Mixed connective tissue disease

➢ Overlap syndromes:
o A group of conditions that have clinical features of, and meet classification criteria for, more than 1 well-
characterized rheumatic disease.
o Classification:
▪ Mixed connective tissue disease >> high titer of autoantibodies U1 ribonucleoprotein (U1 RNP).
▪ Antisynthetase syndromes >> the presence of antibodies directed against various aminoacyl-tRNA
synthetase enzymes (anti-Jo-1, and others).
▪ Polymyositis/Scleroderma syndromes.

➢ Mixed connective tissue disease clinical features:

o Fever may be the presenting feature of MCTD, Commonest skin change is Raynaud phenomenon.
o Swollen hands, Periungual telangiectasia, Palpable purpura, Erythematous plaques resembling as discoid
lupus, Facial erythema or malar rash, localized scarring and diffuse non-scarring alopecia, Painful dermal
nodules on hands and elbows, may calcified, Orogenital ulcerations, nasal septal perforation, and the sicca
complex.
o Absence of severe renal and CNS disease but more severe arthritis and insidious onset of Pulmonary HTN.
o Positive RF is found in 70%, Anti CCP is found 50%.
o Digital erosion in X-Ray.
o Pericarditis is the most common manifestation in cardiac involvement.
o Pulmonary involvement in 75% of the patients.
o The absence of severe renal disease is a hallmark of MCTD.
o The most frequent CNS manifestation is trigeminal nerve neuropathy.

o Criteria for diagnosis of MCTD:

 ▪ Common manifestations. At least one.
▪ Anti-U1-RNP antibody. Positivity
▪ Characteristic organ involvement. At least one.
▪ Overlapping manifestations (SLE, Systemic sclerosis, Polymyositis). At least one feature of two of the
three disorders.
o Antiphospholipid antibodies, brain natriuretic peptide may detect Pulmonary HTN.
o ANA antibody is the first clue to diagnosis, but Anti-U1-RNP is characteristic.
o Other lupus-specific antibodies and Scleroderma-specific antibodies are typically absent.
o Treatment:
▪ NSAIDs, hydroxychloroquine, and Intraarticular corticosteroid may be used for arthritis.
▪ Disease-modifying antirheumatic drug for refractory synovitis.
▪ PPI for GERD.
▪ Phosphodiesterase inhibitors, endothelin receptor antagonists, or prostaglandins can be used for
pulmonary hypertension.
▪ Steroid-resistant myositis may respond to intravenous immunoglobulin.
➢ Antisynthetase syndromes:
o Three cardinal manifestations >> ILD, polymyositis, arthritis.
o 43-60 years, Women more, Black American ethnicity.
o Symptoms:
▪ Fever, Weight loss, Anorexia, Dyspnea, Dry cough, Arthralgia, Joint swelling, Proximal muscle weakness,
Myalgia, Raynaud's phenomenon.
o Signs >> fingers with fissuring and scaling of the skin, calcinosis cuties, malar rash, Cutaneous ulcers, Crackles
on chest auscultation.
o Treatment:
▪ Steroids, azathioprine, mycophenolate mofetil.
▪ Tacrolimus in severe ILD.
▪ Rituximab in refractory ILD.
▪ Cyclophosphamide in Acute respiratory distress.

Behcet’s disease

➢ Autoinflammatory systemic vasculitis (of all sizes) disease.

➢ Characterized by mucocutaneous manifestations (Recurrent oral & genital ulcers, Bilateral uveitis, Bloody diarrhea).
➢ 20-40 years, Both genders are equally affected, More severe course in males and younger age.
➢ May cause epididymitis, salpingitis, urethritis.
➢ Cutaneous manifestations:
o Erythema nodosum-like lesions, Superficial thrombophlebitis, Acneiform or pseudofolliculitis lesions, pyoderma
gangrenosum-like lesions, pustular vasculitic lesions, cutaneous small-vessel vasculitis.
➢ Vascular manifestations:
o Superficial thrombophlebitis, DVT, Budd-Chiari syndrome.
➢ Neurological manifestations are seen in 5-10% of patients.
➢ A positive pathergy reaction (formation of erythematous papules or pustules 24 to 48 hours after needle insertion)
is very specific for Behcet disease.
➢ Inflammatory, non-erosive, and non-deforming arthritis are seen in 50%.
➢ Pulmonary artery involvement with aneurysm formation is unique to Behcet disease and is the leading cause of
death in these patients.
➢ HLA B51 association.
➢ Criteria for diagnosis (≥4):
o Ocular >> 2 points.
o Genital ulcers >> 2 points.
o Oral ulcers >> 2 points.
o Skin >> 1 point.
o Neuro >> 1 point.
o Vascular >> 1 point.
o Positive pathergy test >> 1 point.
➢ Treatment:
o Mucocutaneous >> Topical steroid, Colchicine, Dapsone, Systemic glucocorticoids, Methotrexate,
Azathioprine, Interferon Alpha, Thalidomide, TNFα inhibitors (infliximab, adalimumab, or etanercept),
Cyclosporine, Apremilast.
o Eye & systemic >> Colchicine, Prednisone, Azathioprine, Cyclophosphamide, Anti-TNF drugs, Mycophenolate
mofetil, Rituximab (Eye).
 Sjögren’s syndrome (SS)

