Over the past 2 decades, new discoveries regarding the immunology of rheumatic diseases have led to the rapid development of targeted therapies for various conditions spanning the rheumatological spectrum. In December 2019,
Over the past 2 decades, new discoveries regarding the immunology of rheumatic diseases have led to the rapid development of targeted therapies for various conditions spanning the rheumatological spectrum. In December 2019, HCP Live® hosted an educational seminar series evaluating current strategies in the management of rheumatic diseases, specifically psoriatic arthritis (PsA), rheumatoid arthritis (RA), and nonradiographic axial spondyloarthritis (nr-AxSpA). The meeting was led by Sergio Schwartzman, MD, clinical associate professor of medicine at Weill Cornell Medical College, the NewYork-Presbyterian Hospital, and the Hospital for Special Surgery, all in New York, who presented cases and guided a case-based discussion on treatment strategies. This article provides a summary of key insights from the discussion, including updates in treatment guidelines as well as key data for select agents and challenges to care.
PsA is a chronic disease that develops in up to 30% of patients with psoriasis.1 Prevalence ranges from 6 to 25 cases per 10,000 individuals in the United States.2 Common domains involved in PsA include peripheral joint disease, axial disease, enthesitis, and dactylitis.3 Unlike those with RA, more than half of patients with PsA have involvement of distal joints.1 PsA has been associated with several comorbid conditions, such as metabolic syndrome,4 osteoporosis,5 and inflammatory bowel disease.6 Additionally, PsA has been associated with impaired physical function, depression, and a reduced quality of life.7 There are no specific biomarkers for PsA; therefore, diagnosis is often based on recognition of clinical and imaging features.8
The case discussion focused on a 31-year-old woman who presented to her primary care physician complaining of diffuse achiness and having difficulties with functions of normal daily living, including taking care of her child and cleaning her house. In addition to a long history of scalp psoriasis controlled with OTC shampoos, she had a questionable history of multiple sclerosis (MS). On physical exam, the patient’s joints were tender and swollen. She also had both proximal and distal joint involvement. Neurologically, there were no sensory deficits or focal abnormalities, but limitation in movement was observed, likely as a result of the patient’s pain. The rest of the exam was normal except for mild psoriasis.
Imaging results revealed that the patient had asymmetric erosive changes in the small joints of the hands. Patients with PsA can develop erosive disease within 6 to 12 months from the onset of symptoms. The asymmetrical component suggests the possibility of PsA rather than RA; this was further supported by her history of scalp psoriasis. Testing revealed an elevated sedimentation rate, negative rheumatoid factor, negative antinuclear antibodies, and a slightly elevated C-reactive protein (CRP). With support from the classification criteria for PsA (CASPAR criteria),9 the patient’s history of psoriasis, and the negative rheumatoid factor and positive x-ray changes, a diagnosis of PsA was made. It is understood that these are classification and not diagnostic criteria, but nonetheless they are helpful.
Often, patients with this clinical profile can be broadly described as having psoriatic disease, which is an umbrella term that encompasses not only psoriasis and inflammatory arthritis but other manifestations, including autoimmune eye disease, such as uveitis, and inflammatory bowel disease, such as Crohn disease or ulcerative colitis. Patients with psoriatic disease are predisposed to having hyperlipidemia, diabetes, and hypertension and to being overweight.10 Therefore, additional testing and monitoring may be warranted. Lipid profiles, for instance, should be monitored in patients with psoriatic disease. Other tests that may be considered include complete blood count, chemistry profile, hepatitis B and C profile, Quanti-FERON-TB, and glycated hemoglobin.
In January 2019, updated guidelines from the American College of Rheumatology (ACR) and the National Psoriasis Foundation proposed notable changes for the treatment of PsA.11 Traditionally, oral small molecules (OSMs), such as methotrexate, sulfasalazine, cyclosporine, and leflunomide, have been considered first-line therapies in treatment-naïve patients. The updated guidelines suggest that tumor necrosis factor (TNF) inhibitors, such as etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol (CZP), can now likewise be used as first-line therapies.
