Autoimmune Disorders: Making Sense of Nonspecific Symptoms

Autoimmune disorders occur when the body's immune system inappropriately attacks the body's own healthy tissues.^[1,2] These conditions may be restricted to specific organs (eg, autoimmune thyroiditis, which affects the thyroid, as shown), or they may involve a particular tissue that is present in different parts of the body (eg, Goodpasture syndrome, which may affect the basement membrane in the lungs and the kidneys). There are more than 80 different types of autoimmune diseases^[1]; their onset is typically slow, sometimes occurring over the course of years, and the symptoms are often nonspecific (eg, fatigue, general malaise, fever^[1]).

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The diagnosis of many autoimmune diseases is based upon the detection of specific antibodies with immunofluorescence (IF). However, the same autoantibody (eg, antinuclear antibody [ANA]) can be present in multiple diseases (eg, systemic lupus erythematosus [SLE] [shown], rheumatoid arthritis [RA]). Another diagnostic challenge is that patients with autoimmune diseases are often referred to different medical specialists on the basis of the organ system that is immediately affected. Treatment for autoimmune diseases often involves immunosuppressive agents, which decrease the body's immune response.^[1] The IF stain shown reveals immunoglobulin (Ig) G deposits (arrows) along the epidermal basement membrane ("lupus band") and within the nuclei of epidermal cells (ANA) from a patient with SLE.

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Some autoimmune conditions are benign and easily treatable, such as Hashimoto thyroiditis. However, others can be debilitating, with a slowly progressing course despite treatment, such as RA (shown). Autoimmune diseases have no cure, but different types of treatment can alleviate patients' symptoms or modify the disease process. Advanced therapy is also available, such as monoclonal antibodies (mAbs) against inflammatory factors (anti-tumor necrosis factors [anti-TNFs]) (eg, infliximab, adalimumab, certolizumab pegol, golimumab). Another type of treatment is the use of a circulating receptor fusion protein, such as etanercept.

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A 36-year-old woman presents with a 4-month history of increasing fatigue, periods of low-grade fever, and headaches. She complains of a rash that first appeared on her cheeks, but it now covers the bridge of her nose as well. The rash is not itchy and has not changed significantly over time. In addition, she has become very sensitive to cold temperatures; her fingers turn white and hurt when they are exposed to cold water. Furthermore, she recently walked on the beach for just 30 minutes without sunblock, and her fingers are now covered with a swollen blistering rash (shown).

Which of the following is the most likely diagnosis?
A. Atopic dermatitis
B. Poison ivy
C. SLE
D. Keratosis pilaris

Answer: C. SLE

SLE is a chronic inflammatory disease that has protean manifestations and follows a relapsing and remitting course.^[3] It primarily affects young women ^[3-5] and is characterized by an autoantibody response to nuclear and cytoplasmic antigens. The mnemonic "SOAP BRAIN MD" is used to remember the 1997 revised American College of Rheumatology (ACR) SLE diagnostic criteria^[3,7,8]: serositis, oral ulcers, arthritis, photosensitivity, blood disorders, renal disorder, ANA, immunologic disorders, neurologic disorder, malar rash, discoid rash). Raynaud phenomenon, in which cold temperatures or strong emotions cause blood vessel spasms that block blood flow to the fingers, toes, ears, and nose,^[6] is associated with SLE and other autoimmune disorders.^[3,4] The classic malar rash of SLE ("butterfly rash") (shown) is distributed over the cheeks and nasal bridge.^[3-5] The fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

Discoid rash occurs in 25% of SLE patients and can result in disfiguring scars.^[3] The rash can present as erythematous patches with keratotic scaling over sun-exposed skin areas.^[3,7,8] SLE is frequently confused with rosacea, a chronic condition that is characterized by facial erythema (shown). Pimples or acnelike lesions are sometimes included as a defining characteristic of rosacea.^[9,10] Unless it affects the eyes, rosacea is typically a harmless cosmetic condition. Its cause is unknown; multiple triggers (eg, sunlight, alcohol, cheese, heat, dermabrasion) can affect the course of rosacea. The primary modalities of rosacea treatment are topical agents and oral antibiotic agents.^[9,10] Treatment with topical steroids can aggravate the condition.