➢ A chronic autoimmune inflammatory disorder characterized by diminished lacrimal and salivary gland function with
resultant dryness of the eyes and mouth, with affection of other organs.
➢ 30-70 years, 8 times more in women.
➢ Clinical picture:
o Lymphadenopathy 10%
▪ Unilateral salivary gland enlargement, splenomegaly, skin vasculitis.
o Glandular 30-50%
▪ Nontender swelling of parotid gland.
o Articular 50%
▪ Arthralgia, Arthritis
▪ Treatment >> NSAIDs, Hydroxychloroquine (HCQ), Glucocorticoids (GC), Steroid sparing
immunosuppressants (Ssi), Rituximab (RTX), Azathioprine (AZA).
o Skin 23-67%
▪ Xerosis, Raynaud phenomenon, annular erythema, erythema nodosum, livedo reticularis, lichen planus,
vitiligo, vasculitis.
▪ Treatment >> Sunscreen, Topical GC, Oral Ssi, Retinoids, Cyclophosphamide (CyC),
o Lungs 10-20%
▪ ILD >> GC, Ssi, CyC, RTX, Nintedanib.
o Kidney 30%
▪ Tubular >> Bicarbonate, GC, Ssi.
▪ Glomerulonephritis >> GC, RTX or CyC, Plasma exchange.
o Muscles 44%
▪ Myositis
 o Peripheral nervous system
▪ Mononeuritis multiplex >> GC, Oral Ssi, RTX, CyC with plasma exchange.
▪ Axonal peripheral neuropathy >> IV immunoglobulin, CyC.
▪ Ganglionopathy >> IV immunoglobulin, CyC.
➢ 10–44-fold risk for lymphoma, due to Cryoglobulinemia, Hypergammaglobulinemia, Complement consumption C4.
➢ Thyroid cancer was more frequently found in women with SjS, and lung cancer more frequently in men with SjS.
➢ Ro/SS-A antibodies 73%, ANA 79 %, La/SS-B antibodies 45 %.
➢ Detection of SS-B/La antibodies in the absence of SS-A/Ro antibodies is not relevant for diagnosis.
➢ Criteria:
o Labial salivary gland with Focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm² >> 3 points.
o Anti-SSA/Ro positive >> 3 points.
o Ocular Staining Score ≥5 >> 1 point.
o Schirmer’s test ≤5 mm/5 min in at least one eye >> 1 point.
o Unstimulated whole saliva flow rate ≤0.1 mL/min >> 1 point.
➢ Treatment:
o Alcohol and smoking should be avoided, and thorough oral hygiene is essential.
o Treated by Glucocorticoids and immunosuppressive drugs.

Primary angitis of central nervous system

➢ Rare idiopathic vasculitis restricted to the brain, spinal cord, and meninges.
➢ In the fourth or fifth decades of life (Commonly), Can occur in any age.
➢ Varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and mycoplasma infection have been postulated as the
inciting events & the downstream inflammatory pathways.
➢ Pathological hallmark is transmural inflammation of cerebral blood vessels with subsequent parenchymal infarct
and necrosis.
➢ Venous sinuses of the CNS, other organs, and peripheral nervous system are spared in PACNS.
➢ Clinical features:
o Headache (59.5%) is the commonest symptoms, Cognitive dysfunction (54%), Persistent neurological deficit
(40.5%), Seizures (20.2%), Intracranial hemorrhage (9.8%).
➢ First step in investigations is MRI then angiographic study.
➢ Brain biopsy is the gold standard for the diagnosis of PACNS.
➢ Treatment:
o Induction therapy >> Steroids and Cyclophosphamide.
o Maintenance therapy >> Steroids sparing low risk immunosuppressive agents, started after 4-6 months of
induction therapy.
o Rituximab and anti TNF for failed response to Cyclophosphamide.

