Diese Präsentation wurde erfolgreich gemeldet.
Die SlideShare-Präsentation wird heruntergeladen. ×

Pediatric Sjogren syndrome

Nächste SlideShare
Wird geladen in …3

Hier ansehen

1 von 54 Anzeige

Weitere Verwandte Inhalte

Andere mochten auch (20)


Ähnlich wie Pediatric Sjogren syndrome (20)

Weitere von Ariyanto Harsono (20)


Aktuellste (20)

Pediatric Sjogren syndrome

  1. 1. Pediatric Sjogren Syndrome Prof DR Dr Ariyanto Harsosno SpA(K)
  2. 2. Introduction • Sjögren syndrome, which is rare in pediatric patients, is a slowly progressive inflammatory disorder that involves the exocrine glands. Mikulicz and others recognized the findings of keratoconjunctivitis and xerostomia as an entity in the late 1800s. In 1933, Sjögren recognized the association of this symptom complex with polyarthritis. • Subsequent studies showed that Sjögren syndrome may be a primary disorder or may be secondary to other autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and biliary cirrhosis. Extraglandular manifestations may mimic these other autoimmune disorders. The primary disorder is most common in women in the fourth and fifth decades of life. Sjögren syndrome may overlap with other pediatric autoimmune disorders and, less commonly, may present as a primary condition. Prof DR Dr Ariyanto Harsono SpA(K) 2
  3. 3. Overlapping symptoms consistent with SLE include neuropsychiatric manifestations, nephritis, and severe Raynaud phenomenon. Severe systemic manifestations may also develop without overt features of other autoimmune disorders. Prof DR Dr Ariyanto Harsono SpA(K) 3
  4. 4. Etiology Multiple etiologic factors are likely involved in the pathogenesis of Sjögren syndrome. Lymphocytic infiltration in the glandular lobules is the characteristic abnormality in lacrimal or salivary gland biopsy findings. The disorder appears to be mediated by a complex cascade of immune events and is often characterized as an autoimmune exocrinopathy. Prof DR Dr Ariyanto Harsono SpA(K) 4
  5. 5. Etiology…. Epstein-Barr virus (EBV) replicates in the salivary glands during primary infection and remains latent in these organs. EBV deoxyribonucleic acid (DNA) is recovered from the salivary glands and saliva of patients with Sjögren syndrome. Its etiopathologic role cannot be proven. Human immunodeficiency virus (HIV), human T-cell leukemia-lymphoma virus type 1 (HTLV-1), and cytomegalovirus (CMV) are also being studied as possible inciting agents of the lymphoproliferation observed in the end organs. Prof DR Dr Ariyanto Harsono SpA(K) 5
  6. 6. Etiology…. Multiple etiologic factors are likely involved in the pathogenesis of Sjögren syndrome. Lymphocytic infiltration in the glandular lobules is the characteristic abnormality in lacrimal or salivary gland biopsy findings. The disorder appears to be mediated by a complex cascade of immune events and is often characterized as an autoimmune exocrinopathy. Prof DR Dr Ariyanto Harsono SpA(K) 6
  7. 7. Genetics A higher incidence Sjögren syndrome is found in family members of patients with the disease. The association of Sjögren syndrome with human leukocyte antigen (HLA)–B8, HLA-Dw3, HLA-DR3, and the DQA1*0501 allele supports the notion of genetic susceptibility. Prof DR Dr Ariyanto Harsono SpA(K) 7
  8. 8. Pathology The predominant immune cells are activated memory CD4+ T cells that express alpha/beta T-cell receptors, suggesting a central role in the pathogenesis of this disorder. Activated B cells are also found in the lesions, which may be responsible for the production of the autoantibodies to autoantigens Ro (SS-A) and La (SS-B). Anti-Ro is found in 40-45% of adult patients with Sjögren syndrome, and anti-La is found in 50% of these patients. The presence of anti-Ro and anti-La is associated with earlier onset, longer duration, and more extensive extraglandular manifestations of primary Sjögren syndrome. Prof DR Dr Ariyanto Harsono SpA(K) 8
