Exploring Immune Therapies in a Twin Case of Latent Autoimmune Diabetes in Adults and Generalized Granuloma Annulare

Case Presentation

A 59-year-old woman with a 10-year history of latent autoimmune diabetes in adults (LADA), managed on insulin, presented to the dermatology clinic with a progressive, pruritic rash. Over the course of months, the rash gradually spread to involve her chest, back, flanks, and extremities (Figure 1). Her primary symptom was pruritus. She was without skin pain or mucosal involvement. She had no history of a similar rash. She had previously tried over-the-counter topical corticosteroids without improvement in her symptoms. Interestingly, she reported that her identical twin sister, also diagnosed with LADA, had developed a rash similar in appearance 2 years earlier. Per the patient’s report, her sister’s rash was quite recalcitrant to medical therapy, requiring numerous topical and systemic agents to control it.

FIGURE 1.

Right flank.

On physical exam, pink annular plaques with slightly raised borders admixed with coalescing pink papules diffusely scattered over the flank, extremities, and chest were observed (Figure 1). There was no scale associated with the skin changes, suggesting a dermal-based process. Skin biopsy showed perivascular and interstitial lymphocytes, as well as histocytes and multinucleated giant cells palisading around zones of degenerative collagen, consistent with granuloma annulare (GA). Laboratory workup revealed elevated blood glucose and an A1C of 7%, with an otherwise normal basic metabolic panel and normal thyroid function. Based on both physical exam and histologic findings, the patient was diagnosed with generalized GA. Her identical twin sister had received the same biopsy-proven diagnosis a few years earlier.

Skin-focused treatment was initiated with twice-daily high-potency topical corticosteroids and, later, a topical calcineurin inhibitor, without significant improvement. The patient was then transitioned to oral treatment with hydroxychloroquine 200 mg twice daily. She was treated with hydroxychloroquine plus topicals for almost 2 years without clinical resolution before transitioning to adalimumab 40 mg every other week. After 10 weeks of treatment, she experienced significant improvement in her rash. After 5 months, she had complete treatment response with no remaining GA lesions.

Coinciding with the improvement in her skin disease, her A1C improved from an average of 7.2% in the 2 years before treatment to an average of 6.2% for the roughly 1.5 years she was on adalimumab. Interestingly, the monozygotic twin of the patient, who also had LADA and generalized GA, likewise exhibited a complete dermatological response to adalimumab after lack of response to many first-line treatments. A1C data were not available for the patient’s twin.

Questions

1. What are the genetic implications for LADA and generalized GA, and is there overlap between the two?

2. Could generalized GA serve as a marker of diabetes?

3. Are tumor necrosis factor-α (TNF-α) inhibitors a reasonable and reliable treatment option for generalized GA?

4. How do TNF-α inhibitors affect LADA or type 1 diabetes?

Commentary

LADA has overlapping features with both type 1 and type 2 diabetes. The diagnosis is made in patients with a later age of disease onset (often >35 years), who demonstrate a slower decline in pancreatic β-cell function and insulin dependence (>6 months) and possess at least one pancreatic β-cell autoantibody (1). GAD autoantibodies remain the most sensitive marker. The clinical characteristics of LADA are highly variable across individuals, with differing BMIs, antibody loads, and degrees of insulin dependence (2). The prevalence of LADA varies, with estimates ranging from 2.6 to 10% of all diabetes cases (3). The pathogenesis of LADA is thought to be primarily a cell-mediated autoimmune process (3). The cytokine profile mirrors that of type 1 diabetes (interleukin-1β and TNF-α), with some evidence that TNF-α is more dominant in type 1 diabetes than in LADA (4).

LADA shares genetic characteristics with both type 1 and type 2 diabetes. It is associated with specific type 1 diabetes high-risk MHC haplotypes (e.g., HLA-DQB1 and -DRB1) as well as increased frequency of the TCF7L2 gene seen in type 2 diabetes (5–7). Overall, studies have shown that LADA shares more genetic characteristics with type 1 diabetes (1). Although there is less literature available on the genetic basis of LADA, the similar clinical course seen here between twins further underscores a potential hereditary component.

Although there are no specific guidelines for the treatment of LADA, earlier intervention may serve as a unique opportunity to preserve pancreatic function (3,5). TNF-α and other cytokines are implicated in the inflammatory process and destruction of β-cells in type 1 diabetes (4,8). Thus, blocking these inflammatory pathways may ameliorate β-cell death.

