Systemic lupus erythematosus Connective tissue disease

1. Systemic Lupus
Erythematosus

2. Introduction
SLE is an autoimmune disease with variable
manifestations caused by the production of
autoantibodies and deposition of
complement.
Manifestations can vary from skin and joint
disease to organ dysfunction such as renal
failure.
Prognosis can vary depending on the degree
of organ involvement and damage.

3. Epidemiology
• The typical patient is a female of age range 15 to 45 years.
• Suggesting that sex hormones influence the probability of developing or
expressing SLE.
• The prevalence is three to four times higher in non-Caucasian
individuals (African-American, Asian, and Hispanic)

4. Risk Factors
• A) Environmental: tobacco, viral infection (Epstein–Barr virus [EBV], cytomegalovirus
[CMV], and others), silica exposure, ultraviolet (UV) light, pesticides, gut microbiome,
and demethylating drugs.
• B) Genetic: Risk of SLE increases with affected family members, notably first-degree
relatives and identical twins.
• First-degree relatives with family history of SLE have a 16-fold increased risk of developing SLE
(4%–8%) and a 5-fold increased risk of developing any other autoimmune disease.
• Histocompatibility complex (HLA) DR2 (DRB1∗1501) and DR3 (DRB1:0301) increase the relative
risk of SLE two to three fold.
• The presence of these genes may allow more efficient presentation of self-antigens to self-reactive T and B
cells.
• Complement component deficiencies (C1q, C2, and C4) increase the risk of SLE 5–10-fold.
• It is estimated that it takes 10 to 20 genetic risk alleles to predispose a patient to develop SLE.

5. • C) Gender/hormonal: SLE is approximately 10 to 15 times more common
in women of childbearing age as than in men.
• Some predisposing genes are located on the X chromosome
• Interestingly, men with Klinefelter’s syndrome (47 XXY) have a 14-fold risk of SLE.
• SLE is rare in Turner’s syndrome (XO).

6. Pathophysiology

7. Classification Criteria 1997
Not used as often today, the 1997 ACR criteria are used to generate the mnemonic, SOAP-BRAIN-MD, that
many medical students use to remember the most characteristic manifestations of SLE:
• S-Serositis: pleuritis or pericarditis
• O-Oral or nasal ulcers
• A-Arthritis: nonerosive
• P-Photosensitivity
• B-Blood disorders: hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia
• R-Renal involvement: persistent proteinuria or cellular casts
• A-Antinuclear antibodies (ANAs)
• I-Immunologic phenomena: anti-dsDNA, anti-Sm, antiphospholipid antibodies
• N-Neurologic disorder: seizures or psychosis
• M-Malar rash
• D-Discoid rash
Having 4 of these 11 criteria gave an 83% sensitivity and 93% specificity for having SLE.

8. New Classification
Criteria 2017
• EULAR and ACR collaborated on new
SLE classification criteria that had both
high sensitivity (96%) and specificity
(93%).
• A patient was classified as having SLE if
they had a positive ANA ≥1:80 and had
≥10 points. The following are the
criteria and points assigned to each
manifestation.

9. Different
Types of
Lupus

10. Antibodies
and Clinical
Associations

11. Clinical Manifestations

12. CNS Manifestations

13. Lungs Manifestations
• Pleuritis (common): should be bilateral.
• CRP usually elevated (sometimes very high). Consider infection
if unilateral presentation and a history of immunosuppression.
• Acute lupus pneumonitis with or without pulmonary
hemorrhage (2%):
• Usually seen in a systemically ill patient with diffuse ground
glass changes.
• Bronchoscopy to R/O diffuse alveolar hemorrhage and or
infection.
• Frequently associated with antiphospholipid antibodies.
• Chronic interstitial lung disease/fibrosis: rare in nonoverlap
SLE.
• More common in patients with mixed connective tissue disease
or prior acute lupus pneumonitis.
• R/O medication effects (e.g., nitrofurantoin) or overlap with
antisynthetase antibody syndrome.
• Pulmonary hypertension (HTN):
• R/O secondary causes (chronic emboli and sleep apnea).
• Shrinking lung syndrome: Rare.
• Decreased lung volumes with normal parenchyma.
• May be associated with phrenic neuropathy, myopathy of the
diaphragm, or pleural fibrosis.
• Cryptogenic organizing pneumonia: Rare.
• Alveolar disease that is highly responsive to steroids.
• R/O overlap with antisynthetase antibody syndrome.
• Infection: Typical or atypical. R/O aspiration.

