FINAL Internal topics Flashcards by toki pham (2024)

General characteristics of the polysystemic autoimmune diseases.

Systemic autoimmune diseases are a broad range of related diseases characterized by dysregulation
of immune system which give rise to activation of immune cells to attack autoantigens and resulted in
inappropriate inflammation and multi-tissue damages such as SLE.

Characteristics of autoimmune disease:
Rare disorder, unknown etiology, genetic predisposition, family accumulation, provoking factors,
abnormal/over function of innate and adaptive immune system, chronic course-alteration of active/inactive
phase, affects women, can start with general symptoms, affect more than one organ, autoantibodies can
be detected in the patients’ blood

In systemic autoimmune disease:

§ Balance between recognition of pathogens and avoidance of self-attack are impaired.
§ Failure of self-tolerance.
§ Control of inflammation is lost, resulting in continuous immune activation.

Hypothesis for systemic autoimmune inflammation:
§ Barrier control between innate and adaptive immunity could be disturbed.
§ Impaired reactivity of adaptive immunity with reactivated auto-reactive memory lymphocytes.

Pathogenesis:
1- Genetic predisposition
§ High disease prevalence within families.
§ Prevalence in first degree relatives x5 higher.
§ Concordance in monozygotic twins ~ 20-30%.
§ Inherited susceptibility due to rare genetic polymorphisms, common SNPs and copy number of
variants, epigenetic variations and microRNAs.
§ Strong associations in MHC locus: (study example from each) J

a) Antigen presenting MHC 1 and 2 genes.
MHC2 => HLA DR3 -> SLE, SS, myositis subtypes, anti-DNA and anti-Jo1 production.

• HLA DRB1*03 -> anti-SSA production.

b) Non-classic (non-antigen presenting) MHC 3, several genes activated such as C4A
(complement factor 4 gene) and TNF-alpha.

c) Non-MHC susceptibility genes, typically relating to pathways of B-cells and T-cells
activation or innate receptor signaling such as STAT4, IRF5 and SLE.

2- Environmental triggers
§ Drugs and chemicals
§ Infectious agents such as ssRNA virus.
§ Cigarette smoking.
3- Hormonal factors; more in women than men due to estrogen which is likely to affect the immune
system contributing to disease.

• Immune system activation in systemic autoimmunity leads to production of type 1 IFN which activates
  about 400 genes- denoted The IFN signature which leads to various outcomes such as B and T cell, DC
  activation.
• Steps in generation of systemic autoimmune disease:

Genetic predisposition.
1- Early phase (seropositivity) Autoantibodies arise long before clinical symptoms develop.
2- Non-differentiated autoimmune collagenosis (NDC) = clinical signs and seropositivity.
3- Classical autoimmune disease.

• General symptoms associated with autoimmune diseases: Sub-fever, fever, weight-loss, fatigue.

Lab parameters: Elevated ESR, polyclonal immunoglobulins, Elevated CRP.

Specific symptoms:

• Treatment:
  § CS (corticosteroids).
  § Anti-malarial drugs.
  § CsDMARDs (methotrexate, cyclosporine A, etc…)
  § Biological therapy.
• Important for the patients to follow up to monitor the disease activity, measure chronic damage,
  measure the effectiveness of the therapy, educate the patient and improve the quality of life!

Undifferentiated connective tissue disease (UCTD).

The criterion-symptoms and immunologic features of SLE.

• Radiology and other examinations in SLE:
• Chest X ray, CT (High resolution computed tomography), breath test, abdominal Ultra-sound.
• Echocardiography and ECG.
• Neurology examination: EEG, ENG, EMG, CT, MRI, CSF tests.
• Biopsies: Skin, kidney, muscles, n. suralis.
• Differential diagnosis:

1-Other polysystemic autoimmune disorder:
* Polyarthritis.
* Myositis and muscle weakness.
* Raynaud’s phenomenon.
* Sjogren’s sy.

2- Hematological malignancies:
* Spleen and liver enlargement.
* Lymphadenopathy.
* Weight loss, fever.
* Anemia, thrombocytopenia.

3-Infections:
* Fever, elevated ESR and CRP.
* Subacute inf. Endocarditis, valvopathy.
* Rheumatic fever.
* TB, relapsing serositis.
* Septicemia, hepato-splenomegaly.
* Other infections, lymph-adenomegaly, rashes.

4-Malignant disorders:
* Weight loss.
* Sub-febrility.
* Fatigue.
* Anemia.
* Elevated ESR.
* Recurrent thrombosis.

5-Other diseases:
* TTP.
* AIHA.
* ITP.
* AIDS.

The most common causes of death in SLE are opportunistic infections and renal failure.

The different subgroups of SLE and treatment of SLE.

The clinical features and treatment of MCTD.

Treatment varies according to which specific disease predominates!! J

• Pulmonary disease (ILB or PAH) or renal disease: Medium-high dose of corticosteroids
  (prednisone 1-2 mg/kg).
• Cytotoxic therapy (cyclophosphamide or azathioprine).
• Cyclophosphamide: 600 mg/m2/month 3 months- 1 year.
• Therapy of the Pulmonary arterial hypertension (PAH):
  § Pulsus steroid - 500 mg/day 3 days, and 0.5-1 mg/kg/day 6-12 months
• Cyclophosphamide: 600 mg/m2/ month 3 month- 1 year.
  § Nitrite oxide or prostaglandins.
  § Ca channel blockers and oxygen may be effective.
  § Aerosolized prostacyclin (Iloprost) is effective in early stage.
  § ET-1 R blockers (endothelin receptor antagonists).
  § Anticoagulant therapy (LMW heparin, warfarin).
• Vascular prevention: statins, ACE inhibitors.
• Raynaud’s disease:
• Vasodilators
• Nitroglycerine
  § Ca channel blockers
  § Alpha1-antagonists may also be effective.

-Severe myositis, arthritis: Cyclosporine-A 3 mg/kg/day.

• NSAID- in the inactive stage.
• Antimalaria drugs – hydroxychloroquine.
• Pentoxifylline.
• Mycophenolate mofetil.
• Biological therapy: anti-CD20, TNF-alpha blocker, or TNF-R blockers.

Diagnostic criteria and clinical features of Sjögren’s syndrome

Clinical and immunological features of the Sjögren syndrome.

§ An autoimmune disease (not rare) affecting mostly women. Lymphocytes infiltrate and
destroy the lacrimal and salivary glands. It also affects multiple organs; can involve skin,
lungs, thyroid, vessels, and liver.
§ Patients have increased risk of non-Hodgkin lymphoma (NHL). Malignancy is the most
common cause of death.

Epidemiology:
§ Prevalence: 0.5-1%.
§ Predominantly women of perimenopausal age affected.
§ Female: male ratio 9:1.
§ „autoimmune exocrinopathy”, „autoimmune epithelitis”
§ Primary Sjogren’s syndrome: glandular and extraglandular symptoms.
§ Secondary Sjogren’s syndrome: association to other systemic autoimmune diseases (term
tends to get substituted to „associated Sjogren’s syndrome”).

• Symptoms:

Glandular symptoms

Keratoconjunctivitis sicca (ocular dryness).
§ Sialoadenitis chronica (oral dryness), tooth
decay!
§ Bilateral, asymmetric parotid enlargement
(submandibular, sublingual glands can be
also affected).
§ Respiratory tract manifestations (tracheitis
sicca, bronchitis sicca, interstitial
pneumonia).
§ Gastrointestinal symptoms (atrophic
gastritis, chronic pancreatitis, esophageal
dysmotility).
§ Skin dryness.
§ Vaginitis sicca.

Extra-glandular symptoms

§ Non-erosive polyarthritis.
§ Vasculitis (lymphocytic, leukocytoclastic).
§ Nervous system symptoms (CNS
vasculitis, mononeuritis multiplex,
polyneuropathy, cognitive dysfunction).
§ Myositis (focal).
§ Lymphadenopathy.
§ Pneumonitis.
§ Renal manifestations (interstitial nephritis,
renal tubular acidosis).
§ Frequent association to: Raynaud’s
syndrome, autoimmune hepatitis, primary
biliary cirrhosis, Hashimoto-thyroiditis and
any other systemic autoimmune diseases.

