professor of Rheumatology

professor of Rheumatology
Systemic sclerosis Hadi poormoghim professor of Rheumatology

Scleroderma Sclero= Thick Derma= Skin
Scleroderma: is a chronic disorder of connective tissue characterized by inflammation and fibrosis and by degenerative changes in the blood vessels, skin, synovium, skeletal muscle, and certain internal organs, notably the GI, lung, heart, and kidney. inflammation . fibrosis vasculopathy in the blood vessels, skin, synovium , skeletal muscle, and certain internal organs, notably the GI, lung, heart, and kidney

Systemic Sclerosis Raynaud’s phenomenon
Tightening and thickening of skin Involvement of internal organs, including GI tract, lung, heart. kidney, accounts for increased morbidity and mortality Risk of internal organ involvement strongly linked to extent and progression of skin thickening Raynaud’s phenomenon Tightening and thickening of skin Involvement of internal organs, including GI tract, lung, heart and kidney, accounts for increased morbidity and mortality Risk of internal organ involvement strongly linked to extent and progression of skin thickening

Scleroderma Epidemiology True incidence of scleroderma is unknown
Most reported studies are hospital based Incidence / 1000,000 general population / per year in Iran Prevalence Varying prevalence and severity among different racial and ethnics groups / 1000,000 in in Iran Female to male ratio 3:1 Familial aggregation and concordance of disease in twin pairs rarely occur Anti-topoisomerase & anti-centromere have HLA association Epidemiology True incidence of scleroderma is unknown Most reported studies are hospital based Incidence / 1000,000 general population / per year Prevalence Varing prevalence and severity amoung different racial and ethnics groups / 1000,000 in Female to male ratio 3:1 Familial aggregation and concordance of disease in twin pairs rarely occur Anti-topoisomerase & anti-centromere have HLA association

Pathogenesis of scleroderma
Enviromental factors Viral: retrovirus superAg Chemical agents: vinyl chloride Benzene Toluene Toxic oil Drugs: Bleomycin L-tryptophan Systemic sclerosis is a notable complex interaction of Immunologic abnormalities: T cell activation and autoantibody production Vascular injury, obliteration (role of enothelial cell, macrophage, platelets, mast cells) Fibroblast overactivity, fibrosis Genetic susceptibility Cellular immune activation vascular injury immune mediator release Pathogenesis of scleroderma Most current hypotheses of the pathogenesis of scleroderma focus on the interplay between early immunological events and vascular changes, resulting in the generation of a population of activated fibrogenic fibroblasts generally considered to be the effector cell in the disease Systemic sclerosis is a notable complex interaction of Vascular injury and obliteration (role of endothelial cell, platelets, mast cells) Immunologic abnormalities: T cell activation and autoantibody production Increased accumulation of matrix proteins in the skin and viscera (fibrosis) Fibroblast proliferation Collagen synthesis

Clinical feature in Systemic Sclerosis (SSc)
Peripheral vascular Skin gastrointestinal Muscloskeletal Pulmonary Cardiac Kidney

Vascular involvement Reynaud's phenomenon
Hand blanching Hand cyanosis Reversible skin color change White to blue to red, due to vasospasm Induce by cold or emotion

Vascular involvement Capilloroscopy
Dilation and drop out of capillaries capilloroscopy Dilated, tortous capillary loop and avascular area

Vascular involvement Telangectasia

Vascular involvement calcinosis
Subcutaneous calcinosis: Composed calcium hydroxy apatite deposits at site of trauma More common in limited scleroderma (CREST subset) Associated with anti-centeromere Ab Ulceration and infection may occur Subcutaneous calcinosis: composed calcium hydroxyapatite deposits at site of truma More common in limited scleroderma Associated with anti-centeromere Ab Ulceration and infection may occur

Vascular involvement dig tip ulcer/ Acro-osteolysis/ dig gangren
Digital pitting scars and ulcers associated with Complicated Raynaud,s phenomen in SS Digital pitting scars and ulcers associated with Complicated Raynaud,s phenomen in SS

Skin involvement 1. Puffy phase 2. Indurative phase 3. Atrophic phase

Skin involvement Telangectasia in CREST syndrome mouskopf Skin biopsy
Left: Skin from a patient with systemic sclerosis, coarse bundle of collagen in the lower portion lying parallel to the surface. Atrophy of the epidermis and loss of accessory skin structures can occur (not well demonstrated here). Right: In the subcutaneous tissue, the fat is almost totally replaced by abnormal, newly formed collagen. “Mauskopf: mousehead” Purse lip, shiny skin over cheeks and forehead, and atrophy of muscles in temple, face, and neck. “Scleroderma: CREST syndrome” telangectasia blanch with pressure. CREST is an acronym of Calcinosis , Raynaud’s disease, Esophageal involvement, Sclerodactyly and Telangectasia. mouskopf

Histology of skin in diffuse cutaneous SSc
A, There is perivascular infiltration in the dermis with inflammatory cells of multiple lineages. Microvascular endothelial cell activation and increased extracellular matrix deposition also are seen B, Later, there is regression of the inflammatory features. Secondary structures within the skin, such as hair follicles and sweat glands, are reduced, and rete pegs are flattened. (Hematoxylin and eosin stain, original magnification ×40.)