Although methotrexate has long been a standard first-line therapy, results from the Methotrexate in Psoriatic Arthritis (MIPA) study, a randomized placebo-controlled trial published in 2012, showed no evidence that methotrexate improved synovitis.12 Although the findings showed reductions in patient and assessor global scores and skin scores among patients receiving methotrexate at 6 months, the investigators found no significant treatment effect according to PsA response criteria, nor for tender and swollen joint counts. The target dose of methotrexate was 15 mg, which can be considered low; nevertheless, the findings raised questions about the classification of methotrexate as a disease-modifying agent for PsA. Results from the 12-week, open-label TICOPA study (NCT01106079) were more encouraging regarding the role of methotrexate in the treatment of PsA.13 Specifically, 40.8% of patients achieved 20% improvement in the number of tender or swollen joints (ACR20) compared with 34% in the MIPA study. Also, 18.6% achieved ACR50, and 8.6% achieved ACR70 at weeks; additionally, 22.4% achieved minimal disease activity. The investigators also noted a trend of patients who received doses of methotrexate larger than 15 mg achieving proportionally higher ACR20, ACR50, and 75% reduction in Psoriasis Area Severity Index scores.13
The current guidelines state that OSMs may be used prior to TNF inhibitors in patients without severe PsA and/or severe psoriasis, or in patients who prefer an oral drug or have contraindications to TNF treatment. The guidelines also suggest that the use of a TNF inhibitor or OSM is recommended over an IL-17 inhibitor, such as secukinumab, ixekizumab, or brodalumab, or the IL-12/23 inhibitor ustekinumab. These agents may be used, however, in patients with lack of response or contraindications to TNF inhibitors.
For patients with active PsA despite treatment with an OSM, the guidelines suggest switching to a TNF inhibitor, an IL-17 inhibitor, or an IL-12/23 inhibitor over another OSM.11 If changing treatments, all recommendations are based on moderate- to low-quality evidence; therefore, it is important to discuss the reason for the change with the patient.
Regarding the case study under consideration, particularly the erosive nature of the disease and its impact on the patient’s life, the goal of treatment should be to aggressively intervene to prevent further erosive disease. If this patient can tolerate a higher dose, the clinician could increase it to 25 mg/week of oral methotrexate.
When treating patients with methotrexate, it is important to consider that tolerability can be a concerning issue. In the TICOPA study, adverse events (AEs) associated with methotrexate included fatigue, hair loss, nausea, vomiting, diarrhea, abdominal/gastrointestinal upset, mouth ulcers/cold sores, sore throat, cough, chest infection, lower respiratory tract infection, shortness of breath, fever, urinary tract infection, other infection, headache/migraine, mood disturbance/irritability, liver abnormalities, anemia, and neutropenia.13 If response to methotrexate is not adequate after 3 months, a change may be necessary. Clinicians may switch to a TNF inhibitor or an IL-17 or IL-12/23 inhibitor. In the patient presented, however, a TNF inhibitor would not be recommended because of her history of MS, as TNF inhibitors have been shown to exacerbate MS.14
When weighing treatment options, it is important to recognize that the clinical trial findings that led to FDA approval of these agents are not head-to-head data comparisons. Nevertheless, ACR20 rates reported at 24 weeks provide a broad sense of how individual agents compare with one another.15 Notably, one of the most commonly used drugs to treat psoriatic disease is apremilast, and it yielded an ACR20 of 26.4% in patients receiving 20 mg and of 36.6% in patients receiving 30 mg. These rates are the lowest among the targeted treatments used for psoriatic disease and approximate placebo response in other studies, although comparing across trials may not be appropriate. Yet, despite these low response rates, apremilast has a favorable AE profile, with no need for monitoring. The agents associated with the highest ACR20 responses were intravenous golimumab (76.8%), etanercept 50 mg once weekly (71.7%), and etanercept 50 mg twice weekly (69.0%).