A 30-year-old white woman is evaluated for severe fatigue, depression, and problems with walking. Over the course of a 1-year follow-up, she has experienced similar symptoms that last 2-3 months, with completely symptom-free periods between episodes. Magnetic resonance imaging (MRI) of the brain and spine showed areas of demyelination (lesions or plaques). MRI with gadolinium contrast medium, repeated monthly, highlighted active plaques (shown, arrows).

Which of the following would likely be an additional feature found during evaluation of this patient?
A. Butterfly rash
B. Charcot triad
C. Blood eosinophilia and high IgE
D. Spider hemangiomas

Image courtesy of Medpedia.com (defunct). Derivative work in the form of an animation is available at Wikimedia Commons.

Answer: B. Charcot triad

Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of brain and spinal cord neurons are damaged by autoantibodies, resulting in demyelination and scarring.^[11,12] Signs/symptoms include visual, cognitive, speech, and motor/sensory disturbances. New symptoms may occur in discrete attacks (relapsing forms) or slowly accumulate over time (progressive forms). Between attacks, symptoms may go away completely.^[11,12] Permanent neurologic problems often occur, especially as the disease progresses.

Image of a cervical spine MRI with enhancement in a patient with MS courtesy of the National Institutes of Health (NIH).

A 48-year-old man is admitted to the intensive care unit (ICU) with rapidly deteriorating glomerulonephritis. On physical examination, he has bloody nasal discharge, productive cough, sclerokeratitis (shown), and saddle nasal deformity due to severe nasal septal perforation. Granulomatosis with polyangiitis (GPA) (formerly Wegener granulomatosis) is suspected.

Which of the following laboratory results would confirm the diagnosis of GPA?
A. Calcification of mediastinal lymph nodes and positive Histoplasma polymerase chain reaction (PCR)
B. Neurofibromatosis of the skin
C. Positive ANA and anti-thyroid peroxidase antibodies (anti-TPO)
D. Positive cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA) and vasculitis with multinucleated giant cells on hematoxylin and eosin (H&E) stain

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Answer: D. Positive C-ANCA and vasculitis with multinucleated giant cells on H&E stain

Patients with GPA may present with nonspecific complaints, or they may report ocular; ear, nose, throat; pulmonary; renal; cardiac; nervous system; or cutaneous symptoms/signs.^[13,14] C-ANCAs reveal a diffusely granular, cytoplasmic staining pattern under microscopy (shown, left); the most common protein target is proteinase 3.^[13,15,16] A key finding in active cases of GPA is a positive C-ANCA result, although levels of C-ANCA do not correlate with disease activity.^[13,15,16] Small and medium-sized vasculitis and formation of granulomas with multinucleated giant cells on H&E stain (shown, right) are characteristics of GPA, Churg-Strauss syndrome, and microscopic polyangiitis.^[13,18]

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A 44-year-old women presents with sudden onset of an extremely itchy rash that started on her stomach (shown) but then spread to her wrists and ankles. New lesions consist of blisters filled with whitish exudate that do not heal well if the exudate is scratched off. She does not recall receiving any insect bites, and she is not otherwise sick. The patient is treated with oral steroids, but her condition fails to improve. A complete blood count (CBC) and liver function studies are normal. Biopsy of the blistering rash demonstrates linear IgA bullous dermatosis.

