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Ankylosing Spondylitis

Janus Kinase (JAK) Inhibitors

Muhammad Asim Kahn, MD, FRCP, MACP; Nurullah Akkoç, MD 
Reviewed on June 30, 2023
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Introduction

Inflammatory cytokines play a major role in the pathogenesis of immune-mediated chronic inflammatory diseases. Cytokines are rarely produced alone and play their role in a complex network with others. They perform many functions and can act synergistically or antagonistically. They can be produced by more than one cell and exert redundant and pleiotropic functions, which may be different in different tissues. The release of one cytokine may influence the production of, or response to, several others. These features all point to the complexity of interplay between different immune cell types and between different cytokine networks involved in the pathogenesis of different chronic inflammatory diseases.

Nevertheless, single anti-inflammatory cytokine targeting strategies, using monoclonal antibodies or receptor constructs against tumor necrosis factor-α (TNF-α), IL-1, IL-6, IL-17A and IL-23 have been successful in the treatment of several chronic…

Introduction

Inflammatory cytokines play a major role in the pathogenesis of immune-mediated chronic inflammatory diseases. Cytokines are rarely produced alone and play their role in a complex network with others. They perform many functions and can act synergistically or antagonistically. They can be produced by more than one cell and exert redundant and pleiotropic functions, which may be different in different tissues. The release of one cytokine may influence the production of, or response to, several others. These features all point to the complexity of interplay between different immune cell types and between different cytokine networks involved in the pathogenesis of different chronic inflammatory diseases.

Nevertheless, single anti-inflammatory cytokine targeting strategies, using monoclonal antibodies or receptor constructs against tumor necrosis factor-α (TNF-α), IL-1, IL-6, IL-17A and IL-23 have been successful in the treatment of several chronic inflammatory conditions. Blocking one single cytokine, like TNF-α, is effective in a wide spectrum of chronic inflammatory diseases, including even some seemingly unrelated ones, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and hidradenitis suppurativa. This indicates that common inflammatory pathway(s) may be implicated in the pathogenesis of different inflammatory diseases.

On the other hand, targeting IL-17, may show efficacy in only a subset of diseases, which are known to respond well to anti-TNF therapies, but not in all. AS, psoriasis, and psoriatic arthritis (PsA) are effectively treated by IL17is, but neither RA, which is unrelated to the these diseases, nor inflammatory bowel disease (IBD) or uveitis, which are clinically and genetically related to them show response to IL-17 blocking agents. Targeting IL-23, which is required for the optimal expansion and activation of Th17 cells, is very effective in psoriasis but not in AS. Similarly, IL-1 and IL6 are also among the key regulators in the differentiation of human Th17 cells; however, blockers of these cytokines have not shown any efficacy in AS either.

All of this information suggests that the lack of response to a single anti-cytokine therapy in an immune mediated disease may not entirely exclude an immunopathogenic role for that cytokine, because of the redundant and pleiotropic nature of cytokines. Targeting a combination of such cytokines involved in the induction and/or perpetuation of an immune mediated inflammatory process in such a disease, may still be an effective therapeutic strategy. This section is based on our detailed review on the current and future aspects of inhibitors of Janus kinases (JAK) in the management of AS/axSpA and related spondyloarthritis (SpA). Future prospects of potential use of JAK inhibition for the treatment of chronic inflammatory diseases, including its impact on the treatment of axial spondyloarthropathies have also been reviewed by others.

Cytokine binding to its receptor on the cell surface leads to dimerization of the receptor and activation of the JAKs, which subsequently phosphorylates the tail of receptors on tyrosine, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (STAT) family. Dimers of STATs are then phosphorylated by JAKs and translocate to the nucleus, where they regulate the expression of cytokine‐responsive genes (Figure 17-1).

JAKs are a family of non-receptor protein tyrosine kinases with four members: JAK1, JAK2, JAK3, and Tyrosine kinase 2 (Tyk2). Distinct combinations of JAK proteins selectively associate with different homo- or heterodimeric cytokine receptors, which consist of multiple (usually two) protein chains (Figure 17-2). Hence, the inhibition of each JAK member interfere with the downstream signal transduction of relevant cytokines, which make JAK proteins an attractive target for the treatment of several chronic inflammatory diseases.