The elevation of TNF inhibitors to first-line treatment status in the management of PsA can be attributed to the broadly robust clinical profiles associated with the class. By contrast, IL-17 and IL-12/23 inhibitors are more recent entrants to the treatment landscape and warrant closer examination. As it pertains to the clinical case presented, the phase 3 SPIRIT-P1 trial (NCT01695239) is particularly relevant because it assessed the efficacy of the IL-17 inhibitor ixekizumab in active PsA.16 Patients were randomized to receive either ixekizumab 80 mg once every 2 weeks, ixekizumab 80 mg once every 4 weeks, adalimumab 40 mg once every 2 weeks, or placebo. Patients receiving ixekizumab had a starting dose of 160 mg. At 16 weeks, patients who were randomized to placebo were switched over to a treatment arm. ACR20 response rates were 62.1% for patients in the ixekizumab every-2-weeks group and 57.9% for patients in the ixekizumab every-4-weeks group Additionally, compared with groups receiving placebo, those in the ixekizumab groups experienced improved disease activity and functional disability and less progression of structural damage. Moreover, in terms of clearing plaque psoriasis, patients showed greater response to ixekizumab compared with placebo.
Secukinumab is another IL-17 inhibitor available for the treatment of PsA. It was approved by the FDA in 2016 for PsA based on results of the phase 3 FUTURE 1 and FUTURE 2 trials (NCT01392326, NCT01752634, respectively). In the 24-week FUTURE 1 trial,17 investigators randomized patients to receive intravenous secukinumab 10 mg/kg at weeks 0, 2, and 4, followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks or matching placebo until week 24. The results showed that secukinumab treatment at 150 mg or 75 mg resulted in clinically meaningful improvements in global disease activity, pain, fatigue, and generic and disease-specific measures of health-related quality of life. Through 3 years of a FUTURE 1 extension trial, investigators observed that 76.8% of patients in the secukinumab 150-mg group achieved ACR20 compared with 65.2% of patients in the secukinumab 75-mg group. The authors also noted low rates of radiographic disease progression among patients in the secukinumab groups.18 The FUTURE 2 trial evaluated patients who received 75-mg, 150-mg, or 300-mg doses of secukinumab, or placebo. Investigators reported that 51.0%, 54.0%, and 29.3% of patients in the 150-mg group, 300-mg group, and 75-mg group, respectively, achieved ACR20 compared with 15.3% in the placebo group. At week 16, the most common AEs were upper respiratory tract infections and nasopharyngitis. Serious AEs were reported by 5.0%, 1.0%, and 4.0% of patients in the secukinumab 300-mg, 150-mg, and 75-mg groups, respectively, compared with 2.0% in the placebo group.19 In 2-year results from the FUTURE 2 trial, investigators found that ACR20 response rates after multiple imputation in the 300-mg, 150-mg, and 75-mg groups were 69.4%, 64.4%, and 50.3%, respectively, while AEs remained consistent in type, incidence, and severity as those reported previously, and no deaths were reported.20 On a related note, the IL-17 class does not carry boxed warnings.
Treatment-emergent AEs were seen in 66.4% of patients of the ixekizumab every-4-weeks group, in 65.7% of the ixekizumab every-2-weeks group, in 64.4% of the adalimumab group, and in 47.2% of the placebo group. The rates of serious AEs were also similar across treatment groups: 5.6% in the ixekizumab every-4-weeks group, 2.9% in the ixekizumab every-2-weeks group, 5.0% in the adalimumab group, and 1.9% in the placebo group.
Injection-site reactions were higher in patients treated with ixekizumab (24.3% and 26.5% in the ixekizumab every-4-weeks and every-2-weeks groups, respectively, compared with 5.9% in the adalimumab group and 4.7% in the placebo group), although many were mild or moderate. The likely reasons for the increase in injection-site reactions is that ixekizumab is a humanized monoclonal antibody rather than a fully human monoclonal antibody.
