Chapter 22 Autoimmune connective tissue diseases
1. Discuss the skin changes of lupus erythematosus.
Skin changes occur very frequently in lupus erythematosus (LE) and are second in frequency only to musculoskeletal complaints in this condition, occurring in about 85% of patients. It is useful to classify the eruptions seen in LE as to their possible diagnostic and prognostic significance. Skin lesions that are diagnostic of LE have been called lupus-specific eruptions. Skin biopsies of these lesions show characteristic histopathologic changes of cutaneous LE. Further classification of the lupus-specific eruptions into subtypes of cutaneous LE is also useful, as some lesions of cutaneous LE are more strongly associated with systemic lupus erythematosus.
Lupus patients also develop many skin changes that are not specific for LE, termed lupus-nonspecific eruptions (Table 22-1). These eruptions do not help to establish a diagnosis of LE, but they may still be very important to note, as specific systemic findings may be associated with them. For example, cutaneous lesions of palpable purpura in a patient with LE are not lupus-specific, that is, such lesions may be seen in patients who do not have LE; however, they may be associated with vasculitic lesions of the kidney or central nervous system (CNS), and thus they have significance in the evaluation and treatment of lupus.
Table 22-1. Classification of Cutaneous Disease in Lupus Erythematosus
| LUPUS-SPECIFIC ERUPTIONS | LUPUS-NONSPECIFIC ERUPTIONS |
|---|---|
2. What is acute cutaneous lupus erythematosus (ACLE)?
ACLE presents as an acute malar or more generalized photodistributed eruption. The malar erythema has been described as a “butterfly rash,” since the pattern across the cheeks resembles the wings of a butterfly (Fig. 22-1). Nearly all patients presenting with ACLE will have systemic lupus erythematosus (SLE), often in an acute flare. ACLE is usually transient, improving when the SLE improves, and generally does not result in scarring of the skin. A common diagnostic pitfall is the confusion of rosacea with the malar rash of ACLE. Rosacea is common; it is photo-exacerbated. Nonspecific joint symptoms are common, and 5% of the normal population will have a positive antinuclear antibody (ANA) test, often leading to a misdiagnosis of ACLE. Remember, a patient with ACLE is most often in an acute flare and will be “sick,” whereas a rosacea patient will have a chronic history and no systemic symptoms beyond their baseline “aches and pains.”
3. Are there any common skin eruptions that may be confused with acute cutaneous lupus erythematosus?
Many patients have complaints of erythema of the face due to a wide variety of conditions, but not all of them are photoinduced. The differential diagnosis of photosensitive eruptions of the face is not as broad and includes polymorphous light eruption, photoreactions to systemic medications and topical products, and certain types of porphyria (see Chapter 17). In addition, certain facial eruptions, such as rosacea, occasionally may be triggered or worsened by sun exposure. ACLE is an important cutaneous finding since it is strongly associated with SLE. Thus, patients with ACLE will have additional systemic complaints relating to SLE and will nearly always have a positive ANA test.
4. What is subacute cutaneous lupus erythematosus (SCLE)?
This type of cutaneous LE was first described and characterized in the late 1970s. These patients have an eruption that is more persistent than that of ACLE, lasting weeks to months or longer. The lesions of SCLE consist of scaly, superficial, inflammatory macules, patches, papules, and plaques that are photodistributed, particularly on the upper chest and back, lateral neck, and dorsal arms and forearms. Several different morphologic types of SCLE have been described: annular, serpiginous, and two types of papulosquamous lesions, psoriasiform and pityriasiform (Fig. 22-2). Some patients have more than one morphologic type of lesion.
Figure 22-1. Acute cutaneous lupus erythematosus. Note the classic malar erythema (“butterfly rash”).
5. Do patients with SCLE have SLE?
About one half of patients with SCLE will have four or more criteria for the classification of SLE, though most SCLE patients do not have serious renal or CNS lupus erythematosus. Typically, they have skin disease, photosensitivity, and musculoskeletal complaints. Dry eyes and dry mouth are also common. Some patients with SCLE experience severe manifestations of SLE, and thus all SCLE patients should be monitored for systemic disease.