  9. 9. Pathology….. • Positivity in these antibodies appears to be higher in children, according to a systematic review of the literature rheumatoid factor, 66%; antinuclear antibody, 78%; SS-A, 74%; SS-B, 65%). Because these autoantibodies are also observed in other autoimmune disorders, including SLE, further diagnostic tools must be used for a more definitive diagnosis. • Researchers have found a high prevalence of anti- Muscarinic-3 acetylcholine receptor autoantibodies in Japanese children with primary Sjögren syndrome.These antibodies are postulated to be involved in defective glandular function. Prof DR Dr Ariyanto Harsono SpA(K) 9
  10. 10. Pathology….. An active area of research involves genetic polymorphisms of cytokine genes, including IL10 and TNFa. Associations with these polymorphisms might implicate inappropriate regulation of the immune response in Sjögren syndrome. Altered apoptotic mechanisms have also been implicated in the pathogenesis of Sjögren syndrome–related exocrinopathies. Exocrine gland tissue damage and chronic inflammation lead to fibrotic changes and impaired glandular function. The pathophysiology of extraglandular manifestations is thought to be due to similar immune mechanisms. Prof DR Dr Ariyanto Harsono SpA(K) 10
  11. 11. Clinical Manifestations Clinical manifestations of pediatric Sjögren syndrome may vary more than those seen in adult patients. The constellation of symptoms seen in children (eg, lower frequency of sicca syndrome, higher rates of parotid enlargement, higher prevalence of immunologic markers) may be similar to those found in young adult patients (ie, < 35 y). Prof DR Dr Ariyanto Harsono SpA(K) 11
  12. 12. Lower facial appearance of a 14-year-old adolescent girl with Sjogren syndrome. She exhibits both parotid and submandibular gland enlargement and chapped lips. Prof DR Dr Ariyanto Harsono SpA(K) 12
  13. 13. Clinical Manifestations….. Sicca syndrome • Symptoms of keratoconjunctivitis include dry eyes with reduced tear production, gritty or sandy sensation under the lids, red eyes, and photosensitivity. Keratoconjunctivitis is less prominent in primary juvenile Sjögren syndrome. Lacrimal gland enlargement appears to be a feature in primary and secondary pediatric Sjögren syndrome. The management of keratoconjunctivitis includes the use of artificial tears and conservation of natural tear flow. • Symptoms of xerostomia include decreased saliva production and difficulties with chewing, swallowing, and even speech; abnormality in taste and smell; dental caries; mucosal burning sensation; sensitivity to spicy and acidic foods and beverages; increased risk for oral candidiasis; hoarseness of voice, and dysphonia (common in adults). Recurrent parotitis appears to be the most common oroglandular manifestation in pediatric populations. Prof DR Dr Ariyanto Harsono SpA(K) 13
  14. 14. Intraoral view of a 14-year-old adolescent girl with Sjogren syndrome. Hyposalivation results in erythema of the mucosa, gingivitis, decalcification or white spot lesions of the teeth at the cervical margin, and dental caries with extensive restorations of the posterior teeth. Prof DR Dr Ariyanto Harsono SpA(K) 14
  15. 15. Clinical Manifestations….. Musculoskeletal symptoms Symptoms include the following: • Arthralgia (often noninflammatory), morning stiffness, and nonerosive arthritis • Myalgia and muscle weakness Prof DR Dr Ariyanto Harsono SpA(K) 15
  16. 16. Clinical Manifestations….. Cutaneous findings Symptoms include the following: • Raynaud phenomenon • Nonthrombocytopenic purpura, especially of lower extremities • Nasal, vaginal, and cutaneous dryness Prof DR Dr Ariyanto Harsono SpA(K) 16
  17. 17. Erythema of the labial mucosa with enlargement of the minor salivary glands and superficial mucoceles. Prof DR Dr Ariyanto Harsono SpA(K) 17
  18. 18. Clinical Manifestations….. Gastrointestinal symptoms Symptoms include the following: • Dysphagia, nausea, and epigastric and abdominal pain • Achalasia (in children) • Achlorhydria and chronic atrophic gastritis (adult patients) • Primary biliary cirrhosis Prof DR Dr Ariyanto Harsono SpA(K) 18
  19. 19. The dorsal surface of the tongue demonstrates generalized atrophy of the filiform papillae, mild fissuring, and median rhomboid glossitis. Prof DR Dr Ariyanto Harsono SpA(K) 19
  20. 20. Pulmonary findings Symptoms include the following: • Dyspnea due to mild interstitial disease • Dry cough Prof DR Dr Ariyanto Harsono SpA(K) 20