RA is among the most prevalent chronic inflammatory diseases, affecting approximately 1.3 million individuals in the United States.21,22 The lifetime risk of developing RA is 1.7% in men and 3.6% in women.23 According to ACR and European League Against Rheumatism guidelines, diagnosis relies heavily on patient history and examinations.24 Among the most common characteristics of RA is symmetric polyarticular joint pain/swelling, whereas arthritis in medium/large joints is associated with more severe disease. Criteria for diagnosis include the degree of joint involvement, duration of symptoms, serology results, and increased acute phase reactants. RA has also been associated with an increased prevalence of cardiovascular and metabolic risk factors.25
The case discussion focused on a 48-year-old man who presented to his primary care physician with stiffness in the hands, wrists, and ankles that had lasted for 9 months. He had no significant medical history and was being treated with ibuprofen, which is known to lose efficacy over time. When he was seen by a rheumatologist, he was found to have bilateral synovitis of the hands, wrists, and ankles and a Clinical Disease Activity Index (CDAI) score of 38; any score over 24 is considered high. A CDAI score between 10 and 24 is considered to denote moderate disease activity; between 2.8 and 10.0, low disease activity; and less than 2.8, remission.
The patient had nodules on his left elbow, which is unusual for someone who has had the disease for only 9 months. The development of rheumatoid nodules is more common in patients who have had disease for much longer; for reasons not fully understood, however, some patients develop them early. Additionally, the numbers of patients with nodules have decreased over time, in the era of biologics treatments. Possibly—but speculatively—earlier and more aggressive RA treatment is affecting the rates of rheumatoid nodule development. Nevertheless, when nodules are present, erosions are typically also present. This patient also had periarticular osteopenia and joint space narrowing. Given the high disease activity, positive cyclic citrullinated peptide, positive rheumatoid factor, joint space narrowing, osteopenia, and presence of nodules, this patient is considered atypical.
In 2015, the ACR published an update to its guidelines for the use of disease-modifying antirheumatic drugs (DMARDs) and biologics to treat RA.26 The guidelines note that for patients with early disease (6 months or less) who have never taken a DMARD, monotherapy with a DMARD is preferred, with methotrexate preferred in patients with low disease activity. If disease activity remains moderate or high despite DMARD monotherapy, clinicians may use combination DMARDs or a TNF or non-TNF biologic; all these regimens can be used with or without methotrexate, in no particular order of preference. If disease activity remains moderate or high despite DMARDs, the guidelines suggest use of a TNF inhibitor monotherapy over tofacitinib monotherapy or use of a TNF inhibitor plus methotrexate over tofacitinib plus methotrexate. Adding low-dose glucocorticoids is also an option if disease activity remains moderate or high despite DMARD or biologic therapies. Glucocorticoids may also be used for disease flares, although the guidelines recommend short-term use and lowest possible dose and duration.
In patients with established RA of 6 months’ duration or more, the guidelines suggest a treat-to-target strategy rather than a nontargeted approach. For patients with low disease activity who have never taken a DMARD, methotrexate is preferred over a TNF inhibitor. Methotrexate is also preferred over tofacitinib and combination DMARD therapy in patients with moderate or high disease activity who have never taken a DMARD. If disease activity remains moderate or high despite DMARD monotherapy, the guidelines recommend—rather than continuing DMARD monotherapy—the use of combination traditional DMARDs or adding a TNF inhibitor, non-TNF biologic, or tofacitinib, with or without methotrexate. For patients with moderate or high disease activity receiving TNF inhibitor therapy who are not currently on DMARDs, the recommendation is to add 1 or 2 DMARDs to TNF inhibitor therapy rather than continuing TNF inhibitor therapy alone.
For patients with moderate or high disease activity despite treatment with a single TNF inhibitor, the guidelines recommend use of a non-TNF biologic, with or without methotrexate, over another TNF inhibitor as well as tofacitinib, with or without methotrexate. For patients with moderate or high disease activity treated with a single non-TNF biologic, the guidelines suggest use of a non-TNF biologic with or without methotrexate over tofacitinib.
