DR3 and HLA-DR5 and PM with HLA-DR3. Anti-U1-RNP, which are per definition required as a conditio sine qua non for the diagnosis of MCTD, are also found in 20 - 30 % of patients with SLE. However, the titres of anti-U1-RNP in patients with SLE are normally lower than in MCTD.
MCTD - EPIDEMIOLOGIA
The prevalence of MCTD in Caucasians has been estimated to be 1:10.000. MCTD affects females much more often than males with a ratio of 9-16:1. The mean age of onset is 28 - 37 years.
MCTD - CLINICA
MCTD - CLINICA
Joint involvement is present in a RA-like pattern with symmetric, polyarticular involvement of the small joints of the hands and feet. The arthritis in MCTD can be erosive in 30-70 % of patients by x-Ray. Erosions are observed more often in RF positive individuals. The prevalence of myositis in MCTD varies from 15 - 75 % in different studies. Severe renal disease and CNS manifestations are usually absent in MCTD.