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.