The Balancing Act of Managing Spondyloarthropathies

Clinicians treating patients with spondyloarthropathies are required to walk many tightropes. One is the prevention of infections while treating patients with immunosuppressive drugs. Another is determining where clinical manifestations of spondyloarthritis end and the adverse event profile of the medication begins. Another is deciding when mainstay therapies, like tumor necrosis factor inhibitors, are working and when to move on to an agent with a novel or different target. The backdrop of all of this is little is known about the genetic factors that predispose patients to these diseases. In addition, the research community is beginning to compile metrics for patients to quantify and adequately express opinions on disease development, pain management and palliative care.

For Pedro M. Machado, MD, PhD, consultant rheumatologist at the Centre for Rheumatology and MRC Centre for Neuromuscular Diseases at University College London, understanding the basics is of critical importance. In a presentation at the EULAR Congress in June, he called spondyloarthritis “an umbrella term for a group of diseases that share genetic, clinical, immunological and imaging features, such as arthritis, enthesitis, dactylitis, chronic back pain, loss of spinal mobility, uveitis, psoriasis and inflammatory bowel disease.”

“In the last few years, we have seen a shift from a concept that was more restrictive and based on specific disease entities to one that is more broad-concept, based on phenotypes that led to new classification criteria for axial and peripheral diseases. Axial disease have been further broken into radiographic and non-radiographic classifications,” he said.

Using old nomenclature, ankylosing spondylitis is the most common spondyloarthropathy, along with reactive arthritis, psoriatic arthritis (PsA) and enteropathic arthritis, which has demonstrated links to inflammatory bowel disease (IBD). Although the spine is most commonly impacted, hands, feet, arm and leg joints also may be involved.

A strong genetic association is believed to be at the root of spondyloarthropathies, but apart from an association between HLA-B27 in white people with ankylosing spondylitis, other genetic factors remain uncertain.

Rik Lories, MD, PhD, professor at KU Leuven, head of the Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center and Rheumatologist at University Hospitals Leuven, commented on the ongoing challenges of managing this diverse group of diseases in an interview with Healio Rheumatology.

“The problem with the balancing act is that there are a lot of uncertainties,” he said. “These conditions are highly unpredictable. Herpes zoster or bacterial infections can occur in a patient with any immunosuppressive drug. As patients age, they may get weaker and frailer, so when using drugs in elderly patients, the impact of infections, such as pneumonia or a [urinary tract infection] UTI, can be higher. There are so many variables to account for.”

Lories warned that clinicians should be cautious when approaching patients with spondyloarthropathies. “But, that doesn’t mean we shouldn’t use appropriate drugs to treat signs and symptoms in individual patients,” he said. “It means that we should rise to meet these challenges with our clinical skills. We need to be aware of infections and issues.”

William Tillett, MBChB, BSc, PhD, consultant rheumatologist and lead for Biological Therapies at the Royal National Hospital for Rheumatic Diseases in Bath and senior lecturer in Pharmacy and Pharmacology at the University of Bath in the United Kingdom, has studied self-evaluated patient responses as a metric of assessing disease severity. “The conversation between patient and clinician, combined with a physical examination and shared decision-making on treatment, is more important than any outcome measure,” he said. “That said, the benefits of outcome measures in routine practice in other diseases are well established, such as the treat-to-target strategy in [rheumatoid arthritis] RA.”

With such a diverse group of diseases in play and more therapeutic options consistently emerging, Healio Rheumatology categorizes comorbidities, clinical factors and other aspects in the management of spondyloarthropathies.

Focus on Comorbidities

Norli and colleagues investigated joint distribution and 2-year outcomes in a longitudinal analysis of 347 patients with recent-onset mono-arthritis. The most commonly affected joint was the knee, at 49.3%, followed by the ankle (16.7%) and wrist (14.1%), according to the results. Chronic inflammatory rheumatic disease occurred in 26.2% of the cohort, with 6.1% experiencing RA and 4.6% with PsA. Independent factors that predicted chronic inflammatory disease included joint swelling and localization, along with anti-citrullinated-protein antibody positivity and rheumatoid factor positivity. Chronic disease also occurred in 42.9% of patients with wrist mono-arthritis and in 10.3% of those with ankle mono-arthritis. The 2010 RA criteria served to be a useful tool in the identification of patients at an early stage with seropositive RA, according to the findings. “Our findings facilitate early identification of mono-arthritis patients with unfavorable prognosis,” the researchers concluded.

