Rheumatology E-learning

University of Szeged

Department of Rheumatology and Immunology

This university lecture was compiled on the base of the

following authors’ previous lectures:

Swanthi de Silva, MD

Aleena Farook, MD

Eva Honsova, MD

Emily O. Jenkins, MD

Paul S. Krunka, MD

Leo Martinez, MD

Susan Mcannon, MD

Leslie Proctor, MD

Alka Stieling, MD

Claudio Vitali, MD

What is Sjögren’s Syndrome?

Systemic autoimmune disorder

Princopal targets: salivary & lacrimal glands –almost always involved, although often not thepresenting complaint

Principal symptoms: xerostomia & xerophthalmia(dry mouth and eye)

Lots of other organs are affected

Sjögren’s syndrome

Chronic inflammatory disorder

Diminished function of the lacrimal and salivary

glands (sicca syndrome)

„autoimmune“: predominantly in females

presence of autoantibodies

anti-Ro/SSA, anti-La/SSB

SjS may occur in a primary form or as a

secondary form that overlaps with other

autoimmune diseases most frequently RA. There

is also evident overlap of SjS with subset of SLE

or scleroderma.

History

Henrick Sjögren 1899-1987 Sweden

1930-As ophthalmology resident, discovers women with

rheumatism and corneal abrasions who could not produce

tears when crying and could not dissolve a lump of sugar in

their mouths.

1933-Published his thesis paper on Keratoconjuctivitis

Sicca, describing 15 women with lacrimal gland dysfunction

leading to ulcerative lesions of the eyes. Was not well

received, did not acquire Docenti (Academic PhD).

1951-Sjögren published a series of papers describing 80

patients with the syndrome, in which the majority had

arthritis. Sjögren’s syndrome was then recognized in

literature.

Incidence

As many as 1-2 million people in

the US are affected,

Prevalence of 1-3% of the

population

It is in the top three of rheumatic

diseases behind systemic lupus

erythematosis and rheumatoid

arthritis

Approximately 30% of RA pt have

SS.

Primary Sjögren’sSyndrome has a ratio 9:1 of women to men

Age range from 40-60, with mean of 52.7 years.

However, case reports have been seen in children.

Pathogenesis

Primary Sjögren’s syndrome is associated with HLA-DR3

The histologic hallmark: lymphocytic infiltration of exocrine glands leading to gland degeneration, necrosis, and atrophy4

The primary insult is probably a viral (?) infection of salivary epithelial cells – transformation of the protein-synthetic machinery, appearance of modified self and viral proteins – they will behave as autoantigens

T-cell infiltration of the salivary and lacrimal glands

Lymphoid follicle organisation in the glands – stimulationof B-cells – polyclonal hypergammaglobulinaemia, auto-antibodies to self antigens

Presentation

In a prospective cohort study of 400 patients, 98% presented with dry mouth and 93% presented with dry eyes.2

Associated dry mouth symptoms: difficulty speaking and eating and swallowing, and frequents sips of water.5

Associated dry eye symptoms: grittiness, dryness, pruritis, foreign body sensation.

In one study of 195 Dutch patients, 85% reported fatigue12

5. Kruszka PS and O’Brian RJ. Diagnosis and Management of Sjogren Syndrome. Am Fam Physician. 2009;79(6):465-470.

Sjögren’ syndrome

Intracellular proteins of the salivary gland epithelial cells (SSA, fodrin…) change (translocate to the cell surface, are cleaved by caspases…) probably in consequence of a viral infection

Epithelial cells become antigen-presenting cells

Nakamura H, Transl Res 2006

Sjögren’s syndrome – minor salivary

gland – focal lymphocytic infiltrate

Sjögren’s – Characteristic features

Focal lymphocytic sialadenitis and dacryoadenitis

Spectrum: Local glandular signs (ocular and oral dryness)

Systemic glandular (epithelial) signs (pharyngitis, laryngitis, bronchitis, vaginitis sicca, gastrointestinal, pulmonary, hepato-biliary, renal tubulo-interstitial and thyreoid involvement)

Systemic extraglandular signs (polyarthritis, Raynaud’s phenomenon, vasculitis, glomerulonephritis, polyneuropathy, cytopenias, constitutional symptoms).

Lymphoma

Glandular manifestations

Oral involvement I.

Xerostomia (XS), bilateral parotid

(occasionally other salivary gland) swelling

Symptoms

Complications: Oral candidiasis, angular

cheilitis, early caries, parodontopathy,

purulent sialadenitis

Glandular manifestations

Oral involvement II.Involvement of unilateral or bilateral major and minor salivary

glands

Decreased salivary secretions-loss of lubrication, buffering and

antimicrobial capacities of saliva.

Most common complication is increase in dental caries, especial

root and incisor caries.

Frequent fungal infections

Tongue fissures

Persistent salivary enlargement.

Sjögren’s syndrome - xerostomia

Sjögren’s syndrome - xerostomia

Sjögren’s syndromeOral Signs

Slide reprinted from the Clinical Slide Collection on the

Accelerated tooth decay due to xerostomia – loss of antibacterial and otherprotective salivary factors

Sjögren’s syndrome - parotid

enlargement

Parotid gland enlargement occurs in 1/3 of SjS patients

If acute and painful: probably bacterial infection due toobstruction by salivary stones

If chronic, soft, even surface parotids: chronic lymphocyticsialadenitis due to SjS – risk factor for lymphoma development

If rapidly growing, nodular, hard: lymphoma – biopsy, and treat if necessary!

