LESSON 4

THEMES:

1.               LICHEN SIMPLEX CHRONIC (NEURODERMITIS LIMITED).

2.               DIAGNOSTIC CRITERIA AND DERMATOLOGICAL SYMPTOMS OF COLLAGEN VASCULAR DISEASES.

 SYSTEMIC LUPUS ERYTHEMATOSUS. DISCOID LUPUS ERYTHEMATOSUS.

 3. SYSTEMIC SCLEROSIS (DERMATOSCLEROSIS): PROGRESSIVE SYSTEMIC SCLEROSIS. MORPHEA LOCALISED. SCLERODERMA STRIATA, SCLERODACTYLIA. DERMATOPOLYMIOSITIS.

 

 

LICHEN SIMPLEX CHRONICUS

http://emedicine.medscape.com/article/1123423-overview

http://www.goldbamboo.com/video-t9774.html

Background

Lichen simplex chronicus (LSC) is thickening of the skin with variable scaling that arises secondary to repetitive scratching or rubbing. Lichen simplex chronicus is not a primary process. Rather, a person senses pruritus in a specific area of skin (with or without underlying pathology) and causes mechanical trauma to the point of lichenification.

A proposed variant of lichen simplex chronicus is lichen amyloidosis. Lichen amyloidosis is described as lichen simplex chronicus in which the keratinocytes have necrosed and formed keratinocytic-derived amyloid in the dermis. The initial insult is pruritus with resultant amyloid formation, rather than the reverse.

Pathophysiology

Lichen simplex chronicus is found on the skin in regions accessible to scratching. Pruritus provokes rubbing that produces clinical lesions, but the underlying pathophysiology is unknown. Some skin types are more prone to lichenification, such as skin that tends toward eczematous conditions (ie, atopic dermatitis, atopic diathesis). A relationship likely exists between central and peripheral neural tissue and inflammatory cell products in the perception of itch and ensuing changes in lichen simplex chronicus. Emotional tensions in predisposed subjects may play a key role in inducing a pruritic sensation, leading to scratching that can become self-perpetuating.The possible interplay among primary lesions, psychic factors, and the intensity of pruritus additively influence the extent and severity of lichen simplex chronicus.

A small study looking at lichen simplex chronicus and the use of P-phenylenediamine (PPD)–containing hair dye showed clinically relevant improvement in symptoms after discontinuation of PPD exposure, thus providing a basis for the role of sensitization and contact dermatitis in the etiology of lichen simplex chronicus.

Lichen Simplex Chronicus Clinical Presentation

History

• Patients with lichen simplex chronicus usually describe stable pruritic plaques on one or more areas; however, thickening of the skin occurs on any location that the patient can reach, including the following:
• Scalp
• Nape of neck
• Extensor forearms and elbows
• Vulva and scrotum
• Upper medial thighs, knees, lower legs, and ankles
• Erythema is noted most in early lesions.
• Pruritus is described as worse when patients are still or quiet and as much less or nonexistent when patients are active.
• Pruritus is usually intermittent; the resultant scratching provides temporary relief.
• Patients may have a past medical history of a chronic skin condition or acute trauma. Patients with atopic dermatitis may have lichen simplex chronicus in areas of former atopic outbreaks. Sites of irritant or allergic contact dermatitis, insect bites, or other past minor skin trauma sometimes demonstrate pruritus and, subsequently, lichen simplex chronicus.
• Each palm-sized plaque may have 3 zones. A 2- to 3-cm wide peripheral zone that is barely thickened may have isolated papules. The middle zone has lenticular and hemispheric prurigo papules that may be excoriated. The central zone has the greatest thickening and pigmentary alteration.

Physical

Note the following:

• One or more slightly erythematous, scaly, well-demarcated, lichenified, firm, rough plaques with exaggerated skin lines are noted.
• Pigmentary changes (especially hyperpigmentation) are seen variably as in any dermatitic lesion.
• Rubbing plays a key role in lesion formation and is visualized variably by white scratch marks, erosion, and ulceration from deeper scratching.
• Lichen simplex chronicus is one of the hyperkeratotic processes from which a cutaneous horn may grow.
• Patients may scratch lesions de novo when observed. Some patients may start scratching while discussing the itch or describing the lesions.
• Note the images below:

Plaque of lichen simplex chronicus demonstrating accentuated skin markings. Courtesy of San Antonio Uniformed Services Health Education Consortium Dermatology Program.

 

Area of lichen simplex chronicus originally believed to be chronic contact dermatitis. The true nature was revealed when the patient admitted to rubbing this area while watching television. Courtesy of San Antonio Uniformed Services Health Education Consortium Dermatology Program.

Causes

Note the following:

• Atopic dermatitis results in a higher probability of developing lichen simplex chronicus.
• Insect bites, scars (eg, traumatic, postherpetic/zoster), acne keloidalis nuchae, xerosis, venous insufficiency, and asteatotic eczema are common factors.
• Psychological factors appear to play a role in the development or exacerbation of lichen simplex chronicus. Anxiety has been reported to be more prevalent in patients with lichen simplex chronicus. Neurodermatitis is a term formerly used interchangeably with lichen simplex chronicus, suggesting a role of anxiety or obsession as part of the pathological process of developing lesions.
• Lithium has been linked to lichen simplex chronicus in one reported case. Lichen simplex chronicus was dependent on the administration of lithium as evidenced by the observation that the lichen simplex chronicus remitted when the medication was discontinued and recurred when it was restarted.
• A small study looking at lichen simplex chronicus and the use of PPD-containing hair dye showed clinically relevant improvement in symptoms after discontinuation of PPD exposure, thus providing a basis for the role of sensitization and contact dermatitis in the etiology of lichen simplex chronicus. Several of the patients who cleared after avoiding paraphenylenediamine had widespread, not localized, dermatitis.
• Long-term exposure to street traffic exhaust has been associated with an increase in the frequency of childhood skin diseases, including lichen simplex chronicus.
• Some reserve the diagnosis of lichen simplex for patients who have no known predisposing skin disorder. The term secondary lichenification has been used if the eruption is initiated by a primary dermatosis.

Differential Diagnoses

       Acanthosis Nigricans

       Acne Keloidalis Nuchae

       Alopecia Mucinosa

       Amyloidosis, Lichen

       Amyloidosis, Macular

       Atopic Dermatitis

       Berloque Dermatitis

       Contact Dermatitis, Allergic

       Contact Dermatitis, Irritant

       Cutaneous T-Cell Lymphoma

       Dermatitis Herpetiformis

       Dermatologic Manifestations of Gastrointestinal Disease

       Dermatologic Manifestations of Hematologic Disease

       Dermatologic Manifestations of Neurologic Disease

       Dermatologic Manifestations of Renal Disease

       Extramammary Paget Disease

       Hyperkeratosis of the Nipple and Areola

       Lichen Nitidus

       Lichen Planus

       Lichen Striatus

       Nummular Dermatitis

       Phytophotodermatitis

       Pretibial Myxedema

       Psoriasis, Plaque

       Riehl Melanosis

       Seborrheic Dermatitis

       Stasis Dermatitis

       Tinea Cruris

Laboratory Studies

An elevated serum immunoglobulin E level occasionally supports the diagnosis of an underlying atopic diathesis. Perform potassium hydroxide examination and fungal cultures to exclude tinea cruris or candidiasis in patients with genital lichen simplex chronicus.

Other Tests

Patch testing helps exclude allergic contact dermatitis as an underlying primary dermatosis (eg, allergic contact dermatitis to nickel with secondary lichen simplex chronicus) or as a factor in chronicity (eg, allergic contact dermatitis to topical corticosteroids used to treat lichen simplex chronicus).

Lichen Simplex Chronicus Treatment & Management

http://emedicine.medscape.com/article/1123423-treatment

 

Medical Care

Treatment is aimed at reducing pruritus and minimizing existing lesions because rubbing and scratching cause lichen simplex chronicus. Location, lesion morphology, and extent of the lesions influence treatment. For example, a thick psoriasiform plaque of lichen simplex chronicus on a limb is commonly treated with a highly potent topical corticosteroid or intralesional corticosteroids, whereas vulvar lesions are more commonly treated with a mild topical corticosteroid or a topical calcineurin inhibitor. Widespread lesions are more likely to require systemic treatment or total body phototherapy. Note the following treatments:

• Topical steroids are the current treatment of choice because they decrease inflammation and itch while concurrently softening the hyperkeratosis. Because lesions are by nature chronic, treatment most likely is lifelong. On larger and more active lesions, a midpotency steroid may be used to treat acute inflammation. Occasionally, occlusion is used to increase potency and enhance delivery of the agent. Occlusion also provides a physical barrier to the scratching. Midpotency topical steroids are not recommended for thin skin (eg, vulva, scrotum, axilla, face). Direct long-term therapy more at daily use of low-potency nontrophogenic topical corticosteroids. High-potency topical corticosteroids may be used for 3-week courses on thicker-skinned areas.
• Oral antianxiety medications and sedation may be considered in certain patients. According to individual need, treatment can be scheduled throughout the day, at bedtime, or both. Antihistamines such as diphenhydramine (Benadryl) and hydroxyzine (Atarax) are common. Doxepin (Sinequan) and clonazepam (Klonopin) may be considered in appropriate cases.
• For infected lesions, a topical or oral antibiotic can be considered.
• Other topical medications reported to decrease pruritus include doxepin cream and capsaicin cream.
• One study suggests that topical aspirin/dichloromethane is effective in patients with lichen simplex chronicus who have not responded to topical corticosteroids.
• For topical corticosteroid unresponsive patients or those with lesions on thin skin, a few case reports and small studies have shown efficacy of topical immunomodulators tacrolimus and pimecrolimus.
• A more investigational treatment for patients who fail conventional therapy is local botulinum toxin injections.
• Transcutaneous electrical nerve stimulation (TENS) has been reported as a possible effective treatment in a small, open trial of cases of lichen simplex chronicus resistant to topical corticosteroid treatment.
• A clinical guideline summary from the American College of Obstetricians and Gynecologists, Diagnosis and management of vulvar skin disorders, may be helpful.

Lichen Simplex Chronicus Medication

http://emedicine.medscape.com/article/1123423-medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

1.Corticosteroids

    Clobetasol (Temovate)

       Betamethasone dipropionate cream 0.05% (Diprolene, Betatrex)

       Fluocinolone 0.01% or 0.025% cream (Synalar, Synalar HP, Fluonid)

       Triamcinolone topical (Perrigo)

      Hydrocortisone valerate cream 0.2% (Westcort)

    Fluocinonide

 

2. Antipruritic agents

    Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

    Chlorpheniramine (Chlor-Trimeton)

       Hydroxyzine (Atarax, Vistaril)

       Clonazepam (Klonopin)

       Pramoxine topical (Itch-X)

       Doxepin (Sinequan; Zonalon Cream)

 

3. Immunosuppressant Agent

Tacrolimus ointment (Protopic)

 

4. Immune Modulator

Pimecrolimus (Elidel)

 

5. Neuromuscular Blocker Agent, Toxin

OnabotulinumtoxinA (BOTOX®)

 

 

 References:

1. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther. Jan-Feb 2008;21(1):42-6. [Medline].

2. [Guideline] American College of Obstetricians and Gynecologists. Diagnosis and management of vulvar skin disorders. National Guideline Clearinghouse. May 2008.

3. Pleimes M, Wiedemeyer K, Hartschuh W. [Lichen simplex chronicus of the anal region and its differential diagnoses : A case series.]. Hautarzt. Mar 7 2009;[Medline].

4.Messikh R, Atallah L, Aubin F, Humbert P. [Botulinum toxin in disabling dermatological diseases]. Ann Dermatol Venereol. May 2009;136 Suppl 4:S129-36. [Medline].

5. Engin B, Tufekci O, Yazici A, Ozdemir M. The effect of transcutaneous electrical nerve stimulation in the treatment of lichen simplex: a prospective study. Clin Exp Dermatol. Apr 2009;34(3):324-8. [Medline].

 

DIAGNOSTIC CRITERIA AND DERMATOLOGICAL SYMPTOMS OF COLLAGEN VASCULAR DISEASES.

 

 

 

 

 

 

 

DISCOID LUPUS ERYTHEMATOSUS

http://emedicine.medscape.com/article/1065529-overview

http://www.youtube.com/watch?v=ZvZE1ez0-84

 

 

Distribution of lesions

 

 

 

 

 

Background

Discoid lupus erythematosus (DLE) is a chronic, scarring, atrophy producing, photosensitive dermatosis. (See the images below.) DLE may occur in patients with systemic lupus erythematosus (SLE), and some patients (< 5%) with DLE progress to SLE. Some patients also have the lesions of subacute cutaneous lupus erythematosus (SCLE), and some may have a malar rash. Patients with DLE rarely fulfill 4 or more of the criteria used to classify SLE. Serologic abnormalities are uncommon. Therapy with sunscreens, topical corticosteroids, and antimalarial agents is usually effective. (See Clinical and Treatment.)