  21. 21. A 14-year-old adolescent girl with Sjogren syndrome with painful unilateral swelling of the knee and hyperpigmentation of the overlying skin. Prof DR Dr Ariyanto Harsono SpA(K) 21
  22. 22. Renal symptoms Symptoms include the following: • Interstitial nephritis • Renal tubular acidosis Prof DR Dr Ariyanto Harsono SpA(K) 22
  23. 23. Prognosis • Patients with primary Sjögren syndrome usually have a good prognosis unless severe, extraglandular manifestations develop. The prognosis of secondary Sjögren syndrome depends on the primary autoimmune disorder. • Although most adult patients have a mild and benign course, they often experience painful eye irritation, severe dental caries, and dyspareunia. Pediatric patients often do not have early sicca syndrome symptomatology but often have recurrent parotitis. Because of the insidious nature of these symptoms, patients often do not seek medical attention until more severe symptoms appear years later. Prof DR Dr Ariyanto Harsono SpA(K) 23
  24. 24. Prognosis….. The time from disease onset until diagnosis is often 9 years in adults and perhaps as long as 3 years in pediatric patients. In a multicenter, retrospective review of 40 patients, few major complications were reported from time of onset (follow-up, 0-7.5 y). According to another small report of pediatric patients with at least 3 years’ follow-up, minimal progression in disease status was reported. Some pediatric patients may develop systemic features that involve the nervous system, kidney, and lungs. Prof DR Dr Ariyanto Harsono SpA(K) 24
  25. 25. Prognosis….. Lymphoproliferative disorders increase 40-fold in adult Sjögren syndrome. Although significant lymphoproliferation usually remains confined to the salivary and lacrimal glands, extraglandular lymphoproliferation (eg, lymphadenopathy, hepatosplenomegaly) sometimes resembles lymphoma (eg, pseudolymphoma) and may herald frank malignancies, including non-Hodgkin lymphoma, Waldenström macroglobulinemia, and B-cell lymphoma. Associations with lymphoproliferative diseases are not well described in pediatric populations. Prof DR Dr Ariyanto Harsono SpA(K) 25
  26. 26. Additional findings The following symptoms may also be seen in Sjögren syndrome: • Fatigue • Depression • Insomnia • Cognitive impairment Prof DR Dr Ariyanto Harsono SpA(K) 26
  27. 27. Physical Examination The following may be noted on physical examination: • Parotid gland enlargement and recurrent parotitis (most prominent feature in pediatric populations) • Corneal ulceration, vascularization, and uveitis • Vasculitic lesions - Purpura and erythema nodosum • Lymphadenopathy • Autoimmune thyroiditis • Nervous system manifestations - Peripheral sensorimotor neuropathy; central nervous system disorders such as cognitive impairment, movement disorder, transverse myelopathy, encephalopathy, aseptic meningitis, dementia, optic neuropathy, and cranial neuropathies (in both adult and pediatric patients) Prof DR Dr Ariyanto Harsono SpA(K) 27
  28. 28. Physical Examination….. Musculoskeletal manifestations - Intermittent synovitis, chronic nonerosive oligoarticular or polyarthritis (Jaccoud arthropathy is observed in adults), and myalgias Oral cavity manifestations of Sjögren syndrome may include the following: • Mild erythema and thinning of the mucosa • Dental caries • Traumatic erosions and ulcers, angular cheilitis, and chapped lips • Frothy, ropey, and thickened saliva • Erythema, fissuring, coating, and depapillation of the dorsal tongue • Halitosis • Gingivitis/periodontitis • Superficial mucoceles Prof DR Dr Ariyanto Harsono SpA(K) 28
  29. 29. Differential Diagnosis Conditions to consider in the differential diagnosis of Sjögren syndrome include the following: • Medications that cause sicca symptoms (anticholinergic agents) • Recurrent juvenile parotitis • Oropharyngeal candidiasis • Gingivitis/periodontitis • Retrograde bacterial sialadenitis • Halitosis • Superficial mucoceles Prof DR Dr Ariyanto Harsono SpA(K) 29
  30. 30. Differential Diagnosis….. Compromised nutrition • Dryness of the nasal and vaginal mucosa and skin • Pregnancy complications due to autoantibodies • Mumps • Sarcoidosis • SLE • Systemic sclerosis • Hepatitis C Prof DR Dr Ariyanto Harsono SpA(K) 30