14. Heart Manifestations
• Pericarditis:
• When symptomatic, can be associated with a left-sided pleural
effusion.
• Colchicine may be an effective treatment.
• An asymptomatic pericardial effusion can be seen on
echocardiogram.
• Myocarditis: Rare.
• Presents as heart failure or unexplained tachycardia.
• Obtain a myocardial biopsy if possible.
• Troponin is elevated.
• Vasculitis: (coronary): Rare.
• Secondary atherosclerotic coronary artery disease and
myocardial infarction:
• Very common especially later in disease.
• Secondary hypertensive disease: From steroids or renal
insufficiency.
• Medication effects: Hydroxychloroquine can cause a
cardiomyopathy.
• Valvular disease: More frequent in patients with
antiphospholipid antibodies.
• However, anticoagulation or glucocorticoids do not prevent
destruction of the valve. Thickening of aortic and mitral valves is
seen.
• Libman–Sacks verrucae
• Occur most commonly on the ventricular side of the posterior
leaflet of mitral valve or on aortic valve.
• May cause embolic stroke.
• Transesophageal echo is more sensitive than transthoracic.
• There is an increased risk of subacute bacterial endocarditis due
to immunosuppression.

15. GI Manifestations
• Esophageal dysmotility:
• Usually involves upper third of esophagus in patients with SLE
myositis, common in overlap syndromes.
• Pancreatitis:
• Usually due to gallstones, alcohol, or hypertriglyceridemia.
• Can be due to medications (azathioprine [AZA]). If due to SLE,
the patient will have diffusely active disease.
• Serositis:
• Only occurs in patients with active systemic disease. Rare to get
frank ascites.
• Need to R/O infection.
• Mesenteric vasculitis: Likely associated with active disease.
• Will see bowel wall edema and sometimes fat-stranding on
computed tomography of abdomen.
• Hepatitis:
• Usually as a result of medications or other non-lupus cause.
• If due to lupus, patients do not have anti-smooth muscle or
anti-liver-kidney microsome antibodies.
• Intestinal pseudo-obstruction:
• Rare manifestation with obstruction picture but without
identifiable mechanical or obstructive causes.
• Can present with abdominal pain, vomiting, diarrhea and/or
constipation, abdominal distension, and weight loss along with
an x-ray suggestive of obstruction.
• Protein-losing enteropathy (PLE): Consider in patients with
severely low albumin but no proteinuria.
• Most patients have chronic diarrhea and edema from low
serum proteins. Diagnosis made by measuring fecal alpha-1
antitryspin or transferrin. Stool should not have transferrin
unless there is a PLE.

16. Renal
Manifestations

17. Renal
Manifestations
cont.

18. Renal
Manifestations
cont.

19. Indications of Renal biopsy in SLE patients
• Increasing serum creatinine without a compelling alternative cause
(e.g., hypovolemia and medication)
• Confirmed proteinuria of ≥ 1 g/24 hours
• Proteinuria ≥ 0.5 g/day plus hematuria or cellular casts

20. Tx for Class III/IV Lupus Nephritis
Induction therapy:
• Intravenous (IV) pulse methylprednisolone:
• (500 mg to 1 g) daily for 3 days followed by prednisone 1 mg/kg/day.
• Taper after a few weeks to lowest effective dose; plus
• Mycophenolate mofetil (MMF)
• 2–3 g/day for 6 months (African-American and Hispanic patients may respond to MMF better
than cyclophosphamide [CYC]),
• or CYC: high dose IV (500–1000 mg/m2 monthly × 6 doses) or low dose (Euro-lupus: 500 mg
IV every 2 weeks × 6 doses)
• Patients who fail to respond to both are candidates for:
• rituximab, calcineurin inhibitors (cyclosporine, tacrolimus), or a combination of calcineurin
inhibitors and low-dose MMF.

