Scleroderma systemic M34.0

An autoimmunological multisystem disease belonging to the so-called collagenoses with varying degrees of fibrosis of the skin, subcutis and numerous other organs (vessels, lungs, intestines, skeleton, kidneys, heart, liver) as well as an obliterating angiopathy with fibrosis and obliteration of small vessels (onion-skin angiopathy with intimal proliferation) with skin and organ infarcts.

A distinction is made between limited and diffuse forms. The so-called CREST syndrome (Calcinosis, Raynaud phenomenon, Esophageal hypomotility, Scleroderma, Teleangiectasis) is a subtype of limited systemic scleroderma and characterizes a common disease pattern.

Classification of systemic scleroderma according to disease activity:

• Acute inflammatory (malignant) systemic scleroderma with rapid progression of sclerosis, with or without organ symptoms.
• Chronic inflammatory (often vascular) systemic scleroderma with intermittent progression, with or without organ symptoms.
• Aphlegmatic systemic scleroderma, with or without organ symptoms.
• Burned-out systemic scleroderma in the final sclerotic state, without signs of activity.
• Systemic scleroderma without scleroderma (without signs of sclerosis of the skin).

Clinically, three main types are distinguished:

• Type I: Acral type (most common form with a marked vascular component).
• Type II: Proximal ascending type with ascending sclerosis of the forearms and upper arms. Involvement of the digestive tract, lungs, kidneys and liver (primary biliary cirrhosis).
• Type III: Truncal scleroderma (truncal type) with centrifugal spread. Raynaud's phenomenon may be absent. Involvement of joints and internal organs (heart, kidney, digestive tract). Febrile temperatures.

The American Rheumatism Association (ARA) distinguishes:

• Limited systemic scleroderma (sclerosis).
• Diffuse systemic scleroderma (sclerosis).

Worldwide, common to all populations. Blacks and Hispanics are generally observed to have higher severity levels than whites.

• Incidence: 0,5-1,5/100.000 inhabitants/year
• Prevalence: 10-15/100,000 inhabitants/year.

Systemic disease with humoral and cellular immune phenomena, e.g. depression of T lymphocytes, presence of clonal T cells (about 30% of patients), evidence of antinuclear factors.

Discussed are genetic disposition (correlation with HLA-B8, HLA-DR5), disturbance of microcirculation (initially functional, then lesions of endothelial cells), dysregulation of connective tissue metabolism (increased biosynthesis of proteoglycans and collagen).

Possibly, stimulating antibodies against the PDGF receptor (= receptor of the "Platelet-Derived Growth Factor" [see also below Growth Factors and Tyrosine Kinases]) as well as an abnormal TGF-beta signal transduction play a role; this would explain the clinical effect of the tyrosine kinase inhibitors. Furthermore, it could be shown that the chemokine CCL13 is increasingly expressed in the skin of patients with systemic scleroderma. The serum level of this chemokine (diagnostic marker) is also increased.

Silicosis and systemic scleroderma: A two- to eightfold risk of rheumatoid arthritis and systemic lupus erythematosus and a more than 24-fold risk of systemic scleroderma and ANCA vasculitis have been found in individuals with silicosis (Makol A et al. 2011) .

Usually occurring between 30 and 50 LJ. Women are 10-15 times more frequently affected than men.

Prodromes: Uncharacteristic disturbance of general condition, acrocyanosis, livedo racemosa, sensitivity to cold in the cold season. Raynaud's phenomenon occurs in 60-90% of cases, often as the initial symptom of PSS. Type I is also called limited form, types II and III diffuse forms (in Anglo-American literature).

Skin manifestations: Acras: Raynaud's syndrome (anamnestic, possibly cold provocation), acrosclerosis(sclerodactyly), edematous swelling, hyperpigmentation, spatter-like scarring, sclerosed cuticle, pathologic capillaries on nailfold dermatoscopy (path. structures and decreased density <7 capillaries/mm), telangieectasias, hemorrhages. In the late stage, tight atrophies, sclerosis (= Hoick-Gottron sign), flexion contractures with formation of a claw hand, nail dystrophies as well as extremely therapy-resistant digital ulcers (so-called rat bite necroses occur in approx. 50% of the patients) and circumskripte calcinoses.