• Sjogren’s sy and NHL:
  § In patients with Sjogren’s syndrome, relative risk
  for the development of NHL is 40-44x*.
  § Incidence: 6,4/1000 patients.
  § Indolent, marginal zone type B-cell lymphoma and
  diffuse large B-cell lymphoma are the most
  common.
  § Transformation from chronic inflammation to
  malignant cell proliferation can be modeled step by
  step.

Symptoms suggesting risk for malignant lymphoma:
§ Monoclonal gammopathy.
§ Palpable purpura, necrotizing vasculitis.
§ Low complement levels (c4!).
§ Persisting parotid enlargement.
§ Lymphadenopathy and Splenomegaly.
§ Peripheral neuropathy.
§ Cryoglobulinemia (increases risk to extremely high.
§ Minor salivary gland biopsy focus score>3.
§ High serum β2-microglobulin levels.
§ Disappearance of previous rheumatoid factor positivity.

Treatment of Sjogren’s syndrome:

I. Sicca symptoms-substitution treatment
Oral dryness
§ Artificial saliva.
§ Enzyme-containing
toothpaste.
§ N-acetyl-cysteine.

Muscarinic agonists
§ Pilocarpine (eye drops,
pills).
§ Bethanecol.

Hygienic rules!!

II. Ocular symptoms treatment

Tear substitution (artificial tears, oils,gels)
§ Retinol palmitate.
§ Polyetilene-, polypropylene glycol.
§ Dextran, Hypromellose.
§ Preservative-free products.
§ Autologous serum eye drops.

Tear conservation
§ swimming glasses, therapeutic contact
lenses.
§ surgical: tear point closure (even corneal TX)

Anti-inflammatory topical treatments
§ Glucocorticoids.
§ NSAIDs.
§ Cyclosporine A.

Stimulation of tear production
§ Cholinergic agents (pilocarpine,
cemiveline).

Treatment of extrtaglandular symptoms

§ Glucocorticoids
§ Chloroquine, Hydroxychloroquine
§ Methotrexate
§ Azathioprine
§ Cyclosporine-A
§ Sulfasalazine
§ Cyclophosphamide
§ Biological therapy (antiCD20-rituximab)

Take home messages:
§ Not a rare disease.
§ Causes psychic problems to the affected
patients.
§ Management of glandular symptoms can
be quite simple.
§ Regular follow-up is important in order to
recognize and treat extraglandular
symptoms and to detect malignant
lymphoma development in time.

Pathogenesis:

1- Genetic factor:
§ Strong association with HLA-B8 and DR3 antigens (3,6x RR).
§ HLA-DQA10501/DQB10201.
§ HLA-DQW1 (regulation of polyclonal B cell activation?).
§ IL-10 promoter polymorphism: earlier disease onset?
§ HLA-DQ1/DQ2: High levels of aSS-A, aSS-B, RF.
§ TNF-α polymorphism: renal manifestations and aSS-A, aSS-B positivity.

2- Viruses:
§ Viruses may cause the damage of the thymic selection of autoreactive T-cells.
§ Abnormal reaction against the altered autoantigens of the glandular epithelial cells.
§ Frequently investigated viruses: EBV (primary infection or reactivation), coxsackie A13, B4, HIV,
HCV, HTLV-1.

§ Hepatitis C virus: sialotropic. Sialadenitis caused by HCV resembles to Sjögren’s syndrome
both clinically and serologically – therefore, nowadays HCV infection is an exclusion criterion in
the diagnosis of Sjögren’s.
§ HIV: Diffuse infiltrative lymphocytosis syndrome (but infiltrating cells are predominantly CD8+).

3- Upregulated and aberrant expression of cell adhesion molecules on the surface of glandular
epithelial cells: Lymphocytic infiltration.
Infiltrating cells:

§ T-lymphocytes: 75% (CD4:CD8 ratio 3-5:1).
- Chemoattractant: CXCL9, CXCL10.

§ Th17 cells:
- IL17A: upregulates the expression of IL6, TNF-α, GCSF, IL21, IL22 and chemokines.
- Chemoattractant: CXCL16.

§ B-cells: 20%:
- Chemoattractant: CXCL 12, CXCL 13 (ectopic germinal center formation!).
- Antigen presenting cells, NK cells: 5% Chemoattractant: CXCL 13, CXCR5.

4- Polyclonal B-cell activation:
BAFF (=BLyS): B-cell activating factor.
§ Member of the TNF-superfamily.
§ Regulates maturation, proliferation and survival of B-cells.
§ Pivotal role in SLE, RA.
§ Highest serum BAFF levels measured in Sjögren’s syndrome.
§ Correlation between BAFF levels and B cell dysfunction.
§ Antiapoptotic effect: contribution to lymphomagenesis?

5- Proinflammatory cytokine expression of lymphocytes and epithelial cells:
§ Predominantly Th1 type cytokines.
§ IL18 correlates with aSS-A and aSS-B autoantibody levels.
§ IL-10 levels correlate with the disease severity.
§ Local overproduction of IFN-α in the plasmocytoid dendritic cells of salivary glands promotes
the upregulation of autoimmune processes.

6- Progressively decreasing secretory ability of acini:
§ Water, protein and mucopolysaccharide secretion: through M3 muscarinic receptor stimulation.
§ In Sjögren’s, the response to this stimulus fails.
§ Aquaporin: rapid water-transport through the cell membrane (receptor expression driven by
muscarinergic stimuli, as well).
§ In Sjögren’s, aquaporin-5 levels decrease…

Check details cuz note’s topic is different

ANCA associated vasculitis.

Check details cuz note’s topic is different

Laboratory parameters in vasculitis:

Eosinophilia >10% = EGPA (Churg-Strauss syndrome)
Hepatitis Bs-antigen = Classical PAN
c-ANCA (PR3) = GPA
Cryoglobulinemia = Leukocytoclastic vasculitis
p-ANCA (MPO) = Microscopic PAN
Ab against EC = Kawasaki disease

Indicators of activities:

Dec complement level = Immune complex vasculitis
ANCA titer = Pauci-immune vasculitis
Factor 8 = All kinds of vasculitis
WBC-PLT = All kinds of vasculitis (except SLE)
Acute phase proteins = All kinds of vasculitis

à Therapy of vasculitis*** IMPORTANT!!!
§ Organ involvement determination.
§ Disease activity and severity (vasculitis activity score).
§ Remission induction:
- Corticosteroid (1 mg/bw/day or PULSE) + CYC infusion (7,5-15 mg/bw/ 2-3 weeks) or per (2
mg/bw/day).

• In serious cases (rapid progression of kidney function): + plasma exchange.
• In less serious cases: methotrexate (20-25 mg/week).
• In refractory cases: rituximab (ANCA-associated), tocilizumab (Takayasu).

§ Maintenance therapy:
- azathioprine (2 mg/bw);
- MTX 20-25 mg/week;
- alternatively: leflunomide (30 mg/day), MMF (2 g/day).
§ EULAR/EUVAS guidelines for ANCA-associated vasculitis:

(Check TABLE in note, pg28)

§ RITUXIMAB -indication for ANCA associated vasculitides:
- Rituximab + glucocorticoid combination therapy indicated for serious and active granulomatosis with
polyangiitis (Wegener) (GPA), microscopic polyangiitis (MPA).
- 375 mg/body surface m2 intravenously.
- 1x / week, for 4 weeks (4 infusion cycles).

Check again because note’s topic is different

Giant cell arteritis.

§ Vasculitis of unknown cause, can affect mostly temporal and other arteries such as carotid
and their branches or aorta. Carotid bruits (turbulent-flow sound), decreased pulse in the arm
and aortic regurgitation may be observed.
§ Associated with increased risk of aortic aneurysm and aortic dissection.
§ Often present with polymyalgia rheumatica.
§ Histological findings: Giant cells, intimal hyperplasia and fragmentation, neovascularization
and stenosis.
§ Diagnosis: Biopsy and elevated ESR.