Enlarge  Figure 17-1: Cytokine Binding to the Receptor Leads to JAK Activation and Phosphorylation of the JAKs and Associated Receptors. Key: Cytokine binding to the receptor leads to JAK activation and phosphorylation of the JAKs and associated receptors. Phosphorylation of the receptors in turn initiates recruitment of the STATs via their SH2 domains and subsequent phosphorylation of STAT proteins. The phosphorylated STAT homodimers or heterodimers then translocate to the nucleus where they bind to specific DNA binding sites regulating gene transcription that leads to changes in cellular function. Source: Clark JD, et al. J Med Chem. 2014;57(12):5023-5038.
Figure 17-1: Cytokine Binding to the Receptor Leads to JAK Activation and Phosphorylation of the JAKs and Associated Receptors. Key: Cytokine binding to the receptor leads to JAK activation and phosphorylation of the JAKs and associated receptors. Phosphorylation of the receptors in turn initiates recruitment of the STATs via their SH2 domains and subsequent phosphorylation of STAT proteins. The phosphorylated STAT homodimers or heterodimers then translocate to the nucleus where they bind to specific DNA binding sites regulating gene transcription that leads to changes in cellular function. Source: Clark JD, et al. J Med Chem. 2014;57(12):5023-5038.
Enlarge  Figure 17-2: Overview of Janus Kinase (JAK) Inhibitors Developed for the Treatment of Immune-Mediated Inflammatory Diseases. Key: EPO, erythropoietin; GH, growth hormone; IFN, interferon; GM-CSF, granulocyte macrophage colony-stimulating factor; TPO, thrombopoietin; Tyk2, tyrosine kinase 2. JAK2-specific inhibitors have been developed for the treatment of hematological malignancy, although are omitted here for simplicity. Source: Modified from Baker KF, et al. Ann Rheum Dis. 2018;77(2):175-187.
Figure 17-2: Overview of Janus Kinase (JAK) Inhibitors Developed for the Treatment of Immune-Mediated Inflammatory Diseases. Key: EPO, erythropoietin; GH, growth hormone; IFN, interferon; GM-CSF, granulocyte macrophage colony-stimulating factor; TPO, thrombopoietin; Tyk2, tyrosine kinase 2. JAK2-specific inhibitors have been developed for the treatment of hematological malignancy, although are omitted here for simplicity. Source: Modified from Baker KF, et al. Ann Rheum Dis. 2018;77(2):175-187.

JAK Inhibitors (JAKis) in AS

A significant proportion of patients with active AS treated with tumor necrosis factor inhibitors (TNFis) discontinue their treatment due to failure or inadequate response. Although, IL17is may be effectively used in such patients, response rate is generally lower compared to anti-TNF–naïve patients. Therefore, there is still a considerable number of patients with AS, whose disease activity cannot adequately be suppressed despite the use of currently approved biologic drugs. JAKis may reduce the unmet need for treatment options in AS.

Currently, three JAKis, tofacitinib, baricitinib and upadacitinib, are approved for the treatment of rheumatoid arthritis (RA) in the United States (US) and the European Union (EU). JAKis are also being used to tackle other autoimmune disorders and tofacitinib has been approved also for psoriatic arthritis (PsA) and ulcerative colitis (UC). Phase 3 trials of tofacitinib and upadacitinib and a phase 2 trial of filgotinib all showed good therapeutic response in adults with AS. Baricitinib has no clinical development program. Interestingly, neither the TNF nor the IL-17A signal through JAK-STAT signaling pathway, whereas IL-23 and IL-6 use JAK-STAT pathway. Notably, phase 3 trials with monoclonals targeting the latter cytokines showed no efficacy in AS.

Efficacy of JAKis

Tofacitinib (Xeljanz)

Tofacitinib is a pan JAKi, with greater selectivity for JAK1/JAK3 with minor activity on JAK2 and lesser activity on TYK2. It is approved for the treatment of RA, PsA, UC and polyarticular course juvenile idiopathic arthritis (JIA) in both in the US and the EU. It received Food and Drug Administration (FDA) approval for the treatment of AS in 2021, after the positive results of a phase 3 study of tofacitinib in adults with active AS. The US prescribing information states that tofacitinib is indicated for the treatment of adult patients with active AS who have had an inadequate response or intolerance to one or more TNF blockers.

