Clinical Consultations™: Finding Opportunities to Improve the Management of Patients with Connective Tissue Disease-associated Pulmonary Arterial Hypertension (CTD-PAH)

Clinical Consulations CTD/PAH 

Read the most up-to-date information about the latest developments in psoriatic arthritis

Clinical Updates in Psoriatic Arthritis

The impact of psoriatic arthritis on patients’ quality of life and importance of an early, accurate diagnosis.

Expert Perspective on the Management of Psoriatic Arthritis

Rheumatoid Arthritis Quiz

Learn more about the latest developments in rheumatoid arthritis

Focus on Rheumatoid Arthritis

Chris Wincup, MBBS, BSc, is a consultant Rheumatologist specializing in lupus and vasculitis at King's College Hospital. 

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the world of oncology with the advent of new personalized treatment for a wide array of malignancies. However, a recent study by Mackensen et al has raised the possibility that CAR T cell therapy may also have a role outside of the treatment in cancer, through positive findings that have been published in the treatment of refractory systemic lupus erythematosus (SLE).

CAR T cell therapy is already an established treatment used in a variety of haematological malignancies. This is relatively recently developed technology, which has rapidly expanded over the last decade with more than 350 studies currently ongoing investigating the use of this treatment in an array of settings (predominantly oncological). For therapeutic use, circulating peripheral T cells are harvested from the patient and isolated from whole blood. These ex-vivo cells are then genetically engineered to express a chimeric antigen receptor against the desired target (in the case of this study the target antigen being CD19, found on B lymphocytes). The basis of the therapy is that these CAR T cells will then target and destroy cells expressing this antigen. The newly engineered T cells are then grown in cell culture before being infused back into the patient. The process takes approximately 2 weeks from T cell isolation to subsequent CAR T cell infusion. Prior to receiving the newly generated T cells, a period of “conditioning” treatment, which effectively allows for space for CAR T cell expansion within the bone marrow allowing for these new cells to populate, is required. In this study, the investigated used a combination of fudarabine and cyclophosphamide for this. It is also important to consider that the isolation of circulating T cells requires a sufficient quantity of circulating lymphocytes. As a result, the authors decided to taper immunosuppressive therapy before collection of host T cells (in particular this focused on decreasing T cell cytotoxic medication such as cyclophosphamide and mycophenolate three weeks prior to cell collection).

 publication, the authors demonstrated the use of anti-CD19 CAR T cell therapy in the treatment of 5 patients with severe and refractory SLE. Patients were aged between 18-24 years old and included 4 females and 1 male. Patients had active disease with a SLE Disease Activity Index 2000 (SLEDAI-2K) of 8-16 at the time of treatment. All had cutaneous disease, in addition to proliferative lupus nephritis (Class III or IV) with 2 having overlapping membranous nephritis (Class V). Four of the 5 patients also had joint involvement. All had been treated with glucocorticoids, hydroxychloroquine, mycophenolate and belimumab with 3 receiving cyclophosphamide and 1 treated with rituximab previously. This represents a group of patients with significantly active disease that was refractory to multiple therapies.

Following infusion of CAR T cells, patients were observed in hospital for a total of 10 days prior to discharged (predominantly to monitor for signs of toxicity). In the use of CAR T cells in the treatment of malignancy, an array of side effects can be observed with the therapy. This includes generalized symptoms (such as fevers and headache). More severe effects include cytokine release syndrome and neurotoxicity. Interestingly, in this study in SLE the treatment was very well tolerated without severe consequences noted.

In the subsequent days following infusion of CAR T cells, the authors identified that these cells initially represented only a small subpopulation with the patients circulating T cell repertoire within the first 24 hours, before significantly expanding by day 9 post-infusion (at which point between 11-59% of circulating T cells were CARs). With regards to clinical response, a remarkable improvement was seen within the first 3 months of therapy. Four of the 5 patients achieved a SLEDAI-2K of zero (whilst the remaining patient seeing an improvement from 16 to 2).

Most impressively, there appeared to be a sustained response to this therapy and the authors report not only long-term remission but that this was treatment-free remission! It is quite astonishing that patients with severe disease that was refractory to multiple other agents showed a drastic improvement and ultimately were able to discontinue all therapy including glucocorticoids! The follow-up period is currently only at a maximum of 17 months, however long-term steroid-free response offers hope for a decrease in damage secondary to prolonged exposure to glucocorticoids (including osteoporosis and increased risk of cardiovascular disease).

Aside from being both extremely effective in achieving remission and well tolerated, the authors also importantly showed no significant reduction in vaccine response in the 5 patients treated with CAR T cells therapy, which is of particular interest at present.

In summary, CAR T cell therapy may not be required in many cases of SLE; however, the findings of this study of anti-CD19 directed CAR T cell therapy offers new hope for the most severe and refractory cases. In addition, the sustained long-term effects of treatment plus the ability to withdraw all treatment also confers that the risk of damage and infection (leading causes of morbidity and mortality in SLE) may also be reduced. The future is very exciting!

Mackensen A, Müller F, Mougiakakos D, Böltz S, Wilhelm A, Aigner M, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nature medicine. 2022.

Articles

The findings of this study of anti-CD19 directed CAR T cell therapy offers new hope for the most severe and refractory cases. 

CAR T Cell Therapy Offers a New Hope in the Treatment of Severe and Refractory Systemic Lupus Erythematosus

Lana Dykes is the Editor of Rheumatology Network. She is an experienced editor and technical writer with a demonstrated history of working in the banking and publishing industries. She enjoys cooking, yoga, and drawing. 

Upcoming Trial to Evaluate Safety, Efficacy of Guselkumab for Treatment of Axial PsA

Terence Rooney, MD, discusses the ongoing STAR study in depth and the potential of guselkumab to improve axial psoriatic arthritis.

Kim Bennell, PhD: Benefits of an Online Yoga Program for Patients with Knee Osteoarthritis

Kim Bennell, PhD, discusses her study “Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis: A Randomized Clinical Trial.”

Pirfenidone Slows Decline of Forced Vital Capacity in RA-Associated Interstitial Lung Disease

Although results are promising, findings should be interpreted with caution, as the study was underpowered and terminated early due to the COVID-19 pandemic.