Face: Amimia, facial reduction (comparison with previous images), pointed nose, narrow lips (microcheilia), microstomy (measurement of mouth opening), radial mouth pucker, frenulum sclerosis, atrophic smooth tongue.

Trunk: sclerosis, dermal edema, telangiectasias, hypopigmentation and hyperpigmentation.

Other: Poikiloderma (scleropoikiloderma), ulcerations, alopecia, calcinosis, atrophy of skin appendages, mucosal changes (sclerosis of genital mucosa).

Panniculitis: Rarely diagnosed, but relatively common on subtle inspection of patients.

Involvement of internal organs:

Digestive tract (in 90%): mainly esophagus, stomach, small and large intestine.

Lungs (in about 70%): primary pulmonary lesions: interstitial pneumonia or fibrosing alveolitis. Vessels may also be affected (vasculitis) with subsequent necrosis, granuloma formation and fibrosis. The consequence of vasculitis is pulmonary hypertension with clinical signs such as dyspnea, cough, cyanosis. The triad with dyspnea, quasi-normal chest radiograph, and unremarkable pulmonary function is typical. If there is a complaint of nonspecific complaints such as rapid decline in exercise capacity, chest pain, dizziness, or syncope, then this should be carefully clarified diagnostically: echocardiography is the screening method of choice and also excludes left ventricular dysfunction or cardiac vitiation. ECG is pathologic in only about two-thirds of affected individuals. Radiologic: A dilated pulmonary segment and widening of the descending right pulmonary artery are demonstrable in more than 90% of cases. The peripheral vessels are often rarefied. Doppler echocardiography can confirm pulmonary hypertension and quantify it relatively well. Angiography and cardiac catheterization should be reserved for specialized centers for the purpose of planning optimal therapy.

The concordant occurrence of systemic sclerosis and silicosis is relevant for expert opinion (see also Silicosis and Comorbidities).

Larynx: Laryngeal involvement with hoarse, raspy voice.

Heart: cardiac myopathy.

Kidney: Proteinuria (careful control of urine status with microelectropheresis!), renal insufficiency, hypertension.

Eyes: Cataract formation.

Musculoskeletal: osteolysis, osteoporosis, cystic brightening, arthralgias, tendovaginitis.

Muscles: weakness, pain.

See also Thibièrge-Weissenbach syndrome, CREST syndrome.

Nonspecific signs of inflammation are present.

Rheumatoid factors are positive in 20 to 30% of cases.

Syphilis serology is false positive in 5% of cases.

Cold agglutinins are detectable in 25% of cases. Leukocyturia, erythrocyturia or proteinuria may also be present. Electrophoresis also shows elevated gamma immunoglobulins.

Antinuclear antibodies (ANA) are positive in approximately 94% of cases.

Autoantibodies may be detectable against Scl-70 (topoisomerase I, 36-70% positive), centromeres (ACA) (up to 70%), PM-Scl (approx. 3%), fibrillarin, Ku (up to 50%, indicating overlap syndrome), RNA polymerase I (8%) or single-stranded DNA (4%).

The significance of functional autoantibodies has not yet been clarified.

Early stage: Discrete perivascular and periadnexal (especially around the eccrine sweat glands) and diffuse round cell infiltrates with lymphocytes, plasma cells and few macrophages. Edema of the dermis. Only slight dermal fibrosis detectable. The epidermis and the vessels of the dermis are inconspicuous.

Late stage: The dermis is widened, vessels are rarefied. Perivascular round cell infiltrates are visible in the deep dermis and the adjacent subcutis. Homogenized widened collagen fiber bundles run parallel to the skin surface. The adnexa are atrophic, the vessels are constricted in a slit shape. Eccrine sweat glands appear walled in.