Skin involvement Salt and pepper skin 2nd to perifollicular sparing of pigmented loss Truncal scleroderma Radial furrowing, oral aperture is reduced, Neck sign

Skin involvement Rodnan scoring

Muscloskeletal involvement
Arthralgia/ myalgia Arthritis of fingers, wrist, knees or ankles (destructive arthritis) Tendon friction rub, tendon sheath fibrosis Muscle weakness: 1. result of extension of fibrosis to muscles 2. overlap syndrome 3. dysuse atrophy - Muscle atrophy

TYPES OF PULMONARY INVOLVEMENT IN SSc
Reason of attention to Pulmonary disease in SSc: Pulmonary involvement in > 80% (SSc) 2nd in frequency after esophageal symptoms The availability of treatment Associated with worse prognosis in SSc / the most common cause of death

Pulmonary involvement
disease symptoms sign Pulmonary fibrosis Dyspnea Dry cough Reduce Chest expansion rales, clubbing Pulmonary hypertension Dyspnea-ankle edema Loud P2-RV heave Pleural involvement Pleuritic chest pain dyspnea Pleural rub/ effusion (rare) bronchiectasis Cough/ purulent sputum/ dyspnea Basal crepitation Spontanous pneumothorax Chest pain, hemoptesis Resonance percusion Reduce breath sound Lung cancer(scar type) Alveolar cell Cough/ hemoptesis ? Sign of collapse Respiratory failure Dyspnea, reduce lung expansion hypoventilation

Pulmonary involvement
Account for the greatest , morbidity and mortality PARACLINICAL WORK UP CXR HRCT PFT DLCO

Gastrointestinal involvement
GI difficulty in 80-90% ANATOMICAL SITES: Oropharynx Esophagus Small bowel Large bowel Abnormal bowel motility result from: Micro vascular disease make ischemia in neural tissue Smooth muscle atrophy Sub mucosal fibrosis Malabsorption: Sub mucosal fibrosis, motility disorder lead to bacterial overgrowth GI difficulty in 80-90% Abnormal bowel motility result from: Altered innervation due to microvascular disease and ischemia in neural tissue Smoth muscle atrophy Submucosal fibrosis Malabsorption ANATOMICAL SITES: Oropharynx Esophagous Small bowel Large bowel

Oropharynx Small oral aperture dry mucosa periodontal disease Oropharynx Small oral aperture/ dry mucosa/ periodental disease: thickening of periodental membrane due to fibrosis Esophagous & stomach Esophageal dysfunction in 80-90% of cases Strongly associated with raynaud’s phenomena Dysphagia/ dyspepsia are the most symptoms Regurgitation Delay empty of stomach Small oral aperture/ dry mucosa/ periodental disease Complications of esophageal disease: Horsness Aspiration Unexplain cough Atypical chest pain Localized candida infection

Gastrointestinal (GI) manifestation of SSc
The most visceral complication of SSc Affects 75-90% of SSc patients Difficulty swallowing & reflux Early satisfaction & bloating Bowel pseudo-obstructions Large bowel function abnormalities: Diarrhea, constipation Fecal incontinence, Intussusception rectocele Malabsorption & Weight loss bleeding

Pathology of GI involvement in SSc
Neural damage ( early event) Smooth muscle atrophy and fibrosis (late event) Impaired GI motility Oesophageal and intestinal dysmotility Oesophageal reflux disease Small bowel bacterial overgrowth, malabsorption, psudo-obstraction Slow colon transit Anorectal dysfunction-fecal incontinence Vascular malformation

Esophagus & stomach Esophageal dysfunction in 80-90% of cases Strongly associated with Reynaud's phenomena Symptoms: Dysphagia/ dyspepsia Regurgitation Delay empty of stomach Oropharynx Small oral aperture/ dry mucosa/ periodental disease: thickening of periodental membrane due to fibrosis Esophagous & stomach Esophageal dysfunction in 80-90% of cases Strongly associated with raynaud’s phenomena Dysphagia/ dyspepsia are the most symptoms Regurgitation Delay empty of stomach Small oral aperture/ dry mucosa/ periodental disease Complications of esophageal disease: Horsness Aspiration Unexplain cough Atypical chest pain Localized candida infection Complications of esophageal disease: Hoarseness Aspiration Unexplained cough Atypical chest pain Localized candida infection