“Our understanding of PsA has developed over the last 20 years,” Tillett said. “While in the majority of cases, PsA is not as destructive as RA, the cumulative burden of multiple disease manifestations leads to a similar impact in terms of quality of life, impact and impaired physical function.”

Sobolewski and colleagues wrote that nail lesions occur in nearly half of patients with psoriasis vulgaris and a substantially greater majority of patients with PsA. Common pitting may occur, as may subungual hyperkeratosis, loosening of the nail plate, discoloration or splinter hemorrhages. Diagnostic tools, such as the nail psoriasis severity index, the modified nail psoriasis severity index and the psoriasis nail severity score, can help clinicians assess these symptoms. Treatment can be difficult, and should ideally be based on the extent of dermal, articular and ungual lesions, according to the investigators. Nail psoriasis may improve best with systemic therapies of psoriasis. Biological agents have utility in this group of patients. “However, as their use is limited in scope and safety, topical therapy remains a mainstay, and the combination of corticosteroids and vitamin D3 analogs is considered to be most helpful,” they wrote.

“One of the challenges of studying any aspect of PsA is the variety of clinical manifestations,” Tillett said. “Taking pain as an example, pain may arise from the peripheral articular disease, axial disease, enthesitis/dactylitis or skin. It is well established that each of these domains of disease can flare and remit asynchronously, so this assessment needs to be dynamic and ongoing so that treatment can be phenotype specific.”

Christopher T. Ritchlin, MD, MPH, professor of medicine at the University of Rochester Medical Center, commented on the development of PsA in a symposium presentation at the Biologic Therapies VII Summit.

“The critical question we are struggling with now is, ‘What is it in 30% of psoriasis patients or so that leads to psoriatic arthritis?’” he said. “Is it that there is a spillover of cells from the skin that go into the joint and enthesis? Or is it that some patients with psoriasis have subclinical enthesial or bone involvement and there is a lack of suppression in those patients who develop arthritis? We are working hard to understand both of those mechanisms but, at this point, we are not clear.”

Zagora and colleagues reviewed recent advances in the understanding of the ocular manifestations of seronegative spondyloarthropathies. They found patients with HLA-B27 carry a likelihood of demonstrating these manifestations. While local corticosteroid therapy may have utility, immunosuppressive therapies may be useful in chronic or refractory uveitis. Biologic agents, including tumor necrosis factor (TNF) inhibitors, have also demonstrated efficacy. “Uveitis is the most common ocular manifestation in patients affected by seronegative spondyloarthropathies,” they concluded. “Both genetic and environmental factors play a role in its pathogenesis. As it tends to affect the young adult population, it carries a significant personal and population burden.”

“It is important to understand the differences between comorbidities of disease and comorbidities from these immune drugs,” Lories said. “Clinicians need to understand these extra-articular manifestations, like those that can occur in the eye. They need to understand that patients can develop full-blown Crohn’s disease or colitis.”

Paparo and colleagues described in the spine and sacroiliac joints as a “peculiar” manifestation of seronegative spondyloarthropathies. They suggested a combination of imaging, clinical evaluation and laboratory results are critical in correctly identifying these spondyloarthropathies. In their current analysis, they aimed to analyze a multimodal radiological approach for differential diagnosis of the various disorders under the umbrella of seronegative SpA. Their investigation demonstrated early diagnosis may not be possible with conventional radiography, which is often the first step in the diagnostic process. High spatial resolution of small structural alterations in cortical and spongy bone become clear on CT, while MRI can show bone marrow edema, which they noted “reflects vasodilatation and inflammatory hyperemia.”

“There is an argument for including standardized outcome measures on routine care to inform treatment decisions,” Tillett said. “I would suggest there is still a need to develop a composite that is feasible for use in routine care and capture all aspects of disease.”