§ ACR 1990 criteria: 3/5
1. Age above 50.
2. Recent onset headache.
3. Pain or weakened pulse above temporal
artery.
4. Westergreen exceeds 50 mm/h (blood
sedimentation ESR).
5. Upon biopsy of temporal, vasculitis with
giant cells, mononuclear cells and
granulomas.

§ Symptoms:
- Malaise, fatigue and weight loss.
- Visual disturbances (retinal artery hemorrhage & ophthalmic artery involvement), blindness
due to optic neuritis and amaurosis fugax.
- Difficulties during chewing.
- Fever of unknown origin.
- Tenderness over temporal artery.
- Palpable nodules.

§ Treatment: high dose of steroids (prednisone) prevents blindness, Tocilizumab & DMARDS
for steroid sparing.

Fever of unknown origin!! (FUO)
§ Fever higher than 38.3 degrees on
several occasions.
§ Duration at least 3 weeks!
§ Uncertain diagnosis after 1 week of
study in the hospital!
§ Frequency: systemic rheumatic
diseases (vasculitis, PMR, SLE),
infections, malignancy, but mostly no
diagnosis

Clinical symptoms and management of Systemic Sclerosis (SSc)

Kidney

§ Obliterative vasculopathy; intimal proliferation à vessel narrowing => decreased renal
perfusion => hyperplasia of juxtaglomerular apparat. => increase renin production =>
Renal hypertension and endothelial injury.

§ Scleroderma renal crisis: 15% of cases associated with dcSSc, within the first 3-5
years.
- New onset of HTN.
- Azotemia (high nitrogen containing compounds in blood), uremia.

Muscles § Highly common.
§ Impaired quality life.
§ Involves muscles, tendons, bones and joints.
§ Joint contractures, arthralgia, arthritis, tendonitis, tendon crepitation (tendon friction
rub), myalgia, myositis.

Sicca sy § Dryness of everything.

Cutaneous
symptoms

§ Skin thickening and hardening.
§ Acral parts are involved: sclerodactyly, perioral sclerosis, decreased oral aperture.
§ Early edematous phase: „puffy finger”.
§ Later: atrophic stage.
§ dry skin, itching, hyper-hypopigmentation, telangiectasia, subcutaneous calcinosis.

Raynaud sy

§ Sudden onset of cold fingers (or toes), in association with pain and sharply demarcated color changes of skin.
§ 2 or 3 phases: white color, cyanotic skin, hyperemia.
§ Present in 90-100% of SSc patients, precedes the presence of skin symptoms with
several years in the limited cutaneous form.

Digital
ulcers

§ Result of digital vasculopathy, trophic changes.
§ Present in 50% of SSc patients.
§ Early manifestation of diffuse cutaneous form, more frequent in anti-Scl70 positive
patients, associated with CV manifestations.
§ Complications: infection, gangrene, osteomyelitis, autoamputation!
§ Nailfold capillaroscopy for early diagnosis of vasculopathy, specific pattern
characteristic for autoimmune diseases. Different patterns: dilated, giant capillaries,
stasis, disorganization, ramification, hemorrhages.

• Diagnosis:
  § Diagnostic tests are of limited utility. Almost all
  patients have elevated ANAs (high sensitivity,
  low specificity).
  § Anti-centromere Ab is very specific for the
  limited form.
  § Anti-topoisomerase (anti-Scl70) is specific for
  diffuse form.
  § Barium swallow (esophageal dysmotility) and
  pulmonary function tests are used to detect
  complications.
  § Must follow ACR/EULAR classification criteria
  with >/= 9 points to define SSc.

Classification criteria based on ACR/ EULAR
(European League Against Rheumatism) 2013. SSc
>/= 9 points based on the findings such as ‘skin
thickening of both hands extending proximal to
MCP joints’ is a sufficient criterion alone and
counts for 9 points!! J. Other criteria items have
their own points as well such as telangiectasia = 2
points, Raynaud’s phenomenon and auto-Ab each
count for 3 points…

(Check 1 diagram in note, pg 32)

The management of Systemic Sclerosis (SSc).

No effective cure!! L Treatment is symptomatic depending on the organs involved

Immuno-
modulation

ILD:
§ Pulse cyclophosphamide, followed by mycophenolate mofetil (MMF) or
azathioprine (AZA).
§ MMF is first-line therapy.
§ Biological therapy (anti-IL6, rituximab).
§ HSCT (Autolog hematopoietic stem cell transplantation).

§ Tyrosine kinase inhibitors- nintendanib (anti-VEGF, PDGF, FGF).

Skin and musculoskeletal:
§ Methotrexate (MTX)- early diffuse SSC and arthritis.
§ MMF- early diffuse SSc.
§ Low dose of corticosteroids for arthritis, tendinitis, myositis.
§ Biological therapy (anti-IL 6, rituximab)- early diffuse SSc and arthritis.

HSCT § Improvement of skin score.

§ Stabilized of internal organ manifestation.

Vascular therapy For Raynaud’s sy, digital ulcers, PAH.
§ Calcium-channel blocker.
§ ACE-inhibitors (ACEI)
§ Angiotensin II receptor blocker. (ARB)
§ Iv. Prostasnoids, prostacyclin analog, (iv. Iloprost, epoprostenol).
§ Endothelial-1 receptor antagonist- Bosentan (Tracleer).
§ Phosphodiesterase-5-inhibitor- Sildenafil. (Revatio)
§ Riociguat. (soluble guanylate cyclase stimulator)
§ Selexipag. (prostacyclin receptor agonist)
§ Antibiotics- Raynaud sy and digital ulcers)
§ Supportive treatment (oxygen, diuretics, anti-coagulant)- PAH.

For Scleroderma renal crisis:
§ ACE inhibitor.
§ Anti-hypertensive treatments.
§ AVOID USING GLUCOCORTICOIDS!!

Anti-fibrotic § Microcirculation improvement.
§ No effective drug. (not-known yet)
§ Randomized controlled trials.

Treatment-organ
based

GI symptoms:
§ H2 blockers or proton pump inhibitors for esophageal reflux.
§ antibiotics (bacterial growth) and prokinetic drugs for bowels.
§ Life-style modification diet/ weight loss.
§ Laxatives/ antidiarrheal agents.
§ Argon plasma coagulation.

Cardiac symptoms:
§ ACE inhibitors.
§ Diuretics.
§ Ca channel blockers, selective beta-blockers.
§ ICD, pacemaker, implantation and statins.

• SSc patients must follow up for early diagnosis, new manifestations (early treatment), regular control,
  treatment of other diseases accompanied with drugs used and physiotherapy.
• Survival rate depends on the organ manifestation, bad prognosis for diffuse form, late onset, severe
  cardiopulmonary and kidney manifestation and PAH. L The cause of mortality is ILD!

Clinical symptoms, diagnosis and therapy of idiopathic inflammatory myopathies

Characteristics IIMs:
§ Are a group of chronic, autoimmune conditions affecting primarily the proximal muscles.
§ Constitute a large spectrum of clinical phenotypes:
- Muscle weakness.
- Skin.
- Joint.
- Lung.
- Gastrointestinal tract.
- Heart.

§ Incidence: 2,8-7,7/million.
§ Prevalence: 5-10/million.
§ Male/female: 1:2.
§ Age: 5-10 and 45-50 years.
§ Heterogenous.
§ Subtypes:
- Polymyositis (PM) (does not involve skin).
- Necrotizing autoimmune myopathy (NAM).
- Inclusion body myositis (IBM).
- Dermatomyositis (DM) (associated with skin symptoms such as rash).
- Amyopathic dermatomyositis.
- Juvenile (JDM; JM).
§ Characteristic histology.
§ Rare: IIMs are rare compared with other rheumatic diseases, so individual physician
experience limited, e.g most UK rheumatologists will only see ~ 5-6 cases in a whole
career.
§ Treatment responses are variable, but usually incomplete, so ~75% of cases never regain
normal strength or function.