Small bowel Sign, symptoms: Asymptomatic Abdominal pain Diarrhea/Constipation, obstipation Weight loss Acute abdomen Pathology: Dysmotility /Malabsorption Pneumonitis intestinalis Scleroderma doudenal dilatation. The second and 3rd segments of the douedenum are distended and there is a relative lack of peristaltic activity which may result in the barium remaining in the same location for several minutes. No organic obstraction can be demonstrated.

Colon involvement Dysmotility Constipation/ diarrhea Muscular layer atrophy Wide mouth dierticule Rectal prolapse Stool incontinency Colon involvement Dysmotility Constipation/ diarrhea Muscular layer atrophy Wide mouth dierticule Rectal prolapse Stool incontinency Square-shaped diverticula are located on the anti-mesentric wall. These diverticula are usually remained asymptomatic Wide-mouthed diverticula

renal involvement Proteiurea Microscopic hematurea
Nonmalignant hypertension Normal function kidney with typical renovasculopathy SRC- Scleroderma renal crisis Cortical hemmorhage seen in acute hypertension Proteiurea Microscopic hematurea Nonmalignant hypertension Normal function kidney with typical renovasculopathy SRC- Scleroderma renal crisis

Renal crisis Accelerated hypertension->170/130 mm
Normotensive renal crisis in 11% Microangiopathic hemolytic anemia, thrombocytopenia CHF, asymptomatic pericardial effusion,dyspnea, Headache, fundoscopic changes, seizure, Abnormal urinanalysis Fragmented RBC ,thrombocytopenia Accelerated hypertension->170/130 mm Normotensive renal crisis in 11% RPRF-creatinin increase daily Plasma renin activity increase Microangiopathic hemolytic anemia, thrombocytopenia CHF, asymptomatic pericardial effusion Dyspnea, headache, fundoscopic changes, seizure, Abnormal urinanalysis Intimal fibrosis,luminal stenosis media is perseved The glomeruli and tubules are shrunken Left:normal, right: irregular narrowing OF interlobular vessels in SRC case

Renal crisis Predictive of SRC Not predective of SRC Early disease
New elevation of BP Diffuse subset Abnormal U/A Rapid progression of skin thightening New moderate increase in Cr New anemia Elevated plasma renin activity New cardiac events: Pericardial effusion CHF Pathologic abnormality in renal blood vessel Possible high dose steroid-normotensive Anti-scl70 RNA polymeras

renal involvement pathology
Left:normal, right: irregular narrowing OF interlobular vessels in SRC case Cortical hemmorhage seen in acute hypertension Hand blanching Intimal fibrosis,luminal stenosis media is perseved The glomeruli and tubules are shrunken Fibrinoid necrosis

cardiac involvement Usually subtle in expression, not seen until the late Symptoms: Dyspnea on exertion Palpitation Chest discomfort Clinical manifestation Pericarditis/ temponade CHF Pulmonary hypertension Arrythmia+ Myocarditis* Pericardial effusion Usually subtle in expression, not seen until the late Symptoms: Dyspnea on exertion Palpitation Chest discomfort Clinical manifestation Pericarditis/ temponade CHF Pulmonary hypertension Arrythmia+ Myocarditis* + arrythmia and conduction disorder seen more in SSdc subset and is associated with a worse overall prognosis * Myocarditis :is more common in patients with either SSdc and/ or skeletal myositis. There is associated with anti-topoisomerase or RNA-polymerase Pericardial effusion after treatment

Other common clinical problems
Depression Sexual dysfunction, impotence Problem with conception, decrease fertility, spontanous abortion Sicca complex Trigeminal neuropathy Enterapment neuropathy Hypothyroidism (fibrosis, Autoimmue thyroiditis) Primary biliary cirrhosis with CREST

Other common clinical problems
Sicca complex

SSc is associated with multiple organ involvement
Pulmonary disease Pulmonary fibrosis PAH Cardiac disease Myocardial fibrosis Cardiomyopathy pericarditis Vascular Raynaud’s phenomenon Dig ulcer Renal disease SRC Muscloskeletal disease Arthralgia Arthritis Flexion contractures myositis GI disease Reflux and dyspepsia Constipation/ diarrhea Malabsorption Colonic perforation Skin Skin sclerosis