Glandular symptoms

Ocular involvement

Xerophthalmia (XO), keratoconjunctivitis sicca

Symptoms: sand feeling, feeling of foreign body in the eye, photosensitiviy, feeling of dryness

Decreased lacrimal flow

Corneal and conjunctiva epithelial damage

Leads to dry eyes, foreign body sensation, irritation, photosensitivity, thick secretions at inner canthus, and visual impairment.

Complications: bacterial conjunctivitis, keratitis, corneal ulcer or perforation

Sjögren’s syndrome –

keratonjunctivitis sicca

Sjögren’s syndrome

dry eye

Sjögren’s syndrome – further

glandular manifestations

Pharyngitis, laryngitis, bronchitis sicca

Dry cough, throat pain, repeated infections

Vaginitis sicca

Dyspareunia

Chronic atrophic gastritis (not Helicobacter-

dependent) – common. Duodenum, jejunum,

pancreas involvement – rare. Gluten-

sensitive enteropathy – not rare

Sjögren’s syndrome – further

glandular involvements

Liver involvement: rare. Chronic lymphocytic cholangiolitis.

Renal involvement: not rare. Chronic tubulointerstitial nephritis. (↔ glomerulonephritis – quite rare)

Lung involvement: not rare. Initiating step: lymphocytic bronchiolitis, which may evolve into lymphocytic interstitial pneumonitis (LIP)

Chronic lymphocytic thyreoiditis: not rare. Consequence: hypothyreodism

Sjögren’s syndrome: renal involvement a frequent glandular manifestation of

primary SjS. Clinical signs and renal

pathology are heterogeneous and

variable.

The main clinical manifestation is

presented by renal tubular

dysfunction, especially by

“distal” renal tubular acidosis

(RTA) type I.

SjS represents a rare indication for

the performance of a renal biopsy

Maripuri et al. Renal involvement in Primary

SjS. Clin J Am Soc Nephrol.2009, Aug.

7 276 patients/ 24 with a biopsy (0.3%).

Sjögren’s syndrome: renal involvement

Distal RTA is a disease of defective urinary acidificationthat is caused by dysfunction of α-intercalated cells.

RTA is characterized by: hypocalemic metabolic acidosis:

An impairment of H+ excretion into the tubules is associated with higher

excretion of potassium and hypokalaemia. Instead of the bicarbonates, which

are lost in the urine, chlorides enter the blood and this type of defective

function may leads to hyperchloremic and hypokalaemic metabolic acidosis.

As it is necessary to buffer acid ions, calcium is mobilized from the bones:

nephrocalcinosis or nephrolithiasis.

von Kossa stain

Sjögren’s syndrome: renal involvement

Biopsy samples of patients suffering from SjS with dRTAshowed frequently tubulointerstitial nephritis -focally dense infiltrates of lymphocytes, monocytes and plasma cells,

- varying degrees of tubulitis, -tubular atrophy, and interstitial fibrosis.

Dif. dg.: different types of TIN, IgG4-related sclerosing autoimmune disease

Sjögren’s syndrome: renal involvement Only small percentage of patients

develops immune-complex-

mediated GN . Bossini (Nephrol Dial

Transplant 2001; 16:2328-2336) the

incidence of GN was 5%, and in

the study of Ren (J Rheumatol 2008;

35:278-284) it was 4.6%.

All types of GNs were reported

MGN, MPGN, FSGS, IgA GN and

also pauciimunne GN with positive

ANCA antibodies.

In several cases, the glomerular

lesion, usually MPGN, was

associated with cryoglobulinemia

overlap of SjS with a subset of

SLE

Conclusion: the primary antigenic target is in theepithelial cells of glandular structures withacinary-ductal histological organisation

Most of the exocrine glands (including thetubular system of the liver and the kidney) areinvolved

Hepatic parenchymal cells and the glomeruli areusually not involved in SjS

Therefore, a term „autoimmune epitheliitis” wascoined to describe the exact nature of SjS

Sjögren’s syndrome – „autoimmune

epitheliitis”

Sjögren’s syndrome – extraglandular

symptoms Non-glandular organs are also often affected in SjS

by autoantibodies and circulating autoreactive T-cells

Polyarthritis – common. Non-erosive, butoccasionally deforming. Finger, wrist > ankle, toe, knee> elbow, shoulder

Raynaud’s phenomenon - common

Vasculitis – not rare. Purpura > medium-sizedvessel vasculitis (skin ulcer, gangraene, occasionally hepatic, mesenteric, pulmonary)

Neuropathy – not rare.

Cytopenias – anaemia, leukopenia, lymphopenia

Lymphadenomegaly, hepato-splenomegaly

General symptoms – fatigue!

Skin vasculitis - purpura

Lymphoma in Sjögren’s syndrome

Malignant, non-Hodgkin B-cell lymphoma. Itsprevalence is 44-fold higher than in the generalpopulation.