• Symptoms: usually slow onset

1) Muscles:
§ Symmetrical proximal muscle weakness and pain that develops subacutely over weeks or
several months (eg: difficuilty in climbing stairs, leaving low chairs, combing hair).
§ The earliest and most severely affected muscle groups are the neck flexors, shoulder
girdle, and pelvic girdle muscles.
§ Distal extremities weakness is less frequent and less severe.

2) Cutaneous: characteristic rash in dermatomyositis, light sensitive.

§ Heliotrope rash (butterfly); periorbital edema.
§ Gottron papules; papular, erythematous, scaly lesions over the knuckles (MCP, PIP, DIP).
§ V-sign; rash on the face, neck and anterior chest.
§ Shawl-sign; rash on the shoulders, upper back, elbows and the knees.
§ Subcutaneous calcification (calcinosis) in children (extremely painful).
§ Ulcers.
§ Mechanic’s hand.
§ Periungual capillary changes.

3) General symptoms: fatigue, fever, loss of weight.

4) GI involvement:
§ Dysphagia ~30% due to involvement of striated muscle in the upper GI tract.
§ Reflux dysmotility.
§ Secondary Malnutrition.
§ Aspiration pneumonia.
§ Nasogastric tube.
§ PEG.

5) Lungs:
§ At the time of diagnosis, presence is 60-70 % (may be asymptomatic).
§ Functionally limiting breathlessness due to Interstitial lung disease (ILD).
§ Frequent in anti-synthetase syndrome (anti-Jo-1).
§ Restrictive lung disease
§ Major factor causing morbidity and mortality
§ Detections:
- Physical exam: Inspiratory cracles.
- Imaging: HRCT, Chest Xray (late stages).
- Lung function tests: Diffusion capacity: DLCO.
- Histology: NSIP, BOOP, UIP.

6) Arthritis and arthralgia:
§ Antisynthetase syndrome.
§ Non-erosive.
§ Small joint involvement.
§ Might mimic rheumatoid arthritis.
§ Might precede the muscular symptoms.

7) Heart:
§ Clinical manifestations: 6-75%.
- Cardiac decompenzation (3-45%).
- Angina pectoris.
- Pericarditis.
- Myocarditis.
- Heart failure.
- Arrhythmias

§ Pathophysiology:
- Lymphocyte infiltration in the myocardial septum.
- Similar to striated muscle.
- Heart muscle cell degeneration.
- Fibrosis of the conductive system.

§ Subclinical manifestations:
- ECG abnormalities (SVES, VES, AV block, Bundle Branch blocks, Q waves, ST-T
alterations)

§ Cardial involvement causes the major mortality of IIM patients (10-46.3%).
§ Diagnosis:
- Gold standard: endomyocardial biopsy.
- Non-invasive methods: ECG, echocardiography, scintigraphy.
- Cardiac MRI.
- cTroponin-I is better than cTnT.

• Etiology:
  § Genetic factors.
  § Environmental factors: Smoking,
  Infections, UV light, Drugs (statins).
  § Malignancies.
  § Breakdown of immune tolerance.
  § Production of pathologic
  autoantibodies.
  § Inflammation.
  § Tissue damage and loss of function.

Autoantibodies:
§ 70-80 % presence in the sera of IIM
patients.
§ Different cytoplasmic and nuclear
targets (see the picture).
§ Myositis specific autoantibodies
(anti-synthase; anti-Jo1 antibodies),
vs. Myositis associated antibodies.
§ Distinct autoantibodies determine
distinct clinical phenotype.
§ Associated with organ
complications.
§ Help us to set up the diagnosis.
§ Prognostic/therapeutic markers.

Clinicoserological syndromes

Anti-synthase (anti-Jo1 Ab) = ILD, Arthritis, Mechanic’s hands

Anti-SRP Ab = Acute severe muscle weakness , Myalgias

Anti-Mi-2 Ab = V-sign rash
Shawl-sign rash
Cuticular overgrowth

Pathology:

Polymyositis (PM) = § Cell mediated response
§ CD8+ endomyseal T cells in
PM
§ CD68+ macrophages in both
§ Up regulation of surface
MHC

Dermatomyositis (DM) = § CD4+
perivascular/perimyseal T
cells in DM
§ Perifascicular atrophy
§ Up regulation of surface
MHC

Inclusion body myositis (IBM) = § mononuclear inflammatory
cells
§ rimmed vacuoles
§ degenerating and
regenerating fibers

(Check diagram in note)

Diagnosis:

The goal is to set up the diagnosis and investigate the organ involvement!!
§ Physical examination: muscle force, skin, joints, lung, heart.
§ Muscle:
- Biopsy
- EMG
- Muscle MRI.

§ Laboratory:
- Enzymes (CK, LDH, ALD, AST, ALT).
- Autoantibodies.
§ Lung: DLCO, lung function, HRCT.
§ Heart: ECG, echocardiography, Cardiac MRI.
§ GIT: Esophageal passage.
§ Cancer search (Chest-abdominal-CT/PET-CT, gastroscopy, colonoscopy, mammography,
gynecological examination/urology).

Classification and diagnostic criteria for inflammatory myopathies:

1- Bohan and Peter criteria: 1975.
The Bohan and Peter criteria are outdated due to discovery of myositis specific/associated Ab
that lead to development of clinic-serological criteria and validated classification criteria are
necessary to improve research in IIM. The new EULAR/ACR IIM classification criteria are thus a
definite improvement and an important step forward in the field but it still provides deep
understanding of IIM.

(table in picture)

more in another flashcard

The organ specific autoimmune diseases and their features

Tolerance in adaptive immunity, is the absence of specific lymphocytes auto-reactivity against
self-Ag.

T-cell tolerance

Central tolerance

§ Occurs in the thymus and it’s the thymic
selection.
§ It isn’t complete and a sizable pool of
autoreactive T-cells can escape to the
peripheral immune system.
§ The presence of these cells is to be
considered ‘physiological’, till MHCI/II
accompanied auto-Ag can lead to full
activation in the periphery.
Peripheral tolerance

§ Auto-reactive T-cells may lose their ability to
proliferate and undergoes anergy.

§ They can undergo activation induced cell-
death (AICD) (Fas-FasL).

§ Specific negative signal (B7) turns off specific
T-cell.
§ Regulatory T-cells (T-reg) and APCs.

B-cell tolerance

§ B-cells mature independently of antigens
in the bone marrow and clonally expand in
the periphery (T-helper lymphocytes are
needed), therefore the B-cell responses are
„thymus dependent”
§ T-helper cell independent B-cell activation
(e. g. LPS) very rarely auto aggressive.

Characteristics of organ specific auto-immunity:

§ Certain effector functions will be detrimental only to particular cells or tissues, e. g. pancreatic
β-cells are more sensitive to the damaging effect of inflammatory cytokines, than neighboring
α-cells, and other cells in their vicinity.

§ Some organs provide a microenvironment that suppresses inflammatory responses. E. g. both
the gut and the CNS contain relatively large amounts of TGF-β.

§ Large organs such as the liver may better tolerize lymphocyte aggression.

§ The precise activation state, phenotype, effector function of an autoreactive cells is critical in
determining its impact tissues. In T1DM some molecules will exert beneficial functions (IL-4, IL
-10 and TGFβ), together with antigen specific regulator cells (Treg) may delay or prevent of
clinical disease.

§ The autoreactive regulator cells act on APC cells (M, DC) suppressing their function.

§ The regulatory cells also induce anergy or apoptosis of autoagressive lymphocytes.

§ The overall cytokine milieu of a given inflammatory process, the number and function of
aggressive cells and cytokines/chemokines may be dampened in a localized area.

§ The autoreactivity is not necessarily detrimental.

§ By the studies of animal models and human disorders: Appearance of autoantibodies
precedes the clinical symptoms.