Mycophenolic Acid Treatment Not Associated with More Severe COVID-19 Infection

Throughout the pandemic, rheumatologists have been concerned that their patients may be at risk of developing more severe forms of the COVID-19 disease as a result of their rheumatic disease or treatment.

Non-Pharmacological Therapies may Provide Alternative Treatment Options in Fibromyalgia

The 3-stage Delphi exercise used the expertise of medical and health care professionals with experience in treating patients with fibromyalgia. Treatment recommendations included exercise, education, cognitive behavioral therapy, mindfulness, and mind-body exercises.

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending October 1, 2022.

Rheumatology Network's Top 5: October 1, 2022

No new adverse events or safety signals were reported in a study evaluating the long-term safety of apremilast-treated patients with psoriasis (PsO) and psoriatic arthritis (PsA) in a real-world setting. Results were comparable to those of previous clinical trials, according to a study published in 

“In 2015, apremilast was approved in Europe for the treatment of moderate-to-severe plaque PsO in adults who do not respond to, have a contraindication to, or are intolerant of other systemic therapy, or for the treatment of active PsA, alone or in combination with disease-modifying antirheumatic drugs (DMARDs),” investigators explained. “Following the European Medicine Agency’s approval of apremilast, the European Medicines Agency requested a post-authorization safety study to provide long-term surveillance of adverse events of special interest (AESIs) in patients with PsO and/or PsA exposed to apremilast.”

A 5-year cohort study was performed between January 2015 and June 2020 utilizing patients with PsO and PsA registered in the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) GOLD. Adverse events of special interest were analyzed for patients receiving apremilast as well as 3 non-apremilast cohorts: oral only, injectable only, and oral and injectable PsO and PsA treatments. Non-apremilast drugs included DMARDs, oral or injectable steroids, non-tumor necrosis factor inhibitor biologics, and azathioprine. All patients were matched for age, sex, calendar time, and year of record start with up to 10 patients in each non-apremilast cohort. Eligible patients had a diagnosis of PsO and/or PsA and 1 or more prescriptions for a non-apremilast comparison treatment within 6 months or any time after an apremilast-exposed patient’s first apremilast prescription.

The apremilast cohort included 341 patients, while the non-apremilast cohorts consisted of 4981 patients. Comorbidities were similar across all groups; however, apremilast-exposed patients had a lower prevalence of anxiety and depression. There were no cases of hematologic malignancy, non-melanoma skin malignancy, treated anxiety or depression, suicidal behaviors, or vasculitis in those receiving apremilast during the follow-up period. Incidence rates of all-cause mortality, solid malignancies, tachyarrhythmias, and major adverse cardiac events were similar across all arms.

The incidence rate of both opportunistic and serious infections were similar between the apremilast cohort and the oral and injectable non-apremilast cohorts (61 [40-102]; 50 [42-60]; and 57 [47-69], respectively). However, the incidence rates were lower in the injectable treatment-only group (20 [10-41]).

The small number of apremilast-exposed patients and potential exposure misclassification limited the study. Additionally, the PsO and PsA treatments in the CPRD data is incomplete. Infusion drugs, which are generally received in outpatient clinics, as well as biologics and other oral specialty treatments prescribed by specialists, are not included in the general practitioners (GP) record. There is also a possibility that patients receiving apremilast from a specialist were not included in the record. Lastly, patients in the apremilast cohort may have entered the study further into the disease pathway when compared with non-exposed apremilast patients, as the PsA criteria is less strict, and physicians may experience more delays in diagnosing PsA earlier.

“These results provide evidence that the long-term safety profile of apremilast in PsO and PsA in a real-world setting is comparable to that reported in clinical trials and other real-world publications,” investigators concluded.

Persson R, Cordey M, Paris M, Jick S. Safety of Apremilast in Patients with Psoriasis and Psoriatic Arthritis: Findings from the UK Clinical Practice Research Datalink [published online ahead of print, 2022 Sep 23]. 

. 2022;1-9. doi:10.1007/s40264-022-01235-7

A long-term, post-authorization safety study of adverse events was performed for patients with PsO and/or PsA exposed to apremilast.

Apremilast Safely Treats Patients with Psoriasis, Psoriatic Arthritis in Real-World Setting

Based on evidence-backed expert consensus, investigators created recommendations on non-pharmacological treatments for patients with fibromyalgia to individualize treatments for a variety of symptoms including pain, depression, fatigue, and sleep problems, according to a study published in 

“Non-pharmacological interventions are often recommended as first-line treatment for fibromyalgia,” investigators stated. “However, there are currently no recommendations on which non-pharmacological intervention(s) to offer for the initial management of the different symptoms associated with fibromyalgia and which of these to prioritize as core treatments.”

An international 3-stage Delphi exercise was performed using the expertise of members of the American Pain Society, authors of European Alliance of Associations for Rheumatology (EULAR) and the Canadian Fibromyalgia Guidelines Group, and any medical or health care professional with experience in treating patients with fibromyalgia. Participants selected non-pharmacological interventions that could be helpful for the treatment of specific fibromyalgia symptoms and were asked to further categorize them as either core or adjunctive treatments. Investigators urged professionals to consider efficacy, cost, patient preferences, acceptability, availability, and personal experience when making their recommendations. Evidence summaries were provided to help the decision-making process. All items that received 70% or more of the votes were accepted and those achieving 30-70% of the votes were recirculated for up to 2 additional rounds.

Of the 17 experts included in the exercise, 10 resided in Europe, 6 were from North America, and 1 was from Israel. Of the respondents, there were 7 rheumatologists, 2 physiotherapists, 1 psychologist, 1 nurse, 1 pain specialist, and 5 other health care professionals.

Core treatments for all symptoms included aerobic exercise, sleep hygiene, education, and cognitive behavioral therapy (CBT). The core intervention recommendations for pain, fatigue, and sleep issues were mind-body exercises, such as tai chi and yoga, which focus on breathing, mental focus, and body movement. Mindfulness was a core treatment for symptoms of depression and an adjunctive treatment for all other symptoms. Other adjunctive treatments, which varied between symptoms, included music, relaxation, local heat, and a hot bath.