Fatty tissue: Primary septal panniculitis which may spread to the periphery of the lobules, resulting in a mixed septal/lobular panniculitis. The septa are edematous, loosened, widened and predominantly infiltrated by lymphoid cells. The subcutaneous fatty tissue is partially reduced at the expense of the spreading connective tissue.

• At least three of the following criteria are positive at the active stage:
• BSG > 40 mm/hour
• Leukocytes > 10,000/μl
• ANA > 1:160
• gamma globulins > 16.0 g/l
• Waaler-Rose test: > 1:20.
• Further parameters:
• Capillary Microscopy
• Nail fold capillaroscopy
• AMA > 1:10.

• Circumscript scleroderma (Morphea) especially when it appears as generalized circumscript scleroderma (absence of serological autoimmune phenomena and absence of organ involvement).
• Generalized lichen sclerosus et atrophicus (histology is differentiated; no serological autoimmune phenomena; no systemic infestation).
• Autoimmune diseases that may be associated with sclerosing of the skin. These include: dermatomyositis; lupus erythematosus, systemic (always serological autoimmune phenomena detectable; histological and immunohistological differentiation is important). With SLE and dermatomyositis overlapping clinical pictures are observed(overlap syndrome).
• Of great differential diagnostic relevance is the group "scleroderma-like diseases", the pseudoscleroderma.
• Nephrogenic systemic fibrosis (after administration of gadolinium-containing contrast agents)
• Scleroderma-like clinical pictures due to chemical noxae (vinyl chloride, silicon dioxide - see also silicosis)

• Pulmonary arterial hypertension (PAH)
• HIV infection
• Appetite suppressants (Aminorex, Fenfluramine, Dexfenfluramine)
• Female sex
• Portals hypertension in liver cirrhosis
• Proteinuria (acute nephrogenic crisis)
• Congenital left-right shunt
• L-tryptophan intake
• Thyroid diseases
• Pregnancy
• Systemic hypertension
• Chemotherapeutics
• Metamphetamine and cocaine.

Inflammatory PSS with rapid progression (BSG, ANA, rheumatoid factor pos., polyarthritis):

• Immunosuppressive therapy: Basic therapy is the immunosuppressive combination therapy with glucocorticoids and azathioprine. Prednisone (e.g. Decortin), initial 75-100 mg/day i.v., maintenance dose 5.0-10.0 mg/day p.o., or Cloprednol (e.g. Syntestan) continuous dose of 1.25-2.5 mg/day p.o. are combined with Azathioprine (e.g. Imurek) 1-2 mg/kg bw/day.
• In case of further disease progression exchange of azathioprine against Ciclosporin A (Sandimmun) 2.5-5.0 mg/kg bw/day. Cave! Strict monitoring of kidney function!
• Alternative or complementary: Extracorporeal photopheresis can be used as a complementary procedure with few side effects (method is only used in a few centres). As an immunomodulating procedure, this therapy shows encouraging individual results.
• Alternative or complementary: Plasmapheresis: Is primarily used for the detection of circulating immune complexes or high-titre antibodies.
• Experimental: Encouraging results are reported from the use of the tyrosine kinase inhibitor Imatinib (Gleevec). It is possible that this effect is due to the blockage of the PDGF (= Platelet Derived Growth Factor, see below) or its receptor.
• Colchicine has no safe value; neither does potassium paraaminobenzoate (Potaba Glenwood). Less active PSS in the sclerosing final state: No generally valid therapy modalities can be listed for this PSS which has already been running for years or decades. The therapy depends on the respective organ symptoms and must be individually adapted to these.
• Clinical trials:
  • Individual case reports are available on positive effects of tocilizumab, an Il-6 receptor AK. A phase II study is currently being conducted.
  • Serotinin: In a proof of concept study the 5-HT 2b-receptor antagonist terguride was tested. Results remain to be seen.
  • Stem cell transplantation: In severe rapidly progressive systemic scleroderma, myeloablative haematopoietic autologous stem cell transplantation is a worth considering option. In a study with 36 patients, stem cell transplantation proved to be superior to cyclophosphamide (Sullivan KM et al. 2018).
  • Soluble guanylcyclase (sGC): The sGC stimulator riociguat follows a dual principle: The treatment of the vascular and fibrosing components (Distler O et al. 2017).
  • Lysophosphatidic acid (LPA): LPA acts profibrotically via LPA1 receptors. In a phase IIa study the effect of LPA1-AK on organ fibrosis is being investigated.