Machado described cardiovascular disease as a comorbidity that should not be ignored. “Overall, while there are some conflicting results, there seems to be an increased independent risk in patients with ankylosing spondylitis,” he said. “There is also an increased risk in patients with PsA.”

Advances in Treatment

Ritchlin set the stage for the current state of therapeutic options. “After a decade of anti-TNF inhibitors in the 2000s, we are now into a wave of [interleukin] IL-17 and IL-23,” he said.

For Lories, anti-TNF therapy was successful, but only represented one target. “Most of us welcome these new agents because it gives us more flexibility and more options in subsets of patients for whom anti-TNFs would be a contraindication,” he said. “These drugs are making their way into practice.”

Ritchlin encouraged clinicians to pay attention to how these drugs are used. “Thinking about the mechanistic landscape, there are many ways of looking at it,” he said. “One way is looking at pathway enrichment. You ask the question: Which pathways are enriched in ankylosing spondylitis and which are enriched in diseases that may or may not be related?”

The Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Pfizer) show promise in PsA and psoriasis, according to Lories. “In Europe, we don’t have much experience with this agent yet, so it is difficult to judge how this will play out,” he said.

Data are beginning to trickle in. Cantini and colleagues found rituximab (Rituxan, Genentech) and tocilizumab showed efficacy in TNF failures. In patients with severe psoriasis, articular involvement or enthesitis and/or dactylitis, ustekinumab (Stelara, Janssen), a human monoclonal antibody targeting IL-12 and IL-23, may be preferable in PsA. Secukinumab (Cosentyx, Novartis) may be preferable in ankylosing spondylitis.

Kanekura and colleagues treated 20 patients with adsorptive granulocyte and monocyte apheresis (Adacolumn, Jimro). The treatment regimen was for five sessions, once weekly. Eligible patients had PsA and were treated to determine the effectiveness of selective depletion of myeloid lineage leukocytes. ACR20 served as the primary endpoint. After two patients dropped out, nine patients demonstrated a response to five sessions and nine patients underwent 10 sessions. Assessment at 2 weeks after the last session resulted in a 65% ACR20 rate. Seventy percent of the cohort maintained ACR20 at 8 weeks and 50% maintained this outcome at 20 weeks after the last session. The safety profile of the treatment showed that it was well-tolerated. “The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA,” the researchers concluded.

“In general, all of the drugs we are currently using that will have an impact are based on understanding new mechanisms,” Lories said.

Asahina and colleagues retrospectively reviewed patients with psoriasis vulgaris and PsA treated with ustekinumab between 2011 and 2015. Among 179 patients with psoriasis vulgaris, eight patients developed PsA. Most of these cases occurred more than 8 months after initiation of ustekinumab treatment. Most cases were not severe and well-controlled, and no patients in the cohort had experience with TNF therapies, according to the findings. The researchers suggested this is a signal that the “possibility of unmasking pre-existing subclinical arthritis is minimal.” Among nine patients with pre-existing PsA treated with ustekinumab, improvements were reported in patients who were naïve to biologics, as well as those who switched from TNF therapies. “Altogether, our present study is in agreement with the notion that [ustekinumab] may be less efficient than TNF- [alpha] inhibitors for PsA,” the researchers concluded. “While [ustekinumab] cannot fully prevent new development of PsA, it is unlikely that [ustekinumab] increases the risk of new onset of PsA as a paradoxical adverse reaction.”

“The major value of many of the new drugs is in decision-making, and the effect of these drugs on associated disorders,” Lories said. “In cases of severe psoriasis, IL-17 or IL-23 might be superior to anti-TNF. On the other hand, treatment of IBD has been stopped due to a perceived lack of efficacy or actual worsening of disease with anti-IL-17, so that might not be the first choice in patients who have gut inflammation as a comorbidity. It is a complex play, not one size fits all. At the level of the individual patient, you have to solve the puzzle of picking the best option.”

For Lories, an overarching concern, regardless of the therapy, lies in trying to control an immune system that is too active.

“When you weaken the immune system, you run the risk of paying some price in terms of infections,” he said. “Fortunately, in the last 15 years or so, we haven’t been blown away by the number of serious infections with anti-TNFs. Patients are now consistently screened.”

