18 minute read
Dermatology Clinic
CASE #1
Red Patches Over Face, Chest, and Upper Limbs
DINA ZAMIL, BS; TARA L. BRAUN, MD
A 42-year-old Hispanic man with no prior medical history presents with a 2-month history of a rash on his face, chest, and arms. He reports that the rash gets worse after sun exposure and he has associated joint pain. He has taken over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for the joint pain and topical steroids for the rash with no symptomatic relief. Physical examination reveals erythematous patches over the malar cheeks and dorsal nose sparing the nasolabial fold and erythematous macules on the forearms and chest.
What is your diagnosis? Turn to page 16
CASE #2
Itchy Rash After COVID-19
CHRISTOPHER NGUYEN, BA; TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD
A 54-year-old woman with a history of depression presents to the clinic with a 1-year history of an intermittent rash. She was hospitalized for COVID-19 approximately 1 year ago and soon after developed a rash all over her body. The lesions persist for several days and have a burning sensation. The patient has no associated joint pain or other systemic symptoms. She tried antihistamines for the rash with no symptomatic relief. On examination, erythematous wheals are evident on her arms and legs as well as her back and abdomen.
What is your diagnosis? Turn to page 17
Dermatology Clinic
CASE #1 Systemic Lupus Erythematosus
In systemic lupus erythematosus (SLE), the immune system loses tolerance for self-antigens, resulting in multiorgan damage.1,2 The cutaneous manifestations of SLE were first described by Hippocrates in the fifth century.3,4 In the 13th century, Rogerius reported facial lesions that resembled wolf bites (lupus translates to wolf in Latin).5 Descriptions of lupus written by Cazenave, Bateman, and von Hebra focused on dermatologic aspects of the disease.5 Moritz Kaposi reported systemic symptoms of lupus in 1872, and Sir William Osler is credited as the first to recognize the multiorgan damage that is characteristic of SLE.5,6
Prevalence estimates for SLE vary between 20 and 150 cases per 100,000 individuals and have been increasing with improved recognition of the disease.7 Systemic lupus erythematosus has a predilection for adult women in their 30s or 40s; children comprise only 15% to 20% of cases.5 In the United States, SLE is less common among individuals of European ancestry and more common among the Black population and people of Hispanic and Asian descent. These latter groups also experience greater involvement of internal organs.1,5,7
Studies have linked genes for human leukocyte antigen (HLA) and complement components C1, C2, and C3, as well as at least 70 susceptibility loci to SLE.1 Female hormones have been associated with SLE, explaining the higher prevalence in women.7 Antithyroid antibodies, elevated thyroid-stimulating hormone, and altered autonomic nervous system response to the hypothalamic axis also have been reported in SLE patients.5
Immune dysfunction in SLE is precipitated by a combination of factors such as genetics, emotional factors, and environmental influences (eg, infections and exposure to chemicals or UV light). This dysfunction causes autoantibody development, immune complex deposition, inflammation, and complement activation, which in turn result in tissue injury.8 The lack of self-tolerance depends on how efficiently a patient’s immune system presents antigens to T cells.5 Production of abundant immunoglobulin G (IgG) autoantibodies and circulating abnormal inflammatory cells are mechanisms reported to lead to skin damage in SLE.9 Apoptosis of keratinocytes is also a key event in the development of cutaneous lesions.8
In general, dermatologic findings in SLE are divided into 3 groups: acute cutaneous (ACLE), subacute cutaneous (SCLE), and chronic cutaneous (CCLE).5 These categories are not mutually exclusive and may present concomitantly in any given patient.10
Patients with ACLE display transient photodistributed lesions in the classic dermatologic manifestation of SLE, the bilateral malar erythema or butterfly rash. This rash can appear solely in the center of the face, classically sparing the nasolabial fold, or it may be a generalized maculopapular exanthema. The rash usually is accompanied by systemic effects on other organs, and antidouble-stranded DNA (dsDNA) antibodies may be present.8,10
The other subtypes, SCLE and CCLE, are associated with a relatively lower risk for systemic disease. Although SCLE is also a photosensitive eruption, it lasts longer than ACLE and does not cause atrophy or scarring. The CCLE subtype includes discoid lupus, lupus erythematosus tumidus, lupus erythematosus panniculitis, and chilblain lupus.