Arterial occlusive disease:

• Early infusion of prostaglandin E (e.g. prostavasin) intra-arterial (1-2 times/day 10 μg Alprostadil in 25 ml physiological saline solution for 60-120 min.) or intravenous (40 μg Alprostadil in 50-250 ml physiological saline solution for 2 hours 2 times/day).
• Alternatively, iloprost (ilomedin) 0.5 ng/kg bw/min i.v. can be administered over 6 hours 21 days. In the case of radiographically proven, circumscribed stenoses of the ulnar and radial arteries, the constricted section of the vessel can be bridged or replaced by a piece of vein or a replacement vessel made of special plastic.

Fingertip necroses (FKN):

• In the case of uncomplicated FKN dry wound dressings; in the case of infected FKN polyvidon-iodine ointment dressings, if necessary internal antibiotics after antibiogram. In individual cases with pronounced keratotic marginal wall formation of ulcerations, hydrocolloidal wound dressings are indicated (e.g. Varihesive extra thin can be adapted very well to fingertips, is self-adhesive).
• Therapy of choice: Bosentan. Results of the RAPIDS-1 study (level of evidence Ib) show a positive effect on digital ulcers (improved healing rate, lower rate of new necroses compared to the placebo group). Therapy of the 1st choice!
• Alternative: Even under iloprost (dosage see above) there is a reduction of digital ulcerations.

Calcinosis of the skin:

• Frequently found in the area of the fingertips or above the finger joints. Millet grain-sized, painful, rough, skin-coloured or reddened nodules.
• Conservative approach: etidronic acid, coumarin derivatives, minocycline (50-100 mg/day p.o.).
• Surgical: Removal in LA; curettage if superficially positioned, excision if deeply positioned to protect the tissue. Good results can be achieved with the CO2 laser. Dry wound dressings. S.a.u. CREST syndrome.

Raynaud's symptomatology:

• Calcium antagonists: Nifedipine (e.g. Adalat) 1-3 times/day 5-10 mg p.o. (low initial dose, as headaches often occur in the adaptive phase); find individual maintenance dose!
• Alternatively pentoxifylline (e.g. Trental) 0.4-0.8 g/day i.v., later 0.4-0.6 g/day p.o., possibly in combination with nifedipine (results are not very convincing!).
• Alternative: Low-dose (0.1-0.3 g/day p.o.) acetylsalicylic acid (e.g. Aspirin protect 100). It makes sense to apply ointments containing nitrate locally (e.g. Isoket ointment, 1-2 g evenly distributed on both hands).

Carpal tunnel syndrome:

• Symptoms: First symptoms are the "painful falling asleep of the hands, especially at night. In advanced cases, persistent numbness of fingers 1-4 and problems with fine handwork are added. Clarification and therapy by neurologists.

Sicca symptoms: see below Sjögren's syndrome.

Changes of the stomatognathic system:

• Consistent prophylaxis and maintenance therapy; in the case of dentures in the form of crown and bridge prosthetics, exact analysis of the periodontal situation of the abutment teeth. Changes of the periodontal system in PSS. Difficulties with suction dentures often persist due to pronounced atrophy of the jaws. The aim is to achieve a dental prosthesis by inserting implants.
• Microstomy: If food intake is considerably more difficult, a plastic surgery of the corner of the mouth can provide relief. This procedure, known from burn surgery, involves an incision of several millimetres at both corners of the mouth. The red of the lips can be reconstructed by protruding the oral mucosa outwards (vermillon plastic surgery).