  31. 31. Work Up Criteria for pediatric patients have been proposed but not prospectively validated. Only 76% sensitivity has been noted in studies of retrospective patients. The clinical judgment of a pediatric rheumatologist is the criterion standard. However, the proposed pediatric criteria appear more sensitive than adult AECG criteria in classifying primary pediatric Sjögren syndrome. Diagnosis is based on the presence of 4 or more of the following proposed pediatric diagnostic criteria: Prof DR Dr Ariyanto Harsono SpA(K) 31
  32. 32. Work Up….. • Exclusion of all other autoimmune diseases • Oral symptoms - Dry mouth, parotitis, and parotid gland enlargement • Ocular symptoms - Recurrent conjunctivitis and keratoconjunctivitis sicca • Other mucosal symptoms - Recurrent vaginitis or vulvovaginitis • Systemic symptoms - Fever of unknown origin, noninflammatory arthralgias, and hypokalemic paralysis Prof DR Dr Ariyanto Harsono SpA(K) 32
  33. 33. • Presence of anti-Ro (SS-A), anti-La (SS-B), high titer ANA, or RF • Elevated serum amylase levels • Leukopenia and high erythrocyte sedimentation rate • Polyclonal hyperimmunoglobulinemia • Renal tubular acidosis • Histologic proof of lymphocytic infiltration of salivary gland or other organs Prof DR Dr Ariyanto Harsono SpA(K) 33 Work Up…..
  34. 34. Objective documentation of parotid gland enlargement - Sialography findings On a complete blood count with differential, mild anemia and leukopenia are often present in patients with Sjögren syndrome. Elevated erythrocyte sedimentation rate is observed in 80-90% of patients, which may be related to hypergammaglobulinemia; however, C-reactive protein levels are usually within the reference range. Hypergammaglobulinemia, up to several grams of immunoglobulin G, is observed in 70- 80% of pediatric and adult patients. Prof DR Dr Ariyanto Harsono SpA(K) 34 Work Up…..
  35. 35. ANTIBODIES ANA and rheumatoid factor RF levels are usually elevated in children. Anti-Ro (SS-A) and anti-La (SS-B) are also usually present in children. Various autoantibodies may be found in patients with Sjögren syndrome; however, the clinical or diagnostic implication is often unclear. Autoantibodies include thyroglobulin, thyroid microsomal, mitochondrial, smooth muscle, parietal, peroxisomal, muscarinic receptors, and salivary duct (often present in adults with Sjögren syndrome) autoantibodies. Cryoglobulins and, occasionally, antiphospholipid antibodies are noted. Prof DR Dr Ariyanto Harsono SpA(K) 35 Work Up…..
  36. 36. Histologic findings The characteristic histopathologic findings of the minor salivary glands include an inflammatory infiltrate adjacent to normal-appearing acinar structures. The inflammatory infiltrate consists of primarily lymphocytes and fewer plasma cells. Most of the infiltrating lymphocytes are activated CD4+ memory T lymphocytes. A focal periductal pattern is initially observed, with eventual confluence of the inflammatory infiltrate that replaces the acini. Periductal and perivascular hyaline deposits may be observed. Prof DR Dr Ariyanto Harsono SpA(K) 36
  37. 37. Low-power photomicrograph of a minor salivary gland lobule showing multiple lymphocytic foci that are replacing the acinar structures (hematoxylin-eosin, 40 X). Prof DR Dr Ariyanto Harsono SpA(K) 37
  38. 38. Intermediate-power photomicrograph demonstrating a chronic inflammatory aggregate of more than 50 lymphocytes and plasma cells with a periductal pattern. The inflammatory focus is adjacent to normal appearing acini (hematoxylin-eosin, 200 X) Prof DR Dr Ariyanto Harsono SpA(K) 38
  39. 39. High-power photomicrograph of the chronic inflammatory aggregate consists of lymphocytes and plasma cells around a ductal structure (hematoxylin- eosin, 400 X). Prof DR Dr Ariyanto Harsono SpA(K) 39