Including a multidisciplinary and international group of academics and clinicians strengthened the study. Further, a comprehensive list of interventions was provided, allowing for participants to suggest other interventions, and all respondents completed 3 rounds of the exercise.

However, there may have been a biased perspective towards certain interventions as most panel members were physicians. Another limitation was that some of the interventions were grouped together, such as music intervention referred to as listening to music for pleasure or therapeutically. Effect sizes of interventions were provided based on the research findings of investigators, which may have impacted social desirability bias. Lastly, although depression was included, anxiety, another common symptom of patients with fibromyalgia, was omitted from the survey.

“Personalizing treatment for fibromyalgia using a targeted symptom approach has been suggested as a way to improve outcomes for patients,” investigators concluded. “This Delphi exercise has reached agreement on a set of core and adjunctive non-pharmacological interventions for the 4 different major symptoms of fibromyalgia, specifically pain, fatigue, sleep, and depression. Clinicians may find this useful as an aid to shared decision-making and treatment choices with patients as part of an individualized management plan.”

Kundakci B, Hall M, Atzeni F, et al. International, multidisciplinary Delphi consensus recommendations on non-pharmacological interventions for fibromyalgia, Seminars in Arthritis and Rheumatism, Volume 57, 2022, 152101, ISSN 0049-0172, doi.org/10.1016/j.semarthrit.2022.152101.

The 3-stage Delphi exercise used the expertise of medical and health care professionals with experience in treating patients with fibromyalgia. Treatment recommendations included exercise, education, cognitive behavioral therapy, mindfulness, and mind-body exercises.



Non-Pharmacological Therapies may Provide Alternative Treatment Options in Fibromyalgia 

: When I’m thinking about treating patients with lupus nephritis in a very similar approach that you have as well, I think about those patients who have already developed, who are already on immunosuppressants like mycophenolate or fairly good doses of steroids who then develop lupus nephritis. Those are ones that I’m pulling the newer agents, either the CNIs or belimumab. What a lot of us struggle with is which one to go with. Do you go with voclosporin? Do you go with belimumab? And I look at voclosporin that it’s very quick in onset, you know quickly is it going to help or not, but it’s also associated with the possibility of GFR decreasing, usually because of the arterial or vasal constriction, which may be reversible or may not. Whereas belimumab may take longer but is certainly safer in terms of the renal function. Your thoughts in terms of those kind of 2 agents?

: I’m being torn there with the choice of those 2 medications, with voclosporin you’re right. If patients already have a lower GFR, then we’re worried about using voclosporin, that would be a reason I would potentially not use voclosporin in that patient population. However, the sort of flip side to that is voclosporin can be very helpful with patients who have a lot of proteinuria. That would be another reason for me to think about. If someone has GFR that is mildly impacted but not terrible. If I have someone with class 4 and/or class 5 who has a GFR that’s 20 or 30, then I’d be hesitant to use voclosporin. Also, voclosporin is great to use when there’s the rest of the lupus is doing well or the SLE is doing well or kind of well, but the lupus nephritis is the main thing that is kind of acting out. However, if there are other manifestations of lupus present, then for me that also makes me lean towards the belimumab as a drug. If there’s skin or joints that are acting up in addition to lupus nephritis flaring, or hematologic abnormalities in addition to lupus nephritis, then I would lean more towards belimumab. That would be where I would lean in essence. Now the comfort level is also different between the nephrologist and the rheumatologist because nephrologists are usually uncomfortable with belimumab because they haven’t used it. They’ve never been the prescribers, and it’s been mostly limited to the rheumatology field. Their comfort level when I’ve had those conversations about choice of treatment, they’re leaning more towards the voclosporin or CNI instead because that’s a comfort level. One of the pluses about the voclosporin is that it doesn’t require monitoring like many of the other CNIs may have in the pass. That’s definitely a plus too if you have adherence issues with your patient. Now with the belimumab part, if you want someone to have observed therapy, that’s another good way to go. Unfortunately, particularly when you have young people, young women, who have disease, sometimes they may not be as vigilant about being- taking their medication regularly, going through some of that rebellious stage that we see sometimes when transitioning with a chronic disease from pediatric to adolescent to adult rheumatology. If you’re concerned about that, belimumab is another way to make sure that patient gets their medication. There are a number of different things we have to parse out in making the decision on which drug to use. But you’re right Anne. We’re going through all these little things in our brains as we’re figuring out “OK. What’s the most important thing that would make me say I need the belimumab versus the voclosporin?” But what I will say is that I’m excited we have them as tools now because we didn’t before, and we would just end up with patients on chronic steroids, which what we talked about earlier, it’s not the best. And I’ll use a Michelle Petri aphorism, which is “P is for poison when it comes to prednisone”. And I say that regularly when I talk about lupus because people love it. Well, patients love it because it makes them feel better quickly. That’s often the answer. “Can’t I just stay on the prednisone?” But unfortunately, it is not good in the long term, we must help steer our patients in that way. But I’m excited about having those 2 new agents to help us in this very difficult medical issue with the lupus nephritis.

Videos

Anne E. Winkler, MD, PhD, MACP shares her approach to treatment in patients with lupus post treatment with immunosuppressants with a focus on treatment sequencing.

