. Today, we will be discussing a case presentation of nonradiographic axial spondyloarthritis, a relatively new term defined in 2009, which addresses a group of patients who have inflammatory back pain and fulfill criteria for nonradiographic axial spondyloarthritis.

The patient is a 21-year-old woman who presents to a primary care physician with a 3- to 4-year history of back pain, which is worse at night and in the early morning, associated with significant morning stiffness. She had been attributing the pain to being a very active athlete and mentioned that the pain subsided once she started moving around.

She had no significant past medical history or surgical history. On physical exam by the primary care physician, she was noted to have decreased range of motion in her lumbosacral spine, and actually a Schober’s test measurement was 3.5 centimeters. There was some equivocal thickening of her Achilles’ tendon and when asked by the primary care physician, the patient stated that she may have either injured it or had tendonitis in that area in the past, but that it was not bothering her at that time.

The primary care physician recommended ibuprofen to be given, 400 milligrams 3 times a day and also recommended physical therapy. After approximately 4 weeks, the patient stated that she had mild improvement but that the back pain persisted. She noted decreased ability to move her back, and it was beginning to have an impact on her activities of normal daily living. Importantly, she developed abdominal pain, nausea, and vomiting and had to stop taking the ibuprofen. At that point, the primary care physician referred her to a rheumatologist.

The rheumatologist evaluated the patient and likewise confirmed the issue of the Schober’s test measurement being limited—otherwise, noted no other abnormalities. The clinical workup included laboratory test results that were remarkable for 3 abnormalities. The patient had an elevated CRP [C-reactive protein level] of 4.7, normal is less than 3.0, an elevated sedimentation rate of 38, normal is less than 20), and her blood was noted to be HLA-B27 positive. Imaging performed via x-rays of the sacroiliac joints and the spine showed essentially normal results; however, an MRI of the sacroiliac joints did reveal evidence of inflammation without fusion, but there was a possible erosion.

In terms of my initial impression of this patient, it was clear that she had inflammatory back pain, that she developed this at a young age, and that, indeed, the laboratory test results, including the sedimentation rate, the CRP, and, importantly, the HLA-B27 positivity, were very supportive of axial spondyloarthritis. The fact that her x-ray results were normal but the MRI test result was positive, was further support for the diagnosis of axial spondyloarthritis. But since the x-ray results were normal, this is what is now classified as nonradiographic axial spondyloarthritis.

In terms of therapeutic goals for this patient, number 1, patients come to us for relief of pain. So, my first goal would be to relieve her pain. Number 2, patients come to us, also, for improvement in their function. She had begun to have some symptoms that were having an impact on her day-to-day activities. Therefore, my second goal would be a functional goal and have her reach whatever type of function was appropriate for her. And ideally my third goal, which is difficult to achieve, would be to prevent further progression of this disease.

A 21-Year-Old Woman With Nonradiographic AxSpA 

With regards, now, to nonradiographic axial spondyloarthritis, 1 of the challenges is that it takes many years—and indeed our patient exemplifies that&mdash;from the onset of symptoms to the actual diagnosis. Part of the challenge, there, is that this is a relatively new diagnosis for us. We’ve not had a classification criteria for nonradiographic axial spondyloarthritis for a long period of time. The ASAS [Assessment of SpondyloArthritis International Society] group was the first to make this distinction and that was very recently, in 2009.

So, there is a lack of knowledge across all subspecialties, with regards to nonradiographic axial spondyloarthritis as a distinct entity. And patients are frequently seen by a number of different doctors who may or may not be well educated as to this entity. For example, they can be seen by primary care physicians who do not necessarily always refer their patients to rheumatologists quickly because there is sometimes difficulty in getting an appointment. Number 2, they can be seen by orthopedic surgeons who, likewise, are not familiar with this diagnosis. Physiatrists and pain management physicians, not infrequently, are not knowledgeable of the whole concept of axial spondyloarthritis. And sometimes these patients are seen by a neurologist first because it’s back pain. Believe it or not, they’re seen by podiatrists who sometimes attribute the back pain to issues referable to the gait and the foot. And also these patients are frequently seen by chiropractors. So, the average delay, now, from the time of symptoms to the diagnosis of nonradiographic axial spondyloarthritis is 4 to 8 years.

So, how can community rheumatologists, then, make this diagnosis early? The first, obviously, is an unmet need, which we’re trying to fulfill now, and that is education. We hope that as more people become aware of this entity and this spectrum of disease that occurs in axial spondyloarthritis that they will be a lot more sensitive to this specific diagnosis. So I think that education is a critical element. I must admit, as a rheumatologist, that sometimes this diagnosis is also missed by rheumatologists and, to that point, there is an article that was published that looked at a number of different rheumatology practices and found that there were patients who had axial spondyloarthritis who are identified as having other diseases.