Current studies are investigating the role of immunomodulatory or suppressive therapy (e.g., anti-TNF-α and anti-CD3 treatment). One study demonstrated delayed progression to type 1 diabetes in high-risk patients without diabetes after a 2-week course of teplizumab (Fc receptor nonbinding anti-CD3 monoclonal antibody) (7). However, the sample size was relatively small, and treatment was limited to a single dose of teplizumab. In a small pilot study using etanercept (a TNF-α inhibitor) in pediatric patients with type 1 diabetes, overall 6-month C-peptide levels were higher, while A1C and required insulin doses were lower in the treatment group (9). Future trials are needed to evaluate the potential role of TNF-α inhibitors in slowing diabetes progression.

GA is a granulomatous dermatosis of unknown etiology that is classically characterized by erythematous annular plaques with central clearing and raised, nonscaling borders. Multiple GA variants exist. Localized GA, which represents ∼75% of cases, classically presents as a single to a few asymptomatic annular plaques without surface change. It is most often self-limited, with resolution within 2 years. In contrast, generalized GA presents as numerous (classically >10) smaller papules and plaques, is commonly pruritic, and involves both the trunk and extremities. It is more often chronic, relapsing and remitting, and ultimately treatment-resistant (10).

Whether a true relationship exists between GA and diabetes remains controversial, with numerous studies supporting and refuting a connection. Additional well-controlled studies are needed to assess the strength of this relationship, as previous studies often used differing methodologies for diabetes screening and did not differentiate between the clinical variants of diabetes or GA (11).

In clinical practice, many providers screen for diabetes in patients presenting with generalized GA. Other systemic associations include thyroid disease and, in rare cases, malignancy (11,12). An appropriate workup includes a basic metabolic panel, A1C, and thyroid function testing.

Although the exact pathophysiology of generalized GA remains unclear, many postulate that it stems from a delayed-type hypersensitivity reaction. Various studies have demonstrated that GA skin lesions contain CD3+ helper T cells expressing interferon-γ, which ultimately leads to the differentiation of macrophages and the downstream expression of TNF-α (12,13). This cytokine profile suggests that TNF-α is a potential therapeutic target in the treatment of GA.

In practice, treatment of GA is dependent on the degree of skin involvement (localized vs. generalized) and patients’ symptoms and comorbidities. Although many cases of GA are self-limiting, patients often seek treatment because of the appearance of the rash and its impact on their well-being. Systemic treatments are reserved for symptomatic patients with widespread disease. The first-line therapeutic approach to localized GA focuses on topical or intralesional corticosteroids. However, the widespread skin involvement of generalized GA limits the practicality of topical therapies, and the chronic nature of the disease limits the use of systemic steroids. Additionally, given the special populations at risk for developing generalized GA (i.e., the elderly and people with type 1 diabetes), systemic steroids are not a viable long-term approach. Phototherapy, hydroxychloroquine, dapsone, or isotretinoin are often the first steps in managing more generalized disease, although in practice, there is wide variability given the inconsistencies in disease response and overall lack of randomized controlled studies to guide therapeutic selections (12,14). TNF-α inhibitors have traditionally been reserved for those with therapy-recalcitrant GA (15,16).

Additional research to investigate the shared immunological underpinnings of LADA and generalized GA could include baseline HLA typing of patients with clinically consistent features and, while not done clinically, measuring serum TNF-α concentrations before and during treatment with targeted inhibitors and correlating levels with observed clinical response. Obtaining LADA autoantibody panels before, during, and after treatment is yet another option in evaluating the efficacy of TNF-α inhibitors in LADA.

Twin studies help to distinguish the impact of environmental and genetic factors on disease. The highly concordant presentation of LADA and GA in the monozygotic twins described here supports a genetic basis for this presentation (17). This is further supported by emerging studies suggesting shared immunologic pathways for LADA and generalized GA, along with the potential for shared therapeutic targets.

Clinical Pearls

• In patients presenting with generalized GA and associated risk factors, consider screening for diabetes with a serum A1C and/or fasting blood glucose test. Measuring serum autoantibodies is a reasonable consideration if there is concern regarding LADA or type 1 diabetes.

• TNF-α inhibitors are a reasonable therapeutic option in cases of recalcitrant generalized GA. However, their role in delaying progression or altering the disease course of LADA and/or type 1 diabetes is less clear.

• Given the lack of approved therapies for generalized GA, additional studies are needed to add to the current knowledge of effective and affordable treatment options.