That said, as 15-year and 20-year data with these drugs emerge, clinicians and researchers should be aware of any potential signals, according to Lories. Ongoing vigilance is necessary. “There is a clear role for IL-17 in the defense against Candida and other fungi,” he said. “It hasn’t yet come forward as a major concern, but we have to wait to see what the long-term outcomes will be. We should always be cautious about introducing all these types of drugs.”

Machado summed up the optimism of the clinical community. “We are entering a new era,” he said. “A significant number of new drugs and biosimilars are expected to enter the market over the next couple of years.”

Focus on Patients

Perhaps a key component of this caution is paying attention to what patients are saying. Tillett and colleagues assessed a cohort of 31 patients with PsA to determine which outcomes were most important to them and to assess the extent to which they are represented in currently existing composite measures. There were 16 men and 15 women included in the study, with a mean disease duration of longer than 10 years. The researchers used the seven-nominal group technique at four hospitals, according to the findings. Patients reported pain was the most important outcome they wished would improve with treatment, at 20%. Other important factors for patients included fatigue (13.3%), physical fitness (7.1%), halting or slowing of damage from the disease (6.9%), and quality of life/well-being (6.2%). The researchers suggested no single measure of disease state sufficiently identifies each of these potential outcome measures.

Tillett discussed ways pain and fatigue can be better represented in composite measures in PsA. “There are a number of potential options,” he said. “Composite outcome measures of disease activity are generally comprised of clinician, patient-reported and laboratory measures. Pain and fatigue will obviously be patient reported.”

He suggested pain and fatigue need to be explicitly represented in a composite outcome to achieve face validity.

“One possibility may be to use visual analogue scales that can be bolted on to the modular composites measures,” he said. “This will mean that the total score of the measures will change and new thresholds for high, moderate, or low disease activity and remission will need to be estimated.”

Looking beyond pain and fatigue to more general responses from patients, Ritchlin cited data from a survey of patients in the United States and Canada. “The majority of patients, even with severe psoriasis or psoriatic arthritis, forget about being on any kind of systemic therapy. They are taking no treatments or topical agents,” he said. “Out in the population, there remain patients who we would consider to be inadequately treated.”

Howells and colleagues wrote that psychological problems may be poorly understood and treated in patients with PsA. They conducted a cross-sectional observational study in a cohort of 179 patients who completed the online Commonsense Model of Self-Regulation survey about illness beliefs, coping strategies and disease severity, along with depression, anxiety, and quality of life (QoL) metrics. In a multivariate analysis that controlled for disease severity, anxiety was predicted by self-blame. Depression was predicted by negative beliefs about the consequences of the illness and disengagement as a way of coping. Depression and beliefs about consequences of the illness also had a prognostic impact on QoL.

“This study offers support for the use of the [Commonsense Model of Self-Regulation] in explaining variation on psychological outcomes in individuals with PsA. The illness beliefs and coping strategies identified as predictors in this paper are potential targets for interventions addressing PsA-related distress and QoL,” the researchers concluded.

Simply asking about pain and fatigue in patients with PsA is an important step to managing these comorbidities, according to Tillett. “Without that first step, we won’t have a good understanding of the burden and effect of our treatments,” he said. “The treatment of fatigue in PsA is particularly challenging. Suppressing the inflammatory disease is important and previous work from our group has shown improvement in fatigue with medical treatment of active PsA, but, importantly, not complete resolution.”

For many clinicians like Lories, it simply comes down to being a good physician. “There are different ways of getting better,” he said. “Of course, you should pay attention to your patients, but there are also research and academic strategies. If you analyze things properly, you can find the signal from the noise.”

Continuing medical education (CME) is also critically important, according to Lories. “Don’t live on an island,” he said. “Learn from the experience of other disciplines. CME activities may go increasingly toward what to do in specific populations, like elderly patients with other diseases. Having discussions about what to do in these populations can help control individual patient cases.”

Taking a broad view is also important, Lories said. He suggested migration of patients from developing nations to the western world can bring a host of challenges and infections that a physician in London or Ontario might not have seen before. “We also need to think about how, for instance, patients with HIV and spondyloarthritis, or cancer patients with active joint disease can be controlled,” he said. “Every patient with these diseases tends to bring a lot of open questions.”