A phase 2 dose ranging study noted higher Assessment of Spondyloarthritis International Society criteria for 20% improvement (ASAS20) response rates in adult AS patients treated with 2, 5, or 10 mg twice daily doses of tofacitinib over 12 weeks than with placebo; but the difference did not reach statistical significance in the tofacitinib 2 mg and 10 mg groups. In the same study, significant improvements were observed with 5 and 10 mg tofacitinib relative to placebo, in most of the secondary endpoints assessed, including MRI inflammation scores in the spine and the sacroiliac joints.

The results of the phase 3 study with tofacitinib for the AS indication demonstrated its efficacy in AS. This phase 3, randomized, double-blind, placebo-controlled study enrolled patients aged ≥18 years with a diagnosis of active AS documented with centrally read radiographs, who met modified New York (mNY) criteria, and they had an inadequate response or intolerance to ≥2 NSAIDs. Patients with complete ankylosis of the spine were ineligible. About 20% of the patients had prior exposure to TNFis. In the 16-week double-blind phase, patients were randomized 1:1 to receive tofacitinib 5 mg tablet twice daily or placebo. After Week 16, all patients received open-label tofacitinib until Week 48. The primary endpoint was ASAS20 response at Week 16. It was achieved by 56.4% and 29.4% of the patients taking tofacitinib and placebo, respectively (P<0.0001).

Assessment of Spondyloarthritis International Society criteria for 40% improvement (ASAS40) response at the same time point was the key secondary endpoint and was met by 40.6% of the patients receiving tofacitinib vs 12.5% of the patients on placebo (P<0.0001) (Figure 17-3). Type I error-controlled secondary efficacy endpoints were also improved significantly. The changes from baseline to Week 16 in Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP), high-sensitivity C-reactive protein (hsCRP), AS Quality of Life (ASQoL), Short Form 36 Health Survey (SF36v2) Physical Component Summary (PCS), Bath Ankylosing Metrology Index (BASMI)–linear method, and Functional Assessment of Chronic Illness Therapy (FACIT)-F total score were greater in the tofacitinib group compared with placebo (Table 17-1). ASAS20 responder rates at week 16 in the active treatment vs placebo groups were 61% vs 33% among biologic disease-modifying antirheumatic drug (DMARD)-naïve patients and 39% vs 16% among biologic DMARD-exposed patients. Improvements in ASAS20 and ASAS40 were evident as early as 2 weeks and 4 weeks, respectively. No new safety signals were recorded.

Enlarge  Figure 17-3: Efficacy of Tofacitinib 5 mg Two Times per Day vs Placebo. Key: Tofacitinib 5 mg two times per day<sup>a </sup>over time up to week 48: (A) ASAS20 responseb and (B) ASAS40 response.<sup>b</sup> Data up to week 16 are from the week 16 analysis: data cut- off 19 December 2019; data snapshot 29 January 2020. Data for weeks 24-48 are from the week 48 final analysis. a) Patients receiving placebo advanced to tofacitinib 5 mg two times per day at week 16 (dashed line). b) Up to week 16, response rate was tested in hierarchical sequence to control for type I error: weeks 16, 12, 8, 4 and 2. c) P<0.001 for comparing tofacitinib 5 mg two times per day vs placebo. d) P≤0.05 for comparing tofacitinib 5 mg two times per day vs placebo, according to the prespecified step- down testing procedure for global type I error control. e) P≤0.05 for comparing tofacitinib 5 mg two times per day vs placebo, according to the prespecified step- down testing procedure for type I error control of ASAS response over time. Statistical significance could be declared only if the prior time points in the sequence met the requirements for significance (P≤0.05). After week 16, there was no type I error control. Normal approximation adjusting for the stratification factor (bDMARD treatment history: bDMARD- naïve vs TNFi- IR or prior bDMARD use without IR) derived from the clinical database via the Cochran- Mantel- Haenszel approach was used. Missing response was considered as nonresponse. Source: Deodhar A, et al. Ann Rheum Dis. 2021. doi:10.1135/annrheumdis-2020-219601 (published online ahead of print).
Figure 17-3: Efficacy of Tofacitinib 5 mg Two Times per Day vs Placebo. Key: Tofacitinib 5 mg two times per daya over time up to week 48: (A) ASAS20 responseb and (B) ASAS40 response.b Data up to week 16 are from the week 16 analysis: data cut- off 19 December 2019; data snapshot 29 January 2020. Data for weeks 24-48 are from the week 48 final analysis. a) Patients receiving placebo advanced to tofacitinib 5 mg two times per day at week 16 (dashed line). b) Up to week 16, response rate was tested in hierarchical sequence to control for type I error: weeks 16, 12, 8, 4 and 2. c) P<0.001 for comparing tofacitinib 5 mg two times per day vs placebo. d) P≤0.05 for comparing tofacitinib 5 mg two times per day vs placebo, according to the prespecified step- down testing procedure for global type I error control. e) P≤0.05 for comparing tofacitinib 5 mg two times per day vs placebo, according to the prespecified step- down testing procedure for type I error control of ASAS response over time. Statistical significance could be declared only if the prior time points in the sequence met the requirements for significance (P≤0.05). After week 16, there was no type I error control. Normal approximation adjusting for the stratification factor (bDMARD treatment history: bDMARD- naïve vs TNFi- IR or prior bDMARD use without IR) derived from the clinical database via the Cochran- Mantel- Haenszel approach was used. Missing response was considered as nonresponse. Source: Deodhar A, et al. Ann Rheum Dis. 2021. doi:10.1135/annrheumdis-2020-219601 (published online ahead of print).
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Upadacitinib (Rinvoq)