Discoid lupus erythematosus on the face.

Chronic scarred lesion of discoid lupus erythematosus.

Lesions spread centrifugally and may merge. As lesions age, dilation of follicular openings occurs with a keratinous plug, termed follicular plugging or patulous follicles (see the image below). Resolution of the active lesion results in atrophy and scarring.

Lesions of discoid lupus erythematosus in the conchal bowl demonstrate patulous follicles with follicular plugging.

At any time, individual lesions may have any or all of these features. Early lesions may be difficult to distinguish from those of SCLE. DLE lesions often are photodistributed, but relatively unexposed skin also may be affected. The scalp is a common area of involvement, and permanent alopecia may result (see images below).

Scarring alopecia of discoid lupus erythematosus.

 

 

Widespread scarring alopecia.

Patients with DLE often are divided into 2 subsets: localized and widespread. Localized DLE occurs when the head and neck only are affected, while widespread DLE occurs when other areas are affected, regardless of whether disease of the head and neck is seen (see the image below). Patients with widespread involvement often have hematologic and serologic abnormalities, are more likely to develop SLE, and are more difficult to treat.

Several unusual variants of chronic CLE, other than DLE, have been reported. Mucosal surfaces may be affected by lesions that appear identical to DLE of the skin or by lesions that may simulate lichen planus. Palms and soles may be affected, but this occurs in less than 2% of patients (see the image below).

Palmar lesions of discoid lupus erythematosus.

DLE lesions may become hypertrophic or verrucous (see the image below). This subset is manifested by wartlike lesions, most often on the extensor arms. Hypertrophic lesions of LE must be differentiated from warts, keratoacanthomas, or squamous cell carcinoma. These lesions are more difficult to treat. Lupus panniculitis is a form of chronic CLE that may be accompanied by typical DLE lesions or may occur in patients with SLE.

Hypertrophic lesions of lupus erythematosus on the dorsal hands. Characteristic lesions were observed elsewhere.

 

Differential Diagnoses

       Actinic Keratosis

       Dermatomyositis

       Granuloma Annulare

       Granuloma Faciale

       Keratoacanthoma

       Lichen Planus

       Lupus Erythematosus, Subacute Cutaneous

       Psoriasis, Plaque

       Rosacea

       Sarcoidosis

Discoid Lupus Erythematosus Treatment & Management

Approach Considerations

The goals of discoid lupus erythematosus (DLE) management are to improve the patient’s appearance, to control existing lesions and limit scarring, and to prevent the development of further lesions. Advise patients that the development of serious systemic disease is possible, although rare. Regular repeat clinical evaluation accompanied by simple laboratory studies usually is sufficient to evaluate the possible progression from the primary cutaneous disorder to the disorder accompanied by systemic involvement.

Therapy begins with the use of sun-protective measures, including sunscreens, protective clothing, and behavior alteration. Cosmetic measures, such as cover-up makeup or wigs, may be suggested for appropriately selected patients. Makeup used for camouflage includes Covermark and Dermablend.

Standard medical therapy includes corticosteroids (topical or intralesional) and antimalarials. Topical calcineurin inhibitors have also been used in patients with cutaneous lesions of LE. In addition, topical retinoids have been reported to be helpful. Lastly, topical imiquimod was reported to be effective in 1 patient.

Activity

Since chronic CLE is exacerbated by sunlight or other UV exposure, advise patients to take precautions, eg, to limit exposure to sunlight to the early morning or late afternoon, when the sun is less intense. Advise patients to avoid artificial light sources, such as tanning beds.

Consultations

Consultation with the following specialists may be helpful:

• Rheumatologist – For joint involvement
• Nephrologist – For renal involvement
• Internist – To evaluate systemic involvement
• Ophthalmologist – To monitor therapy with hydroxychloroquine or chloroquine

Antimalarial Therapy

Antimalarial therapy seems to lessen the progression to SLE and to lower the risk of thrombovascular disease. Alternative therapies include auranofin, thalidomide, oral or topical retinoids, and immunosuppressive agents. Thalidomide is regularly used in antimalarial-resistant patients. In most patients, the antimalarial should be continued during thalidomide therapy, unless a complication due to the antimalarial occurs. In addition, lenalidomide may be useful in some patients.

Quinacrine may be added to either hydroxychloroquine or chloroquine.The antimalarial drugs might also prevent the development of SLE in patients with DLE, and they might decrease the risk of cardiovascular disease.

Antimalarials appear to be less effective in patients who smoke; however, DLE possibly is worse in these patients. Efforts regarding smoking cessation are advisable in patients who smoke or who are exposed to secondary smoke.

Corticosteroid and Immunomodulator Therapy

Topical corticosteroids are selected for the type of lesion under treatment and for the site of involvement. For example, lotions or foams are preferred for the scalp, weaker agents are used on the face, and superpotent agents are used for hypertrophic lesions.

Intralesional injection of corticosteroids (typically, this author uses triamcinolone acetonide 3 mg/mL) is useful as adjunctive therapy for individual lesions. Potential for atrophy relates to the amount of corticosteroid injected in any 1 area; therefore, dilute concentrations are preferred. In addition, the treating physician must take care to limit the total dose of the injections at any given office/clinic visit to avoid systemic toxicity from the steroids; eg, if a patient is given 10 mL of triamcinolone 3 mg/mL, this means that the patient has received a total of 30 mg, and toxicity is the same as if it had been delivered orally or by intramuscular injection.

Among immunosuppressives, methotrexate may be considered. In this author’s experience, azathioprine and mycophenolate mofetil have been more successful than methotrexate, while systemic corticosteroids are rarely effective. Two reports have documented the value of mycophenolate mofetil for treatment of cutaneous lesions of lupus erythematosus, including one study that used mycophenolate mofetil in antimalarial-resistant subjects.

Excision and Laser Therapy

Excision of burned-out, scarred lesions is possible; however, reactivation of inactive lesions has been reported in some patients.

Laser therapy may be useful for lesions with prominent telangiectases. Reactivation also is a consideration in this form of therapy. An open trial in a small group of patients has demonstrated the efficacy of pulsed dye laser therapy for discoid lupus erythematosus (DLE) lesions. However, before using this therapy in additional patients, at a minimum, a test area should be treated to make certain that the DLE does not flare.

Medication Summary

Hydroxychloroquine and chloroquine phosphate have shown beneficial effects in treating discoid lupus erythematosus (DLE). Alternative therapies, anecdotal reports, and small, open-label trials (as reported by Callen ) suggest that the following agents may be useful in some patients:

       Dapsone

       Auranofin

       Quinacrine

       Thalidomide

       Isotretinoin

       Acitretin

       Azathioprine

       Mycophenolate mofetil

       Phenytoin

Antimalarial agents

    Hydroxychloroquine (Plaquenil)

     Chloroquine (Aralen)

 

Leprostatic agents

Dapsone

 

Gold compounds

Auranofin (Ridaura)

 

Immunomodulators

 

    Methotrexate (Rheumatrex, Trexall)

    Thalidomide (Thalomid)

    Azathioprine (Imuran, Azasan)

    Mycophenolate (CellCept, Myfortic)

 

Corticosteroids

Triamcinolone (Kenalog-10)

 

Retinoids

    Acitretin (Soriatane)

     Isotretinoin (Claravis, Sotret, Amnesteem).

 

 

References:

 

1. Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965-2005: a population-based study. Arch Dermatol. Mar 2009;145(3):249-53. [Medline].

 

2. Shah A, Albrecht J, Bonilla-Martinez Z, et al. Lenalidomide for the treatment of resistant discoid lupus erythematosus. Arch Dermatol. Mar 2009;145(3):303-6. [Medline].

 

3. Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz M, et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum. Mar 2010;62(3):863-8. [Medline].

 

4. Chang AY, Piette EW, Foering KP, Tenhave TR, Okawa J, Werth VP. Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Arch Dermatol. Nov 2011;147(11):1261-7. [Medline].

 

5. Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep. Feb 2011;13(1):77-80. [Medline].

 

6. Gammon B, Hansen C, Costner MI. Efficacy of mycophenolate mofetil in antimalarial-resistant cutaneous lupus erythematosus. J Am Acad Dermatol. Oct 2011;65(4):717-21. [Medline].

 

SYSTEMIC LUPUS ERYTHEMATOSUS

 

http://emedicine.medscape.com/article/332244-overview

 

 

 

 

Signs and symptoms

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system; thus, its presentation and course are highly variable, ranging from indolent to fulminant.

In childhood-onset SLE, there are several clinical symptoms more commonly found than in adults, including malar rash, ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia, hemolytic anemia, fever, and lymphadenopathy.

In adults, Raynaud pleuritis and sicca are twice as common as in children and adolescents.

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE.

Patients may present with any of the following manifestations:

• Constitutional (eg, fatigue, fever, arthralgia, weight changes)
• Musculoskeletal (eg, arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis)
• Dermatologic (eg, malar rash, photosensitivity, discoid lupus)
• Renal (eg, acute or chronic renal failure, acute nephritic disease)
• Neuropsychiatric (eg, seizure, psychosis)
• Pulmonary (eg, pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, interstitial lung disease)
• Gastrointestinal (eg, nausea, dyspepsia, abdominal pain)
• Cardiac (eg, pericarditis, myocarditis)
• Hematologic (eg, cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia)

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

Diagnosis

The diagnosis of SLE is based on a combination of clinical findings and laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ manifestations.

The presence of 4 of the 11 American College of Rheumatology (ACR) criteria yields a sensitivity of 85% and a specificity of 95% for SLE.

When the Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE classification criteria in 2012, they classified a person as having SLE in the presence of biopsy-proven lupus nephritis with ANA or anti-dsDNA antibodies or if 4 of the diagnostic criteria, including at least 1 clinical and 1 immunologic criterion, have been satisfied.

ACR mnemonic of SLE diagnostic criteria

The following are the ACR diagnostic criteria in SLE, presented in the “SOAP BRAIN MD” mnemonic:

       Serositis

       Oral ulcers

       Arthritis

       Photosensitivity

       Blood disorders

       Renal involvement

       Antinuclear antibodies

       Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)

       Neurologic disorder

       Malar rash

       Discoid rash

Testing

The following are useful standard laboratory studies when SLE is suspected:

       CBC with differential

       Serum creatinine

       Urinalysis with microscopy

Other laboratory tests that may be used in the diagnosis of SLE are as follows:

       ESR or CRP results

       Complement levels

       Liver function tests

       Creatine kinase assay

       Spot protein/spot creatinine ratio

       Autoantibody tests

Imaging studies

The following imaging studies may be used to evaluate patients with suspected SLE:

• Joint radiography
• Chest radiography and chest CT scanning
• Echocardiography
• Brain MRI/ MRA

Procedures

Procedures that may be performed in patients with suspected SLE include the following:

       Arthrocentesis

       Lumbar puncture

       Renal biopsy

Management

Management of SLE often depends on the individual patient’s disease severity and disease manifestations, although hydroxychloroquine has a central role for long-term treatment in all SLE patients.

Pharmacotherapy

Medications used to treat SLE manifestations include the following:

• Biologic DMARDs (disease-modifying antirheumatic drugs): Belimumab, rituximab, IV immune globulin
• Nonbiologic DMARDS: Cyclophosphamide, methotrexate, azathioprine, mycophenolate, cyclosporine
• Nonsteroidal anti-inflammatory drugs (NSAIDS; eg, ibuprofen, naproxen, diclofenac)
• Corticosteroids (eg, methylprednisolone, prednisone)
• Antimalarials (eg, hydroxychloroquine

 

Systemic Lupus Erythematosus (SLE) Clinical Presentation

http://www.youtube.com/watch?v=tCacHFjbJNg

 

History

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system. Its presentation and course are highly variable, ranging from indolent to fulminant.

In a meta-analysis that reviewed the clinical manifestations of childhood-onset and adult-onset SLE, there were several statistically significant clinical symptoms more commonly found in childhood-onset SLE, including malar rash, ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia, hemolytic anemia, fever, and lymphadenopathy. Raynaud pleuritis and sicca were twice as common in adults as in children and adolescents.