Histology: mostly low-grade, the majority is MALT (mucosa-associated lymphoid tissue) lymphoma. Less commonly: high-grade (blastic).

Localisation: mostly extranodal (parotid > stomach > bronchus > other, less commonly nodal (cervical > supraclavicular > axillary > other)

Outcome: the majority can be cured. Requires chemo-or chemo+radiotherapy. Mortality: ~ 25%.

Important: the regular, careful checking of the parotidand the lymphatic nodes. In case of an unusualsymptom (gastric complaint, airway symptom, weightloss, etc.) a malignant lymphoma should always be suspected

Mortality and its Predictors

in primary SjS The standardized mortality ratio was 1.15 (95% CI = 0.86-1.73) compared

with the general population.

In incident cases, the probability of LPD was 2.6% at 5 years and 3.9% at 10

years.

Mortality rates were significantly higher in patients with low C4 levels

(hazard ratio [HR] 4.39, 95% CI 2.18-8.83).

LPD was independently predicted by the presence (at the 1st visit) of:

parotid enlargement (HR 5.21, 95% CI 1.76-15.4)

palpable purpura (HR 4.16, 95% CI 1.65-10.5)

low C4 levels (HR 2.40, 95% CI 0.99-5.83)

Ioannidis JPA et al: Arthritis Rheum, 2002

Diagnosis – American-European

Consensus Classification Criteria 2002 Ocular symptoms: a positive response to at least one of the following questions:

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?2. Do you have a recurrent sensation of sand or gravel in the eyes?3. Do you use tear substitutes more than 3 times a day?

Oral symptoms: a positive response to at least one of the following questions:1. Have you had a daily feeling of dry mouth for more than 3 months?2. Have you had recurrently or persistently swollen salivary glands as an adult?3. Do you frequently drink liquids to aid in swallowing dry food?

Ocular signs - that is, objective evidence of ocular involvement defined as a positive result for at least one of the following two tests:1. Shirmer's test, performed without anaesthesia ( ≦5 mm in 5 minutes )2. Rose bengal score or other ocular dye score ( ≧4 according to van Bijsterveld's scoring system )

Histopathology: In minor salivary glands (obtained through normal-appearing mucosa ) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score ≧1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue

Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result for at least one of the following diagnostic tests:1. Unstimulated whole salivary flow ( ≦ 1.5 ml in 15 minutes )2. Parotid sailography showing the presence of diffuse sialectasias (punctate, cavitary,or destructive pattern ), without evidence of obstruction in the major ducts.3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer

Autoantibodies: presence in the serum of the following autoantibodies:1. antibodies to Ro(SSA) or La(SSB) antigens, or both

Schirmer’s test

Rose Bengal dyeRose Bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a

stain. Its sodium salt is commonly used in eye drops to stain

damaged conjunctiva and corneal cells and thereby identify damage

to the eye.

Non-stimulated whole saliva flow

Spit into graduated test tube every minute for

15 minutes.

Or keeping sterile gauze swabs in the mouth

for 15 minutes and measurement of the

increase in weight

Collection of less than 1.5 mL in 15 minutes

is considered positive

Lymphocytic and plasma cells infiltrate

Two excretory ducts and 3 mucous salivary

gland acini are seen

Laboratory

SS patients of both primary and secondary Sjögren’s

syndrome have marked hypergammaglobulinemia

(IgG>IgA>IgM), elevated total protein and sedimentation rate,

persistent rheumatoid factors, and a decreased WBC count.

SS-A/Ro and SS-B/La (anti-RNA antibodies). Antibodies

occur in approximately 60% of patients with Sjögren's

syndrome and are associated with early disease onset,

longer disease duration, parotid gland enlargement, a higher

frequency of extra-glandular manifestations, and more

intense lymphocytic infiltration

These test are nonspecific, also seen in many autoimmune

inflammatory conditions.

Criteria for Sjögren’s syndrome

Primary SS is defined as the presence of 4 of the 6

diagnostic criteria present.

Secondary SS is defined as presence of connective

tissue disease with a positive category 1 or 2 and a

positive result in 2 of the remaining 4 criteria

Differential diagnosis for dry eyes

Condition Comment

Allergic conjunctivitis Burning eyes, conjunctival injection,

and mucoid secretion

Blepharitis Eyelid erythema and crusting, worse in

morning, does not respond to eye

drops

Environment Wind, dust, low humidity, irritants

Lifestyle Diminished blinking during long

periods of driving, reading, computer

MedicationsDiuretics and anticholinergics. Medications for:

Alzheimer's, Parkinson's, allergic rhinitis,

depression, incontinence

Rosacea Burning, eyelid swelling/erythema

Differential diagnosis for xerostomia

Condition Comment

Diabetes Dryness worsens with poor glycemic

control

Head and neck radiation External beam radiation damages

salivary glands

Hepatitis C Sialadenitis results in 15% of patients

with Hep C

HIV medication

Medications Diuretics and anticholinergics

Obstructed nasal passages Mouth breathing

Sarcoidosis Non-caseating granulomas in salivary

glands

Treatment

Ocular symptoms: artificial tear, tear replacent

gels, humidification of the environment, less

computer use, avoidance of contact lenses

Oral symptoms: frequent consumption of liquids,

dilute lemon juice, (sugar-free) chewing gum,

oral disinfectant, muscarinergic agents

(selective: cevimeline, non-selective: pilocarpin)

