Through the Cracks: Niche Patient Population Battles Dermatopathologic Complications of Rheumatic Disease

Patients with serious skin complications associated with rheumatic diseases may face a host of obstacles. Misdiagnosis is common. They are treated with non-curative therapies that can carry complications. Where rheumatology ends and dermatology begins is often a blurry line, so patients find themselves volleying between specialties. They veer in and out of remission.

Victoria Werth, MD, professor in the Department of Dermatology and Medicine, Perelman School of Medicine at the University of Pennsylvania and chief of dermatology at the Philadelphia VA Hospital, is part of a group of so-called “rheum-derms” who specialize in this patient population. “We see patients who have lupus or dermatomyositis or some other rheumatic disease,” she said. “With many of these diseases, a large percentage have skin manifestations that are the predominant problem, but frequently both dermatologists and rheumatologists do not feel they have the expertise to manage them, so they fall between the cracks.”

Compounding matters is that these patients are not represented in many clinical trials because they do not meet criteria for systemic disease. Consequently, the drug pipeline has been historically suboptimal.

“We have tools for assessing the severity of these skin disorder,” Werth said. “Patients with skin-only disease need to be included in clinical trials. They need access to care.”

Lori Lowe, MD, professor of dermatopathology and dermatology rheumatology at the University of Michigan Health, is focused on questions big and small.

“The mechanisms are still not completely understood immunologically,” she said. “We have a basic understanding of these diseases, but between the disease itself and the individual variations, our knowledge is still limited.”

Even as therapies evolve, the outcomes remain imperfect at best, she said.

“These diseases can go into remission, but they are simply controlled and not cured,” Lowe said. “It is frustrating. These patients have chronic problems and there is still little we can do for them.”

The rheum-derm community is growing. Experts meet at the Rheumatologic Dermatology Society, held just prior to the American College of Rheumatology Annual Meeting, and present abstracts.

“This group has helped define the scientific and clinical areas in autoimmune skin diseases that need investigation. One goal is to raise awareness of this expertise in the management of these skin-predominant patients,” Werth said.

Niche Patient Population

Samar Gupta, MBBS, associate professor of rheumatology at the University of Michigan Health, described dermatopathology as a bridge between rheumatology and dermatology.

“Often, these patients will need a biopsy to get a final diagnosis of the lesion so we can plan treatment accordingly,” he said. “This being the case, a dermatopathologist is important, particularly in dermatomyositis, [cutaneous lupus erythematosus] CLE, or even regular lupus lesions. Many times, they attend a physician’s office but the exact disease entity is not recognized.”

This is where dermatophathologists like Lowe step in. “The beauty of dermatology is you can see the lesion,” she said. “We can get a lot of information from symptoms, history, sensitivity to sun; but, that only takes us so far. Many times, a lesion will have features of this or that disease, but it ends up being something else.”

Laboratory tests can reveal the patient has evolving connective tissue disease, but it is the clinical-pathologic correlation that is key. In skin-predominant patients with autoimmune skin diseases, laboratory tests are frequently negative.

“Sometimes a rash is evanescent and cannot be sampled,” she said. “With these patients, it is considerably more complicated. Diagnosis is often made through a process of elimination.”

Biopsy often confirms the suspicion and confirmation is critical. “The last thing we want to do is give someone heavy medications without being sure of the diagnosis,” she said.

Complicating matters and increasing the risk of misdiagnosis is that criteria for some of diseases do not allow for classification of patients with skin-predominant disease, according to Werth.

“So often, we will see a patient who meets all the criteria for lupus; but, in reality, when you look at them clinically, they have dermatomyositis,” she said.

Gupta said it is a matter of taking it patient by patient. “Lesions can look like many things, so a biopsy always helps us out,” he said, and agreed with Lowe’s point about treatment. “Each drug has an individual area of efficacy and, of course, side effects. Each patient has individualized disease. This means it is always an individual therapy plan. One drug may work better for one patient, but not work at all in a patient with a similar presentation.”

Gideon P. Smith, MD, PhD, director of the Connective Tissue Diseases Clinic, Department of Dermatology at Massachusetts General Hospital, associate director Clinical Unit for Research Trials and Outcomes in Skin and assistant professor at Harvard Medical School, stressed collaboration. “Consultation with a dermatologist knowledgeable in rheumatic diseases is always important,” he said. “Just as not all rheumatologists are the same — some are generalists, some may specialize more in [rheumatoid arthritis] RA or scleroderma, and some generalists may not have seen a case of scleromyxedema, for example, since training — dermatologists are similarly diverse in their interests and clinical experience and practice.”