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE. However, patients may present with any of the following types of manifestations:

• Constitutional
• Musculoskeletal
• Dermatologic
• Renal
• Neuropsychiatric
• Pulmonary
• Gastrointestinal
• Cardiac
• Hematologic

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

Constitutional

Fatigue, fever, arthralgia, and weight changes are the most common symptoms iew cases or recurrent active SLE flares. Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders.

SLE-specific fatigue or fever generally occurs in concert with other clinical markers. Fever may reflect active SLE, infection, and reactions to medications (ie, drug fever). Always exclude an infectious etiology; patients with SLE are considered immunocompromised and are therefore at higher risk for developing infections and complications. Most infections are bacterial in origin, but clinicians should always consider the possibility of atypical and opportunistic infections, particularly when these individuals are receiving immunomodulating or immunosuppressive therapy. Careful history taking may help differentiate between the potential causes of fatigue or fever. Note that an acute infectious process may also trigger SLE and that the two can occur concomitantly.

Weight loss may occur in patients with active SLE. Weight gain may also be due to corticosteroid treatment or active disease, such as nephrotic syndrome (with anasarca) or myocarditis.

Musculoskeletal

Joint pain is one of the most common reasons for the initial clinical presentation of patients with SLE. Arthralgia, myalgia, and frank arthritis may involve the small joints of the hands, wrists, and knees (usually symmetrical, polyarticular). In contrast to rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling.

SLE arthropathy is rarely erosive or deforming. Characteristic hand deformities are swaeck deformities that result from recurrent synovitis and inflammation of the joint capsule, tendons, and ligaments. These deformities are usually reducible and nonerosive (resembling Jaccoud arthropathy, which is a nonerosive arthritis following acute rheumatic fever).

Another important consideration is the increased prevalence of avascular necrosis (AVN) in the SLE population relative to healthy individuals. It may be due to SLE pathogenesis and/or concomitant heavy steroid use.Asymptomatic AVN is seen in up to 44% of SLE patients in the first year of therapy with high-dose corticosteroids. The most commonly affected site is the femoral head.Independent risk factors for AVN in patients with SLE include the use of glucocorticosteroid or cytotoxic agents and the presence of arthritis.

Dermatologic

Cutaneous manifestations of SLE include 3 American College of Rheumatology (ACR) lupus diagnostic criteria: malar rash, photosensitivity, and discoid lupus.

Skin and mucous membrane findings

Malar rash is a fixed erythema that typically spares the nasolabial folds. It is a butterfly-shaped rash that can be flat or raised over the cheeks and bridge of the nose (see the images below).

 

The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

 

 

 

Dermatomyositis. Acute onset of confluent macular erythema in a periorbital and malar distribution (involving the cheeks and extending over the nasal bridge), with extension to the chin in a female with juvenile dermatomyositis. Note the perioral sparing. In some patients, there may be more extensive involvement of the face, including the perioral region, forehead, lateral face, and ears. In contrast to SLE , in dermatomyositis with malar erythema, the nasolabial folds are often not spared.

Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands and generally persists for more than 1 day (see the image below).

 

Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.

Discoid rash occurs in 20% of patients with SLE and can result in disfiguring scars. The discoid rash can present as erythematous patches with keratotic scaling over sun-exposed areas of the skin. Follicular plugging may create scarring that may be well demonstrated in the ears. Systemic manifestations of SLE may be absent (ie, limited discoid lupus).

Lupus should be considered in all patients who experience oral, or less frequently, vaginal ulcers; ulcers classically occur more than 3 times per year and are painless. Palatal ulcers are most specific for SLE.

Many other cutaneous findings are not explicitly diagnostic features but support impressions of SLE. Alopecia in SLE often causes hair loss at the temporal regions or creates a patchy pattern. Vascular lesions such as livedo reticularis (characterized by a lacy, mottled, erythematous skin pattern), periungual erythema (as seen iailfold capillaroscopy, which can be performed with an ophthalmoscope to search for dilated capillary nailfold loops), telangiectasias, and Raynaud phenomenon (blue, white, and red color changes at the distal digital tips) may develop in some patients with SLE or antiphospholipid antibody syndrome. However, these are nonspecific findings, as they can occur in other connective tissue disorders with prominent vascular involvement, such as scleroderma and dermatomyositis. Panniculitis, bullous lesions, vasculitic purpura, and urticaria are other skin lesions that are sometimes seen in SLE.

Other cutaneous manifestations related to, but not specific to, SLE include the following:

       Raynaud phenomenon

       Livedo reticularis

       Panniculitis (lupus profundus)

       Bullous lesions

       Vasculitic purpura

       Telangiectasias

       Urticaria

Renal

The kidney is the most commonly involved visceral organ in SLE. Although only approximately 50% of patients with SLE develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in most patients.Therefore, it is important to correctly classify the extent of renal involvement in SLE to improve the correlation between histologic findings and the prognosis of the renal disease (see Biopsies and Histologic Features under Workup).Glomerular disease usually develops within the first few years of SLE onset and is often asymptomatic.

Acute or chronic renal failure may cause symptoms related to uremia and fluid overload. Acute nephritic disease may manifest as hypertension and hematuria. Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia.

Neuropsychiatric

The CNS lupus nomenclature has been revised to catalog many manifestations.Because of the difficulty distinguishing causal SLE associations with some neurologic symptoms, only seizure and psychosis were typically included in the diagnostic criteria. Seizures related to SLE may be generalized or partial and may precipitate status epilepticus. Psychosis may manifest as paranoia or hallucinations.

However, the American College of Rheumatology (ACR) created standardized case definitions and diagnostic testing recommendations for 19 neuropsychiatric syndromes in SLE, including seizures/seizure disorders and psychosis.The remainder of the neuropsychiatric syndromes are as follows:

       Acute confusional state

       Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome)

       Anxiety disorder

       Aseptic meningitis

       Autonomic disorder

       Cerebrovascular disease

       Cognitive dysfunction

       Cranial neuropathy

       Demyelinating syndrome

       Headache

       Mononeuropathy (single/multiplex)

       Mood disorders

       Movement disorder (chorea)

       Myasthenia gravis

       Myelopathy

       Plexopathy

       Polyneuropathy

Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE. Delirium may be caused by CNS vasculitis, encephalopathy, cerebritis, or the manifestations previously called organic brain syndrome. Aseptic meningitis, myelopathy, optic neuropathy, or other demyelinating disorders may also require urgent evaluation.

Transverse myelitis with spastic paraparesis and sensory loss at a given level is a rare but severe complication of SLE or antiphospholipid antibody syndrome. Stroke and transient ischemic attack (TIA) may be related to antiphospholipid antibody syndrome or SLE vasculitis. Posterior reversible encephalopathy syndrome (PRES) is, as the name implies, a reversible encephalopathy linked to hypertension that even may be a presenting feature for young SLE patients.

Cognitive disorders may be variably apparent in many patients with SLE. Formal neuropsychiatric testing reveals deficits in 21-67% of patients with SLE. Whether this represents true encephalopathy, neurologic damage, medication effects, depression, or some other process is unclear. A 2010 multicenter study found that depression was associated with significantly poorer cognitive function in 111 patients newly diagnosed with SLE.

Migraine headaches may be linked to antiphospholipid syndrome. Headache and mood disorders may be the most commonly reported neurologic manifestation of SLE, but cause and effect may be difficult to distinguish.

Acute psychiatric manifestations in CNS lupus should be considered as a diagnosis of exclusion in an SLE patient.

For additional information, see the Medscape Reference article Neurologic Manifestations of Systemic Lupus Erythematosus.

Pulmonary

Pulmonary features of SLE may manifest acutely or indolently, representing a spectrum of SLE complications. SLE may lead to multiple pulmonary complications, including pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, and interstitial lung disease. The chronic steroids prescribed to patients also place them at increased risk for atypical infections.

Pleuritis is one of the formal diagnostic criteria for SLE, and it can induce chest pain and a pleural effusion. The pleural effusion in lupus is exudative, with an elevated lactate dehydrogenase level. Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute pulmonary involvement in SLE. Shortness of breath or dyspnea may be due to many causes. Pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, pulmonary hypertension, complement-mediated pulmonary leukoaggregation, alveolar hemorrhage, or infection may be related to lupus disease.

Most seriously, hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of SLE.

Gastrointestinal

In general, gastrointestinal symptoms secondary to SLE are less common than adverse effects of medication or nonspecific complaints. Special consideration should be given to infectious causes (bacterial, viral [eg, CMV]), because of immunosuppression. Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult to correlate with objective evidence of gastrointestinal involvement. Peptic ulcer disease is a common complication, especially in SLE patients treated with nonsteroidal anti-inflammatory agents (NSAIDs) and glucocorticoids.

Occasional abdominal pain in active SLE may be directly related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. Jaundice due to autoimmune hepatobiliary disease may also occur.

Cardiac

Heart failure or chest pain must be carefully assessed in patients with SLE. Pericarditis is the most common cardiac feature of SLE, manifesting as positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in SLE with heart failure symptoms. Pulmonary hypertension may present with indolent chest pain or dyspnea.

Coronary vasculitis manifesting as angina or infarction is rarely reported. Libman-Sacks endocarditis is noninfectious but may manifest as symptoms similar to those of infective endocarditis in patients with SLE or antiphospholipid syndrome. More commonly, accelerated ischemic coronary artery disease (CAD) is associated with SLE and may present indolently as atypical anginal equivalents.

Hematologic

A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest SLE, among other etiologies, such as medication-related cytopenias. Leukopenia and, more specifically, lymphopenia are common in SLE; this, coupled with immunosuppression, may predispose persons with SLE to frequent infections.

Anemia is occasionally overlooked in young menstruating women, and a history of lymphopenia may be overlooked. Thrombocytopenia may be mild or part of a full thrombotic thrombocytopenic purpura (TTP)–like syndrome or antiphospholipid antibody syndrome. A history of recurrent early miscarriages or a single late pregnancy loss may be clues to lupus or isolated antiphospholipid antibody syndrome.

Physical Examination

Almost any organ system can be involved in active SLE. The constellation of several physical findings may suggest a diagnosis of SLE. The American College of Rheumatology (ACR) diagnostic criteria are discussed in Workup. Examination findings are discussed by system.

Fever is a challenging problem in SLE. It can be a manifestation of active lupus, infection, malignancy, or a drug reaction. Low-grade fever is observed in patients on immunosuppressive agents, and lymphadenopathy or splenomegaly may be found.

In patients with fever, infectious causes—both viral and bacterial—need to be ruled out. Lupus patients may be functionally asplenic and may be at risk for encapsulated bacterial infections such as meningococcemia. Patients with SLE who are on immunosuppressive therapy are at a higher risk of death due to viral infection (eg, herpes simplex virus [HSV], cytomegalovirus [CMV], varicella-zoster virus [VZV]) and should be treated accordingly if an infection is suspected.An infection can mimic a lupus flare, and delays in diagnosis and treatment can increase the risk of mortality.^]

A postdiagnostic 5-year follow-up study showed that males had a higher prevalence of thromboses, nephropathy, strokes, gastrointestinal symptoms, and antiphospholipid syndrome and that females were more likely to present with arthralgia, hair loss, Raynaud syndrome, and photosensitivity.In addition, male patients were more likely to present with tendonitis, myositis, nephropathy, and respiratory tract infections.

Diagnostic Criteria for SLE

Updated American College of Rheumatology Diagnostic Criteria for SLE

Criterion	Definition
SLE can be diagnosed if any 4 or more of the following 11 criteria are present, serially or simultaneously, during any interval of observation.
1. Malar rash		Fixed, flat or raised erythema over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash		Erythematous raised patches with adherent keratotic scaling and follicular plugging (older lesions may demonstrate atrophic scarring)
3. Photosensitivity		Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers		Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis		Nonerosive arthritis involving =2 peripheral joints, characterized by tenderness, swelling, or effusion
6. Serositis		(A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or
		(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder		(A) Persistent proteinuria >0.5 g/day or >3+ if quantitatioot performed or
		(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder		(A) Seizures: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance) or
		(B) Psychosis: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)
9. Hematologic disorder		(A) Hemolytic anemia: With reticulocytosis or
		(B) Leukopenia: < 4000/mm3 total on =2 occasions or
		(C) Lymphopenia: < 1500/mm3 on =2 occasions or
		(D) Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs
10. Immunologic disorder		(A) Anti-DNA: Antibody to native DNA in abnormal titer or
		(B) Anti-Sm: Presence of antibody to Smith (Sm) nuclear antigen or
		(C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for =6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear antibody (ANA)		An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome
Sources:  (1.) American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at: http://tinyurl.com/1997SLEcriteria Accessed: March 15, 2012 ; (2.) Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997;40(9):1725.

