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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!