Sun exposure can trigger dermatologic findings in SLE, and patients may mistake this rash for a sunburn. Severe facial swelling may occur, although these cutaneous symptoms tend to resolve without residual pigmentation or scarring.11
Patients with SLE also can have nonspecific cutaneous findings. Raynaud phenomenon, livedo reticularis, and urticarial vasculitis are examples of such findings; these conditions suggest a potential underlying autoimmune disease.10,11
The most common areas affected in SLE are the joints, skin, kidneys, hematologic system, central nervous system, and pleural and pericardial serosal surfaces.
Per the 2019 American College of Rheumatology (ACR) guidelines, diagnosis of SLE requires at least 1 positive antinuclear antibody (ANA) test followed by 7 clinical criteria (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal), and 3 immunologic domains (antiphospholipid antibodies, complement proteins, SLE-specific antibodies).12 The Systemic Lupus International Collaborating Clinics require 4 criteria for SLE diagnosis with at least 1 clinical criterion and 1 immunologic criterion or lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.13 In both classification systems, immunologic criteria are required for a definitive SLE diagnosis.5
Mucocutaneous SLE is diagnosed via immunohistology and histopathology. Histologic findings vary depending on the subtype but always include vacuolar degeneration and
lymphohistiocytic inflammation. The ACLE subtype presents with less pronounced dermal involvement and more vacuolar degeneration of the basal layer with some sparse lymphocytic infiltrate in the upper dermis. Discoid lesions tend to have more follicular plugging, periadnexal inflammation, and scarring.10
Recurrent miscarriages and abnormal complete blood cell count and differential, urinalysis, and/or comprehensive metabolic profile support a diagnosis of SLE. Various antibodies also can be present, including antiphospholipid, anti-RNP, anti-SM, anti-SSA, anti-SSB, anti-dsDNA, and antinuclear antibodies. When indicated, clinicians may wish to obtain supportive imaging such as a chest radiograph, renal imaging, and contrast angiography.5
The differential diagnosis for localized ACLE is contact dermatitis, acne rosacea, seborrheic dermatitis, dermatomyositis, erysipelas, and photodermatitis. These pathologies are differentiated via characteristic clinical features. Generalized ACLE can be confused with erythema multiforme and morbilliform drug reactions, but these conditions do not present with butterfly erythema. The differential diagnosis for SCLE includes polymorphic drug eruption, psoriasis, tinea corporis, and superficial gyrate erythema, which also are distinguished clinically. Several conditions may mimic CCLE depending on the stage and evolution of CCLE lesions. Diseases that mimic the nonscaling pattern of CCLE are polymorphic light eruption, Jessner lymphocytic infiltration of the skin, lymphocytoma cutis, granuloma facile, chilblain, and sarcoidosis. The scaling phase of CCLE may look similar to actinic keratoses, seborrheic dermatitis, tinea faciei, psoriasis, and lichen planus. Both clinical features and histology can help differentiate CCLE from these conditions.11
SLE treatment is complex and usually requires consultations with multiple specialists. Before treatment initiation, disease severity, degree of inflammation, and level of organ dysfunction should be ascertained.5 For skin findings, topical or intralesional corticosteroids and topical calcineurin inhibitors are first-line treatments. Rigorous sun protection also is essential for these patients because the lesions are exacerbated by sunlight.10 Lesions resistant to topical medications may require systemic therapy.10 Systemic medications used to treat SLE include glucocorticoids, antimalarial agents, immunosuppressants, NSAIDs, and biologics that target B cells. Recently, inhibitors of B-lymphocyte stimulators such as belimumab have shown potential for treatment of mild to moderate SLE.1
Biopsy results for the patient in this case were consistent with ACLE and his ANA was positive. He was started on topical steroids and hydroxychloroquine. Rheumatology was consulted to assist with his management. Dina Zamil, BS, is a medical student and Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine in Houston, Texas.
Please go to ClinicalAdvisor.com/home/dermatology/dermatologyclinics/ for a complete listing of references noted in this article.