  40. 40. TREATMENT • Many of the symptoms associated with Sjögren syndrome can impair an individual's quality of life. In addition to sicca syndrome, concerns about facial appearance, depression, chronic fatigue, and joint pain must be addressed. Parotid enlargement and weight gain (if corticosteroids are used to manage the disease) may be problematic in adolescents. Artificial tears and conservation of natural tear flow are used in the management of keratoconjunctivitis. • Close attention must be paid to emotional and cognitive functioning of the adolescent coping with a chronic disease such as Sjögren syndrome. • Medical care for children with primary Sjögren syndrome is primarily based on strategies used for adults. No controlled studies in children with this disorder have been reported. Prof DR Dr Ariyanto Harsono SpA(K) 40
  41. 41. TREATMENT….. Discourage patients from smoking. Instruct patients to avoid windy and low-humidity environments. The family dwelling should be well humidified. Support normal school attendance and academic functioning in patients with juvenile Sjögren syndrome. Prof DR Dr Ariyanto Harsono SpA(K) 41
  42. 42. Xerostomia Means of addressing xerostomia include stimulation of salivary flow with sialagogues, such as pilocarpine (shown to be effective in increasing salivary flow in placebo-controlled, randomized adult trials) or cevimeline; mechanical stimulation of salivary flow with sugarless chewing gum or lozenges; and topical tissue hydration or lubrication with drinking water or artificial saliva. These measures are supportive and have only been well studied in adults, yet they may improve quality of life in patients of all ages. Prof DR Dr Ariyanto Harsono SpA(K) 42 TREATMENT…..
  43. 43. In Sjögren syndrome, calcium is leeched from teeth because of a reduction in saliva and as a result of the interaction between simple sugars and acidogenic bacteria. Therefore, good oral hygiene is necessary for caries control. Patients should avoid mouth rinses that contain alcohol, because they desiccate the mucosa. Dental plaque reduction measures include twice-daily cleaning of the teeth with a toothbrush, using a fluoride- containing dentifrice, the daily use of dental floss, and increasing the number of professional cleanings to 3-4 times a year if carious lesions develop. Daily home use of topical fluorides, especially gel or toothpaste that contains 1.1% sodium fluoride or remineralizing gel with 0.05% sodium fluoride, sodium phosphate, and calcium carbonate, is recommended. Prof DR Dr Ariyanto Harsono SpA(K) 43 TREATMENT…..
  44. 44. If the patient has severe xerostomia, use custom fluoride trays or carriers to apply the topical fluorides. Use chlorhexidine gluconate oral rinse concurrently for 2-week periods when high numbers of Streptococcus mutans are found in the saliva (>1 X 106/mL saliva). Limit the intake of sugary food and beverages between meals. Use sweetener alternatives, if tolerated, such as aspartame, saccharin, sorbitol, and xylitol. Prof DR Dr Ariyanto Harsono SpA(K) 44 TREATMENT…..
  45. 45. For the prevention of oral mucosal lesions such as chapped lips, use water- or lanolin-based lip moisturizers. Avoid lip products that are medicated with menthol or phenol, because they cause further drying. For traumatic erosions and ulcers, frequently hydrate and use artificial saliva or oral moisturizing agents, especially under removable oral prostheses. For oropharyngeal candidiasis, recommend good oral hygiene, frequent oral hydration and lubrication, and nightly removal and cleaning of dental prostheses. The intermittent use of topical or systemic antifungal agents may be necessary to prevent recurrent infection. If topical antifungal agents are used, consultation with a compounding pharmacist is recommended in order to formulate sucrose-free suspensions or lozenges. Prof DR Dr Ariyanto Harsono SpA(K) 45 TREATMENT…..
  46. 46. Diet • A nutritious well-balanced diet with the appropriate servings from the basic food groups is recommended. Patients should drink plenty of fluids with meals to aid in chewing, tasting, and swallowing. If tolerated, encourage the intake of dairy products, especially low-fat milk, yogurt, and cheese. Milk provides increased oral lubrication, while cheese has a beneficial anticaries effect. • Recommend that patients avoid dry, crunchy foods, because they are too difficult to swallow and may irritate the mucosa. Patients should also avoid spicy or acidic foods and beverages. In addition, avoiding simple carbohydrates, such as sucrose, and refined, highly processed foods, such as pastries and cookies, is important, to decrease the risk of dental caries. Alcoholic beverages and caffeinated drinks, such as coffee, tea, and cola, increase oral dryness. Prof DR Dr Ariyanto Harsono SpA(K) 46 TREATMENT…..