Upadacitinib is a selective JAK1 inhibitor, with a greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2 as shown in a cell-free isolated enzyme assay. It is approved by both FDA and EMA for the treatment of RA, PsA, EC, AD, AS and nr-axSpA, typically after DMARDs have failed. The FDA-approved indication for upadacitinib is for the treatment of adults with active AS who have had an inadequate response or intolerance to one or more TNF blockers.

The approval for the AS indication was based on a multicenter, randomized, double-blind, placebo-controlled phase 2/3 study (NCT03178487) which evaluated the efficacy and safety of oral upadacitinib 15 mg once daily (n=93) in comparison with placebo (n=94) in adult patients with active AS. Study entry eligibility criteria included fulfillment of mNY criteria, inadequate response to at least two or intolerance or contraindication to NSAIDs and no exposure to biologic treatment. Patients with complete ankylosis of the spine were excluded.

The primary endpoint was ASAS40 response at Week 14 and it was achieved by 52% of the patients on upadacitinib vs 26% of the patients on placebo (P=0.0003). The mean change for each individual ASAS component was noted as early as the first post-baseline visit (Week 2). Accounting for multiplicity adjustment, change from baseline to week 14 in Ankylosing Spondylitis Disease Activity Score (ASDAS), SpA Research Consortium of Canada (SPARCC) MRI spine, and Bath Ankylosing Functional Index (BASFI), and proportion of patients who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) and an Assessment of Spondyloarthritis International Society (ASAS) partial remission were significant for upadacitinib vs placebo (Figure 17-4A). ASAS partial remission was reached by 19% and 1% of the patients taking upadacitinib and placebo, respectively (P<0.0001). Improvements in MASES, BASMI, ASQoL, and ASAS Health Index at Week 14, but not in Work Productivity and Activity Impairment (WPAI), were observed, with upadacitinib versus placebo (nominal P values <0.05) (Figure 17-4). ASAS20 and SPARCC MRI sacroiliac joint score, also improved with upadacitinib relative to placebo (nominal P values (Figure 17-4A, B).

Treatment differences in the proportion of patients who had ASDAS low disease activity, ASDAS inactive disease, ASDAS clinically important improvement, and ASDAS major improvement were greater for upadacitinib versus placebo at week 14 (nominal P<0.0001 for all comparisons) (Figure 17-5A). Improvements in the mean ASDAS and ASDAS major improvement were noted as early as 2 weeks (Figure 17-5B). The improvements observed at primary time point were maintained with an upward trend up to Week 64. Safety findings were in consistent with previous upadacitinib studies in other indications, with no new safety signal.