§ Clinical signs (with rare exception) are due to target organs, cells destruction.

§ Relapses and remissions follow during the course of diseases.

§ The first sign in the tissue is the appearance of DC-s.
§ The presentation of autoantigens in the neighboring lymph nodes comes then.

§ Following the autoreactive T-lymphocytes infiltration in the tissue.

§ In this period the parenchymal cells are becoming antigen presenting ones. (On their surface
MHC class II. antigens appear).

Organ specific autoimmune diseases:

Immunodeficiency in adults.

Part 1, other parts in another cards

Celiac disease, food allergy.

Check note for diagram, part 1

Celiac disease (Gluten-sensitive enteropathy ‘GSE’ or

Non-tropical sprue) was defined
according to Oslo definition (2011) as a chronic small intestinal immune-mediated enteropathy
precipitated by exposure to dietary gluten in genetically predisposed individuals. Classical CD
was defined as CD presenting with signs and symptoms of malabsorption. Diarrhea, steatorrhea,
weight loss or growth failure is required. Suggested that “gluten-related disorders” is the
umbrella term for all diseases triggered by gluten and that the term gluten intolerance is not to be
used.

Pathophysiology:
§ After being taken up by epithelial
cells, gluten peptides are
deaminated by the enzyme tissue
transglutaminase in the
subepithelial layer.
§ They are then able to fit the

antigen-binding motif on HLA-
DQ2/8- positive antigen-
presenting cells.

§ Recognition by CD4+ T cells
triggers a Th1 immune response

with generation of pro-
inflammatory cytokines.

§ Lymphocytes infiltrate the lamina propria, and increased intraepithelial lymphocytes, crypt
hyperplasia and villous atrophia ensue.
§ Gluten is found in wheat and grain. The gliadin in gluten is what triggers the disease!

§ Adaptive or specific immune response (CD4 + T cell mediated - lamina propria and
underlying tissues).
§ Innate immune response (direct toxic effect on epithelium - eg p31-49 peptide of α-gliadin)
– anti-trypsin inhibitor.

Prevalence and frequency:
§ Genetics:
- 1st degree relatives ~10%.
- Trisomies.
- Selective IgA deficiency ~10%.

§ Autoimmune diseases.
- Hashimoto thyroiditis.
- Type I diabetes mellitus.
- Dermatitis herpetiformis.
- Autoimmune liver diseases.

Deficiencies:
- Iron deficiency anemia and
Osteoporosis.

§ Gastrointestinal diseases:
- Irritable bowel syndrome (IBS).
- Increased ASAT and ALAT.
- Malabsorption, weight loss.

§ Others: Female infertility.
§ The results of the meta-analysis found the current worldwide prevalence of celiac
disease to be 1.4% based on blood tests and 0.7% based on biopsy results.

Symptoms:

results in diharrhea (most common), weight loss, abdominal distention and pain,
bloating, weakness. Patients may suffer from vitamin deficiency secondary to fat malabsorption,
leading to osteoporosis (vit D deficiency), easy bleeding (vit K deficiency) and megaloblastic
anemia (secondary to impaired folate and vit B-12 absorption). Dermatitis herpetiformis
(papulovesicular lesion seen on extensor surfaces) is
found in 10-20% of patients.

Diagnosis: supported by a positive tissue
transglutaminase (TG) serologic test but, in general,
should be confirmed by a small bowel (duodenum
mostly) biopsy- graded III on Marsh scale showing the
characteristic histology associated with celiac disease
such as flattening of villi which causes malabsorption.

Genetic results:
§ Genetic combinations of HLA-DQ2/8, can be
either hom*ozygous, heterozygous or
heterodimers in 98% of the patients.
§ The lack of the necessary HLA background can
exclude the possibility of GSE, unless serology is
positive and Marsh III is the histological picture
and the improvement of the histological image is
clearly evident after the gluten free diet.

GSE- Spectrum:
§ TG2, TG3, and TG6 may be similar in their
substrate specificity because of their genetic /
structural similarities.
- TG2 - autoantigen - celiac disease.
- TG3 - autoantigen - dermatitis herpetiformis
(skin).
- TG6 - autoantigen - gluten ataxia (CNS).

Celiac quick test: At-home antibody test: called imawareTM,
the test measures the same antibodies to gluten as the tests that
doctors use in their offices as the first step to diagnose celiac
disease — anti-tissue transglutaminase (tTG) and deaminated
gliadin peptide (DGP) tests.

The mode of action of steroids and their practical use

Features of immunomodulant treatments (metotrexate, azathioprin, cyclosporin-A,
cyclophosphamid).

Part 1

Immune privilege refers to the fact that foreign-tissue grafts (=fetus) placed in the immune-
privileged site are tolerated and survive for prolonged, often indefinite, intervals, while placement

of such grafts at conventional body sites leads to acute irreversible immune rejection.
Multiple mechanisms have been proposed to account for immune privilege:
§ Limited lymphatic drainage.
§ Low level or complete absence of expression of classical MHC class Ia protein on cells.
§ The presence of immunosuppressive cytokines.
§ The presence of APC.
§ Expression pro-apoptotic cell surface molecules such as Fas ligand (Fas-L) which will
induce T cell apoptosis.

Physiological changes of the immune system during pregnancy
§ Fetus= semi-allograft.
§ Healthy immune system changes in order to help implantation, to protect the fetus.
§ Maternal immunity: cellular HUMORAL (TH2 dominance), 3rd month.
§ Fetus lives and grows hidden by trophoblast cells.
§ Trophoblast cells express only HLA-C, E, F and G.
§ Progesterone sensitivity of maternal lymphocytes increase, PIBF (progesterone-induced
blocking factor) is produced.
§ Instead of adaptive immunity, INNATE immunity is activated.

T-lymphocytes
§ Cytotoxic T-lymphocytes
die or minimize CD8-
expression.
§ Production of Th1 type
cytokines (IFN-gamma,
TNF-alfa, IL-2) decreases.
§ Production of Th2 type
cytokines (IL-4,5,9,10,13)
increases.

DCs, mononuclear
phagocytes

§ Phagocytes produce anti-
inflammatory cytokines and

get suppressed.
§ As cell-mediated immune
system is relatively
suppressed, it is less
efficient in clearing viruses
and intracellular pathogens:
pregnants are more prone
to such infections
(INFLUENZA!!)

NK cells
§ number and activity of
peripheral NK cells is
decreased during
pregnancy.
§ uNK cells (uterine NK):
express inhibitory receptors,
are not harmful.
§ They produce cytokines
(colony stimulating factors)
which are responsible for
trophoblast proliferation and
differentiation.

PIBF:
§ progesterone-induced blocking factor.
§ inhibits arachidonic acid liberation.
§ decreases prostaglandin production.
§ inhibits abortion.
§ induces production of Th2 cytokines.
§ helps to keep down NK activity.

HLA-G:
§ Belongs to HLA-Ib antigens (together with
HLA-F and E).
§ expressed on the surface of non-villous
cytotrophoblast cells.
§ alternatively, spliced, 7 transcripts
identified, less polymorph.
§ Main function: TOLERANCE INDUCTION.
§ serves as inhibitory ligand to NK cells,
inhibits their migration and killing functions.
§ regulates cytokine production of

mononuclear cells and cytotoxic T-
lymphocytes.

§ decrease IFN-gamma production * fine-
tunes innate immunity.

If T and NK cells in the presence of trophoblast cells still
become activated, trophoblast cells are able to induce apoptosis in these cells, since they
express apoptosis inducing ligands, such as Fas-L and TRAIL.

Feto-maternal micro-chimerism: the presence of a small population of genetically distinct and
separately derived cells within an individual. A small number of fetal cells circulate systemically in
the maternal blood, and conversely, maternal cells are present in the fetal circulation (MHC II
haplotype different).