  47. 47. • If sweetener substitutes are used, monitor their intake, because some products may cause abdominal distress. • Recommend that patients eat foods at moderate temperatures. Foods can be liquefied or pureed if swallowing is a problem. If an increase in calories is needed because of an eating disorder, consider liquid nutritional supplements. Prof DR Dr Ariyanto Harsono SpA(K) 47 TREATMENT…..
  48. 48. Primary Sjögren syndrome usually follows a benign course in adult patients, and conservative management is indicated. Therapeutic approaches may include increasing lubrication with artificial tears, stimulating salivary flow with sugar-free gum or lozenges, and using vaginal lubricants. Saliva substitutes (eg, carboxymethylcellulose) are not usually effective. Cholinergic agonists have been shown to help increase salivary secretion and are approved by the US Food and Drug Administration (FDA) for this use. The treatment of secondary Sjögren syndrome is determined by the severity of the overlapping autoimmune disorder and may include the use of additional agents, such as methotrexate, cyclophosphamide, rituximab, and mycophenolate. Prof DR Dr Ariyanto Harsono SpA(K) 48 TREATMENT…..
  49. 49. Pilocarpine (Salagen) Pilocarpine is a muscarinic M3 receptor agonist. Cevimeline (Evoxac) Cevimeline is a muscarinic M3 agonist. It has 40-fold less binding affinity to M2 receptors and therefore has the theoretical benefit of causing less stimulation of cardiac tissues. This agent has a longer duration of action than pilocarpine. These agents are used to treat extraglandular disease (ie, interstitial pneumonitis, glomerulonephritis, polyarthritis, vasculitis, pseudolymphoma, neurologic manifestations). Prof DR Dr Ariyanto Harsono SpA(K) 49 TREATMENT…..
  50. 50. Prednisone Prednisone is a corticosteroid with salt-retention properties used for its potent anti-inflammatory effects. The use of NSAIDs in Sjögren syndrome is similar to agents used for juvenile arthritis. These agents may be used to treat polyarthritis associated with Sjögren syndrome. Ibuprofen (Motrin, Advil, Caldolor) Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. It also has anti- inflammatory and antipyretic properties. Ibuprofen is available in 200-, 400-, 600-, and 800-mg doses. Prof DR Dr Ariyanto Harsono SpA(K) 50 TREATMENT…..
  51. 51. Naproxen (Aleve, Naprosyn, Naprelan) Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis. These agents are used for polyarthritis not controlled with nonsteroidal anti-inflammatory drugs (NSAIDs). Prof DR Dr Ariyanto Harsono SpA(K) 51 TREATMENT…..
  52. 52. Methotrexate (Trexall, Rheumatrex) Methotrexate has been shown to be effective in managing polyarthritis. Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions (although it may involve adenosine receptors). The drug, which may affect immune function, ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response. Other DMARDs, such as hydroxychloroquine, may be synergistic when coadministered with methotrexate. Antimalarials agents These agents may inhibit chemotaxis of eosinophils and the locomotion of neutrophils and may impair complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate (Plaquenil) The mechanism of action for this drug is unclear; in the treatment of inflammatory arthritis, the mechanism of action is unknown. Hydroxychloroquine sulfate may inhibit chemotaxis of eosinophils and the locomotion of neutrophils and impairs complement-dependent antigen- antibody reactions. Prof DR Dr Ariyanto Harsono SpA(K) 52 TREATMENT…..
  53. 53. Refference • Muscal E, Jung LK, FlaitzCM: Pediatrics Sjogren Syndrome.http://emedicine.medscape.com/articl e/1008536-overview Prof DR Dr Ariyanto Harsono SpA(K) 53
  54. 54. Prof DR Dr Ariyanto Harsono SpA(K) 54Thankyou

Hinweis der Redaktion

  • http://www.docstoc.com/docs/150860747/Food-Allergy