Classification of Scleroderma
Systemic sclerosis Diffuse Limited Sine scleroderma Overlap Undiffrentiated Localized scleroderma morphea Linear (including “en coup de sabre”) Scleroderma-like syndrome Toxic oil syndrome Eosinophilia-myalgia syndrome Eosinophilic fascitis Systemic sclerosis Diffuse Limited Sine scleroderma Overlap Undiffrentiated Localized scleroderma morphea Linear (including “en coup de saber”) Scleroderma-like syndrome Toxic oil syndrome Eosinophilia-myalgia syndrome Eosinophilic fascitis

Systemic Sclerosis ( ACR preliminary criteria for classification of SSc)
Major criteria Proximal scleroderma (proximal to metacarpophalangeal joints) Minor criteria Sclerodactyly Digital pitting scar or loss of substance from finger pad Bibasilar pulmonary fibrosis Major criteria or 2 minor criteria for diagnosis Proximal scleroderma: this finding is 100% specific and 91% sensitive for diagnosis. However these criteria do not capture all patients with scleroderma; in particular, it excludes some patients with limited scleroderma or CREST syndrome and do not consider cases with other distinct clinical features or serologic data associated with scleroderma.

Systemic Sclerosis (criteria for classification of early & limited SSc)
early SSc Limited cutaneous SSc Raynaud’s phenomen (objective documentation) plus Nailfold capillaroscopy abnormality or SSc specific autoantibodies Previous criteria Distal sclerodermatous skin changes (distal to the elbows and or knees Proximal scleroderma: this finding is 100% specific and 91% sensitive for diagnosis. However these criteria do not capture all patients with scleroderma; in particular, it excludes some patients with limited scleroderma or CREST syndrome and do not consider cases with other distinct clinical features or serologic data associated with scleroderma.

VEDOSS Very Early Diagnosis Of SSc
VEDOSS red flags Raynaud’s phenomenon Puffy fingers Positive antinuclear antibodies

VEDOSS Very Early Diagnosis Of SSc
Precence of red flags rises Suspicious of very early SSc 1st level: suspicious If either one is positive, diagnosis of very early SSc & furthur investigations Capillaroscopy Serology (TOPO I, ACA) VEOSS 1.Oesophageal manometry 2. Chest HRCT 3. Pulmonary function test VEOSS

Patients with a total sore >=9 classified as having definite SSc
Item Sub-item(s) Weight/score Skin thickening of the fingers of both hands extending proximal to the MCP joints (sufficient criteria) 9 Skin thickening of the fingers (only count the higher score) Puffy fingers Sclerodactyly of the fingers ( distal to the MCP and proximal to IP joints) 2 4 Fingertip lesion ( only count the higher score) Digital tip ulcers Fingertip pitting scares 3 Telangectasia Abnormal capillorscopy PAH and/or ILD (maximum score 2) PAH ILD Raynaud ‘s phenomenon SSc-related autoantibodies (ACA, anti-TOPO, anti-RNA polymerase) (maximum score 3) ACA, anti-TOPO, anti-RNA polymerase Patients with a total sore >=9 classified as having definite SSc

Natural history of disease
There are some differences between limited and diffuse subtype Diffuse scleroderma is typified by rapid progression of skin involvement In diffuse subtype, new internal organ involvement occurs early, not remit with time Limited disease slowly increase in severity of skin disease In limited subtype organ involvement is typically delayed until second decade of disease Clinical course is divergent in early years In later disease, improving diffuse and worse limited disease are nearly in distinguished There are some differences between limited and diffuse subtype Diffuse scleroderma is typified by rapid progression of skin involvement In diffuse subtype, new internal organ involvement occurs early, not remit with time Limited disease slowly increase in severity of skin disease In limited subtype organ involvement is typically delayed until second decade of disease Clinical course is divergent in early years. In later disease, improving diffuse and worse limited disease are nearly indistinguished

Natural history of disease Stage of disease
Primary concern Action to consider Diffuse,early < 3 years Joint, lung, heart, kidney Examine every 3 months Frequent monitor BP, Cr Baseline PFT, treatment of esophagitis Disease modifying drug Mouth, hand, joint exercise Diffuse, late +3 years Lung, heart, joints Examine every 12 months Joint reconstructive surgery Limited, early < 10 years Peripheral vascular Vasodilators, endothelial protective agents Limited, late +10 years Esophageal stricture Malabsorption Pulm.hypertension Vasculitis Lung cancer Examine every months Esophageal dilation Rotating antibiotics Hyperalimentation PFT, DLCO Sjogren’s evaluation Chest radiography Stage of disease Primary concern Action to consider Diffuse,early < 3 years Joint, lung, heart, kidney Examine every 3 months Frequent monitor BP, Cr Baseline PFT, treatment of esophagitis Disease modifying drug Mouth, hand, joint exercise