Pregnancy in autoimmune diseases - significance
§ Systemic autoimmune diseases begin most often in fertile women.
§ Both maternal and fetal complications are frequent.
§ Diagnosis and treatment are difficult because of fetotoxic side effects.
§ Autoimmune diseases often flare at pregnancy and/or delivery.
§ Pregnancy is contraindicated at severe cardiac-, renal- or nervous system involvement.
§ If fetotoxic cytostatic treatment is of high necessity, artificial abortion to medical indication
is required.

Lupus and pregnancy:
§ Relapses are frequent during pregnancy.
§ 25-40% of pregnancies end up in abortion, prevalence of preterm birth is 17-37%.
§ Much better fetal chance if pregnancy happens after 6-12 months of remission.
§ Fertility is NOT decreased!
§ Increase of ANA and aDNA titers, presence of rbc casts suggest relapse, even in the
absence of clinical symptoms!
§ Monthly check-up is important to recognize relapses in time!
§ Immunosuppressants used during pregnancy (corticosteroids - beware of hypertension,
diabetes!), azathioprine, cyclosporin-A, hydroxychloroquine).
§ IVIG can be used for immunomodulation.
§ Hypertension and its maternal/fetal complications need attention.
§ Thrombophilia: risk status has to be evaluated in the first trimester.

§ Anticoagulant therapy: salicylate at platelet dysfunction, LMWH in antiphospholipid-
syndrome or other thrombophilia.

§ SLE+APS: individual therapy.
§ Neonatalis lupus.
§ APS- risk for complication: preeclampsia, eclampsia, HELLP.
§ Delivery after the 32nd week if possible * Collaboration of rheumatologist, obstetrician and
neonatologist.

Neonatal lupus:
§ passively acquired autoimmunity.
§ Caused by aSS-A/Ro and aSS-B/La autoantibodies crossing the placenta.
§ Antibodies can be present in maternal sera even in the lack of autoimmune disease or any
symptoms.
§ Characterized by reversible skin rashes and irreversible conduction disorders.
§ Prevalence in aSS-A/aSS-B positive women: 0.7-2%.
§ more frequent if high antibody concentrations are present.
§ Maculo-papulous skin rashes presenting at birth or few days later.
§ often accompanied by hepatosplenomegaly, anaemia, thrombopenia, rashes disappear without
trace after elimination of maternal antibodies (4-6 weeks, max. 9 months).

§ Neonatal lupus cardiac manifestations:
- Pathogenesis: antibody positive sera cause reduction of L- type Ca channel.
- Congenital heart block: 75% requires pacemaker.
- Mainly complete, sometimes 1st or 2nd degree.
- lengthening of QTc interval.
- Sinus bradycardia: can resolve spontaneously.
- Myocardium involvement: late-onset DCM, endocardial fibroelastosis.
- Monitoring: 18-28th weeks of pregnancy: fetal heart sounds, intrauterine
echocardiography.

• HCQ treatment decrease CHB Treatment: - Dexamethasone (crosses placenta)- no
  permanent effect in complete heart block, - neonatal pacemaker implantation.

Sjögren’s syndrome: presence of aSS-A and aSS-B antibodies: neonatal lupus can develop.

Dermatomyositis/polymyositis: risk of small-for-date births and stillbirths.

Systemic sclerosis:
§ Patients with SSc have normal fertility when compared to healthy subjects but they have a higher
risk of preterm delivery, IUGR, and babies with very low birthweight (LBW).
§ Patients with disease duration less than 4 years, diffuse cutaneous subtype or anti-topoisomerase
I or anti-RNA polymerase III antibodies are at higher risk for obstetric complications.
§ disease progression: Scl70-positive patients.
§ pregnancy may cause life-threatening situations: contraindicated heart, pulmonary and renal
involvement.
§ microchimerism (persistence of circulating fetal cells in the maternal body) can play a role in the
pathogenesis of the disease.

Systemic vasculitis:

§ Rare disease => limited reports of pregnancies.
§ the main determinant of pregnancy outcome is the degree of activity of the vasculitis.

§ the worst outcomes, both in term of obstetrical complications and risk of flare, are reported in
those women who started their pregnancy in a condition of active disease or in those whose
disease developed for the first-time during pregnancy.

§ two main obstetrical complications: preterm birth and cesarean section.
§ increasing number of pregnancies are reported in women with Takayasu arteritis (TA) and Behcet’s
disease (BD).
§ 350 pregnancies in TA and 396 cases in BD.
§ in TA maternal complications: gestational hypertension, PE, eclampsia. Fetal complications: IUGR
and neonatal LBW.
§ BD: disease flares are reported in 30–36% of pregnancies.
§ Manifestations of disease activation are oral or genital ulcers. Complications: venous thrombosis
and transient ischemic attacks.

Immunosuppressive drugs in pregnancy:
§ All cross placenta (traces of IgG, & no studies on anti-TNF-alpha)
§ Can use =: Steroids, Azathioprine, Cyclosporin-A, chloroquine, sulfasalazine.
§ Contraindicated L: Cyclophosphamide, Methotrexate, Leflunomide, MMF AND anti-TNF-alpha is
not recommended!!
§ Steroids = Prednisolone= 90% inactivated by placenta.
§ Azathioprine = fetus unable to metabolize the active form.

Laboratory diagnosis and imaging of rheumatic diseases

History taking: A good medical history is a half diagnosis!!

Main guideline:
§ Onset (acute - chronic).
§ Distribution (symmetry, migration, mono-polyart.).
§ Specific complaints.
§ Severity (impairment, hospitalization).
§ Functional capacity (at home, at work)- social history.

§ Family history.
§ Previous and current treatments.
§ Understanding of the disease.
§ Psychosocial, economic considerations.
§ Simple questions are so important and they include ‘do you have any swelling of your joints’
‘do you have any difficulties with going up or down the stairs’ ‘do you dress up normally’ ‘are
you able to comb/brush your hair/teeth easily’ ‘do you have any back pain’?
§ Usage of scales and questionnaires.
§ Summary of the findings.

More specific:
§ Gender (eg. SLE is more common in women, AS, or gout are more common in men).
§ Age (eg. autoimmune diseases are more common amongst young people, RA in middle age,
septic arthritis in elderly people!).
§ Family history of inflammatory, autoimmune diseases.
§ Smoking (an important risk factor in RA!).
§ Alcohol (drinking beer is an important risk factor og gout!).
§ Immunosuppression, other comorbidities (septic arthritis might be associated with diabetes or
surgery, malignant disease may be accompanied with paraneoplastic arthritis).
§ Onset of arthritis (sudden onset in septic arthritis or in the case of acute gouty attacks,
insidous onset in AS).
§ Presence of extraarticular symptoms: fever, subfebrile condition, fatigue, skin symptoms (eg
butterfly rash in SLE, psoriatic plaque in psoriatic arthritis (PsA), rheumatic nodule in RA).

Laboratory diagnosis:
§ Blood test- Hgb, Wbc, Plt (inflammatory anaemia, thrombocytosis, leukopenia are common in
SLE, or Felty’s syndrome, and leukocytosis in Still’s disease, or infectious arthritis).
§ Elevated inflammatory laboratory parameters (high ESR, C-reactive protein, ferritin level).
§ Renal and hepatic function, uric acid measurement.
§ Urinalysis (proteinuria is possible in SLE, you should always look for urine sediment!).
§ Rheumatoid factor (especially in RA, but may also be positive in cryoglobulinaemic vasculitis
and Sjögren’s syndrome), anti-CCP (in RA).
§ HLAB27 test (associated with seronegative spondyloarthropathies).
§ ANA screening, or screening for other autoantibodies (anti-DNA, eg myositis, scleroderma
spec. antibodies) in the presence of certain clinical symptoms.
§ Other specific tests depending on clinical signs (in case of suspected infection culture, viral or
bacterial serology.