Hypertensive circulatory situation:

• ACE inhibitor (e.g. captopril or tensobone) 25-75 mg/day p.o. Alternatively: α receptor blocker e.g. prazosin (Duramipress) 10-15 mg/day p.o.
• Proteinuria: Early use of ACE inhibitors (e.g. Captopril or Tensobon) 25-75 mg/day p.o.

Pain:

• For chronic pain, especially joint pain, administration of NSA such as acetylsalicylic acid (e.g. aspirin), metamizole (e.g. Novalgin) or paracetamol (e.g. Ben-u-ron). If the pain symptoms are severe, switch to weak opioids such as tramadol (e.g. Tramal) or dihydrocodeine (DHC).

Pulmonary hypertension:

• Patients with pulmonary hypertension in scleroderma have significantly elevated endothelin levels. Previous therapy with conventional vasodilators and anticoagulants has been effective in only a few patients. Synthetic prostacyclin analogues are more effective in both primary pulmonary hypertension and secondary pulmonary hypertension due to systemic scleroderma. Good effects are achieved with the endothelin receptor antagonist bosentan.

Pulmonary fibrosis:

• Studies conducted so far with cyclophosphamide (1-2 mg/kg bw/day) have not shown satisfactory results. Subjective symptoms such as dyspnoea are said to have improved underneath.

The therapy of PSS basically depends on the acuteity of the disease (see Table 2) and the type of organ infestation. It consists of a combination of system therapy, local therapy, physiotherapy and psychotherapy.

Mostly protracted, 5-20 year course, with low self-healing tendency. In type III: unfavourable prognosis, death often occurs within 3-5 years. Acute malignant variant (rare): death within a few months (malignant scleroderma).

• Physiotherapy: To be carried out only by physiotherapists who are familiar with PSS!
• Stimulation or reflex therapy: Has become increasingly important in recent years. Acupuncture is indicated as an additional method for chronic pain.
• BMS ( biomechanical stimulation ): The method of biomechanical stimulation leads to a loosening of the musculature in addition to an increase in peripheral blood circulation and can be usefully applied here in scleroderma. The effectiveness of this therapy is currently not scientifically proven and is not covered by health insurance.
• TENS (transcutaneous electrical nerve stimulation): excitation of peripheral nerves by electrical skin stimulation, to activate various pain-inhibiting mechanisms.
• Physiotherapy: The aim is to counteract contractures and tendencies to shrinkage of the muscle and tendon apparatus and to avoid stiffening of joints.
  • Active physiotherapy: The patient's own activity and initiative are required.
  • Passive physiotherapy: Passive stretching, e.g. of muscles and joints.

Note! Strictly avoid painful exercises! No isometric exercises (involving exertion)!

• Massages. Massage principle for PSS: start therapy very carefully, increase intensity slowly, maintain therapy regularly over a long period of time.
• Heat therapy, sauna

Progressive systemic scleroderma/organ involvement.

Practical tools for collagenosis patients

Practical tips for the scleroderma patient in daily life

What the scleroderma patient should pay attention to

Physiotherapeutic measures for PSS

Examples of physiotherapeutic exercises in PSS

Massages for SSc

Heat therapy for acral circulatory disorders

Psychotherapeutic measures in PSS

Rules of thumb for a wholesome diet (half-pound rule according to Kluthe)