Relapsing PolyChondritis

➢ A systemic autoimmune disease with recurrent pattern that compromise the structural and functional integrity of
cartilage and the related connective tissue structures with involvement of Ear, nose, laryngo tracheal, articular,
cardiac, ocular& renal tissues.
➢ 40-60 years, but can occur in childhood, Males and females are equally affected.
➢ Causes:
o Unknown genetic susceptibility HLA-DR4, HLA-DR6.
o Triggers: Trauma, Toxin, Chemical insult.
o Autoantibodies against types II, IX, XI collagen, matrilin-1 & proteoglycans in RPCCICs.
o Immune complex depositions in RPCHLA-DR positive APC and CD4 positive T cells at lesion sites.
➢ Clinical features:
o Auricular involvement is the most common feature.
o Fatigue, Fever, Malaise.
o Ear >> 83%Tragus sparing of the ear lobes “Floppy ear” or “Cauliflower ear”, SNHL, Conductive defect,
tinnitus, vertigo.
o Eye >> 60% Episcleritis/Scleritis.
o Nasal cartilage inflammation.
o The large- and medium-sized bronchi may show patchy widening or extensive narrowing and may collapse.
o Chondritis of SCJ, costochondral & manubriosternal joints are typical.
o Aortic or mitral valvular disease: 10%
o Hematuria &/or proteinuria.
o Unusual cranial neuritis (2,6,7,8), Infrequent Odynophagia and dysphagia due to thyroid, laryngeal or
tracheal chondritis.
o Skin >> Ulcers, Purpura, papules, nodules, pustules, superficial thrombophlebitis, livedoreticularis.
➢ Up to one-third of cases have coexisting disease (Systemic vasculitis, Connective tissue disease, Malignancy)
➢ Diagnosis:
o No specific test but ANA, RF, ANCA –ve.
o Criteria (MacAdams, at least 3):
▪ Bilateral auricular chondritis
▪ Nonerosive, seronegative polyarthritis.
▪ Nasal chondritis.
▪ Ocular inflammation (conjunctivitis, keratitis, scleritis, episcleritis, uveitis).
▪ Laryngo- tracheal chondritis cochlear &/or Vestibular dysfunction: SNHL, tinnitus, vertigo.
➢ Treatment depends on severity:
o First line >> NSAIDs, Glucocorticoids, Dapsone.
o Second-line >> Cyclophosphamide, MTX, Azathioprine, Pulse methylprednisolone, Cyclosporine, Anti-TNF
(Etanercept, Infliximab).
 Immunoglobulin G4-related disease

➢ A new and evolving immune-mediated disease characterized by focal or diffuse organ infiltration by
immunoglobulin G4-bearing plasma cells, If left untreated may lead to irreversible fibrosis, organ dysfunction, and
death.
➢ 50-70 years, Male is more affected.
➢ Clinical picture:
o IgG4-RD patients (40%) may present with symptoms of asthma and allergy.
o symptoms such as fever, malaise, and night sweats are unusual.
o IgG4-RD never affects synovial tissue.
o Bilateral Lacrimal and Salivary glands enlargement, Chronic nasorhinosinusitis, Riedel thyroiditis, Vocal cord
lesions and Supraglottic stenosis, ILD, Lymphadenopathy, Pleural and pericardial effusion, Coronary artery
aneurysms, Autoimmune pancreatitis, Sclerosing cholangitis.
o Skin manifestation (Cutaneous pseudolymphoma) is rare.
➢ Diagnosis
o Serum IgG4 study, as elevated serum IgG4 level, (greater than 135 mg/dL) supports the diagnosis.
o Histological findings >> Dense lymphoplasmacytic infiltrates, Fibrosis, Phlebitis.
➢ Treatment:
o Oral prednisone for 2-4 weeks then taper over 2 months.
o If resistant >> AZA, MTX, or mycophenolate mofetil.
o If refractory >> RTX.
 Vasculitis

➢ An immunologically mediated inflammation of the blood vessel wall leads to vessel wall damage and weakness.
➢ Stages:
o Acute inflammation (Granulomatous, Necrotizing) then healing by fibrosis.