Mavragani CP et al. (2006) The management of Sjögren's syndromeNat Clin Pract Rheumatol 2: 252–261 doi:10.1038/ncprheum0165

Table 1 Management of glandular manifestations of primary Sjögren's syndrome

Treatment

Constitutional symptoms, parotid swelling:

hydroxychloroquin

Severe vasculitis, neuropathy (multiple

mononeuritis), cytopenia, renal involvement,

lymphocytic interstitial pneumonitis: high-dose

corticosteroid, cyclophosphamide, in refractory

cases: rituximab

Clinical evolution: In general the long-term

survival is not decreased (but: in case of

lymphoma or severe organ manifestations it is).

On the other hand: high morbidity, significant

impairment in the quality of life.

THERAPEUTIC GUIDELINES

IN SJÖGREN'S SYNDROMEExtraglandular manifestations (1)

1. arthralgias/ arthritis:

- NSAIDs, corticosteroids (low dosage),anti-malarials(hydroxychloroquine), methotrexate

2. Raynaud's phenomenon

- vaso-active drugs (Ca-antagonists)

3. haemocytopenia (in case of severe forms)

- corticosteroid, azathioprin, cyclophosphamide, rituximab

4. vasculitis (purpura, peripheral neuropathies, etc.)

- corticosteroids, cyclophosphamide, intravenousimmunoglobulin, rituximab

THERAPEUTIC GUIDELINES

IN SJÖGREN'S SYNDROME

Extraglandular manifestations (2)

5. Myositis

- steroids (high dosage or pulse)

- MTX or cyclophosphamide (pulse)

6. Interstitial lung involvement (in active phase )

- steroids (high dosage or pulse)

- cyclophosphamide (iv. pulse )

7. Tubulointerstitial nephritis

- steroid (medium/high dosage)

- bicarbonates to correct acidosis in a late phase

THERAPEUTIC GUIDELINES

IN SJÖGREN'S SYNDROME

Extraglandular manifestations (3)

8. Fatigue and depression

Steroids (low dosage) are indicated in the case of late morning

or early afternoon fatigue, often associated with flulike

symptoms and probably related to disease activity and

production of specific cytokines (IL-1, TNF-a).

Psychoactive drugs in the case of early morning fatigue, often

associated with poor sleep and fibromyalgia symptoms.

Benzodiazepine agents to induce sleep and antidepressant

drugs lacking anticholinergic effects (fluoxetine, fluvoxamine,

etc.) can be tried.

Idiopathic inflammatory

myopathies

Introduction

Idiopathic inflammatory myopathies (IIM) are

a group of systemic diseases characterized

by an immune mediated attack on skeletal

muscle

Characterized by

○ Proximal muscle weakness

○ Nonsuppurative inflammation of skeletal muscle

○ Accompanied by extramuscular manifestations

Is it a myopathy or neuropathy?

Both muscle diseases and nerve diseases

may present with weakness or pain.

Neuropathic processes tend to be:

Asymmetrical

Distal

Myopathic processes tend to be:

Symmetrical

Proximal

How to differentiate between

proximal and distal weakness?

Proximal weakness

If the patient has difficulty

rising from a chair (hip

muscles) or combing his or

her hair (shoulder girdle)

Distal weakness

If the patient has difficulty

standing on his or her toes

(gastrocnemius/soleus) or

doing fine work with the

hands (intrinsics)

Demographics

Idiopathic inflammatory myopathies

Prevalence rates of 1:100,000

F:M 2:1

Peak age range in adults is 40-50 years

PM: rare in childhood

IBM: males after the age of 50

Immunopathogenesis

DM: Complement mediated vasculopathy

cellular infiltrate is located in the perifascicular

regions and is often perivascular

PM: Directed T cell muscle injury

cellular infiltrate is found predominantly within the

fascicle, where there are increased numbers of

cytoxic T-cells

Classification of Inflammatory

Myopathies

1. Adult polymyositis

2. Adult dermatomyositis

3. Inflammatory myositis associated with

cancer

4. Childhood dermatomyositis or

Polymyositis

5. Myositis associated with another

autoimmune disease (SLE, for example)

6. Inclusion body myositis

Genetics

Genetic factors play a part in the development of IIM Occurrence of various forms of IIM in more than one

member of the same family

Higher incidence of other autoimmune disorders in first degree relatives

Specific HLA subtypes are believed to confer increased risk for developing IIM

The strongest link is with HLA DRB1*0301 in Caucasians and HLA DRB1*14 in Koreans DR3 is strongly associated with Anti Jo-1 Ab

Pathogenesis

Etiology and the pathogenesis of the inflammatory myopathies remain elusive

Thought to result from a combination of interactions between environmental and genetic risk factors

Among 13 geoclimatic variables studied in a population of 900 myositis patients, surface ultraviolet radiation was the strongest contributor to the disease

Case

• A 48-year-old woman presents with complaints of diffuse muscle pain, weakness, and fatigue. She reports