6. How do you make a diagnosis of SCLE?
SCLE is a clinical diagnosis based on the presence of a typical photodistributed eruption and a skin biopsy consistent with cutaneous LE. Direct immunofluorescence testing may also be helpful. In addition to granular deposition of immunoreactants at the dermal–epidermal junction, particulate deposition of IgG within the epidermis has been described in SCLE. Most patients with SCLE have circulating antibodies to Ro/SS-A (Sjögren’s syndrome A) and, less commonly, to La/SS-B (Sjögren’s syndrome B). These antibodies are not demonstrable in all patients with SCLE; thus, their absence does not exclude this diagnosis. Additionally, a negative ANA does not exclude the diagnosis of SCLE, and some patients may have positive titers to Ro/SS-A or La/SS-B but test negative for ANA.
7. What is the initial workup of SCLE?
Once a diagnosis of SCLE is made, it is important to evaluate for the presence of SLE:
• History and physical examination data should be gathered to identify manifestations of SLE in other organ systems.
• Laboratory testing should be directed by findings on the history and physical exam but will generally include a complete blood count with differential, urinalysis, serum chemistries including renal function tests, and an ANA panel to include anti–Ro/SS-A, anti–La/SS-B, and anti–native DNA antibodies. Complement determinations may be ordered since some SCLE patients have partial or complete complement deficiencies.
• A medication history is very important since SCLE may be triggered or worsened by a number of medications, especially thiazide diuretics (Table 22-2). Some physicians recommend avoiding estrogens and sulfonamides in any patient with LE.
8. How is SCLE managed?
Cutaneous complaints are often of most concern to these patients, and thus dermatologists are generally the physicians managing this disease. Broad-spectrum sunscreens and sun-protective measures, including lifestyle changes and clothing, are perhaps the most important initial measures. Some patients respond to topical steroids, although potent topical steroids are usually required. Oral antimalarial therapy is also beneficial in many patients. Less commonly used treatments include dapsone, gold, immunosuppressive drugs, retinoids, and systemic steroids.
9. What is chronic cutaneous lupus erythematosus?
There are several types of cutaneous LE that are very persistent, termed chronic cutaneous lupus erythematosus. Discoid lupus erythematosus (DLE) is the most common of these chronic forms of cutaneous LE. An unusual variant of DLE with thick keratotic scale is referred to as hypertrophic DLE. Tumid LE is a variant where scale and other epidermal changes are absent. Lupus panniculitis and lupus mucinotic nodules are other forms of chronic cutaneous LE.
10. Describe the skin changes of discoid lupus erythematosus.
DLE is a chronic inflammatory disease consisting of fixed, indurated, erythematous papules and plaques that are often distributed on the head and neck, although any cutaneous region can be affected (Fig. 22-3A). Without intervention, DLE lesions may last for many years and are associated with extensive scarring, a feature that helps distinguish DLE from SCLE. When DLE occurs on the scalp, permanent scarring alopecia may result. Pigmentary changes, both hyperpigmentation and hypopigmentation, are also frequently associated with lesions of DLE. Epidermal changes, including scale, keratotic plugging of the hair follicles, and sometimes crusting, are also generally present. The external ears are often involved in DLE (Fig. 22-3B); thus, this area should be carefully examined in patients with suspected DLE.
11. Do patients with DLE develop systemic lupus erythematosus?
If the initial workup of a patient with localized lesions of DLE does not reveal evidence of SLE, the risk of developing SLE is about 5%. If lesions are generalized, the risk is slightly higher. However, DLE lesions are not uncommon in patients with an established diagnosis of SLE. About 25% of SLE patients will develop lesions of DLE at some time in the course of their disease (Table 22-3).
12. How is discoid lupus erythematosus treated?
As with other types of cutaneous LE, sunscreens and sun-protective measures are the foundation of therapy. Potent topical steroids and intralesional corticosteroids are often helpful. Antimalarial drugs are also used. Less often, therapy with gold, immunosuppressive medications, or systemic corticosteroids is offered.