21. Tx Class V Lupus Nephritis
• Oral prednisone 0.5 mg/kg/day for 6 months; plus
• MMF 2–3 g/day for 6 months
• Calcineurin inhibitors (cyclosporine/ tacrolimus) can be added to MMF: use
caution in patients with renal insufficiency or hypertension.
• IV CYC (cyclophosphamide) if other therapies fail.

22. Maintenance Therapy
• Oral Azathioprine (up to 2 mg/kg/day) (or 6-mercaptopurine if nausea
on AZA) or MMF generally preferred (1–3 g/day)
• Avoid AZA in patients on allopurinol (gout) or on warfarin (warfarin
resistance)
• CYC IV every 3 months after induction can be given in patients who
cannot tolerate AZA or MMF.

23. Adjunctive Therapy
• Hydroxychloroquine
• Associated with less organ damage in patients with SLE.
• Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor
blocker (ARB)
• If proteinuria ≥0.5 g/24 hours
• Control blood pressure (BP): should be ≤130/80
• Statin therapy:
• If low-density lipoprotein (LDL) cholesterol >100 mg/dL
• Stop smoking
• Rituximab has also been studied in SLE nephritis with controversial results.

24. Hematologic Manifestations
• Autoimmune hemolytic anemia (AIHA)
• Leukopenia
• (lymphopenia [common], neutropenia)
• Thrombocytopenia
• Antiphospholipid antibody syndrome (APLAS)
• Anemia of chronic disease
• Thrombotic thrombocytopenic purpura (TTP)

25. Joint Manifestations
• Arthritis associated with SLE is rarely destructive of bone as opposed
to rheumatoid arthritis.
• Pain and tenderness are more severe than the degree of swelling.
• Joint deformities can occur and when present are categorized as:
• Nonerosive arthropathy (Jaccoud arthritis): seen in 10% to 35% of patients.
• Metacarpophalangeal joint subluxation, ulnar deviation, and swan-neck deformities due to lax
joint capsules, tendons, and ligaments.
• Deformities can be reversible early but can later become fixed.
• Erosive, symmetric polyarthritis (Rhupus): patients resemble RA with fixed deformities
associated with radiographic erosions.
• Rheumatoid factor and cyclic citrullinated peptide antibodies are more commonly present in
these patients.

27. Mucocutaneous
Manifestations

28. Ocular Manifestations
• Keratoconjuntivitis sicca
• (with or w/o Sjögren’s Syndrome)
• Keratitis
• Episcleritis
• Scleritis
• Uveitis
• Retinal Vasculitis
• Retinopathy

29. Lab Test
• CBC (RBC, WBC, platelets)
• Urinalysis
• Sedimentation Rate (ESR)
• CRP
• Rheumatoid Factor
• Skin biopsy
• Kidney Biopsy
• Antinuclear Antibody (ANA)
• Anti DNA
• Anti-Sm
• Anti-RNP
• Anti-Ro
• Anti-La

30. General Treatment
• R/O a cause other than SLE for the patient’s symptoms: R/O infection; R/O thrombosis;
R/O drug side effect; R/O another disease (hypothyroidism, fibromyalgia, and sleep
apnea).
• Mild disease (fatigue, arthritis, rash, serositis):
• NSAIDs: may cause worsening renal function, photosensitivity, aseptic meningitis (especially
ibuprofen)
• Hydroxychloroquine
• Low dose prednisone (<20 mg/day): taper to lowest effective dose
• Methotrexate: can consider leflunomide if methotrexate not tolerated
• Moderate disease (severe minor symptoms unresponsive to standard therapy, especially
in patients with low complement and high anti-dsDNA antibodies):
• MMF or AZA
• Belimumab: use with other immunosuppressives
• Prednisone (20–40 mg/day): taper to lowest effective dose
• Calcineurin inhibitors (cyclosporine, tacrolimus)