CASE #2 Urticarial Vasculitis
Urticarial vasculitis (UV) is a condition characterized by urticarial lesions with histopathologic findings of leukocytoclastic vasculitis (LCV). It was first reported by Wills and Lond in an 1890 case report describing 2 young men who presented with a purpuric rash and wheals accompanied by fever, arthritis, and angioedema.1 Almost 70 years later, in 1956, McCombs et al published a report of 2 patients with wheals and vasculitic characteristics on histology.1 Since first described in the 19th century, the condition also has been called hemorrhagic urticaria and allergic vasculitis.1
The precise prevalence of UV worldwide is unknown, largely because of its rarity; however, in patients presenting with chronic urticarial rash with histology that meets the criteria for LCV, the prevalence is estimated to be about 5%.2 In the United States, the incidence of UV is estimated to be 0.5 per 100,000 personyears with a median age at diagnosis of 51 years and a female predominance (70%-74%).3 The disease rarely affects infants and children, with only 2 reported infantile cases in the literature and diagnosis in only 1% of children with any type of vasculitis.1,2
Urticarial vasculitis is classified as a type III hypersensitivity reaction or an immune complex-mediated complement activation in the lumen of blood vessels. It generally can be divided based on serum complement levels into normocomplementemic and hypocomplementemic subtypes.1 The majority of UV cases are idiopathic in origin, although some have been tied to medications such as cimetidine, diltiazem, fluoxetine, methotrexate, nonsteroidal anti-inflammatory drugs, telmisartan, enalapril, and levetiracetam.2 Associations with underlying diseases such as autoimmune conditions, infection, myelodysplastic disorders, and malignancy also have been reported.1 Up to 20% of patients with systemic lupus erythematosus reportedly have UV (more commonly the hypocomplementemic subtype), and associations with Sjogren
Dermatology Clinic
syndrome and inflammatory bowel disease also have been described.1,2 Infections linked to UV include streptococcal infections, tuberculosis, COVID-19, and hepatitis B and C.2
Urticarial vasculitis most commonly affects women, particularly in the fourth and sixth decades of life.2 The use of specific medications and the presence of certain underlying infectious, autoimmune, or malignant conditions have been linked to UV cases. Some investigators have proposed a genetic component to the disease, citing familial cases of the severe and systemically active form of UV called hypocomplementemic urticarial vasculitis syndrome (HUVS), which has been described in a pair of identical twins and among 3 siblings.2 In HUVS patients, cigarette smoking appears to be a strong risk factor for the development of pulmonary disease, which is a leading cause of death among UV patients.4
Patients with UV typically present with indurated wheals that are nonblanchable or are partially blanchable and have a central dark-red or dark-brown macule. When symptomatic, these lesions generally are described as painful or burning but typically are not pruritic.2 Dermoscopy can be a useful tool to identify small areas of vascular necrosis that do not present as frank purpura.5 In addition to cutaneous symptoms, 9% to 56% of patients with UV present with systemic symptoms and signs, such as angioedema, purpura, fever, asthenia, arthralgia, lymphadenopathy, abdominal pain, and/or ocular, pulmonary, or renal manifestations.1
The most common laboratory abnormalities in UV are an elevated erythrocyte sedimentation rate (ESR) and hypocomplementemia.2 Although both abnormalities are fairly nonspecific, the latter can serve as a useful prognostic marker because hypocomplementemic UV is associated with a higher risk for complications and systemic involvement.4 Biopsy of skin lesions may reveal findings of LCV, such as erythrocyte extravasation, vascular and perivascular infiltration of polymorphonuclear leukocytes with nuclear dust, and fibrinoid necrosis of vascular walls.1 Direct immunofluorescence may show deposition of complement in vessel walls.1 Clinicians also should consider complete blood cell count, renal function tests, hepatitis/liver studies, and measurement of antinuclear antibodies to evaluate for possible extracutaneous manifestations and associations listed above.2
It is important to distinguish UV from acute common urticaria and chronic idiopathic urticaria because these and many
Patients with UV typically present with indurated wheals that are not blanchable or are partially blanchable with macules.
other conditions can present with urticarial rash. Schnitzler syndrome is an autoinflammatory urticarial condition that also may be mistaken for UV. Other diagnoses to consider include Wells syndrome, erythema migrans, and urticaria multiforme.2
Diagnosis of UV requires both clinical manifestations of urticaria and histopathologic evidence of LCV. Lesional biopsy (ideally performed within the first 24-48 hours of rash appearance) is considered the gold standard for diagnosis.2,5 The clinical picture often helps exclude other diagnoses. For instance, unlike in UV in which lesions last longer than 24 hours and often for several days, chronic urticaria wheals generally resolve after 2 to 8 hours. In addition, the lesions of UV can leave behind areas of hyperpigmentation not seen in chronic idiopathic urticaria. Finally, true urticarial lesions are pruritic and coalesce into large (>10 cm) lesions, whereas those in UV are asymptomatic or painful/burning and smaller (0.5-5 cm in diameter). Differentiation from Schnitzler syndrome may require biopsy; although histopathology exhibits neutrophilic infiltrate in both conditions, no evidence of vasculitis is found in Schnitzler syndrome.2
It is difficult to treat UV; no clinical algorithms exist to guide therapy and many drugs have shown limited efficacy and/or adverse effects. Antihistamines and montelukast are ineffective in most patients with UV.1 The most effective treatment is corticosteroids, which allowed for improvement or remission of cutaneous and systemic symptoms in over 80% of patients across 144 studies when used alone or in combination with other drugs.1 However, treatment must be weighed against the unfavorable side effects of steroid use. Patients with more resistant cases of UV may respond to immunosuppressive drugs such as dapsone, colchicine, cyclophosphamide, mycophenolate mofetil, cyclosporine, and azathioprine.2 The combination of 1 or more immunomodulatory agents with steroids may allow for steroid tapering and improved efficacy. Biologics such as omalizumab, anakinra, tocilizumab, and rituximab are additional options.
