Connective Tissue Diseases

Karin Eshagh

Basil M. Hantash

Connective tissues diseases (CTDs), such as cutaneous lupus erythematosus (CLE), dermatomyositis (DM), and scleroderma (Scl), are systemic inflammatory diseases that may present initially with significant cutaneous manifestations that frequently establish diagnosis. Women are more commonly affected than men, with estimates ranging from 2:1 up to 15:1 female predominance.¹,²,³,⁴ This chapter will review the etiology and pathogenesis of 3 common CTDs (lupus erythematosus [LE], DM, and Scl) and will aim to address the current cosmetic treatments available to reduce the disfigurement triggered by the multisystem diseases.

LUPUS

BACKGROUND

About 14 to 122 per 100,000 people are affected by LE, which is a chronic autoimmune disorder that can involve multiple organs and lead to anemia, nephritis,
serositis, arthritis, and/or cardiac conduction defects.⁵ Skin involvement, known as CLE, is very common and occurs at some point in the course of the disease in about 75% patients with LE.¹

PRESENTATION

The most common dermatologic manifestations are malar rash (40%), alopecia (24%), and oral ulcers (19%).¹

DIAGNOSIS

Clinical Diagnosis

CLE is divided into acute (ACLE), subacute (SCLE), and chronic (CCLE) forms. ACLE presents with abrupt-onset oral ulceration and poikilodermatous lesions on the face, upper limbs, and trunk, which heal without scarring. With SCLE, erythematous papules with annular or psoriasiform pattern appear insidiously on the face and extensor surface of the forearms and heal without scarring. CCLE presents with indurated, scaly erythematous plaques on the head and neck, which heal with scarring, dyspigmentation, and telangiectasias. Additionally, patients with CCLE may have scarring alopecia.⁶ In all cases, systemic lupus erythematosus (SLE) criteria must be assessed. SLE is associated with high-titer antinuclear antibodies. Serology testing should be performed in cases of suspected CLE: 70% of SCLE are anti-Ro/La positive. In CCLE, however, serologies are often negative. Skin biopsy is often required to make the diagnosis, revealing a lichenoid infiltrate and a positive direct immunofluorescence demonstrating antibody deposition along the basement membrane.

Histopathology

Histology of CLE lesions reveal a perivascular and periadnexal lymphohistiocytic infiltrate and an interface dermatitis. The epidermal interface activity shows basal layer degeneration, apoptotic keratinocytes, and basement membrane thickening. In well-established lesions there may be follicular plugging and occasionally an epidermal reaction that may mimic a squamous cell carcinoma. Mucin deposition in the dermis is characteristic. Immunohistochemistry is necessary to distinguish TLE from other disorders.⁷

Subtypes

Acute cutaneous lupus erythematosus (ACLE)
Subacute cutaneous lupus erythematosus (SCLE)
Chronic cutaneous lupus erythematosus (CCLE); discoid lupus erythematosus (DLE); hypertrophic lupus erythematosus; tumid lupus erythematosus (TLE)
Lupus panniculitis/lupus profundus/subcutaneous lupus erythematosus (LP)
Neonatal lupus erythematosus

PATHOGENESIS

Genetic predisposition is the highest risk factor associated with developing CLE. Different HLA genes have been associated with ACLE, such as HLA-DR2 and HLA-DR3, and with SCLE, such as HLA-A1, HLA-B8, HLA-DR2, HLA-DR3, HLA-DRw52, HLA-DRw6, HLA-DQ1, and HLA-DQ2.⁵,⁶ Environmental factors also can play a role via photosensitivity because UVB radiation leads to proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-6, IL-10.⁷,⁸ Thus, the patient’s medication list should be reviewed for any photosensitizing medications, such as ACE inhibitors, calcium channel blockers, or sulfonylureas.⁹

In a study by Kuhn (2008), the authors examined skin samples from patients with various subtypes of CLE and found a deficient number of CD4⁺CD25⁺ regulatory T cells (T_reg), which are important for suppression of the immune response to self-antigens.¹⁰ Abnormal cytokine levels, such as increased type I interferons, have also been observed in patients with CLE.

TREATMENT

Medical

Preventive

Most of the treatments for CLE and other autoimmune diseases aim to either prevent progression of the disease or reduce cosmetic disfigurement. One important first step in the treatment of CLE is the emphasis on avoiding heat and sun exposure, which can exacerbate the condition. Patients should be advised regarding the importance of using sunscreens with physical blockers (ie, zinc oxide/titanium dioxide), broad spectrum sunscreens, and ultraviolet protection clothing. Vitamin D supplementation and smoking cessation are helpful.

Algorithm 14.3.1 shows the treatment for CLE.