It is important to know the differential diagnoses for several conditions, including lupus malar rash vs. dermatomyositis, rosacea, flushing, seborrheic dermatitis or a contact dermatitis, according to Smith. “All of these can affect the face and appear as a pink rash to the untrained eye,” he said. “Although there are so-called classic differences, often patients do not fit neatly within these categories and so an experienced dermatologist is important.”

Smith also recommended a dermatopathologist when in doubt, but with a qualification. “A study from an academic center of dermatophathologists showed that even experts find differentiating lupus vs. dermatomyositis under the microscope problematic,” he said. “That is not to say dermatopathology is not useful, but it needs sensible application. For example, differentiating eczema from lupus can be helpful, but lupus from dermatomyositis, not so much. In that case, it is better to be guided by the dermatologist and the macro-cutaneous findings rather than the pathologists micro-cutaneous view.”

Dermatomyositis, CLE

Ghazi and colleagues summarized data showing that diagnosis of amyopathic dermatomyositis is difficult because previously used dermatomyositis criteria developed in the 1970s did not allow recognition of the skin-predominant form of the disease. One population-based study from the Rochester database suggested the amyopathic version of this disorder may account for up to 20% dermatomyositis. Patients with amyopathic dermatomyositis may be at an increased risk for fatal interstitial lung disease. Other recent studies have reported a novel autoantibody, anti-CADM-140, may be associated with interstitial lung disease in certain patients. Amyopathic dermatomyositis patients also may be at risk for internal malignancy. “It is important to formally recognize amyopathic [dermatomyositis] as a subset of [dermatomyositis],” the researchers wrote. “Without appropriate disease classification, the opportunity for [interstitial lung disease] and malignancy screening may be missed.”

Obstacles to dealing with these patients move beyond the clinic. “When we first started the steering committee to update the classification criteria, some folks did not want to study them because it was perceived as so rare that it would be statistically unworkable,” Werth said.

Okon and Werth wrote a paper that included a section on the classification and diagnosis of various subtypes of CLE, including acute, subacute and chronic disease. Further classification indicates chronic CLE encompasses discoid lupus erythematosus, lupus erythematosus profundus, chilblain cutaneous lupus and lupus tumidus. They wrote that the 11 ACR criteria may overestimate the incidence of systemic lupus erythematosus (SLE) in patients who have only cutaneous disease. About half of patients with subacute disease, one-tenth of those with discoid lupus erythematosus and nearly all patients with acute CLE meet criteria for SLE, according to Werth and Okon.

They added that lesional biopsy, paired with the clinical findings, is the optimal method of diagnosing CLE, while direct immunofluorescence and serology are less useful. Patients should be educated about sun protection at the time of diagnosis and initial treatment includes topical agents, such as steroids and/or calcineurin inhibitors, according to the authors. They noted anti-malarial therapies should be first-line treatments for CLE, but that other systemic therapies may be required in patients with widespread or refractory disease, or scarring. However, they also cautioned a substantial minority of patients fail to tolerate current interventions or remain in a refractory state.

“Future studies are needed to better define CLE within the continuum of LE, with recognition that CLE-predominant patients may meet criteria for SLE but not be systemically ill,” they wrote.

Richard Alan Furie, MD, chief of the Division of Rheumatology at Northwell Health, an investigator at The Feinstein Institute for Medical Research and professor of Medicine at Hofstra Northwell School of Medicine, said there are a variety of lupus rashes, some of which are mild and others which are severe and can cause scarring. “One needs to customize treatment depending on whether the patient has acute cutaneous or chronic cutaneous lupus,” he said. “Discoid lupus is most damaging to the skin. After trying relatively simple solutions like topical steroids or antimalarial drugs, there is no consensus on second-line therapy. Therefore, doctors select different drugs for their refractory patients. There are a lot of unmet needs in the refractory patient population.”

Lowe focused on the diagnostic aspect of dealing with these patients. “Rheumatologists can do a work-up and panel of tests, but those tests will be negative,” she said. “A skin exam and biopsy is what the diagnosis is made on.”

The skin manifestations of lupus can have wide variability, according to Lowe. “If a patient has a rash or skin eruption, the findings under the microscope may put it in a category of disease that we had not considered,” she said. “We often find it difficult to differentiate between CLE or dermatomyositis.”