Lupus Treatment Considerations Post Immunosuppressants

: When we see that, my first thought is OK, we’ve got lupus nephritis. What do we need to do now? In my mind, always, I want confirmation of diagnosis. And I’m going to get on the phone with my nephrology colleague and ask them to see her quickly and to do a kidney biopsy. That’s very important. When I’ve talked with some of my nephrology colleagues, because for most patients with lupus, nowadays when there’s lupus nephritis and it’s a very suggestive clinical finding, and you’re improved in creatinine ratio, they will want to start patients on mycophenolate mofetil, that’s not a wrong thing as far as choice of drug per se. However, it’s super important to make sure that we understand what the actual diagnosis is. There can be other things going on that could cause kidney, in manifestations, a nephrotic range proteinuria. We must make sure that we clarify diagnosis. Also, we will never get that opportunity to go back and get this ever again, we won’t have this data 3 years down the road when patients is not doing well, progressing towards end stage renal disease, and we never got a biopsy. There can be coexisting conditions. And we have to make sure that we understand what the appropriate diagnosis is, then that will lead to a choice of appropriate drug. Now as far as lupus nephritis is concerned, the old standard was cytoxan, IV cytoxan. However, studies have been more- have shown often that CellCept or mycophenolate mofetil can be equivalent to and potentially even better than cytoxan and have a better adverse effect profile. Oftentimes, that’s one of the first things you reach for as far as treatment. Our patient had a kidney biopsy, the nephrologist was nice to me and didn’t give me a hard time about doing the biopsy. And it comes back as class 4 mixed with class 5, and there’s some chronicity there. And we'll say it’s a mild to moderate chronicity. That says this has been going on for a little bit. And to me, when we see chronicity, there’s an urgency for treatment. CellCept because there’s already been some damage. Of course, we talked about mycophenolate mofetil, but of course, that takes some time to kick in. And our good old friend corticosteroids come to the rescue for immediate, hopefully to kind of settle down the lupus nephritis immediately, and I would probably start the patient depending on how sick they were, on Prednisone 1 mg per kg per day. And that's standard for most folks who are rheumatologists to do that, and then of course start with steroid-screening medicine fairly quickly with fairly quick escalation to get to appropriate max dose as tolerated without significant adverse effect. And the of course, tamper down that steroid while watching the urine protein creatinine ratio and see how the patient does. Prior to recent drugs that have become available for lupus nephritis, that’s about what we would do. However, in the last 2 years or so, we’ve had several new agents come to the market that can be add-on therapies for lupus nephritis, including belimumab and voclosporin. And those would be options that could be considered initially, just like with many of our other add-on therapies, would be helpful for getting folks off steroids. However, there is some data that suggests starting patients on these things sooner rather than later could help get disease under better control and is superior to just standard of therapy or standard of care. Those are other options that can be used or added on based on your preference and other potential things that might impact your choice of drug, including other medical conditions, etc. We have additional new medications that can be very helpful with the management of lupus nephritis now, and I would have a low threshold to reach for those, especially if patients are not getting to the goals, your outcome, as quickly as you would like. Say the nephrotic is not decreasing the way you want it to. Low threshold to add on additional therapy like belimumab or voclosporin.

Drs Anne E. Winkler and Kristi V. Mizelle explore relevant treatment options for a patient with lupus nephritis and highlight efficacy and safety considerations. 

Treatment Considerations in Lupus Nephritis

Holistic, collaborative, multidisciplinary, and integrated communication between physicians and women of childbearing age is lacking, according to a study published in 

Medical treatment and family planning, particularly among women of childbearing age with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), should be considered within this patient population. Patient-centered care including reproductive choices should be integrated as a part of routine clinical practice.

“The proportion of women being treated with biologics is growing,” investigators explained. “However, data on treatment recommendation awareness among treating physicians and women who are considering pregnancy and family planning are limited.”

An English-language, 55-question survey was developed to identify the current practices of physicians regarding the reproductive health needs of women with RA, PsA, and psoriasis in the Czech Republic, Slovakia, and Hungary. The questionnaire was designed to simultaneously elicit spontaneity of physicians while allowing for the processing of responses, mutual comparison, and overall assessment. The survey obtained information from 120 physicians, including 82 rheumatologists and 38 dermatologists.

Female patients of reproductive age (aged 18 to 45 years) with moderate-to-severe disease encompassed 10-30% of all respondents. Roughly two-thirds of physicians discussed family planning with their patients when making the diagnosis. Rheumatologists collaborated with other specialists more frequently when compared with dermatologists and gynecologist/obstetricians. Pregnancy effects were the top concern for female patients.

Approximately half of the rheumatologists revised treatment 6 months prior to when the patient planned on becoming pregnant (44% [n = 36/81]). However, dermatologists acted much sooner (26% [n = 10/38]), acting 2 to 3 years prior planned parenthood. While rheumatologists selected systemic glucocorticoids as firs-line treatment to counteract pregnancy flares, dermatologists preferred topical corticosteroids.

Although gender alone did not influence treatment choice in 11% of dermatologists and 39% of rheumatologists, all dermatologists and 96% of rheumatologists were influenced by the patient’s fertility and pregnancy. Disease severity and uncontrolled disease were the main risk factors linked to conception in this patient population. In fact, 53% of dermatologists and 79% of rheumatologists believed that poor disease control was associated with poor pregnancy outcomes. Of the most valuable sources of information as determined by physicians, congresses and interdisciplinary forums were the most highly rated. Patient education and collaboration were noted as key factors in reducing unplanned pregnancies.

A cross-border investigation, from the perspective of both rheumatologist and dermatologist, strengthened the study. However, investigators did not evaluate or categorize the individual physicians’ level of experience with biologics or reproductive health and instead based data on actual clinic experience. Investigators theorize that those who have had more exposure to this approach would be more willing to utilize it. The lack of formal survey validation, and the fact that the survey was provided in English, further limits the study.

“To improve the reproductive health of sexually active women of childbearing age in Central Europe who have chronic inflammatory diseases (CID), rheumatologists and dermatologists must improve their education and work with other specialists,” investigators concluded. “More timely discussions with women of reproductive age and family planning are needed to educate them about the disease's effects on their childbearing potential and the selection of treatment options based on their reproductive goals. Best practices in patient-centered care must consider each patient's reproductive decisions in their treatment planning to give the best patient-centered care.”

Olejárová M, Macejová Ž, Gkalpakiotis S, Procházková L, Tóth Z, Prágr P. Reproductive Healthcare in Women with Rheumatoid Arthritis and Psoriatic Diseases in Routine Clinical Practice: Survey Results of Rheumatologists and Dermatologists [published online ahead of print, 2022 Sep 24]. Rheumatol Ther. 2022;10.1007/s40744-022-00488-z. doi:10.1007/s40744-022-00488-z

Although the proportion of women treated with biologics continues to grow, data on treatment recommendations among both physicians and female patients of childbearing age remain limited. 