• Practical behavioural measures for scleroderma patients:
  • Absolute ban on nicotine!
  • Clothing: Warm and airtight clothing, always wear warm gloves in transitional weather, no tight shoes (prolonged pressure reduces circulation; danger of general reduced circulation of the feet and ulceration at pressure points).
  • Showering/care: Long, warm showers in the morning, short cold interval showers are possible (vascular training). Apply oil/water emulsions to the moist skin (Sebamed Lotion, Bepanthen Lotio etc.). Sauna sessions- not too hot, cave heart involvement - and short cooling down.
  • Nail care: Cutting nails may be difficult due to hardening of finger and toe nails; bathe hands and feet with warm soapy water for 10 minutes before cutting nails, then cut carefully. Avoid injury.
  • Oral hygiene: Careful dental hygiene, clean teeth with a soft toothbrush.
  • Face: Teleangiectasias in the area of the face can be covered with a covering make-up (e.g. waterproof Dermacolor, Stiefel company); if necessary laser therapy (e.g. with pulsed dye laser, argon laser) or sclerotherapy.
  • Living rooms: Adequate temperature, with tendency to overheat. Do not place the bed on the weather side. Do not lay cold floors (stone floors), carpet floors are recommended. Use temperature-controlled waterbeds. If possible, move to ground floor flats or flats where lifts are available.
• Sports: Endurance sports (light jogging) without acute overload are recommended (no constricting sportswear), swimming in well-tempered pools, gymnastics in well-heated rooms, dancing. Sports that can lead to injuries (judo, football, handball and volleyball) or sports that lead to unavoidable cooling of the skin (horse riding, sailing, etc.) are not recommended.
• Self-training: In case of microstomies, slowly stretch the mouth opening with the fingers, practice whistling, speech training (loud, clear reading aloud), tense and relax facial muscles (make grimaces). In the case of motor disorders of the fingers, fine gardening, plucking weeds, training tactile skills (handicrafts, carefully kneading plasticine).
• Vacation: Vacation in warm southern countries is recommended (avoid blazing sun!), vacation in the local winter period (principle: shorten cold period in the own country), active vacation with physiotherapeutic applications (e.g. thermal baths). Winter sports are not recommended because of the risk of chilling.
• Occupation: Not recommended (as triggering by specific occupational noxae cannot be excluded): Mining (exposure to stone dust), work in quarries and sandblasting (exposure to stone dust), work with jackhammers or other vibrating machines (activation of vascular symptoms), work in occupations that lead to constant cooling of the skin (e.g. butchers, florists), painting occupations (organic solvents), dental laboratories (exposure to plastic dust when grinding or polishing dentures), handling liquid PVC and similar plastics (PVC disease).
• Sexuality: For people with scleroderma, sexuality is an unjustly neglected topic. Scleroderma sufferers tend to have a low sense of self-respect due to their altered appearance. Sexual relationships begin with social relationships. To appear interesting oneself, one must be interested in others. A positive relationship with one's own body will help the sufferer to establish and maintain relationships with others.
  • Sexual intercourse: It is recommended to experiment with different techniques and methods; prefer lateral positions during sexual intercourse.
  • Scleroderma patient should be active partner in sex.
  • Joint complaints: Before sexual intercourse take a non-steroidal anti-inflammatory (e.g. 20 trp. Novalgin), warm bath; important is a warm bed and a warm room!
  • Women with sicca symptoms: use of water soluble lubricants (e.g. vaginal gel pH5 listed under NRF 25.3. is recommended.
• Nutrition:
  • Eat varied but not too much (as many different foods as possible).
  • Eat spicy but not salty foods.
  • Easily digestible food; no flatulent foods (cabbage, legumes).
  • No constipating foods such as chocolate or bananas.
  • Avoid large portions; rather eat in small amounts and more frequently.
  • Always drink plenty, at least 1.5-2 l/day (mineral water, diluted fruit or vegetable juices; tea and coffee in small quantities).
  • Whole grain products are recommended.
  • Foods that are easy to chew and swallow, e.g. no dry bread rolls or dry meat; remove the crust from bread.
  • High protein and vitamin content.
  • Plenty of potatoes, fruit and vegetables.
  • Alcohol is allowed in small quantities (e.g. 1 glass of red wine, sparkling wine or beer with dinner).