Diagnostic Considerations

Before making a diagnosis of systemic lupus erythematosus (SLE), ruling out drugs as the cause of the condition is important. Table 2, below, shows the many pharmacologic agents associated with a lupuslike syndrome. Procainamide, hydralazine, and isoniazid have been studied the most extensively. Many patients who take these medications have positive antinuclear antibody test results and other serologic findings. Only a few have the clinical manifestations. Drug-induced lupus differs from SLE by the following features:

• Sex ratios are nearly equal
• Antibodies to histones are usually found in 80-90%
• Nephritis and central nervous system features are not commonly present
• There are no antibodies to native DNA or hypocomplementemia
• Discontinuation of the drug leads to resolution of clinical manifestations and reversion of abnormal laboratory values to normal

A syndrome of drug-induced SLE has been observed with minocycline and propylthiouracil. Both drugs have a decreased frequency of antihistone antibodies and anti–double-stranded DNA antibodies, and results for antineutrophil cytoplasmic antibodies are sometimes positive. Anti-TNF drugs are reported to cause severe drug-induced lupus, including production of many SLE autoantibodies and, rarely, eveephritis.

Drugs Associated With Lupus Erythematosus

Definite Association
Chlorpromazine	Methyldopa
Hydralazine	Procainamide
Isoniazid	Quinidine
Possible Association
Beta-blockers	Methimazole
Captopril	Nitrofurantoin
Carbamazepine	Penicillamine
Cimetidine	Phenytoin
Ethosuximide	Propylthiouracil
Hydrazines	Sulfasalazine
Levodopa	Sulfonamides
Lithium	Trimethadione
Unlikely Association
Allopurinol	Penicillin
Chlorthalidone	Phenylbutazone
Gold salts	Reserpine
Griseofulvin	Streptomycin
Methysergide	Tetracyclines
Oral contraceptives
Source:  Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill; 2001.

Other problems to be considered in the differential diagnosis of SLE include the following:

       Discoid skin lesions

       Erythematous macules

       Interstitial lung disease

       Leukemia

       Leukopenia

       Parvovirus or other viral infections

       Photodistributed rash

       Pleuritic chest pain

       Pneumonitis

       Polyarthritis/polyarthralgia

       Renal vasculitis

       Seizures

       Stroke

       Thrombocytopenia

       Vasculitis

Differential Diagnoses

       Acute Pericarditis

       Antiphospholipid Syndrome

       Autoimmune Hepatobilliary Disease

       Fibromyalgia

       Hepatitis C

       Infectious Mononucleosis

       Infective Endocarditis

       Lyme Disease

       Lymphoma, B-Cell

       Mixed Connective-Tissue Disease

       Polymyositis

       Rheumatoid Arthritis

       Scleroderma

       Sjogren Syndrome

       Undifferentiated Connective-Tissue Disease

SJOGREN  SYNDROME

 

http://emedicine.medscape.com/article/332125-overview

 

Background

Physical Examination

The physical signs of primary Sjögren syndrome can be divided into glandular and extraglandular signs.

Glandular signs

Ocular

While it is important to look for corneal lesions and a decreased tear pool in the lower conjunctiva during physical examination, patients with Sjögren syndrome should be referred to an ophthalmologist for more formal testing of keratoconjunctivitis sicca (KCS). This testing applies grading criteria of inflammatory changes that can direct therapy aimed at preventing corneal damage.In addition, conditions that mimic KCS, such as blepharitis, conjunctivitis, and uveitis can be ruled out or treated.

Patients with Sjögren syndrome may have dilated conjunctival vessels, as well as pericorneal injection and dullness or irregularity of the corneal image. Blepharitis may be present as an alternate or additional problem, particularly if the lower eyelid is inflamed.

Mucinous threads and filamentary keratosis can be detected during a slit-lamp examination. The relative lack of the aqueous layer also leads to rapid tear breakup.

In the Schirmer test, a bent piece of Whatmaumber 41 filter paper is placed in the lower conjunctiva, and the amount of tearing on the filter paper is recorded. Normal wetting is greater than 15 mm after 5 minutes, whereas a definitive positive result is less than 5 mm after 5 minutes. This test can help to exclude or confirm significant dryness of the eyes, but it is not disease-specific. Furthermore, false-positive results occur. An evaluation of the diagnostic performance of the Schirmer test yielded a sensitivity of 42% and a specificity of 76% for Sjögren syndrome. (See the image below.)

 

Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis.

Oral

Oral signs include the following:

• Dryness
• Tongue – Red, smooth, and dry (see the image below)
• Dental caries – Severe and progressive
• Parotid duct narrowing
• Lips – Red, dry, and scaly
• Cracks at the corners of the mouth

Chronic oral candidiasis

Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common.

 

Look for a decreased sublingual salivary pool. The tongue may stick to the tongue depressor. Patients with Sjögren syndrome may develop frequent caries, sometimes in unusual locations such as the incisor surface and the gum line.

Patients with Sjögren syndrome are prone to develop oral candidiasis. In addition to white patches, watch for petechial lesions, loss of tongue papilla, erythema and fissuring of the tongue, erythema on other mucosal surfaces, and angular cheilosis. Oral candidiasis can be seen under dentures.

Gingival inflammation has been found to be more evident in the individuals with Sjögren syndrome, particularly those with secondary Sjögren syndrome.Periodontal disease can lead to loss of teeth.

Parotid glands

Sjögren syndrome appears to negatively affect the periodontal condition. Recurrent swelling of the parotid glands (22-66% of patients) occurs; submaxillary and sublingual gland swelling also sometimes takes place.

Bilateral parotid gland enlargement is common in persons with Sjögren syndrome (see the image below). Some waxing and waning of size may occur. Exudates from the parotid gland are largely lymphocytes.

Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding.

Rock-hard or unilateral parotid gland enlargement should prompt referral to an otolaryngologist for biopsy to exclude a tumor. Other causes of parotid enlargement include diabetes, sarcoidosis, amyloidosis, diffuse infiltrative lymphocytic syndrome (DILS) of HIV disease, hepatitis C, and alcoholism. Acute, unilateral parotitis may be caused by Sjögren syndrome, infection, or obstruction, although the latter 2 conditions are more often associated with a very tender parotid gland and accompanying fever.

Other mucous membranes

Other mucous membrane signs include the following:

• Atrophic changes in the mucous membranes of the upper respiratory tract, leading to nasal dryness, recurrent infections, hoarseness, and aphonia
• Atrophic rhinitis
• Atrophic changes in the vulva and vagina resulting in pruritus and vaginitis
• Dryness of the anal and rectal mucous membranes (eg, pruritus, inflammation)

Cutaneous

Dryness of the skin occurs in 50% of patients with Sjögren syndrome; scaling occurs in about 25% of patients. The skin may be irritable, with secondary lichenification. Partial or complete loss of sweating may be present.

Hair may be dry, sparse, and brittle; diffuse alopecia may involve the scalp, limbs, axillae, or pubis. Nail folds may show capillaroscopic abnormalities, which are associated with the presence of antiendothelial cell antibodies.Erythema of the nose and cheeks may be present.

Patients with Sjögren syndrome can develop a nonpalpable or palpable, vasculitic purpura, with lesions that are typically 2-3 mm in diameter and located on the lower extremities. The lesions, which can ulcerate, occur most often in patients with hypergammaglobulinemia or cryoglobulinemia.

Annular erythema with scales, localized especially on the face and neck, is recognized as a cutaneous manifestation of Sjögren syndrome. The patches are recurrent and resolve without hyperpigmentation; no photosensitivity is observed.

In Japanese patients with Sjögren syndrome, annular erythema is divided into 3 types: Sweet disease–like annular erythema with an elevated border; subacute cutaneous lupus erythematosus–like, marginally scaled erythema; and papular erythema. These lesions bear some clinical similarities to the annular lesions of subacute cutaneous lupus erythematosus, but their histopathologic features are distinct from those of subacute cutaneous lupus erythematosus. Significant mucin depositions are observed. Annular erythema is a common cutaneous manifestation in Japanese and other Asian patients; however, it is rarely seen in white patents.

Extraglandular signs

Gastrointestinal

Gastrointestinal tract signs include the following:

• Esophageal motility abnormalities
• Pancreatic involvement
• Splenomegaly
• Digestive symptoms (due to atrophy of the gastric mucous membrane with achlorhydria)
• Hepatitis (13%)

Pulmonary

Pulmonary abnormalities occur in 9-29% of cases; they are similar in primary and secondary Sjögren syndrome. Lung signs include the following:

• Pulmonary fibrosis
• Pulmonary hypertension
• Recurrent chest infections
• Granulomatous infiltration and fibrosing alveolitis
• Restrictive ventilatory defect
• Impaired gas transfer
• Bibasilar rales – Can be heard in patients with interstitial lung disease

Articular

Articular changes (eg, arthritis) occur in 42% of patients with Sjögren syndrome; arthritis can be a component of either the primary or secondary form of the disease. One third of patients with RA have Sjögren syndrome.

Symmetrical, polyarticular, inflammatory arthritis suggests underlying RA or a connective-tissue disease such as SLE or scleroderma. The arthritis in patients with primary Sjögren syndrome is typically nonerosive and mild.

Urinary tract

Patients with Sjögren syndrome have significantly more urinary problems than do those without Sjögren syndrome. Patients may have the following:

• Irritated bladder
• Suprapubic pain
• Renal tubular dysfunction – Patients with primary Sjögren syndrome commonly are first seen because of renal impairment, usually from renal tubular dysfunction
• Renal tubular acidosis – This affects one third of patients with Sjögren syndrome; a correlation apparently exists between hypergammaglobulinemia and distal renal tubular acidosis
• Interstitial nephritis – This is rare, occurring in 4% of cases; it is often accompanied by cryoglobulinemia, a decreased level of complement, and the presence of circulating immune complexes
• Impaired renal concentrating ability, generalized aminoaciduria

Neurologic

A combination of lesions and relapses can suggest multiple sclerosis. Myelopathy rarely occurs in the course of primary Sjögren syndrome. It appears as Brown-Séquard syndrome, acute transverse myelitis, or progressive myelopathy. Clinically, cases with nervous system involvement present with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels.

Peripheral neuropathy occurs in 10-35% patients with primary Sjögren syndrome. Peripheral nerve dysfunction—such as trigeminal sensory neuropathy, mononeuropathy multiplex, distal sensorimotor polyneuropathy, or pure sensory neuropathy—may occur. This tends to be a small-fiber peripheral neuropathy. Painful, distal paresthesias in the feet may be evident, as may abnormal sweating. Examination may reveal findings that include decreased pinprick sensation.

Isolated cranial nerve involvement rarely occurs in primary Sjögren syndrome. CNS involvement also is less common (10-25% of patients with Sjögren syndrome) than are other types of involvement; CNS pathology ranges from neuropathy, hemiparesis, transverse myelitis, and dystonia to encephalopathy and dementia.

In Sjögren syndrome, focal brain lesions can be present in the cerebral white matter. In addition, dysregulation of hypothalamic-pituitary-adrenal and thyroid axes can cause some neurologic disturbances.

American-European Consensus Group classification

A number of classification criteria for Sjögren syndrome were designed primarily for clinical research studies but are also often used to help guide clinical diagnoses. The American-European Consensus Group’s criteria for the classification of Sjögren syndrome are outlined below. These are the most currently accepted criteria for the diagnosis of Sjögren syndrome. These criteria allow a diagnosis of Sjögren syndrome in patients without sicca symptoms or who have not undergone a biopsy.

According to the American-European classification system (as modified by Tzioufas and Voulgarelis), diagnosis of primary Sjögren syndrome requires 4 of 6 of the below criteria; in addition, either criterioumber 5 or criterioumber 6 must be included. Sjögren syndrome can be diagnosed in patients who have no sicca symptoms if 3 of 4 objective criteria are fulfilled. The criteria are as follows:

• Ocular symptoms – Dry eyes for more than 3 months, foreign-body sensation, use of tear substitutes more than 3 times daily
• Oral symptoms – Feeling of dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing
• Ocular signs – Schirmer test performed without anesthesia (< 5 mm in 5 min), positive vital dye staining results
• Oral signs – Abnormal salivary scintigraphy findings, abnormal parotid sialography findings, abnormal sialometry findings (unstimulated salivary flow < 1.5mL in 15min)
• Positive minor salivary gland biopsy findings
• Positive anti–SSA or anti–SSB antibody results

Secondary Sjögren syndrome is diagnosed when, in the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5, above.

