Systemic Sclerosis (Scleroderma)

Systemic Sclerosis (Scleroderma)

• Systemic sclerosis is a multisystem, autoimmune disease marked by cutaneous and visceral fibrosis.
• The disorder ranges from relatively benign to rapidly progressive, possibly leading to significant morbidity or death.
• It is more common in women, with usual onset between 40-60 years old.
• Patients often have family members with autoimmune diseases, but it is not an inherited disorder.
• Three main components contribute to SS: vascular abnormalities, immunologic abnormalities, and extracellular membrane abnormalities, leading to tissue fibrosis.
• Vascular damage involves vascular obliteration, defective vasculogenesis, and tissue hypoxia.
• Vascular changes occur in the skin and potentially in pulmonary, cardiac, and renal blood vessels, affecting arteries, arterioles, and capillaries.
• All 10 recognized SSc-associated autoantibodies target distinct nuclear antigens.

SSc-Associated Autoantibodies

• Diffuse autoantibodies include Scl-70 (ILD 60%, DU), myopathy (non-inflammatory), RNA polymerase III, severe skin, SRC, and U3-RNP (myositis, PH, cardiomyopathy, severe GI).
• Overlap ones include U1-RNP (myositis 25%), PH, ILD, joints, PM/Scl (myositis >50%), calcinosis, Ku (myositis 65%).
• Limited ones include centromere, PH, calcinosis, DU, ILD (30-40%), Th/To, PH (all types), ILD, U11/U12 RNP, and ILD (severe).
• T cell involvement, primarily Th2, is indicated by elevated interleukin levels like IL-1, IL-2, IL-2R, IL-4, IL-8, IL-13, and IL-17.
• Macrophages secrete high levels of TGF-β in SS.
• Cytokines activate fibroblasts and presumed differentiation into myofibroblasts, with overproduction of extracellular matrix, resulting in progressively worsening fibrosis.

Clinical Presentation of Scleroderma

• Raynaud's phenomenon is the most common initial symptom, preceding skin changes by years.
• Patients may develop progressive peripheral vasculopathy, leading to digital-tip ulcers, scars, or gangrene with associated autoamputation.
• Limited cutaneous (CREST) includes calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, telangiectasias, and skin thickening limited to distal extremities and face with increased risk of pulmonary hypertension later.
• Pulmonary arterial hypertension leads to rapidly progressive dyspnea over a few months with reduced DLCO and associated anticentromere antibody.
• Cardiac involvement manifests as pericarditis, myocarditis, and myocardial fibrosis, potentially leading to diastolic CHF and arrhythmias.
• Esophageal dysmotility results in a weakened LES with associated reflux and dysphagia.
• Musculoskeletal symptoms include tendonitis and fibrosis with friction rubs.
• Diffuse cutaneous has distal changes and involves the upper arms, thighs, or trunk, with widespread visceral involvement early in the disease.
• It is often associated with anti-topoisomerase I antibody (SCL70) or anti-RNA polymerase III antibody.
• With anti-RNA polymerase III antibody, there is increased risk of renal crisis; with anti-SCL70, a higher frequency of interstitial lung disease.
• Scleroderma renal crisis (SRC) causes abrupt onset of accelerated arterial hypertension with a rise in serum creatinine levels, microscopic hematuria, and proteinuria, often with MAHA and thrombocytopenia.
• Patients often develop finger joint flexion contractures.
• Treatment requires lifelong ACE inhibitors, avoid Prednisone to avoid SRC and is associated with the development of SRC
• Scleroderma sine scleroderma is SS visceral symptoms with minimal or no skin involvement.
• GI symptoms include neuropathic changes and fibrosis of the muscularis of the small intestine leading to motor dysfunction and symptoms of postprandial abdominal distention.
• Small intestinal hypomotility may cause bacterial overgrowth, bloating, and diarrhea.
• Intestinal pseudo-obstruction can occur with severe atony of the small intestine.
• The internal anal sphincter may become fibrotic, resulting in fecal incontinence.

Diagnosing Scleroderma

• Abnormal nail fold capillaries (megacapillaries, hemorrhages, neovascularization, and avascular areas) can be a sign
• Tissue loss at the tips of the fingers
• Postive ANA test
• Symptoms of mixed connective tissue disease include autoimmune diseases and are U1-RNP antibody positive
• Scleromyxedema and scleredema are cutaneous fibrotic disorders with excessive mucin accumulation on skin biopsy but lack Raynaud's, visceral involvement, or SS antibodies.