Survey Addresses Concerns Regarding Reproductive Healthcare Communication in Women with RA, PsA

Mycophenolic acid (MPA) therapy was not linked to more a severe form of COVID-19 infection. However, investigators not that careful consideration should be taken in patients with inflammatory rheumatic and musculoskeletal diseases (iRMD), who are likely to be treated with MPA, due to an increased risk of developing severe COVID-19, according to a study published in 

“Throughout the pandemic, physicians who treat patients with iRMD have been concerned their patients would develop more severe forms of the COVID-19 disease due to the disruption of their immune systems as a result of their illness or treatment,” investigators stated. “Currently, treatment with MPA is used under very specific conditions in iRMD, which is characterized by a higher risk of poor prognosis, including connective tissue disorders, with pulmonary or renal involvement. Whether iRMD patients treated with MPA have a higher risk of developing severe COVID-19 is still unclear.”

This observational, multicenter study analyzed patients with iRMD with and without MPA treatment who had confirmed or highly suspected COVID-19. The primary endpoint was the death rate from COVID-19 and the secondary objective evaluated the severity of infection and length of hospital stay. Comparisons were evaluated using regression models both with and without adjustment on prespecified confounding factors. Additionally, odds ratios (ORs), sub hazard ratio (sHR), and 95% confidence intervals (CIs) were analyzed utilizing patients who were not treated with MPA as a reference group.

In total, 1977 patients were included in the analysis, of which 1928 were not treated with MPA and 49 patients were placed in the MPA cohort. Most patients in the MPA-treated group were diagnosed with systemic lupus erythematosus (44.9%, n = 22) and systemic sclerosis (SSc) (36.7%, n = 18). Across all cohorts, patients were predominately female (66.6%), had a mean age of 55 years, and 68.1% reported 1 or more comorbidities.

Initially, MPA-treated patients had more severe infection (18.4%, n = 9/49) when compared with 11.1% (n = 219/1928) in those not treated with MPA. In the age-sex adjusted analyses, a higher death rate from COVID-19 and longer hospital stays were also observed in the MPA-treated cohort when compared with non-MPA patients.

However, using the adjusted propensity score overlap weighting (PSOW) method, none of the outcomes were independently associated with MPA therapy. Severity, death rate, and length of hospital stay were not significantly different between MPA-treated patients and those not treated by MPA-eligible (n = 393).

The most vulnerable patients were those with lupus and SSc, particularly for those with interstitial lung disease (ILD), in which limited treatment options are available and the efficacy of MPA has been established. Further, rituximab (RTX), the “gold standard” for alternative treatment in these patient populations, has been associated with worse COVID-19 outcomes. The analysis focused on the risk of mortality and severe outcomes in patients treated with MPA. Future studies should examine the safety of MPA treatment and efficacy of the COVID-19 vaccine with concurrent treatment, which was not evaluated within the current analysis.

“In the present study, we demonstrate that there was no difference among our three study groups in terms of severity, length of hospital stay or death rate from COVID-19,” investigators concluded. “Based on our findings, we claim that the overall excess risk of poor outcome of COVID-19 in patients treated with MPA in an iRMD population after age and sex adjustment is likely due to confounding factors… MPA use should be continued in patients requiring the treatment for autoimmune disease, without fear of an increased risk of severe COVID-19.”

Truchetet ME, Drumez E, Barnetche T, et al. Outcome of COVID-19 in patients with rheumatic and inflammatory diseases treated with mycophenolic acid: data from the French RMD COVID-19 cohort. RMD Open. 2022;8(2):e002476. doi:10.1136/rmdopen-2022-002476

Janus Kinase (JAK) inhibitors, a type of small molecule targeted synthetic disease-modified antirheumatic drug (DMARD), show potential for safety treating patients with moderate-to-severe psoriasis and psoriatic arthritis, according to a systemic review of primary research literature published in 

“Inhibition of the JAK/signal transducer and activator of transcription (STAT) pathway prevents the upregulation of pro-inflammatory genes involved in articular and extraarticular inflammation, by modulating cytokine signaling that are integral to lymphocyte activation, proliferation, and function,” investigators stated. “This class of medication provides an alternative therapeutic option for those that have an inadequate response to conventional DMARDs or biologic therapy. Furthermore, in rheumatoid arthritis, it has been shown to have relatively lower infection rates compared to biologic DMARDs.”

The databases MEDLINE, Cochrane, and EMBASE were used to find randomized controlled trials (RCTs) and observational studies that compared JAK inhibitors with placebo in adult patients with moderate-to-severe plaque psoriasis or psoriatic arthritis (PsA). The primary endpoints included a 75% improvement in the Psoriasis Area and Severity Index (PASI75), a standard outcome measure for psoriasis, as well as a 20% improvement in the American College of Rheumatology composite score (ACR20), a 5-point scale that measures severity. A secondary endpoint was the proportion of patients who achieved either a “0” or “1” score on the static Physician Global Assessment scale. Odds ratio analyzed the proportion of patients who were able to reach these targets in the max dose cohort compared with the placebo cohort.

Ultimately, 15 RCTs, comprised of 6757 patients, were included in the analysis, with 7 comparing oral tofacitinib with placebo. All studies focusing on tofacitinib reported a significant improvement in the proportion of patients that reached PASI75 (odds ratio [OR] 14.35 (95%CI 7.65, 26.90). When calculating the PASI75 among non-tofacitinib JAK inhibiting drugs compared with placebo, OR was 6.42 (95%CI 4.89, 8.43). ACR20 among all JAK inhibitors versus placebo was OR 5.87 (95%CI 4.39, 7.85). No significant differences in the prevalence of serious adverse events (AEs) were reported between intervention and control groups.

The lack of observational studies limits the data. Additionally, data was limited to a maximum of 24 weeks for placebo-controlled treatment and 52 weeks of follow-up in most cases, thus limiting long-term safety and efficacy outcomes. However, only including phase 2 and phase 3 RCTs strengthens the study. The high statistical heterogeneity in some of the analyses may be attributed to the large range of sample sizes throughout the studies, however; no significant clinical heterogeneity was identified.

“More research will need to be done to directly compare JAK inhibitors to each other and to other therapies with different mechanisms of action to determine their optimal role in treating psoriatic disease and its various manifestations,” investigators concluded. “Data will be needed on whether JAK inhibitors can be used as monotherapy or whether they need background conventional DMARDs to be effective. The post marketing information on these medications is limited and more data will be needed to ensure the safety and efficacy of JAK inhibitors in the long term. Further research will also be required on other patient subgroups, including older patients and those with comorbid immunocompromising conditions such as diabetes and chronic kidney disease. This information will be important to estimate real word effects and impact of these therapies.”

