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Paradoxical reactions to biologics provide insight


Paradoxical reactions to biologic treatments can provide clues into related conditions such as granulomatous diseases, genetic polymorphisms and latent infections, says an expert.

Learning more about the mechanisms behind so-called paradoxical reactions to biologic drugs will resolve the paradoxes and yield clues into related conditions, said an expert at New York University (NYU)'s 37th Annual Advances in Dermatology 2017.

With biologic drugs accounting for three of the five top-selling drugs worldwide, Susan E. Katz, M.D., says "These are the medications of the future. They certainly dominate the present." She is clinical assistant professor in NYU's Ronald O. Perelman Department of Dermatology.

Portal to understanding

Since biologic drugs debuted in dermatology in 2002, "Dermatologists have been among the forerunners in implementing these drugs. We've been robust and early adopters."

But the more dermatologists use these drugs, she says, "The more we must learn about what happens with them, in order to use them safely and effectively - and because they provide great hints about not only the diseases we believe we are treating, but also into related diseases that we don't realize" are so interconnected. "I see biologic reactions as a portal into much greater understanding of the human immune system."

Paradoxical adverse events (PAEs) are defined as occurrences during biologic therapy of conditions that usually respond to this class of therapy.1

Explosive psoriasis

One case Dr. Katz presented involved a 28-year-old old male patient on adalimumab (Humira, Abbvie) for Crohn's disease (CD) who developed a painful, itchy rash starting on his hands, feet and knees and progressing over three months to his entire body, including pustules on the hands and feet. He had no family history of psoriasis, she says, but his 10-year history of what had been called dandruff suggested he probably had mild psoriasis that previously went untreated.

"His Crohn's disease had been maintained on adalimumab for several years without incident." But a year and a half after his gastroenterologist increased his dose to address increasing CD symptoms, "He rapidly developed explosive psoriasis. Making this diagnosis was not difficult. The difficulty was essentially understanding what happened" and managing the reaction, considering that his gut continued to respond to adalimumab.

"We decided try another cycle of adalimumab before discontinuing it," but this single dose caused additional flaring. The quandary with this patient, she says, was whether to discontinue all TNF-α blockers, try a different one or try and "power through" the flare and see if he could stay on the original drug with additional immunosuppressants.

The severity of the patient's psoriasis ruled out the latter possibility, she says. After calming the reaction with cyclosporine (4mg/kg daily) plus narrowband UVB and topical nonsteroidal treatments, "We elected to switch class completely, to interleukin (IL)-12/IL-23 suppression. That approach was successful for both his gut and skin."

In considering possible mechanisms for the patient's psoriatic reaction, "One of the factors – which I cannot prove but is a possibility - is that some patients apparently have various forms of IL-23 receptors.1,2 There may be multiple genetic types of IL-23 receptors in a population." And patients with certain forms of receptors apparently have a linkage between CD and a predilection for psoriasis, she says. "It may be that we're selecting out for people who have a particular genetic predisposition. Curiously, when we used ustekinumab (Stelara, Janssen Biotech), the patient did extremely well with both his skin and Crohn's disease."

Additionally, Dr. Katz highlighted the probable increased production of interferon-α by plasmacytoid dendritic cells that are released from inhibition as the TNF-α effect diminishes with biologic therapy. Interferon-α can then immunologically provoke outbreaks of psoriasis, she says.

Although such reactions are officially called PAEs, "They only appear paradoxical because we don't understand the mechanisms. Once we have greater understanding of how these events occur, they won't be paradoxical. Eventually, the term 'paradoxical adverse event' will probably be proven to be a misnomer."

‘Sudden’ sarcoidosis

Another case involved a 54-year-old male with long-standing psoriasis and enthesitis who had failed many psoriasis medications but did extremely well on adalimumab (40 mg biweekly) for one year. Though his initial tuberculosis (TB) screening before starting the drug was negative, Dr. Katz says, "I always do an annual repeat screening. And lo and behold, he suddenly had positive QuantiFERON-TB Gold (Qiagen)," despite being asymptomatic.

Infectious disease specialists found via chest x-ray that the patient had mediastinal and bilateral hilar adenopathy. A biopsy performed during bronchoscopy furthermore revealed sarcoidal granulomas in his lung, Dr. Katz says.

"He was diagnosed with pulmonary sarcoidosis in the setting of a conversion to a positive TB test. He never had actual TB shown on either stains or culture."

Physicians treated the latent TB with a nine-month course of isoniazid, she says. After the patient discontinued adalimumab, "His skin disease flared back to his baseline and failed to respond to ustekinumab and narrowband UVB." Switching to secukinumab allowed the patient to maintain a Psoriasis Area and Severity Index (PASI) 75 response, she says.

"Why does somebody suddenly develop sarcoidosis on adalimumab? We see people who develop sarcoidal disease while on the drug, but his case dovetails two features: the TB conversion and the sarcoid," and their interrelationship beyond the relationship between adalimumab and sarcoid.

"We know TNF-α derangements can cause granuloma formation even without infection." A TNF imbalance alone may lead to sarcoidal granulomas, Dr. Katz says. "But we also know that when we give TNF-α blockers, because there are often derangements of the way granulomas are made,3 and that they form to contain an infection like TB, if someone is exposed to an infectious agent, someone could be made more susceptible to infection." As a consequence of TB, she says, the patient had formed sarcoidal granulomas, "which are unlike the normal caseating granulomas of TB because of the effect of the drug on cytokines.

We have multiple effects here. This case may provide insight into sarcoid outside the arena of the patient on TNF-α blockade who may develop sarcoid from outside factors including infectious agents, and then not present the way we would normally expect."