What is the most likely diagnosis in this patient?
A. Dermatitis herpetiformis (DH)
B. Scabies
C. Poison ivy dermatitis
D. Churg-Strauss syndrome

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Answer: A. Dermatitis herpetiformis (DH)

DH is an autoimmune blistering disorder associated with a gluten-sensitive enteropathy (GSE).^[19-21] This condition is considered a cutaneous manifestation of celiac disease (DH affects 10% of those with celiac disease^[21]), and it is characterized by grouped excoriations; erythematous, urticarial plaques; and papules with vesicles (shown). The rash is typically located symmetrically on the extensor surfaces of the elbows, knees, buttocks, and back^[19-21]; the scalp may also be affected.^[21] The workup of DH includes skin biopsy with direct IF and blood and serologic studies.^[19-21] A gluten-free diet treats the underlying disease, but pharmacotherapy (eg, dapsone, or if the patient is dapsone intolerant, sulfapyridine or sulfamethoxypyridazine) may be required for symptomatic relief.^[19-21]

A 22-year-old male Israeli visitor complains of a 2-month history of intermittent abdominal pain, mouth ulcers (shown), and diarrhea (which has been bloody for the past 3 days). He has previously had 2 similar episodes that resolved spontaneously. His grandfather died of colon cancer; his twin brother has ulcerative colitis. On physical examination, he has 2 perianal abscesses and tender erythematous nodules on the left shin. Endoscopy shows ulcerative changes in the large intestine.

What should be the next step in the management of this patient?
A. Administering antiretroviral therapy
B. Administering infliximab and aminosalicylates
C. Immediately isolating the patient and administering isoniazid, ethambutol, and pyrazinamide
D. Administering chelation therapy

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Answer: B. Administering infliximab and aminosalicylates

The patient most likely has ulcerative colitis (UC) and Crohn disease (CD). CD can affect any part of the gastrointestinal tract,^[22] but UC characteristically affects the lining of the large bowel (shown, sigmoid colon) and rectum.^[23] CD has intermittent symptoms, including crampy abdominal pain, watery diarrhea (may be bloody), and/or mouth ulcers^[22]; its cause is unknown, but risk factors include Jewish ancestry^[22] and a family history of UC. There is no cure for CD; treatment is usually required for remission. Medications include infliximab, aminosalicylates, immunomodulators, corticosteroids, and other biologic agents. Therapy also includes stress control, healthy lifestyle, and dietary modifications.^[22] Symptoms of UC may be mild or severe, may start slowly or abruptly, and may overlap with those of CD. Pharmacotherapy and lifestyle modifications may control mild to moderate disease; removal of the colon cures UC.^[23]

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A 17-year-old girl is admitted to the emergency department after she is discovered unconscious at the local park. High levels of multiple opioids are found in her blood, and she is transferred to the ICU with the diagnosis of drug overdose. Her blood test results are also positive for anti-Scl-70 antibodies (topoisomerase I antibodies). After she regains consciousness, she admits that she tried to commit suicide and refuses to answer any other questions. During the course of recovery, she is noted to have sclerodactyly, difficulty swallowing, and the skin lesions shown.

Which of the following is the most likely cause of the skin lesions?
A. Self-mutilation injuries
B. Complications of human immunodeficiency virus infection
C. Child abuse
D. Localized morphea

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Answer: D. Localized morphea

Scleroderma is a chronic systemic autoimmune disease (primarily of the skin) of unknown etiology that is characterized by fibrosis, vascular alterations, and autoantibodies. Localized morphea, or limited/localized scleroderma (formerly CREST syndrome: calcinosis, Raynaud phenomenon [shown], esophageal dysfunction, sclerodactyly [also shown], and telangiectasia), typically affects the hands, arms, and face.^[24-26] Diffuse systemic scleroderma is a rapidly progressing condition that affects a large skin area and one or more internal organs.^[24-26] A third form of scleroderma is systemic scleroderma, in which one or more organs are affected but not the skin.^[26] Genes associated with scleroderma include BANK1, BLK, IRF5, PTPN22, STAT4, and TNFSF4.^[26] Workup includes testing for autoantibodies (eg, anti-Scl-70, ANA); urinary protein levels; renal, cardiac, and/or pulmonary function studies; and/or skin biopsy.^[27] No treatment exists for scleroderma; management consists of symptomatic control and preventing complications.