31. • Severe disease (nephritis, CNS, pneumonitis, vasculitis, severe cytopenias):
• High dose prednisone (> 60 mg/day) including pulse methylprednisolone (1 g/day ×
3–5 days) if needed.
• Cytotoxic medications: induction therapy with CYC or MMF followed by maintenance
therapy with AZA, MMF, calcineurin inhibitors (cyclosporine, tacrolimus), or
combination of MMF and calcineurin inhibitors.
• Biologics: rituximab can be considered.
• Additional therapies: plasmapheresis (diffuse alveolar hemorrhage, TTP, anti-NMO
spectrum disorder, APLAS), IVIG (autoimmune cytopenias, APLAS), stem cell
transplant (refractory SLE)

32. Preventive Measures
• Sun precautions
• Rest
• Nutrition/diet
• Exercise
• Moist heat
• Prevent infection
• Don’t smoke
• Counsel against pregnancy while nephritis is active or creatinine
>2mg/dL

33. Sjögren’s Syndrome

34. Definition
• Primary SS is diagnosed in a patient with KCS who does not have
another underlying rheumatic disease. Primary SS is serologically
associated with antibodies to Ro/SSA and La/SSB.
• Secondary SS is diagnosed in the presence of another rheumatic
disease, most frequently rheumatoid arthritis (RA), SLE, Scleroderma.

35. Epidemiology
• Primary SS affects 0.1% to 4% of the population depending on criteria
used.
• It typically affects females between ages 30 and 50 years (female: male = 9:1).
It is infrequently seen in children.
• Symptoms progress relatively slowly and there is frequently a delay of 5 to 10
years between symptom onset and diagnosis.
• Secondary SS occurs in up to 15% to 20% of patients with RA and to a
lesser extent in other rheumatic diseases.

36. Pathogenesis
• SS result from a lymphocytic infiltration of glandular and nonglandular organs.
• Over 90% of the infiltrating cells are either CD4+ T lymphocytes with memory phenotype (70%) or
B lymphocytes (20%).
• The remaining 10% include plasma cells, CD8+ T lymphocytes, T regulatory cells, natural killer
cells, and dendritic cells.
• Analysis of T-cell cytokines from biopsies suggests that this is a predominantly Th1- and Th17-
driven response.
• There are two models of pathogenesis in SS:
• One postulates that an autoimmune attack on acinar epithelium results in cytotoxic cell death and
apoptosis.
• The other model includes antibodies against the muscarinic receptor type 3, accelerated
breakdown of acetylcholine by cytokines, and altered expression of aquaporin channels. Both
models likely play a role in gland hypofunction.

37. Clinical
Manifestations

38. Xerophthalmia (Keratoconjuntivitis Sicca)
Dry eyes
• Symptoms include:
• A foreign body or gritty sensation; painful, burning, itchy, or red eyes;
• Blurred vision, and/or photophobia.
• KCS can lead to infections, corneal ulceration, and rarely vision loss.

39. Xerostomia
• Normal saliva production is 1 to 1.5 L/day.
• Dry mouth sensation occurs when the salivary flow rate decreases to <50% of the basal
flow rate. It may result in a variety of problems including:
• Burning sensation.
• Change in taste (metallic, salty, bitter).
• Difficulty swallowing.
• Disturbed sleep (due to dry mouth and/or nocturia).
• Gastroesophageal reflux symptoms (due to lack of saliva buffer).
• Increase in dental caries, cracked teeth, loose fillings.
• “Lipstick sign” (adherence of patient’s lipstick onto front teeth).
• Predisposition to oral candidiasis (atrophic variant, which presents as an erythematous tongue).
• Problems wearing dentures.