In this case, a punch biopsy of the patient’s rash was consistent with UV. Preliminary workup showed elevated ESR, normal antinuclear antibody titer, and normal complement levels. Her liver function tests, renal function test, and complete cell blood count were within normal limits. She was started on oral corticosteroids, which improved her rash. ■
Christopher Nguyen, BA, is a medical student at Baylor College of Medicine in Houston, Texas; Tara L. Braun MD, is a resident physician in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk MD, is a dermatologist at Elite Dermatology in Houston.
Please go to ClinicalAdvisor.com/home/dermatology/dermatologyclinics for a complete listing of references noted in this article.
Conference Roundup
2021 San Antonio Breast Cancer Symposium (2021 SABCS)
December 7 to 10, 2021 San Antonio, Texas
PREMENOPAUSAL ER+ BREAST CA PATIENTS BENEFIT FROM AI RX
Premenopausal women undergoing ovarian suppression for estrogen receptor- positive (ER+) early-stage breast cancer had a lower risk for breast cancer recurrence when treated with an aromatase inhibitor (AI) rather than tamoxifen, according to findings presented at the 2021 SABCS.
The meta-analysis included patient data from 4 randomized clinical trials including 7030 premenopausal women with ER+ breast cancer. All women had undergone ovarian suppression or ablation and were randomly assigned to either an AI or tamoxifen for 3 years (ABCSG XII trial) or 5 years (SOFT, TEXT, and HOBOE trials). The primary outcomes were time to invasive breast cancer recurrence and breast cancer mortality.
The annual rate of recurrence averaged 21% lower for women assigned to an AI compared with tamoxifen (rate ratio [RR], 0.79; 99% CI, 0.69-0.90; P =.0005). At 10 years, a 2.8% absolute gain in any recurrence was found (17.5% for tamoxifen vs 14.7% for AI).
The main benefit from an AI was seen in years 0 to 4 of follow-up when the women were actively taking the treatments (RR, 0.68; 95% CI, 0.58-0.80); no further benefit or loss of benefit was found after therapy was completed during years 5 to 9 of follow-up (RR, 0.98; 99% CI, 0.73-1.32). Subgroup analyses showed that the reduction in recurrence during this period did not vary by age; body mass index; tumor size, grade, histological subtype; or presence and absence of chemotherapy.
Although distant recurrence was reduced with an AI (RR, 0.83; 95% CI, 0.71-0.97; P =.02), no difference in breast cancer mortality was found. Longer follow-up is needed to assess this effect, the researchers noted.
No increase in rates of nonbreast cancer death or fractures was found in women receiving an AI.
RIBOCICLIB/LETROZOLE COMBO HELD EFFECTIVE ACROSS BC SUBGROUPS
The addition of ribociclib to letrozole prolonged overall survival (OS) across multiple subgroups compared with placebo and letrozole among postmenopausal patients with hormone receptor (HR)-positive and HER2-negative advanced breast cancer, according to a prespecified exploratory subgroup analysis of the MONALEESA-2 trial presented at the 2021 SABCS.
“Consistent improvement in long-term survival at 5 and 6 years with ribociclib was observed in all subgroups analyzed,” according to lead author Joyce O’Shaughnessy, MD.
The phase 3 MONALEESA-2 trial evaluated the first-line treatment of postmenopausal patients with HR-positive, HER2-negative advanced breast cancer with letrozole plus ribociclib or placebo. The results demonstrated significantly longer OS with ribociclib compared with placebo in the intention-to-treat population (hazard ratio [HR], 0.76; 95% CI, 0.63-0.93; P =.004). The present prespecified analysis is of 668 patients within subgroups of special interest, but was exploratory and not powered for significance testing.