Overwhelmingly, the most common reason why this diagnosis is made is because back pain is very common in our community. As many as 40% to 60% of people, over time, maybe even a larger group, will have an episode of back pain, which tends to be mechanical back pain. So it's not due to an autoimmune inflammatory disease like axial spondyloarthritis. So most physicians, when they see patients with back pain do not differentiate between inflammatory back pain and mechanical back pain and assume that this is all mechanical back pain. Probably the other mistaken diagnosis and by which patients are missed as having axial spondyloarthritis is fibromyalgia.

And fibromyalgia, frequently, does include a component of back pain. Interestingly, we have found that women who have nonradiographic axial spondyloarthritis are more likely to have symptoms of fibromyalgia, meaning that their pain isn’t classic. They can have more diffuse symptoms and they can have cervical spine symptoms.

Nr-AxSpA Diagnostic Challenges

 What is the treatment strategy in patients who have nonradiographic axial spondyloarthritis? It should really be the same as what we use in ankylosing spondylitis. So a critical element is the nonpharmacological components. In that regard, exercise is important, stretching is very important, and patients should do this every day. Nonsteroidal anti-inflammatory agents are a critical group of medications that are useful in this disease group, as well. And generally, as therapies are implemented to manage these patients, the first approach is to try nonsteroidal anti-inflammatory agents in conjunction with the nonpharmacological components that I’ve mentioned.

If that does not result in success, then biologic therapy should be utilized. And to that point, our current guidelines from a number of societies do recommend that anti-TNF agents should be utilized first in this group of patients. However, there are a number of different types of biologics that have now been approved for the management of patients with axial spondyloarthritis. Only 1 has been approved for nonradiographic axial spondyloarthritis in the United States and that is certolizumab.

In terms of other therapies that are available and utilized to manage these patients, there has not been a great amount of success. I would make a strong argument against the use of opioids, for example, and the DMARD [disease-modifying antirheumatic drugs] group of medications, things like methotrexate, for example, or leflunomide, have not been effective in this group of diseases. Corticosteroids should not be used over the long term, and there may be a role for episodic use of these medications during disease flares or as intra-articular injections, if there are peripheral joint symptoms. Some people have actually utilized direct sacroiliac joint injections; however, this treatment does not usually result in efficacy over the long term.

In terms of nonsteroidal anti-inflammatory agents, these medications have been utilized to manage patients with axial spondyloarthritis for many years—before we even used that term when we were calling all of these patients&mdash;ankylosing spondylitis. And these medications are effective in treating some of these patients.

In fact, there are data that have been published, mostly old data, now, that have looked at prevention of radiographic progression in patients with ankylosing spondylitis or are managed with nonsteroidal anti-inflammatory agents alone. And that has shown some efficacy. So a trial of at least 1, but generally 2, nonsteroidal anti-inflammatory agents for several months is appropriate. However, as our patient care exemplifies, these medications over the long term can result in significant adverse effects such as GI [gastrointestinal] toxicity in our patients.

Treatment Strategy and the Role of NSAIDS 

So once this patient had had a relatively poor response to ibuprofen and importantly developed GI [gastrointestinal] toxicity to this medication, the decision was made to proceed with therapy with an anti-TNF agent for the management of this patient’s nonradiographic axial spondyloarthritis. The therapy that was chosen is the only approved medication for nonradiographic axial spondyloarthritis in the United States, and that is certolizumab.

Certolizumab is an anti-TNF agent, which is a PEGylated Fab’ fragment and in the study that was done the C-AXSPAND study.

In the C-AXSPAND study, there were only 2 treatment arms. These were patients who were treated with either placebo or certolizumab. A 400-milligram loading dose was utilized and then 200 milligrams every 2 weeks. This was a very robust study, a study in which the primary outcome was, indeed, at 52 weeks, although there were a number of other secondary outcomes that were earlier.

The majority of the patients that entered this study did not respond favorably to a nonsteroidal anti-inflammatory agent—over 80%. Some had been treated with DMARD medications, generally in the 30% range, and corticosteroids were also utilized in about 10% of the patients. Interestingly, and surprisingly&mdash;as well as, disappointingly&mdash;as many as 10% of the patients in this study had been on narcotics.

The results of this study were striking. The 52-week data, which was the primary outcome, 47% of patients achieved an ASDAS-MI [Ankylosing Spondylitis Disease Activity Score-Major improvement], which was the primary outcome, with only 7% of patients taking placebo achieved that response rate.

There were data earlier on: at 12 weeks, 35% of patients had achieved their response versus 6% of the control group. Such a low number in the control group actually testifies to the fact that this was a very well-done study with a very low placebo response rate.

The implications of the C-AXSPAND study, I think, really have hit 2 high marks. The first is that based on this study, American rheumatologists are now beginning to really understand and conceptualize the concept of nonradiographic axial spondyloarthritis, so there has been an educational component that has been met. And importantly, the fact that we have 1 therapy approved for nonradiographic axial spondyloarthritis means that we now have the capacity to treat this disease from a regulatory perspective.