Main laboratory tests:

Acute phase
proteins; CRP, ferritin

Urine analysis Blood cell
counts

Immunological
parameters;
cytokines, Ab

Cholestatic
enzymes

Muscle
enzymes

Viral/bacterial
serology

Transaminases Procalcitonin Renal functions Hemostasis ESR

1- Acute phase reactions:
§ Acute phase proteins: normally existing proteins in the blood, which concentrations significantly
increase (positive acute phase proteins) or decrease (negative acute phase proteins) during acute phase
reaction.
§ Acute phase reaction occurs in: infection, autoimmune, inflammation, tumours, tissue damage:
operation, trauma, burn, myocardial infarction.
§ Positive acute phase proteins: C-reactive protein (CRP), alpha1-antitrypsine, haptoglobin, fibrinogen,
complement-components, serum amyloid A (SAA,) prokalcitonin.
§ Negative acut phase proteins: albumin, prealbumin, transferrin.

a) SLE:
§ Serositis- CRP increases
§ Lupus nephritis- CRP normal.
§ Infection- CRP increases (>60 mg/l)
§ All associated with ESR increases

b) Vasculitis:
§ ESR increases
§ CRP increases (100-300 mg/l)

c) RA, adult onset still disease/sJIA:
§ Elevated ESR.
§ CRP increases
§ + ferritin.

Imaging of rheumatic diseases.

Check list:
§ Joint space narrowing (almost all diseases)
§ Osteophytes; main radiographic hallmark in OA.
§ Erosions and sclerosis; main radiographic hallmark in RA.
§ Chondrocalcinosis; main radiographic hallmark in CPPD.

Important notices:
§ Pattern and diseases distribution.
§ Discriminating features; which part of the joint is involved.
- Synovium: thick, opaque, erosions (demineralization and loss of cortex), asymmetrical.
- Cartilage: thick, thin, calcified.
- Enthesitis: erosive, non-erosive.

X-ray
§ Simple, comparative.

§ Erosions – months Juxta-
articulate osteopenia – weeks

§ Early: soft tissue swelling

§ Intermediate: mild juxta-
articular osteopenia, narrowing

of joint space, bone erosion,
joint effusion.
§ Late: large erosions,
anatomical deformities,
ankylosis, calcifications.
§ Special observations include
marginal erosions and

subluxation in RA, pencil-in-
cup lesion in PsA, and

punched-out-erosion in gout.
§ Extraarticular manifestations
include sarcoidosis associated
lymphadenomegaly, ILD.

Ultrasound
§ From the early stages of
arthritides:
- fluid accumulation.
- synovial thickening.
- increased doppler signal
due to increased blood
flow at the site of
inflammation.
- shoulder ultrasound is
important in polymyalgia
to detect synovitis and
bursitis
§ Abdominal US:
- hepatomegaly or
splenomegaly in Still’s
disease.
- search for cancer in case of
suspicious paraneoplastic
arthritis.

Invasive techniques
§ Arthroscopy
- Endoscope inserted into
joint thr. small incision
- Minimally invasive – only 2
small incisions for knee
- Visualization & treatment
§ Arthrography

• Series of images, often X-
  rays, of a joint after

injection of a contrast
medium
- Series of X-rays, CT or
MRI. Joint can be imaged
from many angles in
fluoroscopy, or on a slice
by slice basis in CT and
MRI.
§ Myelography:

• is an imaging examination
  that involves spinal needle
  into the spinal canal and
  injecting a contrast
  material in the space
  around the spinal cord and
  nerve using a real-time
  form of x-ray called
  fluoroscopy.

CT and cardiac echo
§ CT for hernia and tumor.
§ more sensitive to erosions
than MRI.
§ May detect synovitis and
tenosynovitis.
§ Cardiac echo for detected
pericardial fluid in SLE.

Radioisotope scanning
§ serach for cancer in
paraneoplastic arthritis.
§ PET scan for organ functioning
using radioactive isotype drug
(tracer) to show activity such
as FDG (fluorodeoxyglucose).
§ SPECT- integrates CT and a
radioactive tracer.

MRI

§ Soft tissues can be visualized
§ Bone marrow edema, fluid
accumulation, synovitis also
seen in early arthritis
§ Hernia, soft tissue, early
erosions, and synovitis.

Rheumatoid Arthritis (RA): genetics and pathogenesis.

RA: Symptoms and diagnostics.

(cont from pic in the front)

Warning flags!!!
§ 3 or more swollen joints.
§ More than 60 minutes morning joint
stiffness.
§ MCT and MPT joints involvement
(positive squeeze test).
§ NSAIDs are effective to reduce pain.
§ RA in the family.

Differential diagnosis between RA and
Bouchard’s osteoarthritis is that the swelling in
the finger’s joints in RA is soft compared to the swelling in Bouchard’s osteoarthritis which is hard and
bony. Important not to confuse to prevent the delay of RA diagnosis and minimize the complications!!

Cervical spine involvement in RA:
§ C2 compression: facial pain, ear aches, and occipital headaches.
§ Vertebrobasilar insufficiency: vertigo (person feels as if they or the objects around them are moving
when they are not), loss of vision, tinnitus, dysphagia, drop attacks.
§ Myelopathy: muscle weakness, abnormal gait, hand numbness and incontinence.
§ ‘I feel my head falls down’.
§ Musculoskeletal symptoms may overshadow neurological signs.

Extra-articular manifestations:

Rheumatic nodules subcutaneously Vasculitis: splinter hemorrhage, crural ulcers, gangrene

Lungs: pleural effusion- pleural fluid with low
glucose and complement**, pleuritis, pulmonary
rheumatic nodules, ILD (fibrosis),

Neurological: nerve compression sy (carpal tunnel sy),
polyneuropathy, mononeuritis multiplex

Osteoporosis

Pericarditis, rheumatic nodules in heart, pericardial effusion

Eyes: secondary Sjogren sy, episcleritis,
sclerites, uveitis, scleromalacia perforans

Lymphadenopathy

AA Amyloidosis
Accelerated atherosclerosis and CV diseases

Investigations:

Laboratory investigation = Rheumatoid factor: nonspecific.
§ Anti-CCP: >90% specificity.
§ In early stages 1/3 of cases are RF and anti-CCP
negative.
§ Increased ESR, CRP, anaemia,
leukothrombocytosis.

MR

Soft tissues can be visualized (synovitis).
§ With contrast agent the increased blood flow can
be detected.
§ Early detection of erosions.
§ Bone edema preceding the erosions.
§ Costly and the accessibility is limited.

Conventional radiography

Hand and feet.
§ Characteristic sign: marginal erosions.
§ Sensitivity in early cases <50%.

Ultrasonography

Soft tissues are visible (fluid collection, synovitis,
tenosynovitis).

§ With power doppler method the hyper-
vascularization can be seen.

§ Erosions can be detected earlier.

Determination of activity in RA – DAS28 activity index:

Disease Activity Score 28 is a system developed and validated by the EULAR to measure the progress
and improvement of Rheumatoid Arthritis when diagnosed and defined according to ACR criteria. Ranges
from 2-10; higher values mean higher disease activity. Below 2.6 is interpreted as remission. 5.1 and
higher is considered severe. 28 describes no. of different joints.

RA: treatment

Adult onset Still’s disease, Caplan sy., Felty sy., intermittent polyarthritis, palindrome rheumatism.

Part 1

Juvenile idiopathic arthritis.

§ Is the term used to describe arthritis, or inflammation of the joints in children.
§ One of the most childhood rheumatic disease and most chronic as well.
§ Incidence 0.1/1000 children per year.
§ Prevalence 1-1.5/1000.
§ It is considered to be a group of diseases of 3 main and 3 rare.

Criteria:

§ < 16 years.
§ Inflammation of at least 1 joint > 6 weeks.
§ Exclusion of other inflammatory diseases.

Classification by International League Against Rheumatism (ILAR)
1. Systemic Juvenile Idiopathic arthritis (sJIA) (Still-disease).
2. Oligoarthritis (1-4 joints) can be either persistent or extended.
3. Polyarthritis (5 or more joints) can be either RF + or -
4. Juvenile psoriatic arthritis.
5. Enthesitis associated arthritis.
6. Undifferentiated arthritis.