Sarabia S, Ranjith B, Koppikar S, Wijeratne DT. Efficacy and safety of JAK inhibitors in the treatment of psoriasis and psoriatic arthritis: a systematic review and meta-analysis. 

. 2022;6(1):71. Published 2022 Sep 27. doi:10.1186/s41927-022-00287-7

“This class of medication provides an alternative therapeutic option for those that have an inadequate response to conventional DMARDs or biologic therapy.”

JAK Inhibitors may Serve as Additional Option to Treat Psoriasis, Psoriatic Arthritis 

 revealed that treatment with guselkumab improved axial symptoms in patients with psoriatic arthritis (PsA) who had investigator and imaging-confirmed sacroiliitis. As a result, 

, the phase 4, prospective, multicenter, randomized, clinical trial will evaluate the safety and efficacy of selectively utilizing guselkumab to inhibit the interleukin-23 p19 peptide (IL-23p19) subunit in patients with MRI-confirmed axial psoriatic arthritis (axPsA). Terence Rooney, MD, discusses the upcoming study in depth and the potential of treatment with guselkumab to improve axPsA. Rooney is Vice President, Rheumatology and Maternal-Fetal Immunology Disease Area Leader at Janssen.

Guselkumab is a monoclonal antibody and injectable therapy that interrupts cytokine, or chemical messenger, called IL-23, which is important in the pathogenesis of many inflammatory diseases. The drug was previously approved for the treatment of moderate-to-severe plaque psoriasis as well as psoriatic arthritis (PsA).

“Psoriatic arthritis is a complex disorder for patients to deal with. It involves inflammation and all of the features of inflammation, including pain, swelling, stiffness, and redness in multiple parts of a patient's body,” Rooney explained. “Many patients with PsA also deal have to deal with troublesome symptoms in their spine.”

Motivated by previous studies in which large proportions of patients were struggling with symptoms relating to the spine, investigators decided to conduct a new clinical trial to better understand the benefits and risks of treating these patients with guselkumab. The trial is actively enrolling eligible patients and is expected to continue to enroll through 2023.

“It’s an important part of our mission, as drug developers, to fully explore the benefits and risks of our of our medicines,” Rooney emphasized. “What's important about diseases like PsA, though, is that that soft tissue inflammation can lead to irreversible damage of the structural elements of the joint, the bones, and the cartilage. So, it's [imperative] that we show that medications can not only reverse the soft tissue inflammation of the joints, but that by doing so they can prevent long term progressive, irreversible damage to the structure of the joints. In this study, we reevaluate data in a very dedicated way. We look forward to seeing results and sharing in due course.”

View the interview in its entirety below:

Terence Rooney, MD, discusses the ongoing STAR study in depth and the potential of guselkumab to improve axial psoriatic arthritis. 

Ingrid Torjesen is a UK-based freelance health journalist with more than 30 years of experience in health and medical communications. She works for numerous publications including Rheumatology Network, the BMJ and the Economist’s Intelligence Unit. Before her freelance career, her staff jobs included news editor of both Pulse and GP (the two leading UK weekly titles for primary care doctors), and opinion and features editor of the Health Service Journal (the UK’s leading health policy title). She also spent a few years working in Australia, including on Australian Doctor.

T-score at the femoral neck or spine of >-1.0, -1 - -2.5, < -2.5

T-score at the femoral neck or spine of < -2.5, -1 - -2.5, < -1.0

10-year probability of a hip fracture < 1%, 1-3%, > 3%

FRAX 10-year probability of major osteoporotic fracture < 5 %, 5-9%, ≥ 10%

FRAX 10-year probability of major osteoporotic fracture < 10 %, 10-19%, ≥ 20%

People with rheumatoid arthritis are at increased risk of osteoporosis. Test your knowledge of how the risk of osteoporosis can be minimized in these patients.

Rheumatoid Arthritis Quiz: Prevention of Osteoporosis

, results of a 12-week, randomized, controlled trial indicated that physical function was improved in patients with knee osteoarthritis who participated in an unsupervised online yoga program when compared with patients who received online education alone. Using a 2-group superiority parallel design method, patients were assigned to receive either education about osteoarthritis or education plus an online yoga program, in which patients were given 1 new video per week, to be performed 3 times per week. After week 12, patients were given the option to continue the practice up to 24 weeks.

In the following Q&A, Kim Bennell, PhD, co-lead author, discusses the study “Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis: A Randomized Clinical Trial.” Bennell is Director of the Centre for Health, Exercise and Sports Medicine, Department of Physiotherapy at the University of Melbourne.

What first sparked your team's interest in studying the effects of yoga in patients with knee osteoarthritis?

Our research has been concentrated on different types of non-drug management strategies to help people manage osteoarthritis with a particular focus on exercise. We've done a lot of research on different types of exercise, as well as looking at telehealth-delivered interventions (even before COVID). We were looking at ways to deliver them remotely to increase access to programs because Australia's a big country and you want to be able to access services. We had also been interested in programs and services that didn't need a therapist’s input and being able to make them freely available because a lot of people can't necessarily afford to pay for care. We had also been looking at different forms of online exercise interventions and, as there hadn't been research much looking at yoga, we thought we should determine how effective yoga is.

At first, we were talking about doing your typical face-to-face in-person yoga. But then we thought it would be good to do a yoga program that we could kind of roll out. We could do a program that we've modified, developed specifically for people with osteoarthritis, and then do it online so it could be freely available to people. That was how we began looking into an online unsupervised yoga program. Firstly, as I said, because there wasn't a lot of evidence around yoga. And secondly, we were interested in how we might have a program that was more easily accessible to people.

Do you believe that the unsupervised aspect of the program was a hindrance in any way?

I think we know from any sort of online programs that adherence can be problematic because you don't have the therapist or someone helping you with adherence. So, here, adherence is lower. Having said that, ours was probably better than a lot of programs you see out there and that may be because we had people join the study who were motivated to take part in the first place.