There is 1 other element that I’d like to cover in terms of certolizumab—it is a unique molecule. As I mentioned previously, this is a pegylated Fab’ fragment, and the advantage of not having an Fc component to this anti-TNF agent is that it does not cross the placenta because placental transfer of antibodies does require an FC portion. So there have been studies that have looked at the transfer of anti-TNF agents across the placenta that have demonstrated that very little certolizumab actually crosses the placenta.

So 1 of the unique features of certolizumab is that in pregnancy, it does not cross the placenta, nor is it expressed in the milk of mothers who nurse their babies.

So a question that is raised is, when should certolizumab be utilized in patients with nonradiographic axial spondyloarthritis, or really across all of its indications, based on this advantage, that it does not cross the placenta? And there isn’t a uniform answer in that, but I think 1 of the issues that is frequently raised by patients is the pregnancy issue. So, both women and men are concerned about therapies during pregnancy. Technically then, though, if we can present a molecule that does not cross the placenta—even in women who are not pregnant but considering pregnancy in the future&mdash;women of childbearing age, this would be a potential benefit of this therapy for the management of non-radiographic axial spondyloarthritis and the other groups of diseases.

The Role of Anti-TNF Therapy

 Hi, this is Madelaine A. Feldman, MD. I’m on the clinical faculty in medicine at Tulane University School of Medicine. I’m a rheumatologist in private practice in New Orleans, Louisiana. Welcome to this 

 titled “Case-Based Approach for the Management of Rheumatic Diseases.”

Our case today is of a 48-year-old gentleman who initially presented to his primary care physician with a 9-month history of pain, swelling, and stiffness in his hands, wrists, and ankles in the morning. This stiffness would last for several hours. He presented to his primary care doctor, who started him on 800 mg of ibuprofen 3 times a day. Despite this very good dose of an anti-inflammatory, it eventually lost its effectiveness. And so he presented to a rheumatologist.

He has no past medical history. He was on no other medicines, other than the ibuprofen. On physical exam, he has active bilateral synovitis in both hands, wrists, and ankles. And importantly, he’s got nodules on his left elbow. A CDAI [Clinical Disease Activity Index] score was calculated and was 38. Remember that CDAI is the number of swollen and tender joints. We look at 28 joints. We look at the shoulders, the elbows, the wrists, the MCP [metacarpophalangeal]

joints, the PIP [proximal interphalangeal] joints, and the thumbs. Remember, the ankles and feet are not included in the CDAI.

There’s a patient global assessment as well as a physician global assessment, and high disease activity in the CDAI is over 22. This patient was at 36, so he demonstrated very high disease activity. That was also confirmed by his laboratory results. His CRP [C-reactive protein] level was 62. He had a sedimentation rate of 42, a rheumatoid factor of 44, and a highly elevated CCP [cyclic citrullinated peptide] level.

X-rays showed no erosions, but there was joint space narrowing and some periarticular osteopenia. At that time, oral methotrexate was recommended at 10 mg a week. And over the next 4 weeks, it was increased to 15 mg.

He returned to the rheumatologist’s office after 3 months and continued to complain about stiffness, pain, and swelling in his wrists. The CRP level and sedimentation rate continued to be elevated. At this point, his productivity and his general mobility were really being affected by his joint pain. His CDAI score had come down to 22, but it was still demonstrating very high disease activity.

Assessment of a 48-Year-Old Male With Rheumatoid Arthritis

 This patient has a number of hallmarks suggesting that he could have a very advanced and quick progression of his disease activity. A combination of having both a rheumatoid factor and a high CCP [cyclic citrullinated peptide] level is a hallmark of that. In addition, he had what appeared to be rheumatoid nodules on his elbow. So this gentleman does run the risk of not only very quick and advanced disease activity but also perhaps some risk for nonarticular manifestations with his rheumatoid arthritis.

First, he needs to be maximized on methotrexate treatment. We know that GI [gastrointestinal] absorption over 15 mg can be nonspecific, and we are not sure how much the patient is absorbing. With this patient, I would definitely recommend switching to subcutaneous therapy and advancing his methotrexate to 25 mg a week. He’s young, and he’s working. We need to make sure that we can control the inflammation in his joints very quickly. Occasionally, we will use a very low dose of prednisone in someone with this type of a presentation.

I would give him only maybe 8 weeks on the higher methotrexate dose and even the low-dose prednisone. If he is showing any signs or symptoms of continued disease activity, or if the disease activity starts to recur when trying to taper the prednisone, we have to go to the next step.

The next step for this gentleman would be to include a biologic or one of these advanced disease-modifying agents that is nonbiologic. We have a wide array of biologic therapies that we could use in this gentleman. Of course, the ones that have the longest history are the tumor necrosis factor inhibitors. These include certolizumab, adalimumab, etanercept, infliximab, and golimumab. We also have a T-cell costimulator modulator known as abatacept. And then, IL-6 inhibitors are also a possibility for this gentleman. We have sarilumab and tocilizumab. And finally we have JAK inhibitors. They are not biologics, but they are considered to be somewhat advanced in terms of the disease-modifying agents. As of now, we have tofacitinib, baricitinib, and upadacitinib.