➢ Giant cell arteritis and polymyalgia rheumatica (Large vessels)

o Giant cell arteritis refers to temporal arteritis, characteristically involving one or more branches of carotid
artery. But it may affect other arteries.
o Polymyalgia rheumatica occurs in isolation but it may be seen in 40-50% of patients with giant cell arteritis,
characterized by stiffness, aching, and pain & weakness in the muscles of the neck, shoulders, lower back,
hips, and thighs.
o GCA and Polymyalgia rheumatica represent different clinical spectrums of a single disease process.
o GCA symptoms and signs:
▪ Involvement of cranial vessels >> Headache, Jaw claudication, Scalp tenderness, Loss of vision,
abnormalities in temporal artery.
▪ Involvement of great vessels (Aorta) >> Claudication of extremities.
o Diagnosis is confirmed by multiple biopsies of the temporal artery.
o Lab findings:
▪ High ESR, Anemia, Thrombocytosis, Transaminitis.
o Treatment:
▪ Prednisone 40-60 mg/d for 1 month followed by gradual tapering.
➢ Takayasu arteritis (Large vessels)
o Inflammatory and stenotic disease characterized by strong predilection of the aortic arch and its branches.
o Common in adolescent girls and young women.
o Clinical picture (Pulseless disease):
▪ May present with generalized symptoms (Fever, night sweat, anorexia, weight loss, arthralgias).
▪ Common carotid artery involvement >> Headache, syncope, visual loss, epilepsy, stoke, subclavian steal
syndrome.
▪ Aorta involvement >> Aortic stenosis, aneurysm, limb weakness.
▪ Coronary and pulmonary arteries >> Angina, MI, Pulmonary HTN, Sudden death.
▪ Renal artery stenosis, HTN, GI bleeding, Intermittent claudication.
o Diagnosis is confirmed by arteriography.
o Treatment >> Steroids, MTX, AZA, Anti TNF, Tocilizumab.

➢ Polyarteritis nodosa (Medium vessels)

o Striking predilection for certain organs:
▪ Skin, peripheral nerves, GIT, Kidneys.
o Clinical features:
▪ Commonly affects men >50 years. Can be systemic or cutaneous.
▪ Skin >> Livedo reticularis, Ulcers, Subcutaneous nodules, Gangrene.
▪ Nervous system >> Mononeuritis multiplex, asymmetric polyneuropathy.
▪ GIT >> Intestinal angina, malabsorption, aneurysm.
▪ Renal >> HTN, Oliguria, Renal failure, infarction.
▪ Heart >> Heart failure.
o Diagnosis:
▪ Tissue biopsy or angiogram (Microaneurysms).
 o Treatment:
▪ High doses of Glucocorticoids.
▪ Cyclophosphamide for patients with refractory PAN to Glucocorticoids.
▪ Lamivudine or entecavir and plasma exchange improved the treatment of HBV associated with PAN.

➢ Antineutrophil cytoplasmic antibodies (ANCA)

o cANCA:
▪ Diffuse granular cytoplasmic staining pattern.
▪ Against proteinase-3.
▪ Granulomatosis with polyangiitis (Wegener’s).
o pANCA:
▪ Localized perinuclear staining pattern.
▪ Against Myeloperoxidase.
▪ Microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), Isolated
necrotizing crescentic glomerulonephritis.
➢ Granulomatosis with polyangiitis (Wegener’s):
o Usually involves upper and lower respiratory tract, kidney.
o Necrotizing glomerulonephritis is common.
o Diagnosis by biopsy, cANCA.
o Clinical features:
▪ Hearing loss (Sensory, Conductive), Strawberry gingivitis, Proptosis, diplopia, scleritis, conjunctivitis,
uveitis, episcleritis, Subglottic stenosis, Hemoptysis, Subcutaneous nodules, glomerulonephritis, sensory
neuropathy.
➢ Microscopic polyangiitis:
o Associated with pANCA 75%, Granulomatous inflammation is not seen, Necrotizing glomerulonephritis is very
common.
o Elevated creatinine due to kidney impairment.
➢ Eosinophilic granulomatosis with polyangiitis (Churg-Strauss):
o Eosinophil rich (Essential feature), Nasal polyp is common, associated with pANCA.
o Characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma formation,
mononeuritis multiplex.
➢ Treatment of MPA, WG, and Churg-Strauss:
o Should be as early as possible.
o Prednisolone 1 mg/kg daily with continuous oral cyclophosphamide 2 mg/kg daily or Bolus IV
methylprednisolone 10 mg/kg with continuous oral cyclophosphamide 15 mg/kg daily.