Application of these criteria has yielded a sensitivity of 97.2% and a specificity of 48.6% for the diagnosis of primary Sjögren syndrome. For secondary Sjögren syndrome, the specificity is 97.2% and the sensitivity, 64.7%.

Exclusion criteria include past head-and-neck irradiation, hepatitis C infection, acquired immunodeficiency syndrome (AIDS), prior lymphoma, sarcoidosis, graft versus host disease, and the use of anticholinergic drugs.

Complications

Complications related to Sjögren syndrome include the following (see Prognosis, Treatment, and Medication):

• Emergence of disorders associated with Sjögren syndrome, such as SLE and RA
• Infection of the parotid gland, typically staphylococcal, streptococcal, or pneumococcal – Clues include unilateral worsening of symptoms, along with tenderness, warmth, and erythema
• Emergence of parotid tumors – Watch for unusually hard or unilateral parotid enlargement
• Pregnant patients with antiRo/SS-A antidodies are at risk for fetal loss, complete heart block in the fetus ,and neonatal lupus syndrome in the newborn
• Emergence of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin B-cell lymphomas (see the image below)

Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis.

History

The clinical presentation of Sjögren syndrome may vary. The onset is insidious. It usually starts in women aged 40-60 years, but it also can affect men and children. The first symptoms in primary Sjögren syndrome can be easily overlooked or misinterpreted, and diagnosis can be delayed for as long as several years.

Xerophthalmia (dry eyes) and xerostomia (dry mouth) are the main clinical presentations in adults. Bilateral parotid swelling is the most common sign of onset in children.

Extraglandular involvement in Sjögren syndrome falls into 2 general categories: periepithelial infiltrative processes and extraepithelial extraglandular involvement. Periepithelial infiltrative processes include interstitial nephritis, liver involvement, and bronchiolitis and generally follow a benign course.

Extraepithelial extraglandular involvement in Sjögren syndrome is related to B-cell hyperreactivity, hypergammaglobulinemia, and immune complex formation and includes palpable purpura, glomerulonephritis, and peripheral neuropathy. These latter manifestations occur later in the course of Sjögren syndrome and are associated with a higher risk of transformation to lymphoma.

Symptoms of Sjögren syndrome can decrease the patient’s quality of life in terms of its physical, psychological, and social aspects.

Sicca symptoms (dry eyes and dry mouth)

Although dry eyes and dry mouth are the most common symptoms in patients with Sjögren syndrome, most patients who report these symptoms have other underlying causes. The incidence of sicca symptoms increases with age. Indeed, more than one third of elderly persons have sicca symptoms. Whether this is part of the normal aging process (associated with fibrosis and atrophy observed on some lip biopsy studies) or is due to the accumulation of associated illnesses and medications is unclear.

Common medications that can cause sicca symptoms in any age group include antidepressants, anticholinergics, beta blockers, diuretics, and antihistamines. Anxiety can also lead to sicca symptoms. Women who use hormone replacement therapy may be at increased risk of dry eye syndrome.

Patients may describe the effects dry mouth in the following ways:

• Inability to eat dry food (eg, crackers) because it sticks to the roof the mouth
• Tongue sticking to the roof of the mouth
• Putting a glass of water on the bed stand to drink at night (and resulting nocturia)
• Difficulty speaking for long periods of time or the development of hoarseness
• Higher incidence of dental caries and periodontal disease
• Altered sense of taste
• Difficulty wearing dentures
• Development of oral candidiasis with angular cheilitis, which can cause mouth pain

Dry eyes may be described as red, itchy, and painful. However, the most common complaint is that of a gritty or sandy sensation in the eyes. Symptoms typically worsen throughout the day, probably due to evaporation of the already scanty aqueous layer. Some patients awaken with matting in their eyes and, when severe, have difficulty opening their eyes in the morning. Blepharitis can also cause similar morning symptoms.

Parotitis

Patients with Sjögren syndrome may have a history of recurrent parotitis, often bilateral. Although in some patients the parotid glands become so large that the patients report this as a problem, more often the examining physician discovers them.

Cutaneous symptoms

Nonvasculitic cutaneous manifestations in Sjögren syndrome include dryness, eyelid dermatitis, pruritus, and erythema annulare.

Cutaneous vasculitis, such as palpable purpura, develops in some patients with Sjögren syndrome, especially those with hypergammaglobulinemia or cryoglobulinemia.Raynaud phenomenon is observed in approximately 20% of patients.

Pulmonary symptoms

Patients with Sjögren syndrome can develop dryness of the tracheobronchial mucosa (xerotrachea), which can manifest as a dry cough.Less often, patients develop dyspnea from an interstitial lung disease that is typically mild.Patients may develop recurrent bronchitis or even pneumonitis (infectious or noninfectious).

Gastrointestinal symptoms

Dryness of the pharynx and esophagus frequently leads to difficulty with swallowing (deglutition), in which case patients usually describe food becoming stuck in the upper throat.

Lack of saliva may lead to impaired clearance of acid and may result in gastroesophageal reflux and esophagitis.

Abdominal pain and diarrhea can occur. Rarely, patients develop acute or chronic pancreatitis, as well as malabsorption due to pancreatic insufficiency. However, caution is advised when interpreting laboratory results because an elevated amylase level may arise from the parotid gland.

In patients with gastritis, Helicobacter pylori infection should be sought because of its association with gastric mucosa-associated lymphoid tissue lymphomas.

Patients with Sjögren syndrome are at increased risk for delayed gastric emptying, which can cause early satiety, upper abdominal discomfort, nausea, and vomiting.

Cardiac symptoms

Pericarditis and pulmonary hypertension, with their attendant symptomatology, can occur in Sjögren syndrome. Orthostatic symptoms related to dysfunction of autonomic control of blood pressure and heart rate is associated with increased severity of Sjögren syndrome.

Neurologic symptoms

The occurrence of central nervous system (CNS) and spinal cord involvement in Sjögren syndrome is estimated by various studies to be 8-40%, with manifestations including myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy. Attempts must be made to distinguish other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, and Alzheimer disease.

Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be detected in up to 55% of unselected patients with Sjögren syndrome. Symptoms of distal paresthesias may be present. Cranial neuropathies can develop, particularly trigeminal neuropathy or facial nerve palsy. Mononeuritis multiplex should prompt a search for a vasculitis.

Progressive weakness and paralysis secondary to hypokalemia due to underlying renal tubular acidosis can occur and is potentially treatable.

Renal symptoms

Renal calculi, renal tubular acidosis, and osteomalacia, nephogenic diabetes insipidus, and hypokalemia can occur secondary to tubular damage caused by interstitial nephritis, the most common form of renal involvement in Sjögren syndrome.

Interstitial cystitis, with symptoms of dysuria, frequency, urgency, and nocturia, is strongly associated with Sjögren syndrome.

Glomerulonephritis can be caused by Sjögren syndrome but is uncommon and is usually attributable to another disorder, such as SLE or mixed cryoglobulinemia.

Additional symptoms

Nasal dryness can result in discomfort and bleeding. Patients may also have a dry vagina, which can lead to dyspareunia, vaginitis, and pruritus.

Sjögren syndrome is associated with a wide variety of other disorders. Therefore, a careful review of systems is needed to detect problems such as RA, SLE, scleroderma, polymyositis, chronic active hepatitis, idiopathic pulmonary fibrosis, primary biliary cirrhosis, and autoimmune thyroid disease.Patients with Sjögren syndrome may report fatigue, joint pain, and, sometimes, joint swelling.

Women with Sjögren syndrome may have a history of recurrent miscarriages or stillbirths, and women and men may have a history of venous or arterial thrombosis. These are related to the presence of antiphospholipid antibodies (eg, lupus anticoagulant or anticardiolipin antibodies).

Secondary Sjogren syndrome

Secondary Sjögren syndrome appears late in the course of the primary disease. However, in some patients, primary Sjögren syndrome may precede SLE by many years. Secondary Sjögren syndrome is usually mild, and sicca symptoms are the main feature. Unlike patients with primary Sjögren syndrome, persons with the secondary type have significantly fewer systemic manifestations. These manifestations include the following:

• Salivary gland swelling
• Lung involvement
• Nervous system involvement
• Renal involvement
• Raynaud phenomenon
• Lymphoproliferative disorders

In secondary Sjögren syndrome, symptoms of the primary disease predominate. Secondary Sjögren syndrome does not modify the prognosis or outcome of the basic disease. Polyarteritis nodosa and Sjögren syndrome may also coexist, perhaps best viewed as an overlap syndrome.

Diagnostic Considerations

Xerophthalmia, xerostomia, and enlargement of the parotid glands can result from adverse effects of drugs and other diseases. HIV infection can result in diffuse infiltrative lymphocytosis syndrome (DILS), which is characterized by parotid enlargement; involvement of the renal, lung, and gastrointestinal systems; and a low frequency of autoantibody presence. Chronic graft versus host disease may mimic symptoms associated with idiopathic Sjögren syndrome. SLE might be considered, especially at onset of the disease. Autoimmune thyroid dysfunction may be present. Sjögren syndrome can be underdiagnosed or misdiagnosed.

Histology

Histologic findings of the following disorders can be consistent with Sjögren syndrome:

• Sarcoidosis
• Graft versus host disease
• HIV infection
• HTLV-1 infection
• HCV infection
• Keratoconjunctivitis sicca

Sicca

Differential diagnoses to consider in patients with sicca include the following:

       Medications (eg, antidepressants, anticholinergics, beta-blockers, diuretics, antihistamines, some antiarrhythmic and antiepileptic drugs)

       Anxiety and depression

       Viral infections (eg, mumps)

       Complications from contact lenses

       Dehydration

       Hypervitaminosis A

       Neurotropic keratitis

       Mucous membrane pemphigoid

       Environmental irritants

       Mouth breathing

       Chronic blepharitis

       Chronic conjunctivitis

       Rosacea

       Therapeutic radiation or surgery to the head and neck

       Age

       Alzheimer disease

       Parkinson disease

       Bell palsy

       Amyloidosis

       Sarcoidosis

       Lymphoma

Differential diagnoses to consider in patients with parotid enlargement include the following:

       Viral infection (eg, mumps, Epstein-Barr virus, cytomegalovirus, coxsackievirus A, influenza)

       DILS associated with HIV disease

       Granulomatous diseases (sarcoidosis, tuberculosis, leprosy)

       Hyperlipoproteinemia

       Hepatic cirrhosis

       Hepatitis C

       Bulimia

       Recurrent parotiditis of childhood

       Chronic pancreatitis

       Acromegaly

       Amyloidosis

       Gonadal hypofunction

       Diabetes mellitus

       Salivary gland tumor (primarily unilateral)

       Bacterial infection (primarily unilateral)

       Chronic sialadenitis (primarily unilateral)

       Lymphoma

Associated disorders

Importantly, evaluate the patient for disorders associated with Sjögren syndrome, including the following:

       AIDS

       RA

       SLE

       Scleroderma

       Polymyositis

       Primary biliary cirrhosis

       Thyroiditis

       Chronic active hepatitis

       Mixed cryoglobulinemia

       Celiac sprue

Differential Diagnoses

       Amyloidosis, Immunoglobulin-Related

       Bulimia

       IgG4-related systemic disease

       Pancreatitis, Chronic

       Polymyositis

       Rheumatoid Arthritis

       Salivary Gland Tumors, Major, Benign

       Salivary Gland Tumors, Minor, Benign

       Sarcoidosis

       Scleroderma

       Tuberculosis

 

Dermatologic Aspects of Behcet Disease

 http://emedicine.medscape.com/article/1122381-overview#a0104

 

Background

Behçet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behçet, who first described the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis.

Behçet disease is a complex, multisystemic disease that includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs.

Behçet disease is characterized by oral aphthae and by at least 2 of the following: (1) genital aphthae, (2) synovitis, (3) posterior uveitis, (4) cutaneous pustular vasculitis, (5) meningoencephalitis, (6) recurrent genital ulcers, and (7) uveitis in the absence of inflammatory bowel disease or collagen-vascular disease.

Pathophysiology

The cause of Behçet disease is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.

Clinical Presentation

History

Signs and symptoms of Behçet disease, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.

• Prior to the onset of Behçet disease, patients may experience a variety of symptoms.