Rheumatoid Arthritis: Current Treatment Recommendations

 For the most part, the TNF [tumor necrosis factor] inhibitors are generally used along with methotrexate. Certolizumab has been able to be used alone. Particularly, we see its use in pregnant women, and it is used without the methotrexate. Most of the other TNF inhibitors are mostly used in conjunction with methotrexate, not only to help with the disease modification but also to help in preventing neutralizing antibodies. In this gentleman, a TNF inhibitor would not be a bad choice.

There are some studies that suggest that patients who have a high CCP [cyclic citrullinated peptide] level do respond fairly well to abatacept. That generally is also used with methotrexate.

JAK/STAT inhibitors—tofacitinib, baricitinib, and upadacitinib&mdash;are choices that we can use, followed by the interleukin inhibitors, sarilumab and tocilizumab. There are some studies that suggest tocilizumab monotherapy is just as effective as tocilizumab plus methotrexate.

You know, if we looked at this patient and he didn’t have all those hallmarks of the possibility of fairly quickly advanced disease, in some cases we might consider changing the methotrexate to leflunomide, or adding Plaquenil [hydroxychloroquine]. But because of those hallmarks of worrisome, very aggressive rheumatoid arthritis, at this point it would be the time to add one of the biologics that I just spoke about.

Rationale for TNF Inhibition in Rheumatoid Arthritis

There have been studies in the past combining biologics, and the adverse effects and infections and problems that occur definitely do not outweigh any added benefit that they may have. Consequently, at this point, we are not combining biologics. Nor are we combining them with the JAK inhibitors. One of the issues that we see with the JAK inhibitors, perhaps a little bit more than with some of the biologics, is that there is an increased risk of shingles. Consequently, we really do not want to increase any infectious complications, so we do not combine the biologics. Nor do we combine them with the JAK/STAT inhibitors at this time.

There have been studies like the one I mentioned with tocilizumab regarding how the use of methotrexate did not give any added benefit in terms of the clinical response with tocilizumab. Certolizumab can also be used without methotrexate, as I stated, in cases of pregnant women. We have a large number of studies whose results show that it works quite well without methotrexate.

If this patient had some contraindications to increasing his methotrexate—for example, his liver functions continued to be elevated, or he had an alcohol problem that could not be controlled, or perhaps he was experiencing some other type of adverse effect or rash that he was having with methotrexate&mdash;we want to make sure that he is taking folic acid with methotrexate. The patient may be getting mouth ulcers, and that could be mitigated with the use of increasing folic acid. And sometimes we even add methylfolate, the activated folic acid. That can help us if we’re having problems increasing the amount of methotrexate. If we have to take the patient off methotrexate, then 1 of those 2 drugs, either the certolizumab or tocilizumab, would be a good choice.

Occasionally, we will use a different disease-modifying agent in conjunction, such as leflunomide. And occasionally, we will use Plaquenil [hydroxychloroquine] as an additive. Plaquenil is a very safe medication and often can give a little bit of an additive. As long as we’re not combining 2 biologics or a JAK inhibitor with a biologic, we sometimes see an advantage to having multiple medications on board.

All the while, this patient may still be on a low dose of prednisone. The idea is we want to get this patient to, at the very least, low disease activity and, if possible, to a state of remission. Now, a cure would be remission off medications. We’d like to get to that point, but we’re not there yet. Certainly, we’d like to take the patient off prednisone. So we could try one of the drugs that I had spoken about, and if there’s a problem with methotrexate, we could certainly use certolizumab. Or there’s tocilizumab. Then we should follow the patients again. Generally, we like to give it about 3 months. If the patient has not improved or has not gotten to a low disease state with the treat-to-target approach, we need to add on therapy, increase the dose, or change to a new medication.

Regarding the efficacy, in terms of the usual [American College of Rheumatology (ACR)] ACR20, ACR50, and ACR70 scores, we tend to see a similar type of response among most of the biologics. The ACR20s are usually in the 60% to 70% range. The ACR50s are somewhere in the 30% to 40% range. The ACR70s are in the 20% range, although sometimes we can get as high as 30%. With most of the TNFs [tumor necrosis factors], when methotrexate is added, we do see an increase in benefit in those ACR20, ACR50, and ACR70 scores. That is why we tend to use the methotrexate. It does tend to enhance the results and the ACR scores and get patients to more of a low disease activity.

Combination Regimens to Treat Rheumatoid Arthritis

 There have been studies regarding what to do if a patient does not respond to a TNF [tumor necrosis factor] inhibitor. That is your first choice. And you have methotrexate on board. There really is a difference in whether they stop the medicine because they’re having an adverse effect versus having a loss of effect. If the patient never really got a good effect from the TNF inhibitor, your chance of getting a better outcome with another TNF is about 40%. Because we have so many mechanisms of actions that we can use now, we’re finding that rheumatologists are moving to a different mechanism of action. I still think TNF inhibitors tend to be the first choice. They’ve been around the longest. It depends on the patient’s age, their other comorbidities, and whether they’ve had infections. Is it easy for them to come get an infusion? Do they have a problem with giving themselves a shot? Would they rather take a pill? All these things have to come into consideration when we’re trying to figure out the best medication for a patient.