Closer Look at Psoriasis

Armstrong and colleagues suggested that establishing treatment goals in psoriasis would be beneficial for patients and clinicians. The National Psoriasis Foundation conducted a study that involved 25 experts in the profession. The study, which used the Delphi method, involved a literature review, pre-Delphi question selection and input from physicians and patients, and Delphi rounds. Results showed body surface area (BSA) was the preferred method and the optimal time to evaluate patient response is 3 months after initiation of a novel therapy. The acceptable barometer of response is either BSA of 3% or an improvement in that metric of 75% or more from baseline, while the target response at this point is BSA 1% or less. Evaluation at 6 month intervals is preferred, with BSA 1% or less every 6 months as the main target.

“With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient,” the researchers concluded.

Smith said most studies report BSA and Psoriasis Area and Severity Index (PASI) or PASI 75 “While helpful for clinical trials, in clinical practice a PASI score is generally not recorded due to the level of detail required,” he said. “Of interest is that as the medications we are using give better outcomes, we are beginning to see studies that report PASI 90.”

Clinical practice prescribers often only describe the locations of plaques and use this as a guideline for whether there is improvement, according to Smith. “BSA is often approximated to put the patient in a broad category, such as severe cutaneous psoriasis,” he said. “This is often necessary to justify medications or use of narrow-band phototherapy.”

Smith suggested that as imaging becomes easier, it may play a larger role in the clinic. “But this is not without challenges as it requires standardization of factors, such as patient position and image distances, and is often unhelpful with scalp psoriasis, for example,” he said. “It also does not capture how bothered the patient is by the psoriasis. Depending on the patient, large plaques on the body may be less bothersome than involvement of the face.”

It is in these cases that the feelings of patients about their disease must be considered, according to Smith. “We have to think about the degree of itch they experience and the impact on their quality of life, whether it interferes with their ability to participate in daily or social activities.”

Inflammatory Conditions

Regarding other rheumatic diseases, Smith outlined the myriad cutaneous complications in RA.

“The first group are characterized by a neutrophil-rich cell infiltrate, such as palisaded neutrophilic granulomatous dermatitis or Sweet’s,” he said. “Though sensitive to prednisone, long-term use of that is not ideal, so we often go with therapies such as super saturated iodine, colchicine or dapsone.”

Patients also may develop complications, such as interstitial granulomatous dermatitis, which form characteristic hard cords of skin often on the trunk or proximal thighs, according to Smith. “As with many of the skin complications, such entities are rare and so no large scale clinical trials or established treatment protocols exist, but we often us methotrexate or thalidomide, which tend to help more with granulomatous skin reactions,” he said.

Smith also noted complications unrelated to the underlying disease. “These complications are related to the treatments,” he said. “As we see more patients on [tumor necrosis factor] TNF-inhibitors, there is an increase in the rate of non-melanoma skin cancers. We recommend at least annual skin checks with a dermatologist to screen for this.”

“TNF-alpha-induced psoriasis also may occur, according to Smith. “This sometimes raises the question of whether this is indeed a medication effect, or if psoriasis/psoriatic arthritis was present even if they were seronegative for RA.”

Huang and colleagues suggested that when the equilibrium between host defense and tolerance is disturbed, along with immune over-activity, skin manifestations of inflammatory bowel disease (IBD) can occur and the subsequent over-activity of certain immune pathways are responsible for the cutaneous disorders seen so frequently in IBD patients. They wrote that metastatic lesions can cause cutaneous disorders, as can reaction to gut inflammation, complications from the disease or from the treatments, genetic factors or autoimmune processes.

“Ultimately, it is important for health care providers to understand that skin manifestations should always be checked and evaluated for in patients with IBD,” they wrote. “Furthermore, skin disorders can predate gastrointestinal symptoms and thus may serve as important clinical indicators leading physicians to earlier diagnosis of IBD.”

Lowe said some morphea is limited to skin, but other morphea can be deeper and cause further complications. “Scleroderma can be on skin, of course, but also in the lungs or the gastrointestinal system,” she said.

A common issue with rheumatic disease is vasculitis in the skin, Lowe added.

“Inflammation in blood vessels can cause skin breakdown,” she said. “We see crusted lesions and ulcers. A lot depends on the clues when making a diagnosis.”

Bosnic and colleagues wrote treatment options for hidradenitis suppurativa can be limited, unpleasant and complicated. They described a patient with this condition, and ankylosing spondylitis, who underwent treatment with several therapies to moderate impact. It was only after introduction of a TNF inhibitor that the patient demonstrated improvement in both musculoskeletal and skin parameters. Cutaneous manifestations in ankylosing spondylitis, osteoarthritis and Sjögren’s syndrome rarely require biopsy in this setting, according to Lowe.