• Gradual onset over past 6 months

• Morning stiffness lasting 2 to 3 hours

• Difficulty with getting up out of a chair and combing her hair

• No problems with holding a brush or standing on her toes

Case 2: Objective Findings

Minimal muscle

tenderness

No joint tenderness

or swelling

Significant proximal

muscle weakness in

both upper and

lower extremities

No focal neurologic

abnormalities

Diagnosis

Criteria proposed by Bohan and Peter in 19751. Symmetric proximal muscle weakness by physical

exam

2. Elevation of serum skeletal muscle enzymes –CPK, Aldolase, AST, ALT, LDH

3. EMG triad short, small, polyphasic motor unit action potentials

Fibrillations – positive sharp waves and insertional irritability

bizarre high frequency repetitive discharges

4. Muscle degeneration, regeneration, necrosis, phagocytosis and interstitial mononuclear infiltrate

5. Typical skin rash of DM

New diagnostic criteria for PM

Myopathic weakness evolving over weeks to months, sparing facial and eye muscles

Exclude other causes

Disease can be associated with another autoimmune disease or viral infection (rare as a stand alone entity)

Reconsider PM if: Disease onset < 18yrs

Patient has fatigue and myalgia without muscle weakness

Absence of MHC-1 or MHC-1/CD8 complex on histology

Differential Diagnosis

Muscular dystrophies Limb-girdle muscular dystrophy

Dysferlinopathy ( Miyoshi myopathy)

Dystrophinapathy – Duchene muscular dystrophy

Metabolic myopathies Lipid and glycogen storage disorders

Mitochondrial myopathies

Endocrine myopathies Hypo/Hyperthyroidism

Cushing syndrome

Hypo/Hyperparathyroidism

Acromegaly

Drug induced myositis D-penicillamine, Quinidine, Procainamide, IFN alpha, IL-2

HMG CoA reductase inhibitors – noninflammatory, necrotizing myopathy

Think About Generalized Soft-Tissue

Pain Syndromes

Fibromyalgia syndrome

Major depression associated with

musculoskeletal pain

Somatoform pain disorders

Soft-Tissue Pain Syndromes:

Fibromyalgia

Widespread musculoskeletal pain

Decreased pain threshold and tolerance

May have tenderness in specific regions

(tender points)

Associated fatigue, sleep, somatic

complaints

No objective inflammation seen on physical

examination

Normal laboratory findings

Pathology

Key myopathologic features of PM Predominantly endomysial inflammatory infiltrate

Infiltration of intact fibers

Widespread expression of MHC class 1

CD8 +ve T cells

MHC class 1 proteins are not usually expressed on muscle fibers.

In IIM MHC class 1 is present on degenerating and normal fibers

MHC/CD8 is a specific marker because it distinguishes the antigen driven inflammatory cells that characterize PM/IBM from the nonspecific secondary inflammation seen in other muscular dystrophies

Pathology

DM- perivascular B cell predominant inflammation associated with microinfarcts and perifascicular atrophy

Key Features Perivascular lymphocytic infiltration

Lymphocytic infiltrate – B cell and CD4+Tcell

Myofiber necrosis and regeneration

Perifascicular atrophy

Ultrastructural examination○ Capillary loss

○ Tubuloreticular inclusions in endothelial cells

Histology: DM

Skin Biopsy

Direct immunofluorescencestudy of a skin lesion from a patient with dermatomyositis

Intense staining of immunoglobulins along the dermal-epidermal junction

Biopsy was taken from a dermatomyositis patient with the cutaneous finding of flagellate erythema

Pathology

Key features of IBM Congo red positive amyloid deposits

Rimmed vacuoles

EM – whorled membranous material and tubulofilamentous inclusions

The inflammatory cells invade non-vacuolated fibers, while the vacuolated fibers are not invaded by T cells.

Two independent processes Primary T cell driven immune process identical to PM

Degenerative process in which B-amyloid and related proteins participate in vacuolar degeneration

Muscle Biopsy

Definitive diagnostic procedure and should be performed prior to treatment

Open biopsy is preferable to needle biopsy

Site of biopsy Vastus lateralis, biceps brachii or deltoid muscle

Avoid atrophic muscles or muscle on which EMG has been performed

Tissue obtained should be sent for Conventional light microscopy

Immunohistochemical studies – dystrophies

Electron microscopy

Due to patchy nature of histological changes the biopsy may be normal or inconclusive

Close collaboration between clinician and pathologist

Polymyositis: CD8+Tcells, endomysial infiltration

Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration

Lymphocytic infiltration with muscle

necrosis

Electromyography

EMG findings are not specific for IIM

Myopathic motor unit action potentials Polyphasic

Short duration

Low amplitude

Evidence of increased membrane irritability Positive sharp waves

Fibrillation potentials

Complex repetitive discharges

In IBM additional evidence of neurogenic changes Prolonged and large amplitude motor unit action potentials

Muscle Enzymes

Muscle enzymes elevated AST,ALT,LDH, Aldolase, CPK

CPK most sensitive and best measure of muscle injury

Muscle CPK 99% mm, with small amount of MB

CPK can be elevated as much as 50 fold in PM/DM

CPK elevation is relatively modest in IBM

CPK elevation more than 100 fold should call the diagnosis into question

CPK levels may rarely be normal , even in the presence of inflammatory changes on muscle Bx – explanation is unclear