But I think we’re seeing now that if a TNF fails the first time around, we have so many other choices and so many other mechanisms of action. Unless you’re switching the formulation, perhaps you might go from a self-injectable to an infusion with a TNF. Or, because there may be an adherence problem. Those are all the kinds of things that you have to take into consideration when you’re making that choice of what to start the patient with and what to possibly switch them to, regarding another medication.

TNF Inhibitors for Rheumatoid Arthritis: Switching Therapy

 If the question is how often we change from an originator to a biosimilar, I think we realize that they work very similarly. So if the originator or the reference product biologic is not working, I don’t envision many rheumatologists switching to a biosimilar. We don’t expect it to work any worse, but we don’t expect it to work any better. Switching from originators to biosimilars does happen, but generally that happens because of third-party considerations.

If a patient can get the benefit of lower cost from a biosimilar and there is a question of starting them on a higher-priced originator or a lower-priced biosimilar, I will always, and I think this is the tendency among rheumatologists, go with the drug that costs the patient the least. If it’s an infusion that doesn’t necessarily cost the physician or the insurance company the least, but if the patient can benefit from a lower price or a lower cost-share with a biosimilar, all things being equal with the reference product and the biosimilar, I think rheumatologists would choose the lower-cost alternative.

I’ve never been forced to switch from a biosimilar to an originator. There are formularies that are coming out now where the biosimilar may be preferred over the originator. Therefore, the patient will need to be switched to the biosimilar. I don’t think it’s been around long enough, at least in the formularies that my patients have been on, where the patient was on a biosimilar and then would have to switch back to the reference product. One would be preferred over the other at that point.

We don’t have any self-injectable biosimilars yet, so we’re really looking at provider-administered drugs at this point. I have not come across any formularies that have switched from a biosimilar to a reference product as of yet. I’m sure it will happen.

Use of Biologics Vs Biosimilars For Rheumatoid Arthritis

Comorbidities with rheumatoid arthritis have become an extremely important topic. As we have looked over the years, in terms of what are the risk factors for cardiovascular disease, we know obesity, high cholesterol, diabetes, smoking, family history, and hypertension all play a part in increasing the risk of cardiovascular disease. We have found the inflammatory burden from rheumatoid arthritis is probably just as important as any of those risk factors for cardiovascular disease. So it is extremely important that we help patients mitigate any of the risk factors that they may have, other than rheumatoid arthritis, in terms of heart disease. For example, optimizing their blood pressure control. Diet and exercise to improve glucose tolerance as well as their weight. If they have high lipids, making sure that either through diet or medication their bad cholesterol comes down. And obviously, if they’re smokers, doing whatever we can to get them to quit smoking. Family history is something that we don’t have any control over, but there are a number of lifestyle modifications and certainly some medications. So controlling the disease activity of the rheumatoid arthritis obviously plays an extremely important role in mitigating the cardiovascular problems that we can see associated with active rheumatoid arthritis.

We’ve gotten pretty good at setting up an algorithm in terms of what medications you use and when, and treat-to-target, and, after 3 months, either changing the medication or advancing the dose. I think one of the things we may have put on the wayside that I think is extremely important in any patient who has a chronic disease is depression. There are many patients who come in for whom we need to make sure that they’re sleeping well and have good social connectedness. All these things can worsen depression. Obviously, the diet, the exercise. Some physicians are recommending some kind of mindfulness or meditative practice. And then, of course, as I suggested, the social connectedness. All those things that go into a healthy lifestyle are probably even more important for our patients with connective tissue diseases and rheumatoid arthritis. For that matter, any of the autoimmune diseases. Because patients can feel isolated. Sometimes helping them deal with that and screening them for depression and actually creating sort of an empathetic bond with your patient, I have found, is worth its weight in gold.

Comorbidities in Rheumatoid Arthritis

 Today we’re going to talk about a young woman with psoriatic arthritis. She’s a 31-year-old Caucasian woman who presents to her primary care provider complaining of intermittent body aches and difficulty in picking up her child and cleaning her house. That immediately tells me that she’s having a lot of functional consequences. Her past medical history is notable for 6 years of scalp psoriasis, which she has under control with salicylic acid shampoo, and she has a prior history of multiple sclerosis. It has not been clear how that diagnosis was made, or if that was firmly made.

On her physical exam, she has tenderness over multiple joints, which includes both elbows, the metacarpal phalangeal and proximal interphalangeal joints of both hands, as well as the distal phalangeal joints on the right hand and the right knee. She has swollen joints of the right shoulder, the proximal and distal interphalangeal joints of the right hand, really showing that she’s got some joints that have both swelling and tenderness, and others that are just tender, and there’s a bit of a symmetry in her presentation. Her neurological exams showed no sensory deficits or hyperesthesia consistent with the questionable multiple sclerosis diagnosis. Her motor examination was not very accurate because she had significant pain that was limiting her active range of motion. Chest and abdominal findings were unremarkable.