If disease activity remains moderate or high despite use of 2 or more sequential TNF inhibitors, the guidelines recommend use of a non-TNF biologic with or without methotrexate over another TNF inhibitor or tofacitinib. For patients with moderate or high disease activity who are being treated with multiple TNF inhibitors, tofacitinib with or without methotrexate may be used over another TNF inhibitor, if a non-TNF biologic is not an option. If disease activity remains moderate or high despite use of at least 1 TNF inhibitor and at least 1 non-TNF biologic, the guidelines suggest using another non-TNF biologic, with or without methotrexate, over tofacitinib, unless disease activity remains moderate or high with another non-TNF biologic, in which case tofacitinib is acceptable.
Low-dose glucocorticoid therapy may be used if disease activity remains moderate or high despite use of a DMARD, TNF inhibitor, or non-TNF biologic. Glucocorticoids can also be used for disease flares in patients on these agents; however, the guidelines recommend the lowest possible dose and shortest possible duration. For patients with low disease activity, continued use of DMARD therapy or TNF inhibitors, non-TNF biologics, or tofacitinib is preferred over discontinuing the respective medications. Finally, for patients in remission, the guidelines recommend tapering all RA therapies but emphasize that RA therapy should not be discontinued.
The initial recommendation for the patient in the case discussion was methotrexate 10 mg once per week. After 4 weeks, the patient’s CDAI score dropped from 38 to 28, which is still considered high disease activity. Therefore, the dose was increased to 15 mg. At the 3-month visit, the patient presented with continued stiffness, pain, and swelling in his wrists. His sedimentation rate was elevated, he complained of being unproductive at work because of joint pain, and his CDAI score was 26. Based on the guideline recommendations, TNF inhibitors, which have a robust record of clinical data, are broadly favored as a next option. The lack of head-to-head trials makes it difficult to differentiate the agents and make a data-driven decision. Thus, selecting an agent may be based on specific patient characteristics, comorbidities, childbearing potential, etc.
Another decision that clinicians must make when it comes to the use of biologics concerns combination therapy. As the guidelines suggest, methotrexate can be added to most TNF inhibitors for increased efficacy. However, although the combination of methotrexate plus a TNF inhibitor has shown positive results in RA, it is important to note that these results are not seen in PsA. The likely reason is that patients with PsA do not make as many antiproduct antibodies as the B-cell mediated disease seen in RA.
Given the features of this atypical case, consideration toward the use of non-TNF biologics may be warranted if TNF inhibitors fail or are not appropriate. Non-TNF biologics include the CTLA-4 inhibitor abatacept; the B-cell inhibitor rituximab; the JAK-STAT inhibitors tofacitinib, baricitinib, and upadacitinib; the IL-1 inhibitor anakinra; and the IL-6 inhibitors sarilumab and tocilizumab. Among these drug classes, IL-6 inhibitors stand out as potentially being similar in efficacy to anti-TNF monotherapy or combination therapy.
In the JUST-ACT study (NCT01399697), investigators assessed the potential of add-on therapy with the IL-6 inhibitor tocilizumab to background methotrexate in methotrexate inadequate responders with active RA.27 A total of 261 patients completed the initial 16-week period with tocilizumab plus methotrexate. Over the next 12 weeks, 80 patients in the tocilizumab/methotrexate group and 78 patients in the tocilizumab-alone group had completed the study. Both groups showed similar improvements in disease activity, functional disability, and quality of life in clinical remission from 16 to 28 weeks. The adjusted treatment difference in mean change of disease activity score 28-erythrocyte sedimentation rate (ESR) was —0.06 (95% CI, –0.40 to 0.27). Additionally, the percentage of patients in clinical remission was similar. Results demonstrated noninferiority from switching to tocilizumab monotherapy versus continuing with the combination.27 The safety profile of tocilizumab was also comparable with that of TNF inhibitors. In fact, the results showed an increase in infections among patients in the placebo arm over those in the tocilizumab/methotrexate arm.