Wozniacka A, McCauliffe DP: Optimal use of antimalarials in treating cutaneous lupus erythematosus, Am J Clin Dermatol 6:1–11, 2005.
13. What is minocycline-induced lupus?
This condition has been reported in patients taking minocycline for acne. Most patients are young females who have taken minocycline chronically. The most common symptom is symmetric polyarthralgia, but other findings such as fatigue, fever, elevated liver enzymes, pneumonitis, and anemia have also been reported. Lupus-specific skin eruptions, such as acute cutaneous LE or discoid LE, have not been reported. Nearly all patients will have a positive screening ANA test. Once minocycline is discontinued, most patients have resolution of symptoms.
14. What is lupus panniculitis?
In lupus panniculitis, inflammation involves the subcutaneous tissue, resulting in inflamed nodules that often resolve with depressed scars. Lesions tend to favor the proximal extremities and trunk, which is a clinical clue differentiating this form of panniculitis from other forms of panniculitis. There may be overlying lesions of DLE. When lupus panniculitis occurs with an overlying DLE lesion, it may be called lupus profundus. About one half of patients with lupus panniculitis have four or more criteria for the classification of SLE. The diagnosis is confirmed by an adequate excisional biopsy. Small punch biopsies are not adequate to rule out other causes of panniculitis. Direct immunofluorescence examination may be helpful in establishing the diagnosis. The treatment of choice is antimalarial drugs.
Fraga J, García-Díez A: Lupus erythematosus panniculitis, Dermatol Clin 26:453–463, 2008.
15. Describe the bullous eruption of SLE.
This rare blistering eruption has been described primarily in patients with established SLE. The histopathologic findings are quite different from those of other forms of cutaneous LE. Biopsies demonstrate a separation of the epidermis from the dermis and a neutrophil-rich inflammatory cell infiltrate. Antibodies to type VII collagen, a component of anchoring fibrils (see Chapter 1), have been described in some patients with the bullous eruption of SLE. It has been proposed, but not proven, that these antibodies are involved in the pathogenesis of this disease.
17. What is neonatal lupus erythematosus (NLE)?
In NLE, infants develop skin disease (50%), heart disease (50%), or both (10%). The skin lesions occur most commonly on the face and head (Fig. 22-4), morphologically resemble SCLE lesions, and are transient, resolving within a few months, but sometimes leaving atrophic lesions. The heart disease usually manifests as isolated complete heart block, although lesser degrees of heart block have been reported. The heart block is generally permanent and may require a pacemaker. About 10% of infants with NLE and heart disease die from cardiac complications. A few infants with NLE also have thrombocytopenia and and/or liver disease.
Lee LA: Neonatal lupus erythematosus, J Invest Dermatol 100:9S–13S, 1993.
18. Which tests should be done in an infant with suspected NLE?
Serum from both the infant and mother should be assayed for ANA, and specifically for anti–Ro/SS-A, anti–La/SS-B, and anti-U1RNP antibodies. A skin biopsy for routine histology and direct immunofluorescence is also recommended. The biopsy will show histopathologic and direct immunofluorescence changes similar to those seen in SCLE.
19. Once a diagnosis of NLE is made, what workup should be done?
A physical examination should be performed, including cardiac examination and electrocardiogram. Because of reports of involvement of the liver and platelets, liver function tests and a platelet count should also be done. Additional tests or procedures may be done as indicated by physical findings. Mothers of infants with NLE should also be examined, because some will have or develop SCLE, SLE or symptoms of Sjögren’s syndrome.
20. What is the lupus band test?
This direct immunofluorescence test is performed either on lesional skin or on normal, nonlesional skin. Granular deposits of immunoglobulins and complement are detected in a band-like pattern at the dermal–epidermal junction (Fig. 22-5). When this pattern is seen in lesional skin, it supports a diagnosis of cutaneous LE. When found in nonlesional skin, it is suggestive of SLE.