Treatments for Scleroderma

• There is no specific treatment, so therapy manages specific symptoms and complications. Patients should be monitored for new visceral involvement.
• Early diffuse or diffuse SS may be treated with immunosuppression, usually mycophenolate mofetil.
• For SSc patients with ILD options include an anti-fibrotic agent
• PAH treatments include PDE5 inhibitors (sildenafil, tadalafil), endothelial receptor antagonists (bosentan, ambrisentan, macitentan), soluble guanylate cyclase inhibitors (riociguat), and prostacyclin analogues (treprostinil, epoprostenol, selexipag).
• Raynaud's should be treated by cold avoidance, warming measures, avoiding vibratory tools, smoking cessation, calcium channel blockers (nifedipine, amlodipine), and PDE5 inhibitors. Use topical nitroglycerin or botox if the patient develops ulcers.
• Mycophenolate mofetil and methotrexate may treat skin manifestations in the diffuse form.
• Renal crisis requires ACE inhibitors, and CCBs can be added if necessary.
• β-Blockers are relatively contraindicated due to worsening Raynaud's.
• Patients in ESRD may reverse renal damage with ACE therapy and may come off dialysis.
• GERD requires PPI, avoidance of alcohol and caffeine.
• Severe esophageal, gastric, or small bowel dysmotility use prokinetic drugs like metoclopramide, erythromycin, or octreotide.
• Bland myopathy is usually nonprogressive and is treated with physical therapy.
• Hand contractures are treated early with PT and daily stretching.

Rheumatologic Paraneoplastic Manifestations

• Hypertrophic osteoarthropathy (HOA) is digital clubbing, periostitis of the distal ends of long bones, and arthritis primarily in the large joints.
• Bone and joint pain is usually exacerbated with use and relieved with limb elevation.
• The primary form of HOA (primary pachydermoperiostosis) is usually a self-limited disease of childhood.
• The secondary form is associated with lung cancer and suppurative lung disease, as well as cardiovascular diseases, hepatobiliary disorders, and GI diseases.
• Treatment includes NSAIDs and bisphosphonates.
• Rheumatoid arthritis-like polyarthritis is a paraneoplastic syndrome characterized by acute onset, asymmetrical disease involving the lower extremities, large joint synovitis, spares the wrists and hands, without bony erosion, and the results for RF and CCP antibody are negative.
• Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by sudden onset of polyarthritis, pitting edema, and prominent constitutional symptoms.
• Eosinophilic fasciitis is associated with hematologic cancers, characterized by puffy skin, indurated, progressing towards significant subcutaneous thickening, with peripheral eosinophilia.
• Immune checkpoint inhibitors (ICIs) can cause several musculoskeletal symptoms and syndromes.
• Inflammatory arthritis has joint damage and erosions similar to RA, and it is treated with NSAIDs, steroids, and anti-TNF agents.
• Sjögren's syndrome (SS)-like presentation is significant ocular and mucosal dryness, negative serology, biopsy with a diffuse T cell lymphocytic infiltrate and acinar injury.
• Some patients develop polymyalgia rheumatica and giant cell arteritis after treatment with ICIs.
• Malignancies can cause ANAs and mimic autoimmune disorders.
• Multiple myeloma and carcinoid tumors can cause POEMS syndrome, which is polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities.

Hematologic Disorders with Rheumatic Manifestations

• Hemophilic arthropathy is hemophilia which causes repeated episodes of hemarthrosis with acute severe pain, chronic inflammation, synovial proliferation, joint deformity, fibrous ankylosis, and osteophyte overgrowth.
• Treatment is factor concentrate replacement, cold/ice, and joint immobilization followed by intensive PT.
• Musculoskeletal complications of sickle cell disease include painful crises, arthropathy, dactylitis, osteonecrosis, and osteomyelitis.
• Sickle cell crisis is painful arthritis of the large joints and noninflammatory joint effusions adjacent to areas of bony crisis, can occasionally progress to osteonecrosis from repeated local bone ischemia or infarct
• Dactylitis often occurs early in the disease (childhood), bilateral, painful, swollen hands or feet (hand-foot syndrome), associated with fever and leukocytosis, believed to be secondary to local bone marrow ischemia.
• Diabetes has several associated musculoskeletal presentations.
• Diabetic cheiroarthropathy is diabetic hand syndrome, defined by waxy thickening of the skin and flexion contractures.
• Patients cannot press palms together without a gap with the wrists fully flexed (prayer sign)
• Diabetics are likely to develop Dupuytren contracture, trigger finger, carpal tunnel, and adhesive capsulitis (frozen shoulder).
• Charcot joint is painless, swollen, deformed joint, usually in tarsal, metatarsophalangeal joints and can be confused with osteomyelitis on imaging.