SSc diffuse cutaneous vs limited cutaneous
Extent of extermity skin thickening Above elbow Below elbow Pace of extermity skin thickening Rapid Slow Timing of relationship between skin thickening and Raynaud’s Simultaneous / skin first Prolonged raynoud,s before skin Capillary microscopy Loops, dropout loops Joint, tendons Contractures, friction rub Infrequent involvement Calcinosis Uncommon Prominent Visceral involvement Renal, myocardial Pulmonary hypertension Serum auto antibodies Anti-scl70, anti-RNA polymerase Anti-centeromere, anti-Th/To

Systemic Sclerosis (SSc) specific serum Autoantibodies
Pattern of AutoAb recognized: speckle Nucleoli Anti-centeromere

inflammation and autoimmunity as a target of Treatment
Targets of treatment vasculopathy as a target of treatment Fibrosis as a target of treatment imatinib inflammation and autoimmunity as a target of Treatment MTX / AZA Cyclophosphamide / prednisolone

Localized Scleroderma
Morphea Linear scleroderma of the face (coup de sabre): Hemiatrophy of the face caused by linear scleroderma. The structures of one side of the face are shrunken, producing a gaunt, distorted appearance. The process includes, skin, subcutaneous tissue, muscles and sometime bone. The process usually begin in adolescence. Linear scleroderma Coup de sabre

Scleroderma-like syndrome
Eosinophilic fascitis Eosinophilic-myalgic syndrome (l-tryptophan) scleromyxedema Generalized subcutaneous morphea Amyloidosis Carcinoid syndrome Pentazocine-induced scleroderma Eosinophilic fascitis: The arm of this patient demonstrates the puckered “orange-peel” or ‘cobblestone’ skin that may occur in eosinophilic fascitis. The condition is characterized by swelling and tightness of involved extermities. The skin feels firm and is bound the underlying structure. In contrast to scleroderma the fingers are spared. Superficial skin usually maintains its ability to make fine wrinkles. The inflammation causing the induration is located in the subcutaneous area and deep fascia. The epiderms and its appandages are perserved. The skin of the patient’s back appears shiny due to the stretch dermis overlying an inflammed fascia. There is mild diffuse hyperpigmentation, along with a u-shape area of hypopigmentation extending from T10 to L4. The skin of the abdomen and breast is shiny and taut. The tigh reveals puckering or ‘cobblestoning’ overlying dermis due to scattered retraction from scarred fascia. Some patients develoed thrombocytopenia, rarely aplastic anemia, and eosinophilic fascitis may occur as a paraneoplastic syndrome associated with myeloid or lymphoid malignancy.

Scleroderma-like syndrome sclerosis sparing the fingers
Eosinophilic fascitis Some patients develoed : thrombocytopenia, rarely aplastic anemia, may occur as a paraneoplastic syndrome associated with myeloid or lymphoid malignancy ‘cobblestone’ skin Eosinophilic fascitis: The arm of this patient demonstrates the puckered “orange-peel” or ‘cobblestone’ skin that may occur in eosinophilic fascitis. The condition is characterized by swelling and tightness of involved extermities. The skin feels firm and is bound the underlying structure. In contrast to scleroderma the fingers are spared. Superficial skin usually maintains its ability to make fine wrinkles. The inflammation causing the induration is located in the subcutaneous area and deep fascia. The epiderms and its appandages are perserved. The skin of the patient’s back appears shiny due to the stretch dermis overlying an inflammed fascia. There is mild diffuse hyperpigmentation, along with a u-shape area of hypopigmentation extending from T10 to L4. The skin of the abdomen and breast is shiny and taut. The tigh reveals puckering or ‘cobblestoning’ overlying dermis due to scattered retraction from scarred fascia. Some patients develoed thrombocytopenia, rarely aplastic anemia, and eosinophilic fascitis may occur as a paraneoplastic syndrome associated with myeloid or lymphoid malignancy.