The OS benefit with the addition of ribociclib to letrozole was consistent across subgroups, including number of metastases and metastatic sites.
Patients with less than 3 metastatic sites demonstrated a median OS of 68.0 and 56.1 months with ribociclib and placebo, respectively, which translated
Ribociclib combined with letrozole prolonged overall survival across subgroups.
Conference Roundup
to a 6-year survival rate of 47.7% and 36.1%, respectively (HR, 0.78; 95% CI, 0.61-1.00). Survival was lower overall for patients with 3 or more metastatic sites, but ribociclib significantly prolonged survival compared with placebo with a median of 55.5 or 46.5 months, respectively (HR, 0.71; 95% CI, 0.51-0.98). The 6-year OS was 37.9% with ribociclib and 24.2% with placebo.
The OS benefit was similar among patients with or without bone-only metastases as the intention-to-treat (ITT) population. Patients with liver metastases also benefit from the addition of ribociclib, with a 6-year OS of 31.0% compared with 18.9% with placebo.
Prior chemotherapy did not affect the benefit of ribociclib. The OS benefit among patients who received prior endocrine therapy was less clear, and Dr O’Shaughnessy noted that the sample size was small for patients who had previously received an AI.
RACIAL DISPARITIES IN BREAST CANCER-RELATED LYMPHEDEMA RISK
Black women experience higher rates of breast cancer-related lymphedema after axillary lymph node dissection compared with White women, according to the results of a study presented at the 2021 SABCS. Black race was the strongest predictor of lymphedema in this study.
Axillary lymph node dissection remains the main risk factor for lymphedema, but other risk factors are inconsistent in studies. Epidemiologic studies have reported an increased susceptibility to lymphedema among Black women, but prospective clinical data are lacking.
This prospective study included 304 patients with breast cancer who underwent axillary lymph node dissection between November 2016 and March 2020. Of these, 276 had at least 1 longitudinal measurement after baseline. Sixty percent of patients were White, 20% were Black, 11% were Asian, and 6% were Hispanic.
To measure lymphedema, the researchers measured arm volume at baseline, postoperatively, and at 6-month intervals for a total of 2 years. Lymphedema was defined as a relative volume change of 10% or greater.
The 24-month lymphedema rate was 39.4% for Black women, 27.7% for Hispanic women, 23.4% for Asian women, and 20.5% for White women. Women who received neoadjuvant chemotherapy were significantly more likely to develop lymphedema compared with those who had surgery upfront (30.9% vs 11.1%; P =.0066).
Black women were 3.5 times more likely to develop lymphedema compared with White women. Hispanic women had a 3-fold increased risk for lymphedema compared with White women, but the researchers noted that the population of Hispanic patients was small.
Black race was the strongest predictor of lymphedema development in multivariable analysis (odds ratio [OR], 4.41; P <.001). Other independent risk factors for lymphedema development were receipt of neoadjuvant chemotherapy (odds ratio [OR], 2.08), older age (OR, 1.04 per 1-year increase), greater number of lymph nodes removed (OR, 1.05 per 1 additional lymph node), and increasing time from surgery (OR, 1.70 per 6-month increase).
Black women were 3.85 times more likely to have a higher relative volume change compared with White women (P =.007); no difference in lymphedema severity was found among Hispanic and Asian women.
Further research is needed to understand the biologic mechanisms behind the racial disparities found in this study as well as possible preventive strategies, the authors concluded.
MARKER CLIP PLACEMENT LACKING DURING BIOPSY
Half of patients with breast cancer being considered for neoadjuvant chemotherapy do not have a marker clip placed at the time of biopsy, which may delay chemotherapy or result in mastectomy according to findings presented at the 2021 SABCS.
The researchers retrospectively evaluated data from 800 patients with breast cancer who were candidates for chemotherapy at a single center between 2018 and 2019. A marker clip was placed at initial biopsy in 49% of patients. Of patients without initial clip placement, 42% had a clip placed before initiation of neoadjuvant chemotherapy.
Patients without a clip placed at the time of biopsy experienced a 5.5-day delay in the initiation of neoadjuvant chemotherapy compared with patients with a clip placed at biopsy. This delay was associated with significant anxiety among the patients.
Overall, 79% of surveyed radiologists said they were not aware of national guidelines for clip placement. ■
Black women experience higher rates of lymphedema compared with White women.