21. What is scleroderma?
Scleroderma is a chronic disease that involves the microvasculature and connective tissue and results in fibrosis. It may be localized, as in morphea, or more generalized and involving visceral organs, as in progressive systemic sclerosis. In morphea, sclerotic, indurated plaques develop that may be solitary, multiple, linear, or generalized. The surface is usually smooth, with the center of the lesion a whitish to brown color (Fig. 22-6), whereas the border of active lesions is often violaceous. Morphea usually involves the skin and subcutaneous tissues but may involve deeper structures, even bone. Patients with morphea generally do not develop systemic sclerosis.
22. What is the CREST syndrome?
• Telangiectasia
CREST syndrome, or Thibierge-Weissenbach syndrome, is generally considered a type of limited systemic sclerosis. In addition to the cutaneous changes of calcinosis cutis, Raynaud’s phenomenon, sclerodactyly, and telangiectasia, these patients often develop hyperpigmentation, particularly in sun-exposed areas (Fig. 22-7). Most patients with the CREST syndrome have circulating antibodies to centromeres, called anticentromere antibodies.
23. Describe the early cutaneous findings in progressive systemic sclerosis (PSS).
The earliest cutaneous complaints of PSS are often swelling of the hands and feet or symptoms associated with Raynaud’s phenomenon. Telangiectasia may also develop early in the course of disease. The proximal nail folds show changes in the capillaries, including avascular areas (dropout) and marked dilatation. Over time, the skin of the digits becomes thickened and sclerotic (Fig. 22-8). Sclerotic changes are often progressive, involving the face and extremities, and may eventually involve large areas of the body. Other late changes include digital ulcers and even loss of the digits.
24. What is dermatomyositis?
Dermatomyositis is a chronic inflammatory disease involving the skin and skeletal muscles. Its etiology is unknown. Polymyositis is the term used for involvement of the skeletal muscles without cutaneous involvement. The muscle involvement usually presents as proximal muscle weakness, sometimes with pain, and later with muscle atrophy. Muscle involvement may precede, follow, or occur simultaneously with skin disease and, in some instances, may not be detectable, a condition called amyopathic dermatomyositis. A number of cutaneous changes are present, including blotchy erythema, erythematous to violaceous papules and plaques particularly on extensor surfaces, poikilodermatous changes, and calcinosis cutis.
25. Are there skin changes diagnostic of dermatomyositis?
Two cutaneous findings have been described as pathognomonic of dermatomyositis: Gottron’s papules and Gottron’s sign. Gottron’s papules are erythematous to purplish flat papules on the extensor surfaces of the interphalangeal joints. Gottron’s sign consists of symmetrical violaceous erythema, sometimes with edema, over the dorsal knuckles of the hands, elbows, knees, and medial ankles (Fig. 22-9A). Other skin findings that are characteristic of dermatomyositis are periorbital edema with a lilac-colored erythema (heliotrope, Fig. 22-9B), periungual telangiectasia with cuticle dystrophy, and a photodistributed violaceous erythema of the forehead; also, sun-exposed areas of the neck, upper chest, shoulders, dorsal arms, forearms, and hands. A diagnostic clue favoring dermatomyositis over lupus erythematosus is the violaceous erythema or papules over the knuckles. Lupus, on the other hand, shows erythema over the dorsal phalanges, but often spares the knuckles.
Callen JP, Wortmann RL: Dermatomyositis, Clin Dermatol 24:363–373, 2006.
Key Points: Dermatomyositis
1. Gottron’s papules (erythematous to violaceous papules over the knuckles) are a cutaneous finding that is pathognomonic of dermatomyositis.
2. Patients with dermatomyositis frequently demonstrate lilac-tinged erythema of the upper eyelids that is referred to as a heliotrope sign.
26. How do you diagnose dermatomyositis?
• Skin biopsy may be helpful, although the histopathologic changes are consistent with, rather than diagnostic of, dermatomyositis.
• Serum levels of muscle enzymes are typically elevated, with the creatine phosphokinase (CPK) level the most reliable indicator of disease activity.