More questions

In another case, a 55-year-old female with psoriasis, psoriatic arthritis (PsA) and a lengthy history of routine sinus infections initially achieved and maintained PASI 75 response and joint relief for approximately three years with adalimumab and low-dose methotrexate. Suddenly, Dr. Katz says, the patient's sinuses worsened to the point where a preoperative exam by an ear, nose and throat (ENT) specialist revealed a highly friable, cobblestone-like mass in her nasopharynx.

"On biopsy, she had necrotizing granulomatous disease. But there was no inflammation or vasculitis. Other than the blood vessel picture, she looked a lot like she had granulomatosis with polyangiitis. But her granulomas were not sarcoidal," Dr. Katz says.

One biopsy slide suggested the presence of histoplasma.

"But we don't have histoplasmosis in New York, and she hadn't traveled to areas where there is histoplasmosis," she says.

She also had no serologic or urinary markers of histoplasmosis, and this organism did not grow on her cultures.

"Nor did she have positive antineutrophil cytoplasmic autoantibodies (ANCA), to allow us to make a granulomatosis with polyangiitis-type (formerly known as Wegener’s) diagnosis. We don't know exactly what her diagnosis was," which can be the case with a significant number of necrotizing granulomas.4

However, the patient's condition resolved spontaneously when, with permission from her ENT and infectious disease specialists, Dr. Katz withheld her immunosuppressants.

"And she has had no recurrence. She's been put on apremilast and has done very well with her skin and joints."

She says that perhaps immunologically, this patient's granulomas stemmed from immunosuppression and infection.

"But there are other possibilities," including cytokine imbalance.5 "It may be that antibodies were allowed to proliferate - in other words, there were increased strains of Th2 versus Th1 cells"1,2 because she had used immunosuppressants against Th1 and Th17 cells. Ultimately, "Her case raises more questions than answers."

Interstitial granulomatous dermatitis

Dr. Katz also presented two cases involving interstitial granulomatous dermatitis in female patients on TNF blockers for psoriasis and PsA. Though they presented somewhat differently, "Both cases involved histiocytes doing things unexpectedly in the skin or elsewhere, which is what causes granulomas."

Interstitial granulomatous dermatitis has been described in patients with autoimmune diseases such as lupus, and in the setting of some drugs, she said. But as Dr. Katz's cases illustrate, it does not present monomorphously.

"The first patient presented with explosive, painful, juicy annular plaques on the hands, feet, arms and legs," she says. She was able not only to manage, but also to calm down her reaction by switching from infliximab to etanercept, Dr. Katz says, but she flared again severely and somewhat unexpectedly on an IL-17 drug (secukinumab) she was prescribed after developing chorioretinitis and a positive Lyme test while on etanercept. After undergoing treatment for the chorioretinitis and possible Lyme disease with varying success, Dr. Katz says the patient restarted etanercept and methotrexate and has avoided flareups by avoiding infliximab and secukinumab.

"The other patient had a quieter, more indolent form of interstitial granulomatous dermatitis, more like we might see in an autoimmune patient."

Her reaction (intensely pruritic dermal papules and plaques on the upper arms and forearms) appeared, along with evidence of brain demyelinating disease, after eight years on adalimumab. Switching this patient to secukinumab plus topical steroids resolved her interstitial granulomatous dermatitis, Dr. Katz says.

"In some patients, you're going to see a derangement and imbalance in cytokine homeostasis that will predispose to disease" and can be caused by drugs from two different classes. And yet the reaction resolves on a drug from the same class as one of the offending agents, she says. "You can't extrapolate which drugs would cause this" because a drug which proves problematic for one patient may not for another.

"There's a lot we do not understand. I wonder if it's host-dependent - flashing back to the IL-23 receptor difference in the first case. Are there host differences we don't know about?"

Differing reactions could stem from subtle variations in the way some patients produce TNF-α, she says, or from telomeric derangements in IL-1 or IL-17 that researchers are unaware of, secondary to pharmaceutical manipulation of TNF-α. "It's all conjecture. And unfortunately we proceed as if we know it all. We're really in our infancy here," she says.

Dermatologists look forward to using more biologics, Dr. Katz says.

"In my own practice, 25% to 30% of my patients are on biologics. I love biologics - I just would like to open the door to greater knowledge and questioning. I would like people to think, observe and document more as they increasingly use these drugs, so that we learn more."

When a reaction occurs, she encourages dermatologists to try to distinguish whether it represents persistent or new associated underlying disease (signaling inadequate treatment), a paradoxical (drug-related) event or other underlying disease (especially infection, and perhaps malignancy).

Disclosures: Dr. Katz reports no relevant financial interests.


1.Toussirot É, Aubin F. Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview. RMD Open. 2016;2(2):e000239.

2. Brown GWang ELeon A, et al. Tumor necrosis factor-α inhibitor-induced psoriasis: systematic review of clinical features, histopathological findings, and management experience. J Am Acad Dermatol. 2017;76(2):334-341.

3. Chakravarty SD, Zhu G, Tsai MC, et al. Tumor necrosis factor blockade in chronic murine tuberculosis enhances granulomatous inflammation and disorganizes granulomas in the lungs. Infect Immun. 2008;76(3):916-26.

4. Aubry MC. Necrotizing granulomatous inflammation: what does it mean if your special stains on negative? Mod Pathol. 2012;25 Suppl 1:S31-8. 

5. Grine L, Dejager L, Libert C, Vandenbroucke RE. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev. 2015;26(1):25-33.

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