Relationship between serum CPK level

and disease activity

Most reliable biochemical indicator of

disease activity

Usually starts to decline before clinical

improvement occurs

Rising CPK level may be the first indication

of disease reactivation, even before muscle

weakness develops

ELEVATED MUSCLE ENZYMES IN THE ABSENCE OF

MUSCLE DISEASE

Exercise

Iatrogenic muscle injury

Motor neuron disease – ALS

Asymptomatic elevations in creatine kinase

African Americans

Certain manual labor occupations

Macro-CK. Complexes of CK and immunoglobulin

Idiopathic

Autoantibodies in IIM

Classified as

Myositis associated antibodies

Myositis specific antibodies

Although called myositis specific, they are not pathognomic or tissue specific

Myositis specific antibodies

Antisynthetases

Anti-Mi-2 ( anti helicase )

Anti SRP ( signal recognition particle)

What is an anti-synthetase

syndrome?

•It is a subcategory of the inflammatory myositisdefined by the presence of autoantibodies to aminoacyl-tRNA synthetases (20%). •Specific clinical manifestations: ILD, arthritis, Raynaud's phenomenon, fever, and mechanics hands. •Examples: Antibodies to Jo-1 (histydil-tRNA synthetase), PL-12, OJ, EJ, PL-7, KS, and Zo are some that have been reported.

Myositis specific Antibodies

Anti-Mi-2 ( anti helicase)

Specific for DM

Present in 10% of patients

Good prognosis

Anti SRP ( signal recognition particle)

Associated with severe acute onset of PM

Responds poorly to treatment

Possible cardiac involvement

Myositis associated antibodies

Anti-U1-RNP

Highly specific for MCTD

Overlap of SLE, PM and scleroderma

Anti-PM/Scl

Seen in patients with scleroderma/myositis overlap

ANA

Seen in association with other connective tissue diseases

Presentation - Polymyositis Polymyositis tends to become evident in adulthood, presenting with

1. bilateral proximal muscle weakness often noted in the upper legs due to early fatigue while walking. Sometimes the weakness presents itself as an inability to rise from a

seated position without help or an inability to raise one's arms above one's head.

The weakness is generally progressive, accompanied by lymphocytic inflammation (mainly cytotoxic T lymphocytes).

Polymyositis, strikes females with greater frequency than males.

The skin involvement is absent in Polymyositis.

2. Interstitial lung disease.

Investigations to detect interstitial lung disease should be performed during the initial evaluation as well as during follow-up of patients with myositis, because ILD is a frequent manifestation in patients with Polymyositis or

dermatomyositis

ILD is associated with increased morbidity and mortality.

This evaluation should include

Chest radiograph

CT of lungs

Pulmonary function tests including diffusing capacity, and

Serum levels of anti-Jo1 antibodies.

Symptoms - Polymyositis

Symptoms include:

Pain, with marked weakness and/or loss of muscle mass in the proximal musculature, particularly in the shoulder and pelvic girdle.

The hip extensors are often severely affected, leading to particular difficulty in ascending stairs and rising from a seated position.

Thickening of the skin on the fingers and hands (sclerodactyly) is a frequent feature, although this is non-specific and occurs in other autoimmune connective tissue disorders.

Dysphagia (difficulty swallowing) and/or other aspects of oesophageal dysmotility occur in as many as 1/3 of patients.

Low grade fever and peripheral adenopathy may be present.

Foot drop in one or both feet can be a symptom of advanced Polymyositis(PM)

and inclusion body myositis.

Associated with interstitial lung diseases.

Polymyositis is linked to an increase in the occurrence of certain cancers, particularly ovarian, lung, pancreatic, stomach, and colorectal cancers

Clinical Features

PM/DM are typically of subacute onset

Characterized by

Initially myalgia/soreness and “charley horse” sensation

Progressive, symmetric and usually painless proximal muscle weakness

Weakness is more severe in the pelvic girdle> shoulder girdle

Facial muscles innervated by the cranial nerves is spared

Major symptoms of muscle weakness

Difficulty raising the head when supine

Weakness of neck flexors with difficulty holding the head up “dropped head

Difficulty arising from the supine position

Difficulty lifting carrying, placing items on a shelf

Difficulty climbing stairs

Impaired ability to arise from a seat – knee extensors more affected than flexors

Muscle weakness

Dysphagia – Due to weakness of the tongue,

pharynx and esophageal muscles

Weakness of respiratory muscles is rare –

seen in only severe cases

Complications

Interstitial lung disease 10% of cases respiratory failure may result from diaphragmatic and chest muscle weakness can result in rapid respiratory failure and death

Esophageal disease weakness of the striated muscle of the upper 1/3 of the esophagus and/or oropharyngeal muscles can lead to nasal regurgitation, dysphagia, aspiration More common in elderly patients leads to increased incidence of bacterial pneumonia

Myocarditis Malignancy

Signs and symptoms - Dermatomyositis

The main symptoms include

1. Skin rash

2. Symmetric proximal muscle weakness which may be accompanied by pain.

The pain may resemble the type experienced after strenuous exercise.