Lories added that having a strategy and sticking to it is most important, but that clinical decision-making often comes down to basics.

“First, you start with a highly targeted approach to get remission,” he said. “Then, you search for a strategy to stay in remission.”

Zeroing in on IBD

Deora and colleagues investigated the utility of therapeutic drug monitoring in making clinical decisions in a cohort of 73 children treated for IBD with infliximab. Investigators evaluated infliximab trough levels from 107 consecutive serum measurements. Results showed therapeutic drug monitoring was used in 22.4% of children as a result of clinical disease activity, while this approach was used in 77.6% of the cohort as part of routine evaluation. Infliximab trough levels were suboptimal — defined as less than 3.5 µg/mL — in 35.5% of these cases. More frequent doses of infliximab were prescribed in 34% of the cohort. Improvements in disease biomarkers were reported among those with increased dosing. Thirty-two percent of the cohort experienced interval changes in dosing, with 17% experiencing shorter intervals. Additional immunomodulators were used in 6.5% of patients with infliximab trough-level data. Four patients switched to adalimumab. “Therapeutic drug monitoring was helpful in guiding the decision-making process for children with IBD on infliximab,” the researchers concluded.

For Paolo Gionchetti, MD, associate professor in the IBD unit in the department of medical and surgical sciences, S. Orsola-Malpighi Hospital at the University of Bologna in Italy, simply knowing these basics is a good place to start. In a recently published paper, he and colleagues described spondyloarthropathies as a group of diseases with similar clinical, radiologic and serologic features. They suggested SpA is a common comorbidity of IBD and that clinicians should note differences in recommendations for axial and peripheral SpA, along with different guidelines for Crohn’s disease and ulcerative colitis. “SpA is the most frequent extra-intestinal manifestation in IBD,” Gionchetti told Healio Rheumatology. “Patients with symptoms of SpA can be underdiagnosed and effective treatment delayed, which might lead to a chronic debilitating disease course and decreased quality of life. A multidisciplinary approach with gastroenterologists and rheumatologists collaborating would be the best way to manage these patients.”

Clinicians are encouraged to recognize red-flag warnings that will help assure a timely and correct diagnosis of IBD-associated SpA. “From the point of view of the gastroenterologist, the presence of chronic back pain and stiffness that does not improve with rest but does improve with exercise, peripheral joint pain and/or swelling, signs of enthesitis and the presence or a history of dactylitis or other types of tenosynovitis might suggest a SpA,” Gionchetti said. “In these cases, the patients should be referred to a rheumatologist.” Swelling in the arms and legs may occur, along with inflammation in the heart or intestines, fatigue, eye pain and psoriasis in the skin. Clinicians should be aware of these symptoms and that imaging tests may also be used for diagnosis.

There are effective therapies for both axial and peripheral diseases, according to Gionchetti. These include sulfasalazine or anti-TNF drugs. NSAIDs may also be used, along with corticosteroids, disease-modifying antirheumatic drugs, and antibiotics in cases of reactive arthritis. Gionchetti stressed that treatment is only half the battle. “Early diagnosis and treatment are important to modify disease progression and decrease the disease burden,” he said. “The therapeutic strategy should be modulated taking into account the variable manifestations of IBD in terms of intestinal and extra-intestinal features and the clinical manifestations of SpA, and an integrated management of the different clinical scenarios should be adopted.”

Imaging

In a brief overview of imaging modalities in spondyloarthritis — specifically vertebral and sacroiliac involvement — Leone and colleagues suggested CT is a sensitive in evaluating structural bone changes, but has limits in terms of clinical utility. They suggested MR is preferable for early diagnosis due to its capacity to show inflammation before the onset of structural damage. MR is also useful in monitoring disease activity and evaluating therapeutic response, according to the findings.

“Talking about sacroiliitis on imaging, when you look at MRI lesions on scans, you can look at inflammatory or acute lesions,” Machado said. “These are best seen on water-sensitive images. Structural or chronic lesions, such as fatty deposition and erosions, are best seen on T1-weighted images.”