Miscellaneous Disorders

• Diffuse idiopathic skeletal hyperostosis (DISH) is usually in older obese diabetics with neck and back stiffness more than pain, imaging shows 4+ vertebrae are fused.
• Diabetic amyotrophy is seen in older male diabetics who have relatively well-controlled diabetes, characterized by acute or subacute onset and thigh pain followed by progressive weakness.
• Myxedematous arthropathy is in hyperthyroidism, characterized by large joint swelling and stiffness.
• Hyperthyroidism is also associated with carpal tunnel, osteoporosis, nonspecific arthralgias and a myositis-like syndrome.
• Thyroid acropachy is a rare complication of Graves' disease, digital cramping, and periostitis.
• Hyperparathyroidism is associated with pain, proximal muscle weakness, chondrocalcinosis, tendon ruptures, and osteoporosis.
• Osteitis fibrosa cystica is seen in ESRD, radiographs show subperiosteal resorption and resorption of the tuft of the distal phalanx.
• Acromegaly causes degenerative disease of weight bearing joints, carpal tunnel. Radiographs display periosteal apposition.

Connective tissue diseases with rheumatic manifestations

• Whipple disease often affects the GI tract, is caused by Tropheryma whippelii, migratory arthritis.
• Synovial fluid is inflammatory with predominant mononuclear cells.
• Hemochromatosis has osteoarthritis-like arthropathy, pseudogout. Hook-like osteophytes (iron fist sign).
• Multiple myeloma can trigger bone pain, fractures, hypercalcemia and renal insuffiency .
• AL amyloidosis is from light chains. produces joint stiffness with deposition anterior shoulder.
• HIV has seronegative polyarthritis, which affects weight-bearing joints.
• Reactive arthritis- plantar fasciitis can lead to inflammation and erosive arthritis
• Acute sarcoidosis causes fever, skin lesions, lymphadenopathy and arthritis

Sjogren's Syndrome

• Definition → a chronic systemic autoimmune disease characterized by lymphocyte infiltration of salivary and lacrimal glands that leads to mucosal dryness and salivary gland enlargement, and by autoantibody production
• Sjögren's has a 9:1 female predominance
• Presentation → sicca syndrome (persistent dry eyes and mouth), keratoconjunctivitis sicca (chronic dry eyes leads to damage of the cornea and conjunctiva with possible ulcers, scarring, infection, and visual impairment), difficulty swallowing dry food, dental caries, vaginal dryness and dyspareunia, dry skin, salivary gland enlargement, arthralgia, myalgia, fatigue, and malaise
• Atrophic oral candidiasis leads to burning mouth syndrome/ tongue without white.
• Sjögren's is often associated with other autoimmune diseases such as Hashimoto's
• Pathogenesis → glandular epithelial cells are inappropriately activated (autoimmune epithelitis) and act as nonprofessional antigen presenting cells by expressing MHC I and II molecules and toll-like receptors, secreting cytokines and chemokines necessary to attract other inflammatory cells and activating both innate and adaptive immunity

Management of Sjogren's Syndrome

• Treatment of dry eyes: Avoid dry environment, use Moisture chamber goggles/glasses, artificial tears (preservative free if used more than four times daily), lubricating gels (at bedtime), tear drainage duct plugging (reversible) or cautery (irreversible), topical anti-inflammatory therapy (cyclosporine, lifitegrast, corticosteroids)
• Treatment of dry mouth: Avoid or discontinue medications with anticholinergic properties, when possible. Optimize oral hygiene (regular brushing, flossing). Sugar-free lozenges (to stimulate saliva). Artificial saliva. Fluoride-based topical products. Oral secretagogues (pilocarpine, cevimeline)

The Skin

• Squamous epithelial cells (keratinocytes) → normally “glued” tightly together by cell junctions known as desmosomes and produce abundant amounts of keratin protein, both of which serve to create a tough, durable physical barrier
• Keratinocytes also secrete cytokines and defensins that induce and regulate cutaneous immune responses
• Melanocytes produce melanin, a brown pigment that absorbs and protects against potentially injurious UV radiation in sunlight
• Dendritic cells (Langerhans cells) → process microbial and nonmicrobial antigens and migrate from the skin to regional lymph nodes where they present their antigenic cargoes to T lymphocytes and stimulate the adaptive immune system
• Lymphocytes after stimulation by dendritic cells, expressing an adhesion molecule, leave the lymph node and home back to the dermis directed by chemokines secreted by activated keratinocytes. Small numbers of B cells are in the dermis.
• Microbiome act in a symbiotic relationship with the skin, preventing colonization by potentially harmful organisms, and also helping educate the immune system
• Nerves relay pain, touch, vibration, itchiness, cold and heat, while autonomic efferent nerve fibers regulate adnexal components
• Merkel cells are located in the epithelial basal cell layer, have neuroendocrine/mechano fxns
• Adnexal components help control body temperature, and protect from stem cells