The efficacy of upadacitinib in patients with AS who have had an inadequate response (IR) to biologic DMARDs (bDMARDs) was assessed in a 14-week, randomized, double-blind, placebo-controlled, phase 3 trial (NCT04169373). This study enrolled adult (≥18 years) patients with AS who fulfilled mNY criteria and had an IR to one or two bDMARD therapies (TNFi or IL-17i) either due to lack of efficacy or because of intolerance; patients with an IR to two bDMARDs were eligible only if the IR resulted from a lack of efficacy for one drug and intolerance for the other – a lack of efficacy for two bDMARDs was not allowed. Exclusion criteria included total spinal ankylosis and prior exposure to JAKis. Patients were randomized 1:1 to oral upadacitinib 15 mg once daily (n=211) or placebo (n=209).

In the upadacitinib group, 45% of the patients achieved the primary endpoint of ASAS40 response at Week 14, compared to 18% in the placebo group (multiplicity-controlled P<0.0001); a nominal difference in the proportion of patients achieving an ASAS40 response was detectable at Week 4 and maintained thereafter (Figure 17-6). At Week 14, a significantly higher proportion of patients in the upadacitinib group also achieved the key secondary endpoints of ASAS20, ASAS-PR and BASDAI50 response (multiplicity-controlled P<0.0001 for all comparisons). Upadacitinib treatment also resulted in a greater reduction from baseline in the SPARCC MRI inflammation score for the spine (multiplicity-controlled P<0.0001) and sacroiliac joint (nominal P<0.0001), as well as in improvements in additional secondary outcome measures, including ASDAS-CRP, BASFI, BASMI, MASES (assessed in patients with baseline enthesitis), nocturnal back pain and total back pain (multiplicity-controlled P<0.0001 for all comparisons). Finally, upadacitinib also significantly reduced the ASQoL and ASAS Health Index scores compared to the placebo (multiplicity-controlled P<0.0001). The safety profile of upadacitinib among patients with IR to bDMARDs was consistent with data from earlier trials in AS, RA and PsA.

Upadacitinib has also demonstrated efficacy in nr-axSpA, receiving FDA and EMA approval for this indication in 2022 (see the nr-axSpA section below).