Machado added that for an MRI to be considered positive, the inflammation must be clearly present and located in a typical anatomic area. “The MRI appearance must be highly suggestive of spondyloarthritis,” he said. “Of note, the decision to define a lesion as highly suggestive of spondyloarthritis, may be influenced by the presence of concomitant structural damage. However, structural damage itself does not suffice to classify an MRI as positive.”

Regarding whether MRI should be the first-line imaging modality in axial spondyloarthritis, Machado suggested that T1-MRI could replace conventional radiography in detection of structural damage of the sacroiliac joints, but that its still limited availability and relatively high cost could be prohibitive. “Also, there should be agreement about the definition of MRI positivity from a structural point of view,” he said. – by Rob Volanksy

• References:
• Asahina A, et al. J Dermatol. 2017;doi:10.1111/1346-8138.13987.
• Cantini F, et al. Semin Arthritis Rheum. 2017;doi:10.1016/j.semarthrit.2017.03.008.
• Deora V. Acta Paediatr. 2017;doi:10.1111/apa.14008.
• Francavilla ML, et al. Pediatr Radiol. 2017;doi:10.1007/s00247-017-3877-y.
• Gionchetti P, et al. J Rheumatol Suppl. 2015;doi:10.3899/jrheum.150628.
• Howells L, et al. Arthritis Care Res (Hoboken). 2017;doi:10.1002/acr.23330.
• Kanekura T, et al. J Dermatol. 2017;doi:10.1111/1346-8138.13975.
• Manara M, et al. Clin Exp Rheumatol. 2017;Epub ahead of print.
• Norli ES, et al. Arthritis Care Res (Hoboken). 2017;doi:10.1002/acr.23334.
• Paparo F, et al. Radiol Med. 2014;doi:10.1007/s11547-013-0316-5.
• Ritchlin CT. Keeping your eye on the target: Immune targets in PsA and SpA. Presented at: Biologic Therapies VII Summit; April 5-8, 2017; Cleveland.
• Sobolewski P, et al. Reumatologia. 2017;doi:10.5114/reum.2017.68912.
• Tillett W, et al. J Rheumatol. 2017;doi:10.3899/jrheum.161459.
• Zagora SL, et al. Curr Opin Ophthalmol. 2014;doi:10.1097/ICU.0000000000000098.
• www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Spondyloarthritis

• For more information:
• Paolo Gionchetti, MD, can be reached at Policlinico S. Orsola-Malpighi, DIMEC, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; email: paolo.gionchetti@unibo.it.
• Rik Lories, MD, PhD, can be reached at University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; email: rik.lories@kuleuven.be.
• Pedro M. Machado, MD, PhD, can be reached at 1st Floor, University College London, Russell Square House, 10-12 Russell Square, London WC1B 5EH, United Kingdom; email: p.machado@ucl.ac.uk.
• Christopher T. Ritchlin, MD, MPH, can be reached at University of Rochester Medical Center, 400 Red Creek Dr., Rochester, NY 14623; email: christopher_ritchlin@urmc.rochester.edu.
• William Tillett, MBChB, BSc, PhD, can be reached at 2.18 5 West, University of Bath, Bath, United Kingdom; email: w.tillett@nhs.net.

Disclosures: Gionchetti reports no relevant financial disclosures. Lories reports he receives grant support and speaker or consultancy fees from AbbVie, Celgene, Johnson & Johnson, Pfizer, Novartis, and UCB. Machado reports he receives consultancy/speaker’s fees from AbbVie, Centocor, Janssen, Merck, Novartis and Pfizer. Ritchlin reports he is a consultant for AbbVie, Bristol-Myers Squibb, Janssen and Novartis; is a consultant and an independent contractor for Amgen; and is a consultant for and receives research support from UCB. Tillett reports he receives grants or consulting fees from AbbVie, Celgene, Janssen, Novartis, Pfizer and UCB; has independent research funded by the NIH Research (program grants for applied research, early detection to improve outcome in patients with undiagnosed psoriatic arthritis, RP-PG-1212-20007); and the views expressed in this story are those of Tillett and not necessarily those of the NHS, the NIH Research or the Department of Health.