Many factors enter into the selection of a therapeutic regimen for patients with RA. As this case presentation demonstrates, not all patients fit the standard clinical profile. Given the compelling data from the JUST-ACT study, it may reasonable in some cases for clinicians to consider changing biologic modalities if TNF inhibitors fail. However, given the robust data profile of many TNF inhibitors, clinicians may also consider starting another TNF inhibitor after a patient fails initial TNF inhibitor therapy before moving to non-TNF inhibitors.
NONRADIOGRAPHIC AXIAL SPONDYLOARTHRITIS
nr-AxSpA is a form of axial inflammatory arthritis that can evolve into ankylosing spondylitis but has not yet caused substantial erosive damage to the patient’s sacroiliac joints.28 Features associated with AxSpA include inflammatory bowel disease and uveitis. Importantly, the disability rate for patients with AxSpA is very high and is likely to occur at a young age.29 Many patients need to change jobs or become totally disable by age 40.
In 2009, the Assessment in Ankylosing Spondylitis classification criteria for spondyloarthritis divided the class into peripheral spondyloarthritis (which implies peripheral involvement) and AxSpA.30 It also separated the axial category into 2 groups: nr-AxSpA and radiographic AxSpA. Ankylosing spondylitis is equivalent to radiographic AxSpA, but nr-AxSpA is a new entity altogether.
The concept and natural history of AxSpA and nr-AxSpA are still being defined. Although nr-AxSpA has only recently been described through advances in MRI technology, its significant impact on the quality of life of patients has been well documented.28 Classification criteria for nr-AxSpA have been proposed and discussed among specialists in the international rheumatology community. Studies are ongoing to further define the classification and diagnosis criteria of nr-AxSpA.
Radiographs are often conducted years after symptoms have begun, and they can be difficult to interpret because of the complexity of sacroiliac joint anatomy. Disease progression occurs in as many as 75% of cases. As MRI technology continues to evolve, the classification of stages of nr-AxSpA will become more defined and treatments could be better matched to patients.
The case presentation focused on a 21-year-old woman with severe back pain that caused her to awaken in the middle of the night. Although she attributed the pain to being an active athlete, she also noted that the pain improved when she moved around.
Back pain has 2 classifications: mechanical and inflammatory. Inflammatory back pain is worse when the patient is at rest or in 1 position for a long time, and it improves with exercise. Importantly, it does not occur acutely but rather gradually over time. Mechanical back pain, which often has a precipitant event, gets worse with exercise and improves with rest. A significant percentage of patients with inflammatory back pain have AxSpA.31
The patient was treated with ibuprofen 400 mg 3 times daily, along with physiotherapy. After 4 weeks, the back pain persisted, with ibuprofen delivering mild but not long-lasting relief. The patient reported decreased mobility and productivity because of the back pain, and she also experienced diarrhea, vomiting, and abdominal pain as a result of treatment. X-ray of the sacroiliac joints revealed no inflammation and no visible damage. Her CRP was 4.7 mg/dL (normal is <3 mg/dL), her ESR was 38 mm/h (normal is 0-20 mm/h), and she was HLA-B27 positive.
This patient likely has AxSpA, and her normal x-ray results suggest that it is nonradiographic. As clinicians and investigators continue efforts to better elucidate nr-AxSpA, the question remains of whether nr-AxSpA can progress to radiographic. Five-year results from the DESIR cohort (NCT01648907) suggest that roughly 5% of patients with recent-onset AxSpA had sacroiliac radiographic progression.32 Additionally, although spinal radiographic progression is limited in early AxSpA, findings suggest that it can be captured after 2 years.33 Markers of higher radiographic progression include inflammation and damage in the sacroiliac joint.33
In the case presented, the patient has been on nonsteroidal anti-inflammatory agents and has had only partial response. A reasonable next step would be a TNF inhibitor. In 2019, CZP was approved by the FDA for the treatment of nr-AxSpA, making it the first treatment approved for such an indication. The approval was based on results of the phase 3 C-AXSPAND study (NCT02552212), in which investigators assessed the effects of CZP on patients with nr-AxSpA who had objective signs of inflammation.34 A total of 317 adults were randomized 1:1 from 80 different centers in Australia, Europe, North America, and Taiwan to CZP or placebo (N = 317); both groups also received nonbiologic background medication (NBBM). CZP was administered at 400 mg at weeks 0, 2, and 4; beginning at week 6, the dosage was 200 mg once every 2 weeks, continuing through week 50. At 52 weeks, 47.2% of patients who received CZP achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (P <.0001) compared with 7.0% of patients who received NBBM alone.34 Regarding AEs, 5.7% of patients in the CZP group experienced hepatic events and 1.3% of patients had malignant or unspecified tumors. Serious treatment-emergent AEs were observed in 5.0% of patients in the CZP group.