Her initial work-up confirmed that this is someone with psoriasis, and probably psoriatic arthritis because she had multiple joints involved. She was placed on methotrexate, escalating her dose with an ultimate increase to 25 mg per week. On her imaging studies, it was noted that she had erosive changes in the small joints of the hands, and those were in fact asymmetrical, paralleling her clinical presentation. She also had narrowing of the joint space in the interphalangeal joints of the hands. Laboratory values were remarkable for elevated inflammatory markers, so her erythrocyte sedimentation rate was elevated to 35 mm/hour; normal in this lab is 0 to 20 mm/hour. Rheumatoid factor was negative, her antinuclear antibody test was negative, and her C-reactive protein was 7 mg/dL; normal is less than 3 mg/dL.

Three months after this initial plan was initiated, she still complained of similar symptoms, so she really had not improved. Her sedimentation rate, however, was now 30 mm/hour, just minimally improved. Her CBC [complete blood count] and chemistries were normal, and her C-reactive protein at this point is down from 7 to 3 mg/dL.

We’re left now with a young woman with a history of scalp psoriasis, inflammatory markers on her laboratory analyses, and evidence of synovitis with swelling and tenderness in multiple joints. This is someone who I would diagnose with psoriatic arthritis. And just to point out 1 thing: When we see scalp psoriasis, the likelihood of psoriatic arthritis in this individual is 4-fold. This is someone we should have been watching and be mindful of. Scalp psoriasis is not a benign finding in patients.

When we look at patients like this, we’ve already done the laboratory analysis. It was important to exclude other inflammatory arthritides by having an elevated rheumatoid factor. That’s actually a part of our CASPAR [Classification Criteria for Psoriatic Arthritis] criteria. She does not have an elevated rheumatoid factor, and that’s a plus in saying that this is psoriatic arthritis, and we have the elevated sedimentation and C-reactive protein. The fact that we have erosions and joint space narrowing on x-rays already tells me that this person has significant burden of disease. The 1 thing we have not looked at is her axial skeleton. It’s important to really examine that, because even though patients may not complain—she’s stiff, she’s in pain, she’s barely moving, she can’t lift, she can’t clean&mdash;there are a lot of things that she has already altered just to get through her day. She might have sacroiliac or lumbar thoracic cervical spine involvement, so we need to image those, because she may not be aware that she also has disease in those domains, and that may ultimately significantly impact her ability to function. Yes, the labs are important, but we also always have to do imaging where we suspect we may find hidden disease, even if the patient is not complaining.

My therapeutic goals for this patient really are to have her feel well, be well, and function well. She has a child at home, and she wants to be able to function in her home environment. It’s important to engage her in that conversation of, “What are the things that you need to do?” From my perspective, I want to see the swollen joints disappear. I need to halt the erosions, because eventually, as you damage joints, you will destroy joints, and then we have permanent disability. I want to see that her inflammatory markers go down, that her erosions are halted, but that functionally she also feels well. Another hidden complaint we’ve uncovered is that depression is a really important part of this group of diseases. When patients come in and they’re feeling poorly, we attribute everything to, “OK, she’s just feeling poorly.” But we need to assess her mental health. Is she anxious? Is she depressed? Is that part of her disease? We can address those at the same time and get her to a good level of functioning. All the things I mentioned that are abnormal, I want them gone. I want her well. That’s my therapeutic goal for her.

Assessment of A 31-Year-Old Woman With Psoriatic Arthritis

 There are lots of discussions about, “What do you do next?” She was already put on methotrexate, and I’m going to bring in the point that she’s got a young child. This is somebody who’s having children—maybe this is her first, maybe it’s her last. We need to have that discussion, because methotrexate may not be a sustainable drug for her. If she’s thinking of a pregnancy at some point in the near future, we might want to choose a therapy that allows her to be well without methotrexate as backbone therapy.

The options we have include the TNF [tumor necrosis factor] inhibitors. Many people would say let’s put her on some NSAIDs [nonsteroidal anti-inflammatory drugs]. NSAIDs over the long haul have their own layers of toxicity, and they don’t alter the disease. They’re not going to treat her psoriasis, and they’re not going to treat her erosive disease. A biologic DMARD [disease-modifying antirheumatic drug] is the place I would go, and whether we choose to use a TNF inhibitor, a self-administered TNF, or an infusion TNF. We have the IL-17s as well, which have shown to be effective in this classification. With or without methotrexate, I want to see efficacy. And in a young person, in a young woman, I also want to see efficacy. We have lots of data to guide us.