Anifrolumab

Furie and colleagues conducted a phase 2b, randomized, double-blind, placebo controlled study to assess anifrolumab in a cohort of 305 patients with moderate to severe SLE. The study included 99 patients who received 300 mg of the study drug every 4 weeks for 48 weeks, 104 patients treated with 1,000 mg of anifrolumab at the same interval and 102 patients treated with placebo. The percentage of patients reaching SLE Responder Index response at week 24 with a sustained reduction of oral corticosteroids from day 85 through week 24 served as the primary outcome measure. Results indicated 34.3% of patients in the 300-mg group and 28.8% of those in the 1,000-mg group met the primary endpoint compared with 17.6% of those in the placebo group. The effect size was increased among patients with an elevated baseline interferon signature.

Week 52 SLE Responder Index rates (excluding the steroid taper requirement) were 40.2% for placebo, 62.6% for 300 mg and 53.8% for 1,000 mg of anifrolumab. Other findings demonstrated superiority of anifrolumab to placebo across many metrics, including the modified SLE Responder Index, BILAG-Composite Lupus Assessment (BICLA), CLASI, joint counts, low disease activity and major clinical response. Herpes zoster and influenza occurred more frequently in the study drug arms compared with placebo, but serious adverse events were not more frequent with anifrolumab than placebo.

“The interferon pathway is activated in most lupus patients,” Furie said. He noted there are three types of interferon and five subtypes within the type 1 group. “The original hypothesis was that inhibition of the interferon pathway might reduce lupus disease activity.”

Early attempts at blocking alpha interferon, a member of the type I interferon family, yielded mixed results. “If one inhibit just one interferon subtype, the patient is still left with the other four unchecked,” Furie said. “Anifrolumab binds to the type I interferon receptor and thus blocks all five type I interferons. The prediction was there would be greater inhibition of the interferon pathway with anifrolumab as opposed to inhibitors of single interferons. The prediction was correct with results of early studies demonstrating greater interferon pathway inhibition with anifrolumab that with its predecessors.”

The drug has been studied in both scleroderma and now lupus. “The data are robust, showing activity in different organ domains,” Furie said. “But clearly, the most dramatic effect was in the skin. Phase 3 testing is underway.”

More Therapeutic Options

Menter and colleagues presented a data set from the UNCOVER series of trials which assessed the efficacy of ixekizumab, an interleukin (IL)-17 monoclonal antibody, in moderate to severe plaque psoriasis. The current analysis of three phase 3, double-blind, placebo-controlled trials, nearly 4,000 patients were randomly assigned subcutaneous 80-mg ixekizumab (Taltz, Eli Lilly) every 2 weeks or 4 weeks following a 160-mg initiation dose, or placebo for 12 weeks. The subpopulation included 1,092 patients with moderate to severe palmoplantar involvement. Results indicated 80% of patients in the study drug arm reached PPSAI50 compared with 32.9% for placebo and 67.8% for etanercept. For PASI 75, the rates were 70% for ixekizumab, 18.8% for placebo and 44.1% for etanercept. Half of patients in the ixekizumab arm reached PASI 100 compared with 8.2% in the placebo group. The study drug maintained or improved outcomes from week 4 through week 60, according to the results.

“Over the last decade, a proliferation of options has come to market, including biologic and non-biologic therapies, and now biosimilars,” Smith said. “This has been a boon in the way we treat psoriasis, arthritis and connective tissue diseases. However, we still lack good treatments for many of the diseases, such as scleroderma, and often use more traditional immunosuppressants. Therefore, there remains an enormous need for new therapies directed at things like scleroderma, lupus and dermatomyositis.”

That said, Gupta offered a warning. “Biologic therapies can cause reactivation of latent native infection,” he said.

Shwin and colleagues investigated the way inflammasomal and nucleic acid sensing pathways contribute to the development of disorders mediated by IL-1 and type I interferon. They suggested that proinflammatory signaling of cytokines, including IL-1beta, IL-18 and TNF, lead to poor regulation of the immune system. Their paper addressed “the concept of targeting proinflammatory cytokines and their signaling pathways with cytokine blocking treatments that have been life-changing for some patients.”

“There are many ways to interfere with the interferon pathway,” Furie said.

Werth noted the utility of antimalarials. “We have been looking at how they work, particularly the heterogeneity of response,” she said. “Not everybody responds to hydroxychloride.”

Immunosuppressants, such as thalidomide, lenalidomide and belimumab, remain a mainstay, according to Werth. “We sometimes consider azathioprine, but this might not work for skin. It is approved for SLE but there are no systematic studies in the skin,” she said.