Official rosemary oil (see below Rosmarinus officinalis leaf oil) has been proven to have a caring effect on the skin as well as a distinct vasodilatory (warming) component and can be recommended as an additive therapy (von Schoen-Angerer T et al. 2018).

• The connective tissues of the lungs, kidneys, esophagus, and heart are considered particularly at risk. Lung involvement is now the most common cause of death in systemic scleroderma. Scleroderma is not curable, but the course of the disease can be slowed or stopped with medication and specialized rehabilitation.

• Notice. The former name"progressive systemic scleroderma" has therefore been changed in favour of the current name"systemic scleroderma".

• Diagnosis and treatment of scleroderma require special medical experience with these diseases. The Ministry of Research and Technology (BMBF) has therefore named clinics and centres in Germany with sufficient expertise in this disease as part of a research programme.
• It is recommended to join a self-help group to exchange practical experience for everyday problems ( http://www.sklerodermie-selbsthilfe.de/startseite.html).
• In ANA-negative patients (about 10% of scleroderma collectives), males are in the majority, showing lower levels of skin sclerosis and vasculopathies, and increased frequency of malabsorption. Pulmonary involvement including pulomonal hypertension as well as mortality rates are comparable to the ANA-positive group.

1. Altmeyer P et al: Scleroderma working group of the Arbeitsgemeinschaft Dermatologische Forschung (ADF) (1986) Clinic of progressive systemic scleroderma (PSS). Dermatologist 37: 320-324
2. Baroni SS et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354: 2667-2676
3. Bibi Y, Gottlieb AB (2008) A potential role for imatinib and other small molecule tyrosine kinase inhibitors in the treatment of systemic and localized sclerosis. J Am Acad Dermatol 59: 654-658
4. Distler O et al. (2017) RISE-SSc: Riociguat in diffuse cutaneous systemic sclerosis. Respir Med 122 Suppl 1:S14-S17.
5. Kawald A et al. (2008) Low versus high-dose iloprost therapy over 21 days in patients with secondary Raynaud's phenomenon and systemic sclerosis: a randomized, open, single-center study. J Rheumatol 35: 1830-1837
6. Kreuter A et al. (2004) Low-dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis. J Am Acad Dermatol 50: 740-747
7. Makol A et al. (2011) Prevalence of connective tissue disease in silicosis (1985-2006)-a report from the state of Michigan surveillance system for silicosis. Am J Ind Med 54:255-262.
8. Mecoli CA et al.(2018) An update on autoantibodies in scleroderma. Curr Opin Rheumatol 30:548-553
9. Mosler N (2003) Endothelin antagonist bosentan-double effective with a logical principle. Int World 1: 2-4
10. Morita A et al. (2000) Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 43: 670-674
11. Ramming A et al. (2014) Antifibrotic medication in immune diseases. Drug therapy 32: 289-190
12. Rencic A et al (2002) Bullous lesions in scleroderma. Int J Dermatol 41: 335-339
13. Salazar GA et al. (2014) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum doi: 10.1016/j.semarthrit.2014.11.006
14. Sapadin AN, Fleischmajer R (2002) Treatment of scleroderma. Arch Dermatol 138: 99-105
15. Scalapino K et al. (2006) Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol 33: 1004-1013
16. Schuster J et al. (2010) Pathologic urine microelectrophoresis in systemic scleroderma: benefit of ACE inhibitor therapy. JDDG 8:945
17. Sullivan KM et al. (2018) Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.
18. N Engl J Med 378:35-47.
19. Tashkin DP et al. (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354: 2655-2666
20. von Schoen-Angerer T et al. (2018) Effect of topical rosemary essential oil on Raynaud phenomenon in systemic sclerosis.Complement Ther Med 40:191-194.
21. White B (2003) Interstitial lung disease in scleroderma. Rheum Dis Clin North Am 29: 371-390
22. Yanaba K et al. (2010) CCL13 is a promising diagnostic marker for systemic sclerosis. Br J Dermatol 162: 332-336