40. Laboratory
Findings in
SS

41. Diagnosis
• Minor salivary gland (MSG) biopsy (sensitivity 80%, specificity 82%)
• Is the gold standard for SS diagnosis.
• An incisional biopsy through the lower labial mucosa yielding 5 to 10 minor
glands is adequate for assessment.
• An area of ≥50 lymphocytes is defined as a focus, with a focus score (FS) of ≥1 foci/4
mm2 supporting a diagnosis of SS.

42. SS 2016 Criteria
• The 2016 ACR/EULAR classification criteria were created to identify a uniform population of SS patients
suitable for research studies.
• The 2016 criteria have a sensitivity of 96% and specificity of 95% for SS.
• A patient is considered to have primary SS if they have at least one symptom of ocular or oral dryness and have a score of ≥4
points out of 9 from the following items:
• Labial salivary gland biopsy with lymphocytic sialadenitis and a FS ≥1 foci/4 mm2 (3 points).
• Anti-SSA/Ro positive (3 points).
• Ocular Surface Staining ≥5 in at least one eye (1 point).
• Fluorescein dye for the cornea, followed by lissamine green dye to assess the conjunctiva.
• Fluorescein dye targets areas of cellular disruption (indicating dryness)
• Schirmer’s test ≤ 5 mm/5 minutes in at least one eye (1 point).
• Unstimulated whole salivary flow rate ≤0.1 mL/minute (1 point).
• Using Sialometry

43. Extraglandular Manifestations
• Lung manifestations: includes xerotrachea/xerobronchitis,
• nonspecific interstitial pneumonitis,
• lymphocytic interstitial pneumonitis, usual interstitial pneumonitis, bronchiolitis (constrictive), and bronchial-associated lymphoid tissue
lymphoma.
• Due to thick secretions and recurrent pneumonias, patients can develop bronchiectasis.
• Renal disease:
• type I distal renal tubular acidosis (10%),
• tubular interstitial nephritis (<5%),
• glomerulonephritis, and
• nephrogenic diabetes insipidus
• GI: Higher prevalence of celiac disease.
• Suspect in patients with diarrhea and vitamin D deficiency.
• Primary biliary cholangitis (5%), autoimmune hepatitis, and recurrent pancreatitis (<5%) have also been described.
• Vasculitis: cutaneous vasculitis (palpable purpura) is most common
• CNS involvement: Multiple sclerosis-like brain lesions, seizures, sensory/motor deficits

44. Risk of Cancer in SS
• 5-44 fold greater risk in developing lymphoma compared to general
population.
• Lifetime frequency 5-10%
• Usually are Non-Hodgkin’s B-cell Lymphoma and occur in a median
age of 8 years following Dx of SS.

45. Treatment
• Modify the environment
• Increase fluid and Omega 3 fatty acids
• Reduced caffeine intake and smoking
• Limit time at computer
• Turn off ceiling
• Eye drops
• Free artificial tears
• Topical corticosteroids for moderate to severe disease
• Cyclosporine: 1 drop BID
• Cholinergic drugs: Stimulate to produce more tears and saliva.
• Pilocarpine 5mg QID
• Cevimeline 30 mg TID
• Lubricant ointment

46. Extraglandular manifestation Tx
• Arthritis
• NSAIDs
• Antimalarials
• Low dose prednisone < 5mg
• Severe extraglandular manifestations (Systemic organ ivolvement)
• High dose steroids
• Azathioprine
• Mycophenylate mofetil
• Methotrexate
• Cyclophosphamide
• Rituximab

47. Prevention
• Vaginal Dryness
• Topical lubricants
• Complications of xerostomia can be prevented with:
• Regular Dental visits
• Daily use of fluoridated toothpaste and mouthwash
• Sugar free gums may stimulate salivary flow
• Regular water intake
• Avoid coffee, tea, smoking