       Malaise

       Anorexia

       Weight loss

       Generalized weakness

       Headache

       Perspiration

       Decreased or elevated temperature

       Lymphadenopathy

       Pain of the substernal and temporal regions

• A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.
• A diagnosis of Behçet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases.
• The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied.
• More recently, the diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis.
• The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of Behçet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behçet disease, although this is, in fact, a far-advanced form of the disease.
• Therefore, the authors recommend that both sets of criteria be applied concurrently until a more exact system is devised.
• Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) are as follows:
• Major features

§     Recurrent aphthous ulceration of the oral mucous membrane

§     Skin lesions –Erythema nodosum –like lesions, subcutaneous thrombophlebitis, folliculitis (acnelike lesions), cutaneous hypersensitivity

§     Eye lesions – Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis

§     Genital ulcers

o                  Minor features

§     Arthritis without deformity and ankylosis

§     Gastrointestinal lesions characterized by ileocecal ulcers

§     Epididymitis

§     Vascular lesions

§     Central nervous system symptoms

o                  Diagnosis

§     Complete – Four major features

§     Incomplete – (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features

§     Possible – (1) 2 major features or (2) 1 major and 2 minor features

·                     International criteria for the classification of Behçet disease (1990) are as follows:

o                  Recurrent oral ulceration – Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following:

§     Recurrent genital ulceration – Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient

§     Eye lesions – (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist)

§     Skin lesions – (1) Erythema nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with Behçet disease, observed by a physician, and in postadolescent patients not receiving corticosteroids

§     Positive pathergy test – An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours

Physical

Oral ulcers

Oral aphthae that occur in patients with Behçet disease are indistinguishable from common aphthae (canker sores). Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin. They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars. The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months.

Oral ulcers can be classified into the following 3 types:

Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days (see the image below).

Minor aphthous ulcer.

Major ulcer: This is 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing (see the image below).

Major aphthous ulcer.

Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers (see the image below).

Herpetiform oral ulcer.

Genital manifestations

Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers. In males, the ulcers usually occur on the scrotum (see the image below), penis, and groin.

A characteristic genital ulcer on scrotum.

In females, they occur on the vulva (see the image below), vagina, groin, and cervix.

A single ulcer on vulva.

Ulcers have also been found in the urethral orifice and perianal area. Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behçet Disease Research Committee of Japan. An additional genital symptom is orchiepididymitis, observed in 10.8% of men.

Cutaneous manifestations

A variety of skin lesions may appear in patients with Behçet disease (58.6-97%), including the following:

• Erythema nodosum –like lesions, which are most common (see the image below)

 Erythema nodosum–like lesions on skin.

Papulopustular eruptions (see the image below)

 Papulopustular eruptions.

• Erythema multiforme–like lesions
• Thrombophlebitis
• Ulcers
• Lesions resembling Sweet syndrome (see the image below)

Sweet syndrome–like lesion.

• Bullous necrotizing vasculitis
• Pyoderma gangrenosum

Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation of these lesions, ie, pathergy (see the image below).

Typical positive pathergy reaction at injection site.

Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions). Follicle-based pustules or acne lesions are not considered specific lesions of Behçet disease.

Ocular manifestations

Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with Behçet disease. Childhood-onset Behçet uveitis is more common in males.

The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis (see the image below). Other lesions include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. Hypopyon, which was considered the hallmark of Behçet disease, is now uncommon.

Ocular involvement showing posterior uveitis.

Eye disease is usually present from the outset but also may develop within the first few years. Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. Blindness has been reported to occur within 4-5 years from the onset of ocular symptoms. Retinal vein thrombosis leading to sudden blindness is not rare.

Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behçet disease. The main complication of CVT was severe visual loss from optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients.

Vascular involvement

Vascular involvement occurs in 7-29% of patients, mostly men. Histologic findings include media thickening, elastic fiber splitting, and perivascular round cell infiltration. The 4 types of vascular lesions recognized in persons with Behçet disease are arterial occlusions, venous occlusions, aneurysms, and varices. Venous involvement is usually limited to occlusion, with the varices rarely affected. Affected sites of the venous system are the superior vena cava, inferior vena cava, deep femoral vein, and subclavian vein.

Arterial complications account for 7% of cases. Aneurysm and occlusion are most common. The subclavian artery and pulmonary artery are the most common arteries occluded. Depending on the site, arterial occlusions can have different clinical presentations. Pulseless disease is due to subclavian artery occlusion. Hypertension can originate from renal artery stenosis. Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.

Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis. Aneurysm formation accounts for most vascular deaths. Common sites of aneurysms are the abdominal aorta, femoral artery, and thoracic artery. Because the vascular involvement of Behçet disease can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.

Gastrointestinal involvement

The clinical spectrum of gastrointestinal effects^[is enormously varied and occurs in more than 10% of patients with Behçet disease. Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur.

Joint manifestations

More than half the patients develop signs or symptoms of synovitis, arthritis, and/or arthralgia during the course of the disease.^[The most frequent minor feature in childhood-onset Behçet disease is reported to be arthritis, occurring in 11 of 40 patients. Multiple-joint involvement is common. Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.

Neurologic manifestations

The rate of neurologic involvement in persons with Behçet disease varies from 3.2-49% according to the reports of different populations. Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosis–like illness, acute myelitis, stroke, or pseudotumor cerebri.

Three categories of neurologic involvement are (1) brain stem syndrome, (2) meningomyelitis syndrome, and (3) organic confusional syndrome. Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset. Severe headache is the most frequent initial neurological symptom.

Pregnancy-associated manifestations

Pregnant women with Behçet disease may experience more severe symptoms during the course of the pregnancy, especially in the first trimester. Overall, pregnancy does not seem to markedly affect the course of Behçet disease.^[11] Close follow-up is necessary to monitor the health of the mother and baby.

Other organ manifestations

Myocarditis and cardiac vessel disease may occur. Major hemoptysis may result from pulmonary vascular thrombosis, aneurysms, or vasculitis. Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. However, most patients have been asymptomatic.

Pathergy (skin hyperreactivity)

The presence of pathergy strongly suggests the diagnosis of Behçet disease. Following a needle prick or intradermal injection with saline or dilute histamine, the puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult. The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis. Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions.

Causes

1. Immunogenetics

o                  HLA-B51 or its B101 allele is significantly associated with Behçet disease in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of Behçet disease, their neutrophils show excessive function.

§                The MICA allele is a polymorphic MHC class I–related A gene (MICA) family.

§                The MICA6 allele has recently been shown to be significantly associated with Behçet disease (74%), compared with controls (45.6%) in Japan.

§                The relationship between MICA6 and Behçet disease was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to Behçet disease continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with Behçet disease, but it showed a strong association with HLA-B51; therefore, the association between MICA6 and Behçet disease may be a secondary phenomenon related to HLA-B51

o                  MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with Behçet disease. This mutation has been associated with vascular Behçet disease.

o                  Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in Behçet disease patients; thus, reports of TNF-alpha blockers having therapeutic benefits have been reported. Park et al analyzed TNF-alpha haplotypes in the promoter response element that affect the binding affinity of certain transcription factors. Their study showed that TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles were significantly associated with Behçet disease. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to Behçet disease.

o                  Single nucleotide polymorphism (SNP) of the gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has been strongly genetically linked to human autoimmune diseases; however, an inverse relationship exists between Behçet disease and this gene.

 

2. Viral and bacterial infection

o                  Investigations of the etiology of Behçet disease have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens.

o                  Behçet suggested the herpes simplex virus as a causative agent in his first report. Polymerase chain reaction studies have remarkably improved the diagnostic significance of viral infections, especially herpes simplex virus. Herpes simplex virus DNA has been detected in saliva, genital ulcers, and intestinal ulcers of patients with Behçet disease. Behçet disease–like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.

o                  Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of Behçet disease.

o                  The multiplicity of etiologic factors may have a common denominator in the 65-kd microbial heat shock protein (HSP), which shows significant homology with the human 60-kd mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in Behçet disease cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen.

o                  T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65-kd HSP that specifically stimulates T-cell receptor (TCR⁺) lymphocytes from patients with Behçet disease.

§                These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60-kd HSP.

§                B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes, and both immunoglobulin G and immunoglobulin A antibodies have been identified.

§                Among the 4 T- and B-cell epitopes, peptide 336-351 of the 60-kd HSP is significantly associated with Behçet disease in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of Behçet disease skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of Behçet disease.

§                An experimental model of Behçet disease uveitis was established in rats, in which subcutaneous immunization with peptide 336-351 and adjuvants elicited uveitis in approximately 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with Behçet disease.

3.Immunological abnormalities

o                  In persons with Behçet disease, the Th1 cytokine interferon (IFN) level is elevated in serum, in skin T cells, and cerebrospinal fluid, and interleukin (IL)–12 is generated by the stimulation of CD4⁺ T cells with the HSP peptide 336-351, although IL-12 can also be secreted by neutrophils in persons with Behçet disease. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with Behçet disease, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell.

o                  Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with Behçet disease suggests that Th1-type mRNA is induced (IL-2 and IFN).

o                  Investigations of intracellular IFN and IL-4 suggest that polarization toward the Th1 type of cells occurs in patients with active Behçet disease because of a significant increase in the intracellular IFN that was not observed with IL-4. However, the converse was found in another investigation by stimulating peripheral blood mononuclear cells, with increased Th2 cytokines (IL-10 and decreased IL-2 or IFN) in active Behçet disease.

o                  The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with Behçet disease, and this may have induced increased adhesion of T cells to the endothelial cells.

o                  Levels of the proinflammatory cytokines tumor necrosis factor (TNF)–alpha, TNF receptor 1, IL-1, and IL-8 are elevated in the serum of persons with Behçet disease and remain unregulated in peripheral blood mononuclear cells and neutrophils of patients with Behçet disease. Levels of IL-10 and IL-13 may also be elevated.

o                  IL-23 p19 mRNA has been detected in erythema nodosum-like lesions of Behçet’s disease. This finding suggests that anti – IL-23 therapy may be an option for treatment.

o                  Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behçet disease.

o                  Neopterin is produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells; thus, it serves as a marker for cellular immune activation. Kose et al showed that serum levels of neopterin were significantly higher in active and inactive Behçet disease patients than in controls. Those with active disease had higher levels than those with inactive disease.

o                  Polymorphisms in toll-like receptor 4 have been associated with Behçet disease.

4.Endothelial and vascular dysfunctions

o                  Vascular changes leading to vasculitis and thrombosis are important pathological features of Behçet disease.

o                  A recent study proposes that immunoglobulin to carboxy-terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen in Behçet disease. Interestingly, this autoantigen level was not only elevated in 41% of Behçet disease patients, but also in 45% of those patients with primary vasculitis, thus this marker may also point at endothelial dysfunction in vasculitis.

o                  Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in Behçet disease.

o                  T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly.

o                  Esmat et al showed much higher serum lipoprotein(a) levels in patients with vascular complications and lower levels of serum nitrites during disease activity.

o                  Another study demonstrated an association of factor V Leiden and G20210A prothrombin mutation with thrombosis in Behçet disease patients.

o                  Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane, and thrombomodulin are increased.

o                  The level of endothelin 1 and 2 is increased in patients with Behçet disease vascular involvement.

o                  Endothelial cell–dependent vasodilator function is significantly impaired in patients with Behçet disease and is demonstrated by high-resolution ultrasound imaging.

o                  Thrombomodulin is a receptor on vascular endothelial cells, which, when down-regulated, leads to a procoagulation state. Most of the high levels of thrombomodulin are observed in persons with skin pathergy reactions. This may help explain vasculitis and vascular symptoms associated with Behçet disease.

o                  Thrombin activatable fibrinolysis inhibitor levels are higher in Behçet disease patients than in those without the disease, possibly contributing to the increased thrombosis observed in these patients.

Differential Diagnoses

       Acute Febrile Neutrophilic Dermatosis

       Aphthous Stomatitis

       Erythema Multiforme

       Erythema Nodosum

       Herpes Simplex

       Lupus Erythematosus, Acute

       Pyoderma Gangrenosum

       Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Laboratory Studies

Behçet disease cannot be confirmed through clinical laboratory results.

Mild anemia and leukocytosis are observed in some patients with chronic disease.

The erythrocyte sedimentation rate, C-reactive protein value, and other acute phase reactants may be elevated during the active stage of Behçet disease, but they do not correlate well with the clinical activity.

An increase in alpha-2 globulins is often observed. Serum immunoglobulin levels, especially immunoglobulin A, may be elevated.

Circulating immune complexes are often present.

Rheumatoid factor and antinuclear antibodies are absent.

Antineutrophil cytoplasmic antibody and antiphospholipid antibody test results are usually negative.

Medical Care

Although multiple therapeutic modalities have been used, treatment is far from satisfactory. Treatment of Behçet disease seems to be symptomatic and empiric. Therapeutic efficacy has been difficult to evaluate because of the variable course of the disease and the limited number of cases for clinical investigation.