We also saw that adherence does affect results. We did perform a secondary exploratory analysis, which was removed, where we looked at hypothetical adherence and the effect of being more adherent. We found that if you had more adherence, if you did the program 2 times or more a week, there were better improvements in pain and improvements in function compared with if you didn't do it. Adherence plays a part and you're going to get better results if you stick to the program. It'll certainly reduce the results in terms of reducing the benefits that you can get, but if it's something that you want to do or want to try it, and you haven't got access to go and see a therapist, I think it's a good option for people to try.

Absolutely. Not to mention, you're also giving them the education aspect of it as well, in addition to the yoga instruction. Results indicated that physical function was improved at week 12 but wasn't sustained at week 24. Do you think that that has to do with adherence?

 Yes, and we weren't surprised by that. In fact, we were wondering if we should have included that time point at all. In previous studies, we give the patients a program and then tell them to keep going with it. But in this one we didn't really emphasize that we wanted them to continue, we just made it optional. Generally, people complete the 12 weeks and don't do it anymore. And then, as you would expect, they lose the benefits. It’s no different from if a strengthening program or a walking program; if you stop doing the exercise, you're going to lose the benefits.

Regardless, improvements in physical function were seen within the 12-week study period. What are the clinical implications of these results?

We didn't find that, as a group, there was a statistical improvement in pain. However, the percentage of people who had clinically relevant improvements in pain was better in the older group. So, I do think there's something there from a pain perspective for some people that that more are more likely to show some benefits for pain and, as you said, physical function did improve. Physical function is a key problem for people with osteoarthritis, so if you can improve physical function, it’s highly recommended.

Clinically, it's another exercise option for patients to try that can help improve physical function. We also found other secondary outcomes like improvements in knee stiffness, quality of life, and self-efficacy. Exercise is a core recommended treatment for people with osteoarthritis.

Does your team plan on doing any further research on the impact of yoga in this patient population?

We were very fortunate when we were designing the study that 1 of our research assistants, Sarah Schwartz, MScPT, was a physical therapist and yoga instructor. She did a large part in assembling the yoga panel of yoga therapists and getting the patients with osteoarthritis to help design the program and ensure that it was safe for people to do. So, we may look at some other different types of yoga because we looked at a form that was more concentrated on the physical aspects. But as you would be aware, there are lots of different types of yoga, including ones that are more focused on the meditative aspect. Regarding other ways boost adherence, we could also look at how we might get people to stick to programs.

Kim Bennell, PhD, discusses her study “Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis: A Randomized Clinical Trial.” 

Kim Bennell, PhD: Benefits of an Online Yoga Program for Patients with Knee Osteoarthritis 

Although the composite primary endpoint was not met, pirfenidone was able to slow the rate of decline of forced vital capacity (FVC) in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), according to a study published in 

 However, investigators emphasize that results should be interpreted with caution, as the study was underpowered and terminated early due to the COVID-19 pandemic.

“Respiratory system involvement is common in rheumatoid arthritis (RA) and leads to increased morbidity and mortality,” investigators stated. “Although any lung compartment can be involved, interstitial lung disease is the leading cause of excess morbidity and mortality associated with pulmonary complications in patients with rheumatoid arthritis. The prevalence of RA-ILD ranges from 19% to 63% depending on the population screened,with a lifetime risk of the disease developing in any one patient of 7.7%.”

) was a randomized, double-blind, placebo-controlled, phase 2 study performed in 34 academic centers within the United Kingdom, the United States, Australia, and Canada. Eligible patients were aged 18-85 years, met the 2019 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for RA, and had diagnosed interstitial lung disease via high-resolution computed tomography (HRCT) scan imaging and, if possible, lung biopsy. Patients who had a history of other known causes of ILD, a history of smoking, and co-existent clinically significant chronic obstructive pulmonary disease (COPD) or asthma were excluded.

Patients were assigned (1:1) to receive either 2403 mg oral pirfenidone (267 mg tablets taken 3 times a day) or placebo daily for a total of 52 weeks. Patients in the pirfenidone group were titrated to full dose over the course of 14 days. The primary endpoint was defined as the incidence of the composite endpoint of a decline from baseline in percent predicted FVC (FVC%) of 10% or more or death during the treatment period. Other endpoints included changes in absolute and FVC%, the proportion of patients with a decline in FVC% of at least 10%, and the frequency of progression, as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) for those in the pirfenidone group.

Between May 15, 2017, and March 31, 2020, 123 patients were ultimately included in the study, of which 63 patients (51%) received pirfenidone and 60 (49%) were assigned to placebo. Unfortunately, the trial was stopped early due in part to slow recruitment and the shutdown of clinical and research operation activities because of the COVID-19 pandemic. Most patients were men (60% in the pirfenidone cohort; 65% in the placebo cohort), aged 60 years or older (mean age 66.0 years in the pirfenidone group; 69.5 years in the placebo group), and White (89% in the pirfenidone group; 93% in the placebo group).

Differences in proportions of patients who met the primary endpoint was not significant, with 7 (11%) of patients in the pirfenidone group and 9 (15%) of patients in the placebo group reporting a decline in FVC% from baseline of 10% or more or death (odds ratio [OR] 0.67 [95% CI 0.2 to 2.03]; p=0.48). Decline in FVC% by 10% or more was similar among both groups (5 [8%] patients in the pirfenidone cohort vs 7 [12%] in the placebo cohort; OR 0.52 [95% CI 0.14–1.90]; p=0.32). Frequency of progression as evaluated via OMERACT was also similar among the pirfenidone-treated group and the placebo group (25% vs 32%, respectively; OR 0.68 [0.30–1.54]; p=0.35)

However, patients receiving pirfenidone had a slower rate of decline in lung function, as determined by the estimated annual change in absolute FVC (–66 vs –146; p=0.0082) as well as FVC% (–1.2 vs –3.21; p=0.0028). Rates of treatment-emergent serious adverse events were comparable between both arms, with 100% of patients receiving pirfenidone reporting adverse events compared with 94% in the placebo group. The most common adverse events were nausea, fatigue, and diarrhea. There were no treatment-related deaths.