• Biopsy of an affected muscle may be diagnostic, but nonspecific changes are also seen. The use of magnetic resonance imaging has been reported recently to be helpful in identifying muscle groups that would most likely yield significant findings on muscle biopsy.
27. Are any diseases associated with dermatomyositis?
Adults with dermatomyositis have been reported to have a variety of malignancies that sometimes follow a clinical course of exacerbation and remission in concert with the dermatomyositis. Screening with a careful history, physical examination and age appropriate laboratory screening tests is recommended in adult patients with dermatomyositis. Female patients should be carefully screened for ovarian cancer.
28. What is the antisynthetase syndrome?
The antisynthetase syndrome is seen in both polymyositis and dermatomyositis patients and is associated with the anti–Jo-1 antibody, in addition to anti-PL7, -PL12, -OJ, and -EJ autoantibodies. In addition to skin and muscle involvement, patients may develop arthritis, Raynaud’s syndrome, and interstitial lung disease.
29. What is an overlap syndrome?
Many patients diagnosed with autoimmune rheumatic disease display overlapping features of different connective tissue diseases and cannot be categorized easily into one of the established clinical entities, such as systemic lupus erythematosus, dermatomyositis, or systemic sclerosis. The term “overlap syndrome” has been used to classify these patients and is useful for descriptive purposes, clarifying prognosis and facilitating disease management.
30. What is mixed connective tissue disease?
Mixed connective tissue disease (MCTD) is a disorder characterized by a mixture of other well-defined connective tissue disorders such as systemic lupus erythematosus, progressive systemic sclerosis, dermatomyositis, and even Sjögren’s syndrome. Most patients with MCTD have anti-U1RNP ribonuclear protein (U1RNP) antibodies. Patients often present with Raynaud’s phenomenon, swelling of the digits (dactylitis), and arthritis. Patients may develop myositis, sclerodermoid lesions of the skin, and, later, sclerodactyly. Interstitial lung disease and renal disease may ensue.
Venables PJ: Mixed connective tissue disease, Lupus 15:132–137, 2006.
31. What is the antiphospholipid antibody syndrome?
Antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant antibodies, and anti–β2-glycoprotein I antibodies) are associated with an increased risk of both arterial and venous thrombosis and recurrent spontaneous abortions. Patients may present to the dermatologist with livedo reticularis, retiform purpura, ulcerations, deep venous thrombosis, or superficial thrombophlebitis. Sneddon’s syndrome is livedo reticularis/retiform purpura associated with CNS thrombosis (stroke). Catastrophic antiphospholipid antibody syndrome involves multiple other organ systems with thrombosis involving the CNS, lungs, kidneys, gastrointestinal tract, and skin.
32. What are some other connective tissue diseases with cutaneous manifestations?
• Autoimmune urticaria: May affect up to 30% or more of chronic idiopathic urticaria patients (>6 weeks duration of urticaria) with associated autoantibodies to the high-affinity IgE receptor or, less frequently, against IgE.
• Juvenile idiopathic arthritis: High episodic fever daily for 2 weeks with symmetrical polyarthritis or oligoarthritis, as well as one of the following: exanthem, generalized adenopathy, hepatosplenomegaly, serositis.
• Adult-onset Still’s disease: Recurrent episodes of high spiking fevers, frequently in the late afternoon; a salmon-pink exanthem that may demonstrate Koebnerization; arthritis with subsequent carpal ankylosis is characteristic.
• Sjögren’s syndrome: Xerostomia and xerophthalmia; arthritis; petechiae and purpura, urticarial vasculitis, and annular erythema.
• Relapsing polychondritis: Patients present with inflammation of the cartilaginous portions of the ear and nose, eventually causing a deformed ear or saddle-nose deformity. Acute involvement of the tracheal cartilage may cause collapse of the airway. Arthritis most often involves the costochondral joints. Other manifestations include audiovestibular damage, heart valve disease, and neurologic, ocular, and renal disease. Patients may die of rupture of the chordae tendineae of the heart valves.