1. Local therapy

o                  Tetracycline remains the drug of choice for aphthous stomatitis and oral ulcers of Behçet disease.

o                  The patient dissolves the contents of a 250-mg tetracycline capsule in 5 mL of water or flavored syrup and holds the solution in the mouth for approximately 2 minutes before swallowing. This is repeated 4 times daily.

o                  Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration.

o                  Other useful drugs include lidocaine gel (2%), sucralfate suspension, and 5% amlexanox.

o                  Twice daily usage of topical 0.2% hyaluronic acid gel improved inflammation and healing periods and reduced oral ulcers.

2. Systemic therapy

o                  No single drug has proven effective.

o                  Corticosteroids are the mainstay of treatment for all the various clinical manifestations. Although they have a beneficial effect on acute manifestations, no definite evidence indicates they are effective for controlling progression.

o                  The adverse effects of long-term steroid therapy must be considered.

o                  Mucocutaneous lesions and arthritis have been treated with nonsteroidal anti-inflammatory drugs, zinc sulfate, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide (use is strictly limited because of its teratogenicity). Immunosuppressive therapy with azathioprine, chlorambucil, or cyclophosphamide has been used.

o                  Uveitis and central nervous system involvement is treated with systemic corticosteroids, azathioprine, or cyclosporine. However, in patients with central nervous system involvement, risks and benefits of cyclosporine need to be considered given the medication may have neurological side effects.

o                  Anticoagulants are given to patients with thromboses.

o                  Other therapeutic approaches have included cyclosporine, IFN alfa, IFN gamma, acyclovir, high-dose corticosteroids or cyclophosphamide pulse therapy, and FK506 (tacrolimus, an immunosuppressive agent similar to cyclosporine).

o                  FK506 (tacrolimus) has been particularly noteworthy. The Japanese FK506 study group reported that FK506 was effective in treating refractory uveitis in a dosage-dependent manner. Adverse effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%). The study group also noted the need for further clinical investigations on FK506 before more widespread application.

o                  Subcutaneous IFN alfa-2a therapy has resulted in reduced ulcers and eye disease. Flulike symptoms were the most common adverse effect. Leukopenia, hair loss, and development of antinuclear and antithyroid antibodies were reported less commonly.

o                  A patient with Behçet disease presenting with oral ulcers resistant to prednisone, azathioprine, colchicine, dapsone, and cyclosporin responded well to lenalidomide.

o                  In a single patient previously diagnosed with Behcet syndrome with recurrent oral aphthous ulcers, quadruple therapy (proton pump inhibitor, bismuth, tetracycline, and metronidazole), for histologically positive H pylori determined by upper gastrointestinal endoscopy, reduced the development of new ulcers and frequency of recurrent attacks for less than one month. Evaluation of breath test for H pylori was negative in the first month after discontinuation of therapy.

o                  A patient with Behçet disease with ocular involvement, dependant on corticosteroids and refractory to azathioprine, showed improvement with the addition of pentoxifylline.

o                  A case of Behçet disease resistant to prednisone, cyclosporin, azathioprine, infliximab with methotrexate, and colchicine has been successfully treated with anakinra.

o                  With the possible role of TNF-alpha in the pathogenesis of Behçet disease, infliximab, a chimeric monoclonal immunoglobulin G antibody that inhibits TNF-alpha, and etanercept, a TNF receptor blocker, have steroid-sparing effects and have decreased the frequency of attacks in patients with Behçet disease.

§                Case reports describe treatment of patients with recalcitrant disease or those in whom conventional immunosuppressive agents have failed.

§                Pediatric case responding to infliximab has been reported.

§                Infliximab has resulted in responses after etanercept failed.

§                Infliximab infusions of 5-10 mg/kg have been used with variable dosing schedules.

§                Infliximab infusions, at a starting dose of 5 mg/kg, have been beneficial in Behçet disease patients with ocular involvement who were unresponsive to standard immunosuppressive therapy.

§                Tuberculosis was a reported adverse effect of infliximab infusion in one Behçet disease patient.

§                Several patients not responding to infliximab have been treated with adalimumab.

§                Etanercept has been used at 25 mg twice a week.

Surgical Care

Surgical therapy becomes necessary in serious conditions, including the following:

• Gastrointestinal perforation
• Enterocutaneous fistula formation
• Spontaneous arterial aneurysm formation
• Thrombotic obstruction in large-caliber vessels
• Cardiac involvement
• Proper timing for surgical treatment is important.
• Delayed wound healing or inflammation at operative sites may be related to pathergy.

Consultations

• Dermatologist – For evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions)
• Ophthalmologist – For evaluation of eye involvement
• Rheumatologist or orthopedic surgeon – For evaluation of joint involvement
• Neurologist or psychiatrist – For evaluation of CNS involvement
• Internal medicine specialist – For evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement
• General surgeon – For evaluation of gastrointestinal involvement
• Chest surgeon or cardiologist – For evaluation of cardiovascular involvement
• Ear, nose, and throat specialist or dentist – For evaluation of oral cavity

1. Corticosteroids

Class Summary

These agents modify the body’s immune response to diverse stimuli and therefore have anti-inflammatory properties. In addition, they cause profound and varied metabolic effects. Corticosteroids are immunosuppressive and affect the replication, movement, and activity of virtually all cells involved with inflammation.

    Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

     Hydrocortisone (Solu-Cortef)

 

2. Nonsteroidal anti-inflammatory drugs

Ibuprofen (Ibuprin, Advil, Motrin)

 

3. Antibiotics

Tetracycline (Sumycin) 

4. Antiulcer agents

Class Summary

    Amlexanox (Aphthasol)

       Sucralfate (Carafate, Sulcrate)

 

5. Immunosuppressive agents

Class Summary

 

    Azathioprine (Imuran)

       Chlorambucil (Leukeran)

       Tcrolimus (Prograf, Tacrine, FK506)

       Cyclosporine (Sandimmune, Neoral)

 

6. Immunomodulators

Class Summary

    Thalidomide (Thalomid)

       Infliximab (Remicade)

       Etanercept (Enbrel)

 

 

References:

 

1. Baranathan V, Stanford MR, Vaughan RW, Kondeatis E, Graham E, Fortune F. The association of the PTPN22 620W polymorphism with Behcet’s disease. Ann Rheum Dis. Nov 2007;66(11):1531-3. [Medline].

 

2. Lew W, Chang JY, Jung JY, Bang D. Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behcet’s disease. Br J Dermatol. Mar 2008;158(3):505-11. [Medline].

3. Menashi S, Tribout B, Dosquet C, et al. Strong association between plasma thrombomodulin and pathergy test in Behcet disease. Ann Rheum Dis. Jun 2008;67(6):892-3. [Medline].

4. Ricart JM, Ramon LA, Vaya A, et al. Fibrinolytic inhibitor levels and polymorphisms in Behcet disease and their association with thrombosis. Br J Haematol. May 2008;141(5):716-9. [Medline].

5. Lee JH, Jung JY, Bang D. The efficacy of topical 0.2% hyaluronic acid gel on recurrent oral ulcers: comparison between recurrent aphthous ulcers and the oral ulcers of Behcet’s disease. J Eur Acad Dermatol Venereol. May 2008;22(5):590-5. [Medline].

6. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A. Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease. Ann Rheum Dis. Oct 2009;68(10):1528-34. [Medline].

7. [Best Evidence] Saadoun D, Wechsler B, Resche-Rigon M, et al. Cerebral venous thrombosis in Behcet’s disease. Arthritis Rheum. Apr 15 2009;61(4):518-26. [Medline].

 

8. Borhani Haghighi A, Safari A, Nazarinia MA, Habibagahi Z, Shenavandeh S. Infliximab for patients with neuro-Behcet’s disease: case series and literature review. Clin Rheumatol. Jul 2011;30(7):1007-12. [Medline].

 

9. Capella MJ, Foster CS. Long-term efficacy and safety of infliximab in the treatment of Behçet’s disease. Ocul Immunol Inflamm. Jun 2012;20(3):198-202. [Medline].

 

 

 

 

 

 

 

 

 

DERMATOMYOSITIS

http://emedicine.medscape.com/article/332783-overview

Background

Dermatomyositis is an idiopathic inflammatory myopathy (IIM) with characteristic cutaneous findings. It is a systemic disorder that most frequently affects the skin and muscles, but may also affect the joints, the esophagus, the lungs, and, less commonly, the heart.Calcinosis is a complication of dermatomyositis that is observed most often in children and adolescents. An association between dermatomyositis and cancer has long been recognized.

In 1975, Bohan and Peter first suggested a set of 5 criteria to aid in the diagnosis and classification of dermatomyositis and polymyositisFour of the 5 criteria are related to the muscle disease, as follows: progressive proximal symmetrical weakness, elevated levels of muscle enzymes, an abnormal finding on electromyography, and an abnormal finding on muscle biopsy. The fifth criterion was compatible with cutaneous disease.

Bohan and Peter suggested 5 subsets of myositis, as follows:

• Dermatomyositis
• Polymyositis
• Myositis with malignancy
• Childhood dermatomyositis/polymyositis
• Myositis overlapping with another collagen-vascular disorder

In a subsequent publication, Bohan et al noted that cutaneous disease may precede the development of the myopathy.In addition, the existence of another subset of patients with dermatomyositis that affects only the skin (ie, amyopathic dermatomyositis [ADM], or dermatomyositis sine myositis) has been recognized. Finally, another subset of patients with dermatomyositis have controlled myopathy but continue to have severe and sometimes debilitating skin disease (ie, postmyopathic dermatomyositis).

ADM is diagnosed in patients with typical cutaneous disease who show no evidence of muscle weakness and in whom serum muscle enzyme levels are repeatedly normal over a 2-year period in the absence of the use of disease-modifying therapies such as corticosteroids, immunosuppressive agents, or both for 2 months or longer.

When studied, some ADM patients may have abnormal findings on ultrasonography, electromyography, magnetic resonance imaging (MRI), magnetic resonance spectroscopy, or muscle biopsy. These patients have muscle involvement, and their condition may be better classified as hypomyopathic dermatomyositis. Patients with ADM or hypomyopathic DM may also reflect an underlying malignancy, and some develop severe pulmonary disease, particularly persons in Asian countries.

Patients exist in whom myositis resolves after therapy but whose skin disease remains an active and important feature of the disorder. These patients are not classified as having ADM, even though by this point, the skin is the major and often only manifestation of the disease. Germani and colleagues have suggested the term postmyopathic dermatomyositis for these patients.

Rare cutaneous manifestations include vesiculobullous erosive lesions and an exfoliative erythroderma. Biopsy samples from patients reveal an interface dermatitis similar to that seen in biopsy samples of heliotrope rash, Gottron papules, poikiloderma, or scalp lesions. These cutaneous manifestations may be more common in patients with an associated malignancy than in those without a malignancy.

Therapy for the muscle component of dermatomyositis involves the use of corticosteroids, with or without an immunosuppressive agent. The skin disease is treated with sun avoidance, sunscreens, topical corticosteroids, antimalarial agents, methotrexate, mycophenolate mofetil, or intravenous (IV) immunoglobulin. Rituximab may be useful in the treatment of muscle disease of dermatomyositis and has had mixed results in treatment of skin disease.

Physical therapy and rehabilitative measures are necessary in selected patients. Sun protective measures are necessary for patients with skin disease. Patients may visit The Myositis Association Web site for more information.

The prognosis of dermatomyositis depends on the severity of the myopathy, the presence of malignancy, and/or the presence of esophageal and/or cardiopulmonary involvement. Residual weakness is common, even in patients who fully recover.

 

Dermatologic Manifestations of Dermatomyositis

http://emedicine.medscape.com/article/1064945-overview

 

Overview

Dermatologic manifestations of dermatomyositis are only one of a set of features of this disease. Dermatomyositis is not only an idiopathic inflammatory myopathy (IIM) with characteristic cutaneous findings but also a systemic disorder that frequently affects the joints, the esophagus, the lungs, and, less commonly, the heart.

Classification of dermatomyositis and myositis

In 1975, Bohan and Peter first suggested a set of criteria to aid in diagnosing and classifying dermatomyositis and polymyositis (PM).Of the 5 criteria, 4 relate to the muscle disease (eg, progressive proximal symmetrical weakness, elevated muscle enzyme levels, abnormal findings on electromyograms [EMGs], and abnormal findings from muscle biopsy], and the fifth is compatible cutaneous disease.