Scleroderma-like syndrome sclerosis sparing the fingers
Eosinophilic myalgia syndrome Associated with tryptophan ingestion Cutaneous sclerosis of extremities sparing the hands and feet The patients usually lack: Raynaud, nailfold abnormalities and body telangiectases peau d’orange is common myalgias , polyarthritis are common Biopsy: The fascial inflammation exclude scleroderma Eosinophilic fasciitis 84 and eosinophilic myalgia syndrome associated with tryptophan ingestion might be suggested in a patient with cutaneous sclerosis of the extremities sparing the hands and feet. These patients usually lack Raynaud’s phenomenon nailfold abnormalities and body telangiectases. Development of peau d’orange is common. Severe myalgias are common and polyarthritis has been described. The presence of fascial inflammation upon biopsy may be helpful in excluding scleroderma 85. Sclerodactyly and bound down skin over the dorsum of the hands with joint contractures are common findings in the patient with long standing diabetes mellitus 86. Obese, non-insulin-dependent diabetes mellitus patients may develop a benign skin tightening called scleredema that develops rapidly over the neck and upper back 86. Patients with monoclonal gammopathies with scleroderma-like skin lesions have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is associated with hyperpigmentation and thickened, tight, but not bound down, skin 87,88.

Scleromyxedema (papular mucinosis, lichen myxedematosus) Scleromyxedema is a rare disorder associated with monoclonal gammopathy , hypothyroidism dermal deposits of hyaluronic acid induration of the hands, face, arms and, lesser degree, the trunk , lower extremities associated with: multiple fine waxy papules myopathy , polyarthritis Reynaud's phenomenon, are rare Scleromyxedema (papular mucinosis, lichen myxedematosus):Thickening of the face skin -Clubbing nail- cobblestonning of forearm skin Collagen fibers are spread apartly by dense gray-pink mucopolysaccaride Hypothyroidism and gamapathy frequently with the disease Thickening of the face skin -Clubbing nail- cobblestonning of forearm skin Collagen fibers are spread apartly by dense gray-pink mucopolysaccaride (hylaronic acid) in dermal region. Hypothyroidism and gamapathy frequently with the disease

Scleroderma-like syndrome sclerosis
scleredema : in Obese, non-insulin-dependent diabetes mellitus patients a benign skin tightening develops rapidly over the neck and upper back Sclerodactyly : in long standing diabetes mellitus Eosinophilic fasciitis 84 and eosinophilic myalgia syndrome associated with tryptophan ingestion might be suggested in a patient with cutaneous sclerosis of the extremities sparing the hands and feet. These patients usually lack Raynaud’s phenomenon nailfold abnormalities and body telangiectases. Development of peau d’orange is common. Severe myalgias are common and polyarthritis has been described. The presence of fascial inflammation upon biopsy may be helpful in excluding scleroderma 85. Sclerodactyly and bound down skin over the dorsum of the hands with joint contractures are common findings in the patient with long standing diabetes mellitus 86. Obese, non-insulin-dependent diabetes mellitus patients may develop a benign skin tightening called scleredema that develops rapidly over the neck and upper back 86. Patients with monoclonal gammopathies with scleroderma-like skin lesions have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is associated with hyperpigmentation and thickened, tight, but not bound down, skin 87,88.

Scleroderma-like syndrome sclerosis
monoclonal gammopathies / POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is associated with: hyperpigmentation and thickened, tight, but not bound down, skin Eosinophilic fasciitis 84 and eosinophilic myalgia syndrome associated with tryptophan ingestion might be suggested in a patient with cutaneous sclerosis of the extremities sparing the hands and feet. These patients usually lack Raynaud’s phenomenon nailfold abnormalities and body telangiectases. Development of peau d’orange is common. Severe myalgias are common and polyarthritis has been described. The presence of fascial inflammation upon biopsy may be helpful in excluding scleroderma 85. Sclerodactyly and bound down skin over the dorsum of the hands with joint contractures are common findings in the patient with long standing diabetes mellitus 86. Obese, non-insulin-dependent diabetes mellitus patients may develop a benign skin tightening called scleredema that develops rapidly over the neck and upper back 86. Patients with monoclonal gammopathies with scleroderma-like skin lesions have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) is associated with hyperpigmentation and thickened, tight, but not bound down, skin 87,88.

A paraneoplastic condition Palmar fasciitis, and polyarthritis syndrome may be confused with scleroderma Bound down palmar or plantar fascia Carcinoid tumor: Scleroderma-like lesions of the lower extremities Primary amyloid may rarely be associated with scleroderma-like lesions, but waxy cutaneous papules and purpura are more characteristic 83. Scleromyxedema is a rare disorder associated with monoclonal gammopathy where dermal deposits of hyaluronic acid are observed. Patients develop induration of the hands, face, arms and, to a lesser degree, the trunk and lower extremities associated with multiple fine waxy papules. Patients may have myopathy and polyarthritis, but other features of scleroderma, like Raynaud’s phenomenon, are rare 83,89. Scleroderma-like lesions of the lower extremities have been described in carcinoid patients 87. A paraneoplastic condition, palmar fasciitis, and polyarthritis syndrome may occasionally be confused with scleroderma 90. Bound down palmar or plantar fascia may be helpful diagnostically. History of vasomotor instability in the early phase of illness and unilateral expression may be helpful in distinguishing the late phase of reflex sympathetic dystrophy from scleroderma. Disorders of childhood associated with scleroderma-like skin include Werner’s syndrome, progeria, and phenylketonuria 83.