In addition to the rapid response with CZP, the low rates of response with placebo are notable. Often, in rheumatology studies, placebo response rates are between 23% and 35%. In this study, the 7% placebo response rate may further confirm the efficacy data for the patients receiving the CZP regimen.
CZP has also been studied in pregnancy. In the CRIB study (NCT02019602), investigators evaluated placental transfer of CZP from CZP-treated pregnant women to their infants.35 A total of 16 women who were pregnant for 30 weeks or more received CZP 200 mg every 2 weeks or 400 mg every 4 weeks. The median patient age was 31 years. Eleven patients had RA, 3 had Crohn disease, 1 had PsA, and 1 had AxSpA. Additionally, 2 infants were delivered via cesarean birth and 14 were delivered vaginally. Two infants were disqualified: 1 because of missing data at birth and 1 because of implausible pharmacokinetic data. Both patient and infant blood were sampled, and results showed that 13 infants had no quantifiable CZP levels at birth (<0.032 ug/mL), and 1 showed minimal levels. At weeks 4 and 8, no quantifiable CZP levels in the infants were shown. These results support the continuation of CZP therapy during pregnancy, if necessary. Safety results were comparable to those of previous studies.
Another study, called CRADLE (NCT02154425), tested CZP levels in human breast milk to estimate the average daily infant dose.36 Samples were collected after 3 or more CZP doses. Seventeen of 21 CZP-treated mothers were entered into the sampling period (4 tested below the lower limit of quantification), and a total of 137 samples were collected. All samples showed minimal CZP (below the lower limit of quantification), whereas 56% of samples showed no measurable CZP at all. Additionally, the infants’ safety profile was similar to that of unexposed similarly aged infants. These results indicated that CZP transfer to infants through breast milk is unlikely and that treatment can continue while breastfeeding.
In June 2020, the IL-17 inhibitor ixekizumab was approved by the FDA for the treatment of nr-AxSpA. The approval was based on results from the phase 3 COAST-X trial (NCT02757352). Investigators randomly assigned patients (n = 303) to receive subcutaneous 80-mg ixekizumab every 4 weeks, every 2 weeks, or placebo, with the primary end point of Assessment of Spondyloarthritis International Society 40 (ASAS40) response criteria compared with placebo. At 52 weeks, the results demonstrated that 30% of patients who received ixekizumab 80 mg every 4 weeks achieved ASAS40 response, compared with 13% of patients treated with placebo at week 52 (P = .0045). Response was also seen as early as 16 weeks in 35% of patients receiving ixekizumab compared with 19% receiving placebo (P < .01). The FDA noted that the safety profile for ixekizumab in patients with nr-AxSpA was consistent with previous experience with ixekizumab in other approved indications.
Despite innovations in therapeutic interventions for rheumatic diseases over the past 2 decades, several unmet needs remain. As pharmacologic development and research contribute to a rapidly evolving treatment spectrum, arguably the most significant current need in rheumatic disease treatment is for reliable biomarkers to help predict the likelihood of response to treatment and to anticipate safety issues. With more targeted approaches to therapy, clinicians can deliver personalized care and potentially optimize outcomes.