We now have coming into the market JAK inhibitors that also can be used with or without methotrexate. The field is becoming crowded from my perspective. But from her perspective it’s, “I have choice.” She gets to choose if she wants a pill, an infusion, or an injectable, and then we can take it from there. There are really lots of therapeutic options for her at this point that can address the damage in her joints and the level of physical dysfunction she feels.

First line is methotrexate. When we think about erosive damage, typically we’re going on to a biologic agent pretty rapidly, and that is where we have lots of choices. TNF inhibitors have been very effective. IL-17 inhibitors have also been very effective. So she has choices. There are other oral agents, whether it’s a PD4 inhibitor or a JAK inhibitor on the market as well. I think our staple would be between the IL-17s, the TNF inhibitors, and also the IL-23s coming in. There’s really an increasing flexibility and increasing availability of a lot of products to help manage this. But TNFs and IL-17s would be my first choice.

When we think about the totality of this patient, I think of nonsteroidals as the Band-Aid. For somebody who has some swollen joints, it may help with feeling a little better because you’re not so swollen, not so stiff. But when I think about somebody with an eroded joint, nonsteroidals really have no benefit here. She has evidence of peripheral erosion, so this is not just somebody who says, “My spine feels stiff.” And this is mostly axial disease. She has erosive disease and joint space narrowing, so cartilage is going, and she’s only 31 [years old]. We’re thinking that if I don’t do anything to inhibit damage, by the time she’s 41, she won’t be able to play with this child. So nonsteroidals really do not have a huge impact on this disease.

In addition, when we look at other agents, like flutamide and sulfasalazine, we’ve borrowed those from rheumatoid arthritis, but they are really not terribly effective or studied as extensively in psoriatic arthritis. Again, I think we have better choices than going in than combination or triple therapy with oral agents.

Corticosteroids really should be the last thing we do, especially to a young person, because we are looking at the burden and the longevity of corticosteroids and all the potential adverse effects. We also know that corticosteroids can cause flair of the skin, and the skin is 1 of the important domains you want to control with psoriatic arthritis, so corticosteroids are not the best choice for managing this person. The truth is, yes, you may get some initial calming down of the joint swelling, but we’re doing nothing for the joint erosion as well.

Psoriatic Arthritis: Current Treatment Recommendations

 Within the TNF [tumor necrosis factor] world, there are a variety of choices. If we go back to some of the earlier ones, we had adalimumab as a monoclonal antibody protein, etanercept as an infusion, and also infliximab, which is another monoclonal. After that we had golimumab both as a subcutaneous form and as an intravenous form. Finally, certolizumab is a pegylated subcutaneous, whether it’s physician administered or patient administered. Across all these we’re looking at something that is going to block the TNF pathway. How do they differ? Look across the entire class: These are all very effective drugs. Some patients may prefer 1 over the other. For instance, there are data with certolizumab looking at transfer across the placenta, transfer in breast milk. For a young woman that may be an option, because if she’s trying to get pregnant or is pregnant, she may prefer something that may not cross the placenta and get into her baby.

In terms of efficacy, there are lots of data with adalimumab, etanercept, and infliximab, so there are lots of choices across that spectrum. Some of these agents can be used as monotherapy, meaning no background therapy required, and the most common background therapy is methotrexate. I may have someone who cannot use methotrexate because they’ve had toxicity or adverse effects—liver damage, her cell counts are low, she’s losing her hair. A 31-year-old going bald with methotrexate is not so inviting. But outside that, some people get nauseated and very fatigued. Not everyone can tolerate methotrexate, so we look for those agents that we have substantial evidence that they are effective and sustainable in the absence of methotrexate. TNF inhibitors are a class. Then we have the IL-23 inhibitors. Ustekinumab is the prominent 1 that we’ve had for some time. It really has been used for psoriasis extensively and more now with psoriatic arthritis, with efficacy being shown there in various routes of administration with ustekinumab. Finally, in the IL-17 inhibitor class, we have ixekizumab and secukinumab, both inhibitors of IL-17 and both with data that show effectiveness in the skin and in the joints with or without methotrexate.

There are lots of efficacy data and lots of discussions about what’s going to work best. There are data showing even superiority, in some cases, of 1 drug class over another in certain studies. But for that individual patient, that’s a discussion based on her choice.

Rationale for Biologics to Treat Psoriatic Arthritis

 As I mentioned, we have studies for some of these drugs as monotherapy, meaning you need only the biologic; you don’t need the background agent. In some patients, the combination is more effective. Even though the data say it should work as monotherapy, the combination may be better for that individual. That’s something you have to figure out. No data set is going to tell you if that person can do without that. When we look at apremilast, tofacitinib, and currently approved others in clinical trials in development for this, and the JAK inhibitor class, we also see agents that can be used as monotherapy. I always say, if she won’t or can’t take background agents, then find a drug that’s going to work well by itself. For data in rheumatoid arthritis, we talk about this a lot, but in psoriatic arthritis it becomes critical, especially since we tend to be dealing with a slightly younger population. We have young women who may be thinking of continuing or starting families, and many of those are agents we have to think through very carefully. But the data are there to help guide us, to say that I can use etanercept, secukinumab, or ixekizumab. I can use these agents without any background methotrexate and have a very good response.