These investigators also suggested 5 subsets of myositis:

(1) dermatomyositis,

(2) polymyositis,

(3) myositis with cancer,

(4) childhood dermatomyositis/polymyositis, and

(5) myositis overlapping with another collagen vascular disorder.

Subsequently, Bohan and Peter noted that cutaneous disease might precede the development of the myopathy. However, another possible subset of patients with disease that affects only the skin has been recognized; this condition is known as amyopathic dermatomyositis (ADM), or dermatomyositis sine myositis. The association between dermatomyositis (and possibly polymyositis) and cancer has long been recognized.

Rare cutaneous manifestations of dermatomyositis include vesiculobullous, erosive lesions and an exfoliative erythroderma. Biopsy samples from patients reveal an interface dermatitis similar to that of biopsy samples of heliotrope rash (see the images below), Gottron papules, poikiloderma, or scalp lesions. These cutaneous manifestations may be more common in patients with an associated malignancy than in those without a malignancy.

 

The heliotrope rash is a characteristic and possibly pathognomonic cutaneous feature of dermatomyositis. The heliotrope flower from which the manifestation is named is pictured.

 

Amyopathic, hypomyopathic, and postmyopathic dermatomyositis

Amyopathic dermatomyositis (dermatomyositis sine myositis) is diagnosed in patients with typical cutaneous disease in whom no evidence of muscle weakness exists and in whom serum muscle enzyme levels are repeatedly normal for a 2-year period in the absence of disease-modifying therapies such as corticosteroids, immunosuppressive agents, or both. When studied, some patients with amyopathic dermatomyositis have abnormal ultrasonographic, magnetic resonance imaging (MRI) or MR spectroscopy, or muscle biopsy findings. These patients have muscle involvement, and their condition may be better classified as hypomyopathic dermatomyositis. Patients with these variations may also reflect an underlying malignancy, and some develop severe pulmonary disease, particularly persons from Asian countries.

Patients exist in whom myositis resolves following therapy but whose skin disease remains as an active, important feature of the disease. These patients are not classified as having amyopathic dermatomyositis, despite the fact that, at this point in time, the skin is the major and often only manifestation of the disease. Gerami and colleagues have suggested the term postmyopathic dermatomyositis for these patients.

Pathophysiology

The pathogenesis of the -+cutaneous disease of dermatomyositis is poorly understood, but it is believed that similarities exist with that of cutaneous lupus erythematosus, in which T-cells are involved and antibody-mediated cell cytotoxicity may play a role. Dermatomyositis-associated myopathy appears to be due to vascular inflammation.

Clinical Presentation

Patients with dermatomyositis often present with skin disease as one of the initial manifestations. In as many as 40% of patients, the skin disease may be the sole manifestation at the onset. Muscle disease may occur concurrently, it may precede the skin disease, or it may follow the skin disease by weeks to years. In addition, systemic manifestations may occur; therefore, a review of systems should assess for the presence of arthralgias, arthritis, dyspnea, dysphagia, arrhythmias, and dysphonia.

Several reports have also described drug-induced dermatomyositis or existing dermatomyositis exacerbated by certain drugs, including statins and interferon therapy. Dermatomyositislike skin changes have been reported with hydroxyurea in patients with chronic myelogenous leukemia or essential thrombocytosis. Other agents that may trigger the disease include penicillamine, statin drugs, quinidine, and phenylbutazone.

Skin eruption/hair loss

Patients ofteotice an eruption on exposed surfaces. The disease is often pruritic, and, sometimes, intense pruritus may disturb sleep patterns. Patients may also complain of a scaly scalp or diffuse hair loss (see the image below).

 

A diffuse alopecia with a scaly scalp dermatosis is common in dermatomyositis.

Muscle involvement

Muscle involvement manifests as proximal muscle weakness. Patients often begin to note fatigue of their muscles or weakness when climbing stairs, walking, rising from a sitting position, combing their hair, or reaching for items in cabinets that are above their shoulders. Muscle tenderness may occur, but it is not a regular feature of the disease.

Malignancy

Malignancy is possible in any patient with dermatomyositis, but it is much more common in adults older than 60 years. Only a handful of children with dermatomyositis and malignancy have been reported. The history should include a thorough review of systems, as well as an assessment for previous malignancy.

Juvenile dermatomyositis

Children with dermatomyositis may have an insidious onset that hides the true diagnosis until the dermatologic disease is clearly observed and diagnosed. Calcinosis is a complication of juvenile dermatomyositis (see the following image), but it is rarely observed at the onset of disease. Black persons and patients in lower socioeconomic groups are more likely to have a delay in their diagnosis. The prognosis in children with dermatomyositis is worse in those in whom diagnosis is delayed.

Calcinosis due to dermatomyositis in childhood can be seen in apatient who had active dermatomyositis 15 years before the time of this photograph.

Physical Evaluation

Dermatomyositis is a disease that primarily affects the skin and the muscles, but it might also affect other organ systems.

The characteristic and possibly pathognomonic cutaneous features of dermatomyositis are the heliotrope rash and Gottron papules. Several other cutaneous features are characteristic of the disease despite not being pathognomonic. They include malar erythema, poikiloderma in a photosensitive distribution, violaceous erythema on the extensor surfaces, and periungual and cuticular changes.

Heliotrope rash and Gottron papules

The heliotrope rash consists of a violaceous to dusky erythematous rash with or without edema in a symmetrical distribution involving the periorbital skin (see the image below). Sometimes, this sign is subtle and may consist of only a mild discoloration along the eyelid margin. Similar to other areas, scales may be present on the eyelids. A heliotrope rash is rarely observed in other disorders; therefore, its presence is highly suggestive of dermatomyositis.

Heliotrope rash in a woman with dermatomyositis.

Gottron papules are found over bony prominences, particularly the metacarpophalangeal joints, the proximal interphalangeal joints, and/or the distal interphalangeal joints (see the following image). They may also be found overlying the elbows, the knees, and/or the feet. The lesions consist of slightly elevated, violaceous papules and plaques. A slight scale may be present, and, occasionally, a thick psoriasiform scale is observed. These lesions may resemble lesions of lupus erythematosus, psoriasis, or lichen planus.

Nail fold changes consist of periungual telangiectases and/or a characteristic cuticular change with hypertrophy of the cuticle and small, hemorrhagic infarcts in this hypertrophic area (also seen in the image below). Periungual telangiectases may be clinically apparent, or they may be appreciated only by capillary microscopy.

Gottron papules and nail-fold telangiectasia are present in this patient.

Poikiloderma and photodistribution

Poikiloderma may occur on exposed skin, such as the extensor surfaces of the arm, the vee of the neck (see the image below), or the upper part of the back (Shawl sign) or on the lateral thighs (Holster sign).

Dermatomyositis is often associated with a poikiloderma in a photodistribution.

With the exception of the heliotrope rash, the eruption of dermatomyositis is photodistributed and photoexacerbated (see the following image). Patients rarely complain of photosensitivity, despite the prominent photodistribution of the rash.

The lesions on the dorsal aspect of the hand demonstrate the photodistribution of dermatomyositis. Note the sparing of the interdigital web spaces.

Face, scalp, and knuckle involvement

Facial erythema may also occur in dermatomyositis. This change must be differentiated from lupus erythematosus, rosacea, seborrheic dermatitis, or atopic dermatitis. A study from Japan highlighted the finding of disease on the face that mimicked seborrhea. Scalp involvement in dermatomyositis is relatively common and manifests as an erythematous to violaceous, psoriasiform dermatitis. Clinical distinction from seborrheic dermatitis or psoriasis is occasionally difficult. In some patients, nonscarring alopecia may occur and often follows a flare of systemic disease.

In some patients, particularly those with antisynthetase antibodies, ulceration over the knuckles occurs (see the image below). These lesions may require surgical intervention.

Ulceration over the dorsal and lateral fingers in a patient with dermatomyositis.

Other cutaneous findings

Other cutaneous lesions have been described in patients with dermatomyositis or polymyositis that do not reflect the interface changes observed at histopathologic examination with pathognomonic or characteristic lesions. These include panniculitis (see the following image) and urticaria, as well as changes of hyperkeratosis of the palms known as mechanic’s hands. Other findings include cutaneous mucinosis, follicular hyperkeratosis, hyperpigmentation, ichthyosis, white plaques on the buccal mucosa, cutaneous vasculitis, and a flagellate erythema.

Calcifying panniculitis in a patient with dermatomyositis.

Calcinosis of the skin or the muscle is unusual in adults, but it may occur in as many as 40% of children or adolescents with dermatomyositis. Calcinosis cutis manifests as firm, yellow or flesh-colored nodules, often over bony prominences. Occasionally, these nodules can extrude through the surface of the skin, in which case, secondary infection may occur.

Muscular and systemic findings

As noted in Clinical Presentation, muscle disease may occur concurrently with, precede, or follow the skin disease by weeks to years. Proximal symmetrical muscle weakness may be found. Patients may have difficulty rising from a chair or squatting and then raising themselves from this position. Sometimes, in an effort to rise, patients use other muscles that are not as affected. The careful examiner may note this finding. Testing of the muscle strength is part of each assessment of the patient. Often, the extensor muscles of the arms are more affected than the flexor muscles. Distal strength is almost always maintained. Muscle tenderness is a variable finding.

Other systemic features include joint swelling, changes associated with Raynaud phenomenon, and abnormal findings on cardiopulmonary examination. Joint swelling occurs in some patients with dermatomyositis. The small joints of the hands are the most frequently involved. The arthritis associated with dermatomyositis is nondeforming. Patients with pulmonary disease may have abnormal breath sounds. Patients with an associated malignancy may have physical findings relevant to the affected organs.

Clinical Management

The therapy for dermatomyositis involves general measures, measures to control the muscle disease, and measures to control the skin disease. In addition, in some patients, treating other systemic manifestations or complications may be necessary. Whereas therapy of the muscle component involves the use of corticosteroids with or without an immunosuppressive agent, therapy for the cutaneous disease is often difficult. Patients who present primarily with skin disease (amyopathic dermatomyositis) and those in whom the muscle component is controlled but who still have significant skin disease exist. The first-line of therapy is recognizing that the patient is photosensitive and advising the patient to avoid sun exposure and to use sun protective measures, including broad-spectrum sunscreens. Topical corticosteroids have also been used.

Hydroxychloroquine and chloroquine have been beneficial in small open-label case studies. Methotrexate is also useful, and mycophenolate mofetil has been reported to be useful. In addition, intravenous immune globuliot only benefited the muscle but also cleared the skin lesions in the patients in whom it was used.Rituximab has been used for skin disease, but the results are mixed.

Aggressive early treatment of the myositis, particularly in children, may aid in the prevention of calcinosis. Once established, the process is debilitating in many patients. Although spontaneous remission is possible, it often occurs after many years. The use of the calcium channel blocker diltiazem (240 mg BID) is reportedly associated with gradual resolution of calcinosis in a small number of cases.In addition, the use of an oral bisphosphonate might be helpful.Intravenous pamidronate has also been demonstrated in several cases to result in resolution of the calcinosis.Some patients with local areas of calcinosis may wish to have them surgically removed, although surgical intervention is usually not necessary.

References:

1. Antiochos BB, Brown LA, Li Z, Tosteson TD, Wortmann RL, Rigby WF. Malignancy is associated with dermatomyositis but not polymyositis in Northern New England, USA. J Rheumatol. Dec 2009;36(12):2704-10. [Medline].

2. Fardet L, Dupuy A, Gain M, et al. Factors associated with underlying malignancy in a retrospective cohort of 121 patients with dermatomyositis. Medicine (Baltimore). Mar 2009;88(2):91-7. [Medline].

3. Antiochos BB, Brown LA, Li Z, et al. Malignancy is associated with dermatomyositis but not polymyositis in Northern New England, USA. J Rheumatol. Dec 2009;36(12):2704-10. [Medline].

4. Fardet L, Dupuy A, Gain M, et al. Factors associated with underlying malignancy in a retrospective cohort of 121 patients with dermatomyositis. Medicine (Baltimore). Mar 2009;88(2):91-7. [Medline].

5. Na SJ, Kim SM, Sunwoo IN, Choi YC. Clinical characteristics and outcomes of juvenile and adult dermatomyositis. J Korean Med Sci. Aug 2009;24(4):715-21. [Medline]. [Full Text].

6. Bendewald MJ, Wetter DA, Li X, Davis MD. Incidence of dermatomyositis and clinically amyopathic dermatomyositis: a population-based study in Olmsted County, Minnesota. Arch Dermatol. Jan 2010;146(1):26-30. [Medline]. [Full Text].

7. The Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol. Sep 2011;70(3):427-436. [Medline]. [Full Text].