Topical Treatment

Calcineurin Inhibitors. A double-blind, randomized, split-face controlled trial in 20 subjects with CLE comparing tacrolimus 0.1% with clobetasol propionate 0.05% ointment showed comparable efficacy, but areas treated with clobetasol developed more telangiectasias, suggesting that tacrolimus may be preferable to avoid the unfavorable effects of steroids.¹¹ Long-term use may not show sustained efficacy, however; another randomized, double-blind, vehicle-controlled trial in CLE with tacrolimus 0.1% ointment showed significant improvement after 28 and 56 but not after 84 days.¹²

Systemic Treatment

Antimalarials. Antimalarials, including hydroxychloroquine, chloroquine, and quinacrine, remain the first-line treatment for CLE. Hydroxychloroquine 400 mg per day is the first choice for widespread CLE without systemic involvement, although maintaining high blood levels of the drug are important to achieve long-term remission. Improvement of the cutaneous lesions may start 6 to 8 weeks after treatment. Quinacrine 100 mg per day can be added for lesions that do not respond to hydroxychloroquine. Smoking cessation should be emphasized to improve efficacy of the medications.³

Immunosuppressants. Methotrexate, mycophenolate mofetil, and azathioprine are considered second-line treatments for CLE.

Other Drugs. Retinoids, dapsone, intravenous immunoglobulin, and thalidomide and its analogs are all third-line options for refractory CLE.

Immunotherapy. Monoclonal antibodies, including belimumab, which is approved by the Food and Drug Administration for SLE, and rituximab, and interferons are options for patients with concurrent SLE.

ALGORITHM 14.3.1 Treatment algorithm for cutaneous lupus erythematosus (CLE). CCLE, chronic cutaneous lupus erythematosus. For Scalp LE, See Chapter 7.1, Algorithm 7.1.9 (Courtesy of Macrene Alexiades, MD, PhD).

Cosmetic

Lasers

CO₂ Laser

The CO₂ laser can be used to treat scars from chronic DLE. In a case reported by Walker (2000), 1 woman with severely deep pitted follicular scars along her chin from chronic DLE was treated with CO₂ resurfacing laser at 16 W with multiple passes targeting dermal collagen until there was successful smoothing of skin.¹³ The authors also reported that the argon laser has been successfully used for similar scarring patterns.

Pulse Dye Laser

The pulse dye laser (PDL), wavelength 585 to 595 nm, has been used on patients with LE, SCLE, and DLE. In 2 studies that used the PDL on 19 patients, 12 of the patients showed clearance of their cutaneous symptoms with reduction in size, erythema, edema, and no complications. In another case report using PDL, only a few patients with CLE experienced side effects from the PDL, and when side effects were present, they were limited to hyperpigmentation or slight scarring.¹⁴,¹⁵,¹⁶,¹⁷ Thus, most of the patients tolerated PDL treatments with good outcomes.

Argon Laser

Kuhn et al (2000) reported using the 488/514-nm argon laser in a patient with DLE who demonstrated chronic telangiectatic plaques nonresponsive to other forms of therapy. The patient showed drastic improvement after 2 laser applications and complete clearance after 5 sessions.¹⁸

Er:YAG Laser

In a case report by Tremblay JF (2001), a woman with severe DLE lesions present on the face for 25 years was treated with erbium:YAG laser after failing systemic steroids, isotretinoin, azathioprine, thalidomide, hydroxychloroquine, and methotrexate.¹⁸ The Er:YAG 2940-nm, 2-J laser was utilized by first treating the upper lip and nose areas and then the chin and lower lip 3 weeks later. About 6 to 10 passes were performed with 3 to 5 mm spot size, 10.2 to 28.3 J/cm², and 5 pulses/s. Postoperatively, a hydrogel sheet was applied daily for 5 days. There was minimal erythema at 3 weeks, and the treated areas reepithelialized smoothly. The patient did not demonstrate any scarring, and she maintained her aesthetic results at 2-year follow-up without reactivation of her disease.¹⁹

Dermal Fillers

The treatment of atrophic burned-out lupus lesions with hyaluronic acid filler injections without untoward events has been reported in a case series.²⁰

Surgical

Excision of burned-out, scarred lesions has been conducted; however, reactivation of inactive lesions has been reported. Fat grafting has been reported for lupus profundus.

DERMATOMYOSITIS

BACKGROUND

DM is an autoimmune inflammatory condition causing symmetric proximal extensor myopathy along with a cutaneous eruption that is often difficult to treat. There is a strong female predilection, and the mean age of onset is 52 years. Unfortunately, there is also a higher risk of malignancy associated with DM, and thus the cutaneous findings often serve as a warning of internal organ involvement.²¹

PRESENTATION

Patients with DM present with skin disease in approximately 40% of cases. Patients report muscle fatigue 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. Presenting infrequently are arthralgia, arthritis, dyspnea, dysphagia, arrhythmia, and dysphonia.