I always say, never double biologic. Why? Because the data say that when you do, the likelihood of increased adverse events is enhanced, the most common thing being higher infections with very little in the way of increased efficacy. We just don’t have a cocktail combination that’s going to work and be safe and effective. When we talk about combination therapy, we’re often talking about an oral agent, a conventional synthetic DMARD [disease-modifying antirheumatic drug], combined with a biologic—not combining 2 biologics together, even if their MOA [mechanism of action] is different.

There are some interesting molecules being investigated that might have 2 different MOAs on the same molecule. That’s a different story because you’re going to study safety and efficacy of that combined bimodal pathway. But for me, to take drug 1 and drug 2 together, and they’re both biologics, I’m probably going to run into trouble with more adverse events and serious infections.

There are times when we have to combine agents, simply because they work better, and the most common background agent would be methotrexate, whether that’s a subcutaneous methotrexate injection, or oral methotrexate tablets. There are data that say, in some patients, the more recalcitrant the patient and the more advanced their disease, the heavier the weight of burden of the disease they have, they may need combination therapy. I always say, “What’s the goal?” The goal is to get you well. The goal is to have you functioning. The goal is to have you get up in the morning, and go, and not have to think, “Oh my gosh, I need 45 minutes just to move my hip.” That’s not the goal. Sometimes that goal has to be met by adding on additional therapies. Sometimes to do that we have to have background methotrexate. Not all the time, but sometimes for sure.

This is another big controversy in rheumatology. They say if 1 mechanism of action is not working, switch to another. Then we get into the discussion of, are you a primary nonresponder or a secondary nonresponder? Meaning that it worked really well and then stopped. The same class can work really well again, versus the person who takes that first thing, and there’s zilch. Absolutely no response. We like to switch when you see someone who’s just not responding to that pathway. Sometimes we don’t know what biologic pathway is driving an individual’s disease. We don’t have a really simple way of figuring that out right now. We can certainly research the lots of ways we can stratify things, but with a patient, it’s really trial and error. If I see that, and I’ve tried a TNF and it fails, maybe I’ll try a second TNF. If that fails, I should not be on to the fifth TNF. Because we have other choices, other classes, and a different pathway may work.

Monotherapy vs Combination Regimens to Treat PsA

 If you don’t have access to a therapy, it can’t work for you. One of the big issues we face is just getting drugs to patients if their insurer doesn’t cover this or it’s a very high co-pay, so the patient can’t afford that. There are multiple strategies that have allowed that to happen to patients, where their out-of-pocket cost is hundreds of dollars a month. That is not helpful. It’s not beneficial. The sad part is that if I don’t get this 31-year-old under control, she’s going to drop out of the workforce because she’ll be so damaged and destroyed. And when her joints are damaged and destroyed, I will have very little to offer besides trying to replace them. If I want to think about her for not just the next 6 to 18 months but 60 years, then it behooves me to control her disease. This idea of having access to therapies is critical—access to therapies that can be tolerated. It’s possible that I can say, “Well, I’ll give you 3 of these things, or you’ll take 7 tablets in the morning, 5 at night.” Nobody is going to say it’s not going to succeed. It’s accessible, but it’s not sustainable. It’s access and sustainability that have to go hand in hand, and if we don’t have that, we don’t control this disease. We don’t control this class of diseases, and we have an entire group of young people who get removed from the workforce&mdash;forget the workforce, they get removed from their lives. There’s no joy. There’s no fun. The family, the children, all the things that would normally bring a human pleasure&mdash;we’re really removing that from their lives. This is a huge unmet need, and we have to fight to always make sure that therapies are accessible the patients who need them.

It’s really important, when we’re in the community and treating patients that we make it our job and our primary goal to hear them. To listen to them. She’s telling you that she’s almost dropping her child, she can’t keep a clean home, she probably can’t stand up to cook a meal. That’s affecting not just her but her entire grouping, her entire social structure. If we start to hear that, we can say, “Well, the job is to get her functionality.” Not just to say, “I’m going to put you through step 1, then step 2, then step 3.” Hear her, hear him, understand what the problem is, and then there are all these resources to help us walk through and figure out the next-best step. Patients are very good at saying what doesn’t work for them. They may not be able to quantify, but they can say, “That makes me feel really awful.” They don’t know what awful is, but awful is just not a good place to be. Or they’re very nauseated, or they’re very depressed, and they can’t get up and go to work because it takes them 4 hours to get dressed and go out. We need to listen. And a listening ear then becomes a thinking brain that becomes and effective prescriber. It’s all tied together, and that’s really something that we just always remember. Listen, listen, listen. Then consult. If you don’t know it, ask somebody else. There’s a rheumatologist somewhere who will have an answer to share. We love to talk, we love to share, and we love to help. So find somebody. We’ll be there.

Case-Based Approach for the Management of Rheumatic Diseases