Macroscopic Skin Lesions

• Excoriation is caused by trauma. A raw linear defect (deep scratch) is often self-induced
• Lichenification is thickened, rough skin; result of repeated rubbing
• Macule/Patch is circumscribed, flat lesion distinguished from surrounding skin by color
• Macules are ≤5 mm in diameter, patches are >
• Onycholysis is separation of nail plate from nail bed
• Papule/Nodule is elevated dome-shaped or flat-topped lesion
• Papules are ≤5 mm across; nodules > 5 mm in size
• Plaque is elevated flat-topped lesion, usually > 5 mm across (may be caused by coalescent papules)
• Pustule is discrete, pus-filled, raised lesion
• Scale is dry, horny, plate-like excrescence; result of imperfect cornification
• Vesicle/Bulla/Blister is a fluid-filled raised lesion
• Wheal is itchy, transient, elevated lesion with dermal edema

Microscopic Skin Lesions

• Acanthosis is diffuse epidermal hyperplasia
• Dyskeratosis is abnormal, premature keratinization within cells below the stratum granulosum
• Erosion is discontinuity of the skin showing incomplete loss of the epidermis
• Exocytosis is Infiltration of the epidermis by inflammatory cells
• Hydropic swelling (ballooning) is when keratinocytes are infected
• Hypergranulosis is often due to intense rubbing
• Hyperkeratosis is thickening of the stratum corneum-abnormality.
• Lentiginous is a Linear pattern of melanocyte proliferation
• Papillomatosis is caused by hyperplasia and enlargement
• Parakeratosis is Keratinization with retained nuclei in the stratum corneum (normal membrnes)
• Spongiosis is intercellular edema of the epidermis
• Ulceration is the Discontinuity of the skin reveals dermis or subcutis
• Vacuolization is caused often refers to basal cell

Disorders of Pigmentation and Melanocytes

• Freckle (Ephelis), appear as tanned-red after sun exposure
• Hyperpigmentation within basal keratinocytes
• Lentigo is a common benign localized hyperplasia. Doesn't darken
• Histology- restricted
• Melanocytic Nevus is common neoplaism.

Growth factors

• Dysplastic nervi precursos increase
• dysplastic tend to develop melanoma
• CDKNA encodes
• Dysplastic nevi are usually raised, irregular
• Histology- nevus cell nests epidermal
• The most deadly skin causes mutations by acquired
• melanomas in cells can cells cycle grow faster
• Melanoa often arises from the mucosal

Benign Epithelial Tumors

• These tumors are derived from the epithelium of the epidermis
• Cowden syndrome tumors may lead life threatening illnesses.
• Seborrheic keratosis is most common.
• The tumors activate multiple FGFR3.
• Multiple small tumors face a dermatsis.

Benign Tumors

• Leser-Trelat syndrome
• a flat, coin-shape plaque with granular surface
• Histlogy- keratosis
• Irritated
• nigrians skin with a texture to a region
• tumors- they can be responsive.
• Epithelial follicle damage and granulamas

Acne Vulgaris

• Affects all teenagers, males have a more sere disease
• open comedones have keratins with black plugs, oxidized
• closed comedones- the surfaces are white
• Pathology - factors by andengons
• presentation-pustules

Other skin disorders

• Rosacea- more females cutaneous and immune issues 4 stages
• Catgellicicins can causes rosacea.
• histology : lymphocytes
• The development can be associated with hypertrophy

Panniculitis

• in layers of fat.
• Erythema nodosum-plaques
• Can ahve a companying fever
• The septum is widened.
• Erythem main affects
• It's hard to fat.

Infections

• Verrucae Lesions caused by direct contact.
• Epidermayl causes hyper
• types of the epidermis
• The virus shows DNA.
• Impetigo superficial most common on children
• Bacterial
• the bacteria creates exudate

Fungle Infections/Superficial

• cause skin to primarily
• have cell walls
• symptoms- hair loss on scalp
• can cause scale of tinea on the body
• versicolor- colored upper trunk

Clinical Manifestations of Renal Diseases

• Most glomerular diseases are mediated immunologically, where tubular and inter disorders are caused by toxic or infectious agents
• Most vascular affects all
• destruction causes vascular
• End stages blood vessels BUN AND CREATINE.
• Azemia is high BUN AND CREATIONE.
• POSTAzemoia is distal to the post

Nephrotic Sysndrome

• renal is a failure
• visible hematuria
• progression - decline of GFR.
• Albima, Edema AND hIdUIa
• Acute
• Kidmey Injury

GLOMERULUS

• Urinary space
• Podicytes contain foot processes
• transmembrane protein
• nephron protein.
• The tisse is composed
• Collagen

Pathologic Responses

• Hyper cellular proliferations etc
• Membrane etc
• Glycalosis
• Sclerosis/ matrix

Pathogenesis of Gulmery

• Most from to the processes = Antibodies
• Antibodues localized

Manifestaions

• Tubular affects etc
• utirns can occur at the bladde
• Nephoria etc.

Syndrome etc