The early termination of the study did not allow investigators to reach the primary endpoint and may have hindered them from finding a safety or tolerability signal. Further, the inclusion criteria of at least 10% of fibrosis on HRCT may have incorporated an element of selection bias. As only 12% of patients in the placebo group had a decline of 10% or more in FVC over 1 year, and previous guidelines suggest a decline in 5% or more in FVC is a meaningful threshold for disease progression in patients with progressive pulmonary fibrosis, future trials should consider less severe physiology endpoints.

“Our data suggest that patients with a usual interstitial pneumonia pattern on HRCT have a faster progression and might have a more robust response to therapy,” investigators concluded. “Future studies in patients with RA-ILD with antifibrotics should be stratified by HRCT pattern.”

Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study [published online ahead of print, 2022 Sep 2]. 

. 2022;S2213-2600(22)00260-0. doi:10.1016/S2213-2600(22)00260-0

Although results are promising, findings should be interpreted with caution, as the study was underpowered and terminated early due to the COVID-19 pandemic. 

Pirfenidone Slows Decline of Forced Vital Capacity in RA-Associated Interstitial Lung Disease 

CLEC2B and Ferroptosis: The Link Between Psoriatic Arthritis and High Cancer Risk?

CLEC2B, a key gene linked to ferroptosis regulators in psoriatic arthritis, is differentially expressed in a variety of cancers and is associated with immune cell infiltration as well as immune checkpoints.

Yoga Program Improves Physical Function in Patients with Knee Osteoarthritis

"Online interventions have the potential to reach a wide audience, allowing exercise to be undertaken from the comfort and convenience of home and thereby overcoming some of the barriers to exercise reported in the osteoarthritis population.”

Patients with Severe Lupus Achieve Remission with Anti-CD19 CAR T Cell Therapy

The highly encouraging results of the small study may lead to a new therapeutic approach in lupus. However, long-term safety and efficacy need to be evaluated in a larger cohort.

Fatigue May Artificially Increase Disease Activity Scores in Lupus

Fatigue, a highly multifactorial manifestation of lupus, can be related to disease activity or independent of the disease itself. Investigators determined whether fatigue could be a significant confounder of Physician Global Assessment ratings.

Rheumatology Research Foundation to Award Grant to Clinical Practice Rheumatologist

The Rheumatology Research Foundation has recently announced a grant, called the Community Practice Innovation Award, which focuses on supporting rheumatology practitioners to conduct their crucial, and potentially life-changing, research.

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending September 24, 2022.

Rheumatology Network's Top 5: September 24, 2022

Rheumatology Network interviewed Bonnie L Bermas, MD, to discuss the ways in which the Supreme Court decision to overturn Roe v Wade, a ruling that had guaranteed the right to abortion in the United States since 1973, will change the way rheumatologists are able to care for their patients. She emphasizes the negative effects this legislation will have on marginalized populations, explains how the ruling will impact pregnancy in patients with rheumatic disease, and what rheumatologists need to know moving forward. Bermas, Professor in the Department of Internal Medicine at UTSouthwestern Medical Center, co-authored the article “Overturning Roe v. Wade: Toppling the Practice of Rheumatology,” published in 

What was the motivation for you and your team to want to address the recent decision to overturn Roe v Wade?

We as rheumatologists, and in particular this collection of rheumatologists, amongst many other rheumatologists, have an interest in reproductive issues in our rheumatic disease patients. We think about this a lot because we care for a lot of patients who are in their reproductive health years. This ruling has tremendous impact on our patients. Our motivation was the impact it has in our patients.

Overturning Roe v Wade will obviously affect patients with a constellation of rheumatic diseases. However, it might disproportionately affect women with lupus, who are often diagnosed in their reproductive years. What are your thoughts on how this decision might impact this particular patient population and pregnancy in general?

We know that lupus pregnancies are high risk pregnancies, and they have a higher incidence of adverse pregnancy outcomes both amongst the mothers and the developing fetus and infant. One of the crucial things in controlling those or preventing adverse pregnancy outcomes, which can be progression of disease or an adverse pregnancy outcome in the fetus, is that the disease really needs to be under good control. And, as you know, no contraception is perfect. Inadvertent pregnancies do occur, or people will get pregnant when their disease is active. And that can be really detrimental and dangerous. The maternal mortality rate for lupus patients is during pregnancy is significantly higher than in general population.

Our patients are frequently treated with medications that can cause birth defects. And so that is another issue in terms of this rule. Also, lupus disproportionately impacts minoritized patient populations. Those patient populations, unfortunately, often live in the states that have the most restrictive abortion laws, and some of these patients may not have the resources to travel out of state if they need to have a pregnancy termination.

What are some of the potential outcomes of this legislation on the practice of rheumatology in terms of prescribing medications and treating patients?

That's a really important point. The first thing is that we try to encourage rheumatologists to tell their patients up front about the risks of unplanned pregnancies and emphasize the importance of contraception in women who are sexually active. We need to make sure that we're discussing this a lot with our patients.

The second thing is there are going to be providers who are possibly reticent to prescribe teratogenic medications to their patients. The 2 most common medicines that would fall under that category would be methotrexate and Mycophenolate Mofetil. Methotrexate is the first drug of choice for the treatment of inflammatory arthritis issues such as juvenile idiopathic arthritis and rheumatoid arthritis. Mycophenolate Mofetil is one of our key medications in treating lupus and lupus kidney disease. You can imagine that there will be some hesitancy in prescribing these medications. Potentially, we're talking about rheumatologists not prescribing the best medication for their patients.

What do rheumatologists need to know moving forward?

They need to know that pregnancy across all rheumatic diseases does best when pregnancies are planned. So that means really ramping up our understanding of what the most effective contraceptive methods are. And it is also about asking if patients are sexually active, if they're planning to get pregnant, and referring them appropriately for contraception if they're not already on contraception. Providers also need to understand which medications are teratogenic.

Is there anything else that you would like to add before we wrap up?

What really motivated us to write this is that this ruling is not good for patient care and it's not good for our patients. Like the vast majority of providers, we care about our patients and their wellbeing. So, it's pretty devastating to feel that there's been a politicized ruling that is going to negatively impact our ability to provide our patients with the best care.

Bonnie L Bermas, MD, discusses the ways in which the Supreme Court decision to overturn Roe v Wade will change the way rheumatologists are able to care for their patients. 

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