Primary amyloid rarely associated with scleroderma-like lesions, but waxy cutaneous papules and purpura are more characteristic

Scleroderma-like syndrome Affecting the fingers
Diabetic digital sclerosis Vinyl chloride disease Vibration syndrome Bleomycine-induced scleroderma RSDS Amyloidosis Acrodermatosis chronica atrophican Scleroderma-like syndrome Affecting the fingers Diabetic digital sclerosis Vinyl chloride disease Vibration syndrome Bleomycine-induced scleroderma RSDS Amyloidosis Acrodermatosis

Scleroderma-like syndrome Affecting the fingers
reflex sympathetic dystrophy vasomotor instability in the early phase of illness , unilateral expression helpful in distinguishing the late phase of from scleroderma

Werner’s syndrome, progeria, and phenylketonuria : Disorders of childhood associated with scleroderma-like skin Taken from Rheumatology by Klippel and Dieppe 2.2 ARTHRITIS WITH SKIN AND NAIL CHANGES David L George Primary amyloid may rarely be associated with scleroderma-like lesions, but waxy cutaneous papules and purpura are more characteristic 83. Scleromyxedema is a rare disorder associated with monoclonal gammopathy where dermal deposits of hyaluronic acid are observed. Patients develop induration of the hands, face, arms and, to a lesser degree, the trunk and lower extremities associated with multiple fine waxy papules. Patients may have myopathy and polyarthritis, but other features of scleroderma, like Raynaud’s phenomenon, are rare 83,89. Scleroderma-like lesions of the lower extremities have been described in carcinoid patients 87. A paraneoplastic condition, palmar fasciitis, and polyarthritis syndrome may occasionally be confused with scleroderma 90. Bound down palmar or plantar fascia may be helpful diagnostically. History of vasomotor instability in the early phase of illness and unilateral expression may be helpful in distinguishing the late phase of reflex sympathetic dystrophy from scleroderma. Disorders of childhood associated with scleroderma-like skin include Werner’s syndrome, progeria, and phenylketonuria 83.

Primary vs secondary raynaud’s
features Primary Reynaud's Systemic sclerosis Sex F:M 20:1 4:1 Age at onset Puberty 25 yrs or older frequency <5 /day > 5-10 attack/day precipitant Cold, emotion cold Ischemic injury Absent present ANA 90-95% ACA 50-60% Ant-scl 70 20-30% Abnormal capillaroscopy >95% In vivo platlet activation >75%

Differential diagnosis of Reynaud's phenomenon
Structural vasculopathy Large & medium arteries TOS / Takayasu’s arteritis / Crutch pressure Small artery and arteriolar SLE / DM / Overlap / Vibration disease / Thromboangitis obliterans Bleomycine, vinblastine , PVC Normal vessel- abnormal blood elements Cryoglobulinemia / paraproteinemia/ PCV Normal blood vessels- abnormal vasomotion Primary raynoud’s / Drug induced (beta blockers, ergots, metylsergide) / pheochromocytoma / Migrine, prinzmetal / carcinoid syndromes Diffrential diagnosis of Raynoud’s phenomenon Structural vasculopathy Large & medium arteries TOS / Takayasu’s arteritis / Crutch pressure Small artery and arteriolar SLE / DM / Overlap / Vibration disease / Thromboangitis obliterans Bleomycine, vinblastine , PVC Normal vessel- abnormal blood elements Cryoglobulinemia / paraproteinemia/ PCV Normal blood vessels-abnormal vasomotion Primary raynoud’s / Drug induced (beta blockers, ergots, metylsergide) / pheochromocytoma / Migrine, prinzmetal / carcinoid syndromes

Primary biliary cirrhosis Idiopathic intestinal hypomotility
Diffrential diagnosis of visceral features Primary PHT Primary biliary cirrhosis Idiopathic intestinal hypomotility Collagenous colitis Idiopathic pulmonary fibrosis Diffrential diagnosis of visceral features Primary PHT Primary biliary cirrhosis Idiopathic intestinal hypomotility Collagenous colitis Idiopathic pulmonary fibrosis