Some dermatomyositis patients have little pain, while in others (esp. in JDM), the pain may be severe.

3. Muscle may deteriorate and render the infected temporarily paralyzed unable to walk, run, get out of bed, or even swallow food and liquids.

4. Skin findings occur in dermatomyositis but not PM Are generally present at diagnosis.

a. Gottron's sign is an erythematous, scaly eruption occurring in symmetric fashion over the MCP and interphalangeal joints (can mimic psoriasis).

b. The heliotrope or "lilac" rash is a violaceous eruption on the upper eyelids and in rare cases on the lower eyelids as well, often with itching and swelling (most specific, though uncommon)

Signs and symptoms - Dermatomyositis

c. Shawl (or V-) sign is a diffuse, flat, erythematous lesion over the back and shoulders or in a "V" over the posterior neck and back or neck and upper chest, worsens with UV light.

d. Erythroderma is not a flat, erythematous lesion similar to the shawl sign but located in other areas, such as the malar region and the forehead.

5. Periungual telangiectasias and erythema.

6. Mechanic's hands (also in PM) refers to rough, cracked skin at the tips and lateral aspects of the fingers forming irregular dirty-appearing lines that resemble those seen in a laborer (this is also associated with the anti-synthetase syndrome)

7. Psoriaform changes in the scalp

8. Centripetal flagellate erythema comprises linear, violaceous streaks on the trunk (possibly caused by itching pruritic skin)

9. Calcinosis cutis (deposition of calcium in the skin) is usually seen in juvenile dermatomyositis, not adult dermatomyositis.

10. Dysphagia (difficulty swallowing) is another feature, occurring in as many as 33% of cases.

Cutaneous manifestations of DM

Rash usually present on sun exposed parts

Gottron’s papules

Symmetric, palpable, “heaped up” appearing

erythematous eruptions overlying the MCP/IP joints of

the fingers

Heliotrope rash

Violaceous/erythematous discoloration of the upper

eyelids with peri-orbital edema

V sign – macular erythema over lower neck and

upper chest in a V distribution anteriorly

Clinical Manifestations

Skin Findings

Gottron’s

Sign:

Scaly,

symmetric

eruption over

the MCP and

interphalangeal

joints

Clinical Manifestations

Skin Findings

Erythroder

ma:

Erythema,

often

involving

extensive

areas of skin

redness

Cutaneous manifestations of DM

Shawl sign – shawl like distribution in the posterior thorax and over the upper, outer proximal extremities

Periungal abnormalities – telangiectasias and cuticular over growth

Calcinosis – usually arise over bony prominences and areas of repeated trauma

Shawl Sign

Flagellate Erythema Erythematous linear

streaks on the trunk

probably induced by

scratching pruritic

skin

Skin biopsy usually

demonstrates an

interface dermatitis,

typical of other skin

lesions in

dermatomyositis

Nail Changes

Capillary Loop

Dilatation

Articular manifestations

Arthralgia in 25% of patients

Morning stiffness is common

Non-deforming symmetrical arthritis of

hands, wrist, feet and ankles

Occurs early in the disease and responds to

treatment of the underlying muscle disease

Clinical Manifestations

Skin Findings

Mechanic’s Hands:

Roughening and cracking of skin of the tips and lateral aspects of the fingers, resulting in irregular, dirty-appearing lines

Childhood dermatomyositis

* commonly affect the children between the age of 4 -10 years .

Muscle weakness

is usually associated with typical rash of dermatositis .

Ulcerative skin vasculitis and recurrent abdominal pain

due to vasculitis are also common featured .

*Muscle atrophy, subcutaneous calcification and contractures may be

wide spread and severe.

Inclusion Body Myositis

Recognized as the most common acquired

muscle disease in those older than 50 yrs of

age

Muscle weakness develops insidiously

Asymmetric pattern of muscle involvement

Weakness and atrophy are first observed in the

quadriceps muscles

Frequent falls

Early involvement of the long finger flexors

Inability to grip the examiners fingers

Inclusion Body Myositis

Polymyositis IBM

Age Average age 50 Elderly

Gender Female : Male 2:1 Males > Females

Onset Insidious (2-3 months) Even more insidious

(6 months)

Myopathic-

Neuropathic

Myopathic Mixed myopathic and

neuropathic

Pathology Lymphocytic infiltrates Red-rimmed

inclusions

Response to

Treatment

Good response to steroids Resistant to steroids

Interstitial Lung Disease

Pulmonary manifestations in PM/DM

Aspiration pneumonia

Community acquired pneumonia

Drug induced pneumonitis

Malignant disease

Interstitial lung disease

Interstitial Lung Disease

The association of ILD with PM/DM is widely

accepted (infrequent in IBM)