“It is important to understand that none of these treatments are easy to use,” Gupta said. “For example, when we use immunosuppressive [treatments], of course the immunity to fight infection goes down. Then, it goes down further with each successive treatment.”

Most immunosuppressive therapy regimens are complex and demand the presence of a subspecialist, Gupta added. “Once a patient has been started on any of these therapies, we are committed to following them long-term,” he said. “If we start on one therapy, we may have to choose a different therapy. Each therapy has its own set of cleaning labs and monitoring labs. To add to the complexity, we have oral therapies, we have subcutaneous injections and some IV therapies. We have to account for logistics about the availability of an infusion center. Methotrexate requires monitoring and lab testing. There are no easy solutions.”

All of that being said, there is cause for hope in novel approaches, according to Gupta. “[Bruton’s tyrosine kinase] BTK inhibitors show some promise,” he said, and added that guselkumab, an IL-23 inhibitor for psoriasis, is in phase 2 trials. “[Janus kinase] JAK inhibitors are being studied in psoriasis and psoriatic arthritis.”

For Gupta, this broadened therapeutic armamentarium has “revolutionized” treatment.

A Look Ahead

Gupta said guidelines for the treatment of psoriasis and psoriatic arthritis exist, but there are differences between the guidelines of the EULAR, the National Arthritis Foundation and other organizations.

“With other diseases, like lupus, there is no cut-and-dried algorithm,” he said.

While no curative therapies exist, there has been progress, according to Gupta. “Current therapies are getting toward 90% of disease control, which was not possible a few years ago,” he said. “We are also seeing that partial remissions are possible now. This is still not a cure, but a significant percentage of patients go into remission to the point where we are able to stop treatment.”

Werth has been part of basic science investigations, including studies of the impact of ultraviolet light on cell migration. Her group is also researching issues ranging from the potential associations of immunostimulatory herbs with the onset or exacerbation of autoimmune disease to codifying individual patients.

For Lowe, dealing with these complications is a matter of sustained effort.

“You just have to keep looking,” she said. “Sometimes the rheumatologist manages the patient, sometimes the dermatologist. The important thing is that we work together to try to make the right diagnosis.” – by Rob Volansky

• References:
• Armstrong AW, et al. J Am Acad Dermatol. 2017;doi:10.1016/j.jaad.2016.10.017.
• Bosnic D, et al. Reumatologia. 2016;doi:10.5114/reum.2016.64910.
• Furie R. Arthritis & Rheumatology. 2017;doi:10.1002/art.39962.
• Ghazi E. Clin Exp Rheumatol. 2013;31:128-134.
• Huang BL, et al. Front Physiol. 2012;doi:10.3389/fphys.2012.00013
• Menter A. J Eur Acad Dermatol Venereol. 2017;doi:10.1111/jdv.14237.
• Okon LG, Werth VP. Best Practice & Research Clinical Rheumatology. 2013;doi:10.1016/j.berh.2013.07.008.
• Shwin KW, et al. Dermatol Clin. 2017;doi: 10.1016/j.det.2016.07.005.

• For more information:
• Richard Alan Furie, MD, can be reached at 865 Northern Blvd., Great Neck, NY 11021; email: rfurie@northwell.edu.
• Samar Gupta, MBBS, can be reached at Taubman Center Floor 3 Reception A,1500 E Medical Center Dr. SPC 5358, Ann Arbor, MI 48109; email: kylieo@med.umich.edu.
• Lori Lowe, MD, can be reached at University Hospital Floor 2 Reception Pathology, 1500 E Medical Center Dr. SPC 5054, Ann Arbor, MI 48109; email: kylieo@med.umich.edu.
• Gideon P. Smith, MD, PhD, can be reached at the Department of Dermatology, Massachusetts General Hospital, 50 Staniford St., Suite 240, Boston, MA 02144; email: gpsmith@mgh.harvard.edu.
• Victoria Werth, MD, can be reached at Perelman Center for Advanced Medicine South Pavilion, 1st Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: werth@mail.med.upenn.edu.

Disclosures: Furie reports he is a consultant, investigator and receives research support from AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Exagen, Genentech/Roche, GlaxoSmithKline, MedImmune, Pfizer, Mallinckrodt Pharmaceuticals, Sanofi and UCB; he is a consultant for Chugai, Estrela (Janssen) and EMD Merck; is an investigator for and receives research support from Takeda; and is a committee member of the American College of Rheumatology, Lupus Foundation of America, Lupus Alliance of America, SLE Foundation, Alliance for Lupus Research and The Lupus Academy. Gupta, Lowe, Smith and Werth report no relevant financial disclosures.