A 27-year-old female, with previous diagnosis of chronic myeloid leukemia, underwent allogeneic bone marrow transplantation. Two days later, she developed acute graft-versus-host disease (GVHD) on the intestine, which resolved. Over the past 4 months, she has developed a rash around her eyes (shown) and mouth as well as a progressive cough, and her liver enzymes have become elevated. She presents with sclerotic skin changes, hyperkeratosis of the hands, xerophthalmia, atrophic lesions on the buccal mucosa, xerostomia, and microstomia.

What is the most likely diagnosis in this patient?
A. New-onset scleroderma
B. Cushingoid syndrome caused by treatment with high-dose steroids
C. Scleroderma-like GVHD
D. Drug hypersensitivity type IV

Image courtesy of Pereira et al.^[28]

Answer: C. Scleroderma-like GVHD

Chronic GVHD may occur either as a late phase of acute GVHD or as a distinct entity.^[29] The skin is the primary organ involved in chronic GVHD, which can manifest as a lichen planus–like eruption or as scleroderma. Typical lacy, white patches of lichen planus on the buccal mucosa or tongue (shown) are often present.^[29] Other symptoms/signs may include keratoconjunctivitis sicca, xerostomia, polyserositis, esophagitis and stricture, intrahepatic obstructive liver disease, obstructive pulmonary disease, morphea, and fasciitis.^[28] Lichenoid and scleroderma are the two main types of cutaneous chronic GVHD. The differential diagnosis of GVHD includes Behçet disease,^[28] allergic/irritant contact dermatitis, drug eruptions, staphylococcal scalded skin syndrome, Stevens-Johnson syndrome/toxic epidermal necrolysis, toxic shock syndrome, and scleroderma.^[29] Workup includes skin biopsy^[29] and detection of autoantibodies (eg, anti-dsDNA, anti-smooth muscle autoantibody, anti-cytoskeletal antibody, ANA).^[28] Therapy includes continued immunosuppression therapy plus methylprednisolone and other modifying agents.^[28,29]

At her annual checkup, a 45-year-old woman states that she is doing fine, except that she is more fatigued than in the past, is losing hair, and has dry skin. On physical examination, her thyroid is mildly enlarged, painless, and mobile. Her heart rate is 58 bpm, and her blood pressure is 95/50 mm Hg. She has nonpitting edema of the feet; partial alopecia; and rough, dry skin. Laboratory tests show a normal CBC, a thyroid-stimulating hormone (TSH) level of 4.2 IU/mL, and the presence of thyroid peroxidase antibodies. An ultrasound study (shown) is performed; scintigraphy is also ordered.

What is the most likely diagnosis in this patient?
A. Graves disease, with diffuse increased uptake in both thyroid lobes
B. Plummer disease
C. Toxic adenoma
D. Hashimoto thyroiditis

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Answer: D. Hashimoto thyroiditis

Hashimoto thyroiditis (chronic lymphocytic thyroiditis or autoimmune thyroiditis)^[30,31] is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune processes. It is the most common cause of hypothyroidism in the United States.^[31] The diagnosis is made histologically, although thyroid function studies are used to diagnose primary hypothyroidism and to assess thyroid function.^[30-32] Typically, biopsy of the thyroid gland shows diffuse lymphocytic and plasma cell infiltration, with formation of lymphoid follicles from follicular hyperplasia and damage to the follicular basement membrane (shown).^[32] Atrophy of the thyroid parenchyma is usually evident. The presentation may be subclinical, although the typical finding is an elevated TSH level.^[30-32] The treatment of choice for Hashimoto thyroiditis is thyroid hormone replacement.^[30-32]

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