Pathophysiology , treatment
Pathology Small vessel vasculopathy (endothelial cell damage) T and B cell , macrophage , mast cell activation Fibroblast proliferation, platelet activation Vasculopathy and fibrosis arise in the setting of autoimmunity Slide10.13 Slide 11.3 A current theory of the pathogenesis of SSc includes several components. Some unknown inciting event triggers endothelial cell injury and some immune system activation. The immune system may be the cause of, and almost certaily enhances, endothelial injury. This injury results in release of platelet constituents capable of causing fibroblast proliferation and matrix synthesis. When activated, fibroblasts can also synthesized these materials, leading to a positive feedback loop. Immune cell activation also results in production of materials capable of mesenchymal cell activation. Whether the production of autoantibodies is an epiphenomenon or wether they are important in cellular activation or injury themselves remains as an open question.

Pathophysiology , treatment Interaction between:
Endothelial cells, leukocytes, fibroblasts in scleroderma 1 6 5 3 2 4 Possible sites for theraputic intervention: Prevent endothelial cell cytotoxicity by mononuclear cells Alter communication between mononuclear cell subsets Prevent mononuclear cell stimulation of fibroblasts Prevent mast cell degranulation Block fibroblast production of procollagen Increase solubilization of performed collagen Possible sites for theraputic intervention: Prevent endothelial cell cytotoxicity by mononuclear cells: MTX, AZA, prednisolon Alter communication between mononuclear cell subsets: cyclosporine on TH Prevent mononuclear cell stimulation of fibroblasts: interferon alfa, gamma Prevent mast cell degranulation: ketotefen Block fibroblast production of procollagen: colchecin Increase solubilization of performed collagen; D-pencillamine, bosentan

Management of lung involvement

Management of lung involvement
Slide 11.8

Prognosis and survival
Poor prognosis Arrythmia dcSSc DLCO< 40% Pulmonary hypertension SRC Male sex Older age Anti-scl70, antiRNApolymerase Survival with renal crisis with and without ACE inhibitors. Scleroderma renal crisis had a very poor outcome prior to the availability of ACE inhibitors as demonstrated in this survival graph. The use of these drugs has helped to turn an almost uniformly fatal complication into a treatable problem.

Taken from Rheumatology by Klippel and Dieppe 6.10 Fig. 6.10.6
Fig Survival in diffuse disease treated with and without D-penicillamine. Survival of 152 patients with early diffuse scleroderma treated with D-penicillamine (DPA) is significantly better than the 80 untreated comparison patients. The 5-year survival from date of diagnosis of treated patients was 80%, which is one of the best outcomes in any survival study.

Pregnancy in scleroderma
Advised against pregnancy in the first 4-6 years of disease, especially with aggressive skin involvement Consider scleroderma pregnancy as a high-risk pregnancy Assess extent and severity of system involvement at pregnancy onset Discontinue D-pencillamine Follow every month for the first 4-6 months for pregnancy, and more frequent thereafter: blood pressure creatinine, urine analysis PFT at onset and monthly or prn ACE inhibitors for renal crisis and dialysis if necessary Corticosteroids may be used for aggressive fibrosing alveolitis, pericarditis, and inflammatory myopathy, without fear of harming the fetus

PHYSIOTHERAPY

Trigeminal neuropathy
is the most common cranial nerve manifestation In one series of 442 patients with SSc, trigeminal neuropathy occurred in 4 % most frequently in those with clinical features of the MCTD It may be the initial SSc manifestation

Trigeminal neuropathy
Pathophysiology The pathophysiology of trigeminal neuropathy in SSc patients is unknown Electrophysiologic studies suggest that site of disease is gasserian ganglion

Trigeminal neuropathy Clinical manifestations and findings , Symptoms
slowly progressive unilateral /bilateral facial numbness pain (50% of patients) Paresthesia (60%) Quality of pain: burning Numbness is most common in the mandibular or maxillary divisions of the nerve, with symptoms in the cheek or around the mouth the maximal deficit is usually reached after 6 to 24 months Trigeminal motor function (muscles of mastication) usually is not affected Sensory loss is present upon physical examination The corneal reflex is sometimes depressed or absent

Trigeminal neuropathy Differential diagnosis
It includes neuropathy associated with Diabetes mellitus Sinus disease Multiple sclerosis Trauma Vertebrobasilar ischemia Tumors: brain stem, CP angle, skull base, nasopharynx

Trigeminal neuropathy Treatment
Glucocorticoids is probably not beneficial Chronic pain may require the use of analgesics, antidepressants and/or Anticonvulsant medications Anticonvulsant medications as utilized in a manner similar to that for patients with chronic neuropathic pain due to other etiologies

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