6- Systemic Juvenile Still-disease sJIA: 10-15%
§ Intermittent fever (> 2 weeks) 98%
§ Macular salmon-pink rash 81%
§ Arthritis (one or more)/ arthralgia 8% monoarthritis, 45% oligoarthritis and 47% polyarthritis.
§ Lymph adenomegaly (31%), hepato-splenomegaly, serositis

§ Severe complications: macrophage activation sy (life-threatening emergency, persistent rash,
atypical rash, coagulopathy, decreasing WBCs, RBCs and platelets count, and hepatitis)

Laboratory parameters:
§ Leukocytosis (neutrophilia)
§ Thrombocytosis
§ Increased ESR, CRP and ferritin.
§ Increased transaminase (AST, ALT).
§ Anaemia.
§ ANA, RF –
Diagnosis of exclusion:
§ Infections.
§ Malignancy (lymphoproliferative diseases)
§ Other autoimmune/ autoinflammatory disease.
§ Malaria.

7- Oligoarthritis (1-4 joints) 50-60%
§ Female > male.
§ Age 2-3 years (rare >10 years)
§ Persistent 1-4 joints; ankle, knee, elbow.
§ Extended 1-4 joints at the beginning then > 5 joints.
§ ANA +, high risk of uveitis.

Spondylarthritides, Ankylosing spondylitis.

Part 1

Infectious arthritis.

Cont from the 2 pics attached

Diagnosis:
§ Basis: history (tick bite in endemic region), clinical picture.
§ Verification: serology (antibody response within 4 weeks).
§ In doubtful cases:
- PCR (blood, skin, SF, CSF,).
- T cell proliferative assays with Borrelia antigens.

Therapy:
§ Oral therapy: ECM, acrodermatitis, isolated facial palsy, I degree AV block, Lyme arthritis at beginning.
- adult: Doxycycline 100 mg, amoxycillin 4x500 mg; cefuroxime 2x500 mg, erythromycin 4x250 mg
for 10-30 days.
- child: amoxycillin 3x250 mg (20 mg/kg); cefuroxime 2x125 mg; erythromycin 3x250 mg for 10-30
days.
§ Iv. therapy: neuroborreliosis, II-III AV block, refractory arthritis.
- 2g ceftriaxone, 3g cefotaxime, 6x3-4 ME penicillin G, 50mg/kg chloramphenicol for 30 days.
§ Chronic arthritis: NSAID, i.a. steroid, HQL, synovectomy.

Preventions:
§ Endemic region: long trousers, tucked into the socks.
§ Antibiotic prophylaxis: questionable benefit.
§ If the patient asks: oral doxycycline th.for 10 days.
§ Vaccination: available soon, 90% efficiency.

Enteropathic arthritis:
§ Is an inflammatory condition affecting the spine and other joints that commonly occurs in the
inflammatory bowel diseases – Crohn’s disease and ulcerative colitis.
§ Crohn, colitis ulcerosa, Whipple-disease, intestinalis bypass.
§ General characteristics:
- peripheral and axial forms.
- axial: 75% HLA-B27 positive.
§ Epidemiology:
- peripheral form: Colitis ulcerosa 12%, Crohn 20%.
- axial form: 6%.
- sex: peripheral ≈, axial: men. age: 25-45 years.
§ Pathogenesis:
- genetic background.
- infective agents (gut bacteria?) - cross reactivity.
- MALT: gut and synovium (common antigens).
§ Types:
- Type 1: for mono-oligoarthritis in the lower limbs for a few weeks/months and no joint destruction.
- Type 2: symmetrical polyarthritis, small joints of the upper limb. Activity is not parallel to bowel
symptoms.
- Type 3: coexistence of axial and peripheral symptoms.
§ Symptoms:
- usually starts with gastrointestinal symptoms.
- oligoarthritis (knee, ankle).
- < 2months attacks.
- 75%: follow the activity of gut.
- Spondylitis ~ SPA.
§ Diagnostics: synovial histology: ≈ RA, ESR, leukocytosis, X ray: non-specific (RA, SPA), stool blood
test: benzidine test, enteropathy activity: stool calprotectin.
§ Therapy:
- Therapy of gastrointestinal disease.
- In Crohn’s disease and ulcerative colitis: TNF blocker, mesalazine.
- NSAID carefully in gut symptoms.
- Steroid: local.

Undifferentiated SpA:
Cases that meet the criterias but are not classified as specific or have overlapping symptoms. Later, they often
add new symptoms, radiological abnormalities, and become a specific form of the disease.

Gout.

Part 1

Osteoarthritis.

Part 1

Discopathy, low back pain.

Osteoporosis.

Part 1

Humeroscapular periarthritis. Regional syndromes of the shoulder

Carpal-tunnel syndrome. Entrapment syndromes.

Reflex sympathyc distrophy (algoneurodystrophy). Aseptic bone necrosis.

Non-steroidal anti-inflammatory drugs (NSAIDs) and pain management in rheumatology.

Part 1

Physiotherapy, balneotherapy, rehabilitation.

Clinical symptoms, diagnosis and therapy of idiopathic inflammatory myopathies

(cont)

• Inclusion body myositis (IBM):

§ More common in men (elderly).
§ Slowly progressive proximal and distal
weakness, often leads to delay in
diagnosis and always chronic.
§ There is early weakness and atrophy of
quadriceps, forearm flexors and tibialis
anterior muscles. Involvement is
asymmetrical.
§ Facial weakness occurs in 1/3 of the
patients and dysphagia in one-half of
patients.
§ Patients can also have loss of deep
tendon reflexes (nerves are not
involved in PM/DM).

§ Extramacular manifestations are rare.
§ Diagnosis- slightly elevated CK levels;
up to 15-fold elevated.
§ Autoantibody- cN1A.
§ Muscle pathology: Endomysial CD8+ T cells, MHC class I, amyloid, vacuoles,
tubulofilaments, mitochondrial impairment (COX, paracr. inclusions).
§ Muscle biopsy: rimmed vacuoles.
§ Poor response to therapy.

IIM summary:
§ Idiopathic inflammatory myopathies are uncommon autoimmune diseases caused by
inflammation in striated muscles, leading to muscle weakness as the main symptom.
§ Frequent extra muscular involvement can be seen, affecting mainly skin, lungs, joints,
esophagus and heart.

§ Disease is diagnosed by complex investigations, including assessment of muscle
weakness, muscle biopsy, electromyography, measurement of increased enzymes of
muscle origin and autoantibodies.
§ About 10–15% of cases are associated with malignancy, more often in the case of DM.

§ Serum autoantibodies can be found in about 70% of patients. These antibodies are often
myositis specific and are associated with differential and distinctive clinical phenotype
subsets within the growing IIM disease spectrum.

§ The mainstay of treatment is the use of glucocorticoids. These should be combined
with other immunosuppressive drugs to reduce the side effects of high doses of
glucocorticoids and to enhance the efficacy of immunosuppressive treatment as this
treatment often has to be maintained for prolonged periods.

§ Active physical exercise should be introduced early, and in combination with
immunosuppressive treatment, and be guided by a physical therapist, based on individual
ability.

(to be continued)

Clinical symptoms, diagnosis and therapy of idiopathic inflammatory myopathies

Immunodeficiency in adults.

Part 2

Immunodeficiency in adults.

Part 3

Part 4 (last part)

Celiac disease, food allergy.

Part 2

Celiac disease, food allergy.

Part 3

Part 2

Adult onset Still’s disease, Caplan sy., Felty sy., intermittent polyarthritis, palindrome rheumatism

Part 2

Part 3

Spondylarthritides, Ankylosing spondylitis

Part 2

Gout

Part 2

Osteoarthritis.

Part 2

Part 3

Osteoporosis.

Part 2

Osteoporosis

Part 3

Carpal-tunnel syndrome. Entrapment syndromes.

Non-steroidal anti-inflammatory drugs (NSAIDs) and pain management in rheumatology.

Part 2

Part 3

Physiotherapy, balneotherapy, rehabilitation.

Part 2