Reported incidence varies from 35% to 60%

Can appear concomitantly with, before or

after the onset of skin/muscle manifestations

Interstitial Lung Disease

Screening for ILD should be included in the

initial investigation of PM/DM patients

CXR

PFT

○ Restrictive ventilatory defect with decreased

diffusion capacity

HRCT

BAL and lung biopsy if indicated

Interstitial Lung Disease

Histological correlation of HRCT findings

Ground glass pattern

○ prominent interstitial infiltration by inflammatory

cells without major distortion of the alveolar

architecture

○ Indicates progressive interstitial lung disease

Reticular opacities

○ fibrosis in association with gross distortion of

alveolar structures

○ Indicates non progression of lung disease

Interstitial Lung Disease

Clinical manifestations

Asymptomatic

Cough

Dyspnea on exertion

Bibasilar inspiratory crepitations

ILD is considered to be a major risk factor for premature death in patients with myositis

DM/PM and Malignancy

There is a six fold increase in the risk of

malignancy in DM and two fold increase risk in

PM

Factors that increase the probability of an

associated malignancy

Patients over the age of 50yrs

Refractory disease

Acute onset of disease and recurrence of disease

Elevated ESR

Female sex

DM/PM and Malignancy

Temporal relationship

Period of increased risk includes 4 yrs prior to

diagnosis and 4 yrs after diagnosis

Tumor type

Parallels those observed in the general

population

Carcinoma of breast, lung, ovary and stomach

being the most common

DM/PM and Malignancy

Evaluation for Malignancy Complete history and physical exam including breast, pelvic and

rectal exam

CBC, CMP, stool guaiacs and urine analysis

CXR PA/Lat

Mammography and Pap smear

Colonoscopy/sigmoidoscopy

PSA

Consider pelvic US in females

Repeat testing annually or with an unexplained flare of symptoms

More extensive investigations in patients with a prior malignancy and more resistant disease

Therapy

Treatment of IIM has traditionally relied upon

the use of corticosteroids and

immunosuppressive agents

Treatment causes generalized

immunosuppression and is not organ or

antigen specific

Corticosteroids

Remains the first line treatment of choice

60% to 70% response rate

Starting dose – oral prednisone 1mg/kg for 4 to 6 weeks then taper by 5 mg per week

Combination with a steroid sparing agent such as methotrexate/azathioprine is associated with a lower relapse rate and a better long term outcome

Pulse IV Solu-Medrol Patients with severe myositis

ILD

GI angiopathy

Steroid resistant disease

20%-30% of cases response is slow or incomplete

Methotrexate and azathioprine have both been shown to be effective

Combination of Methotrexate and Azathioprine have a synergistic effect

For the more difficult cases IVIG

Cytoxan

Mycophenolate Mofetil (Cellcept)

TNF alpha inhibitors

Rituximab

Glucocorticoid Sparing Agents

Starting a sparing agent at the time prednisone is initiated is recommended

First line agents include azothioprine or methotrexate

Azothioprine is preferred if patients have ILD, underlying liver disease, or are unwilling to abstain from alcohol A randomized trial compared prednisone + azothioprine to pred alone; no

difference in clinical outcomes at 3 months, but at 3 years combination group required less maintenance prednisone

Response to azothioprine may take as long as 4-6 months

Before beginning azothoprine, patients should be screened for thiopurine methytransferase deficiency (TPMT); if heterogeneous for this allele, pts can tolerate azothioprine but require lower daily doses

Homozygous negative pts, occuring in 1:300 people, cannot metabolize the drug and should not receive under any circumstances can lead to disasterous BM toxicity

Initial dose of azothioprine is 50 mg/day

Treatment

• Rapidly progressive interstitial lung disease– Cytoxan 0.5g/BSA IVSS Q 3weeks for 6 cycles

+prednisone 100mg po

– Prednisone 50 mg per day tapered over 6 –8 wks to 5mg/7.5mg po qd.

– Then switched to MTX or imuran as dictated by extrapulmonary findings

• Non progressive interstitial lung disease– Treated as dictated by extrapulmonary findings with

MTX or imuran and prednisone

Corticosteroid Myopathy

Steroid Myopathy should be suspected when

there is persistent / increasing weakness, after

the serum CK level has declined or normalized

Usually affects proximal lower limb muscles

TX

Reduce prednisone dose

Alternate day regimen

Regular exercise program

IVIG

Used for refractory disease

Mechanism of action

Blockade of Fc receptors

Inhibition of complement

Direct neutralization of autoantibodies by anti-idiotypes

Dose – 2 grams/kg ( for immunodeficiency 400-600 mg/kg)

Monthly infusions for 6 to 8 months

Therapy for IBM

Resistant to treatment with conventional forms of immunotherapy is a characteristic feature of IBM

Continued clinical deterioration in spite of reduction of muscle inflammation

No firm guidelines for treatment

Consider trial of prednisone and a steroid sparing agent

No significant benefit from IVIG

Exercise Therapy

Improvement of muscle strength, endurance

and cardiovascular fitness

Both resistant strength training and aerobic

training programs have been shown to be

beneficial

Prognosis

90% 5 year survival

Features associated with a poorer outcome

Delayed initiation of therapy

Presence of severe weakness

Dysphagia

Presence of malignant disease

Respiratory muscle weakness

Cardiac involvement

Presence of myositis specific antibodies (Except Mi-2)

Summary

Idiopathic Inflammatory myopathies are uncommon diseases characterized by muscle weakness

Accurate diagnosis is essential due to treatable nature of the disease and toxicity associated with treatment

Need close monitoring for associated conditions and treatment related side effects

Thank you for your attention!