Enlarge  Figure 17-4: Upadacitinib for AS: Multiplicity-controlled and Key Secondary Endpoints at Week 14. ASAS20, ASAS40, ASAS partial remission, and BASDAI50 responses at week 14 (A), change from baseline in SPARCC MRI spine and sacroiliac joint scores (B), and other multiplicity-controlled key secondary efficacy endpoints at week 14 (C). All endpoints were multiplicity controlled, except for ASAS20 and SPARCC MRI sacroiliac joint. The multiplicity-controlled secondary endpoints were tested in a sequential manner: ASDAS, SPARCC MRI spine, group of endpoints tested by Hochberg procedure (BASDAI50, ASQoL, ASAS partial remission, BASFI, BASMI, MASES, and WPAI), and ASAS Health Index (appendix p 4). (A) NRI analysis. (B, C) Mixed-effect model for repeated measures analysis; decreases from baseline indicate better outcome in all endpoints. (C) MASES assessment includes patients with baseline enthesitis; WPAI assessment includes patients currently employed; SPARCC MRI assessment population as prespecified in the statistical analysis plan (baseline included MRI data ≤3 days after first dose of study drug, and week 14 included MRI data up to first dose of period 2 study drug). Error bars show 95% CI. a) Nominal P values are shown. Significant in multiplicity-controlled analysis. Source: van der Heijde D, et al. Lancet. 2019;394(10214):2108-2117.
Figure 17-4: Upadacitinib for AS: Multiplicity-controlled and Key Secondary Endpoints at Week 14. ASAS20, ASAS40, ASAS partial remission, and BASDAI50 responses at week 14 (A), change from baseline in SPARCC MRI spine and sacroiliac joint scores (B), and other multiplicity-controlled key secondary efficacy endpoints at week 14 (C). All endpoints were multiplicity controlled, except for ASAS20 and SPARCC MRI sacroiliac joint. The multiplicity-controlled secondary endpoints were tested in a sequential manner: ASDAS, SPARCC MRI spine, group of endpoints tested by Hochberg procedure (BASDAI50, ASQoL, ASAS partial remission, BASFI, BASMI, MASES, and WPAI), and ASAS Health Index (appendix p 4). (A) NRI analysis. (B, C) Mixed-effect model for repeated measures analysis; decreases from baseline indicate better outcome in all endpoints. (C) MASES assessment includes patients with baseline enthesitis; WPAI assessment includes patients currently employed; SPARCC MRI assessment population as prespecified in the statistical analysis plan (baseline included MRI data ≤3 days after first dose of study drug, and week 14 included MRI data up to first dose of period 2 study drug). Error bars show 95% CI. a) Nominal P values are shown. Significant in multiplicity-controlled analysis. Source: van der Heijde D, et al. Lancet. 2019;394(10214):2108-2117.
Enlarge  Figure 17-5: Upadacitinibfor AS: ASDAS Responses Through Week 14. Key: MMRM, mixed-effect model for repeated measures; NRI, non-responder imputation. (A) Proportion of patients with ASDAS low disease activity, ASDAS inactive disease, ASDAS clinically important improvement, and ASDAS major improvement at week 14, (B) change from baseline in mean ASDAS over time, and (C) ASDAS major improvement over time. (A, C) NRI analysis. (B) MMRM analysis. Error bars show 95% CI. Nominal p values are shown. a) Significant in multiplicity-controlled analysis. Source: van der Heijde D, et al. Lancet. 2019;394(10214):2108-2117.
Figure 17-5: Upadacitinibfor AS: ASDAS Responses Through Week 14. Key: MMRM, mixed-effect model for repeated measures; NRI, non-responder imputation. (A) Proportion of patients with ASDAS low disease activity, ASDAS inactive disease, ASDAS clinically important improvement, and ASDAS major improvement at week 14, (B) change from baseline in mean ASDAS over time, and (C) ASDAS major improvement over time. (A, C) NRI analysis. (B) MMRM analysis. Error bars show 95% CI. Nominal p values are shown. a) Significant in multiplicity-controlled analysis. Source: van der Heijde D, et al. Lancet. 2019;394(10214):2108-2117.
Enlarge  Figure 17-6: Upadacitinib in Patients with AS and Inadequate Response to bDMARDs: ASAS40 Responses Through Week 14. Key: ASAS40, Assessment of SpondyloArthritis international Society 40 response; NRI-MI, non-responder imputation incorporating multiple imputation; QD, once daily. ASAS40 response through week 14. NRI-MI analysis was used. Error bars show 95% confidence intervals. Significant in multiplicity-controlled analysis: ***P<0.0001. Without adjustment for multiplicity (nominal): †P<0.05; †††P<0.0001. Source: van der Heijde D, et al. Ann Rheum Dis. 2022;81:1515-1523.
Figure 17-6: Upadacitinib in Patients with AS and Inadequate Response to bDMARDs: ASAS40 Responses Through Week 14. Key: ASAS40, Assessment of SpondyloArthritis international Society 40 response; NRI-MI, non-responder imputation incorporating multiple imputation; QD, once daily. ASAS40 response through week 14. NRI-MI analysis was used. Error bars show 95% confidence intervals. Significant in multiplicity-controlled analysis: ***P<0.0001. Without adjustment for multiplicity (nominal): †P<0.05; †††P<0.0001. Source: van der Heijde D, et al. Ann Rheum Dis. 2022;81:1515-1523.

Filgotinib (Jyseleca)

Filgotinib is a selective JAK1 inhibitor as shown in biochemical assays, with greater than 5-fold higher potency for JAK1 over JAK2, JAK3 and TYK2. It has been approved for the treatment of RA in Europe and Japan, but not in the US. The FDA has issued a complete response letter in response to the drug maker’s filing for approval of filgotinib in RA and requested safety data from the two ongoing phase 2 trials which aim to assess the testicular toxicity of the drug. Thereupon the drug maker has announced that it will no longer pursue FDA approval for RA and paused the two ongoing phase 3 trials for AS, as well as the ongoing trials for PsA and uveitis. Thus, it is unlikely the clinical development will continue for the AS indication.

Safety

The results of phase 3 studies of tofacitinib and upadacitinib conducted in AS patients showed no new safety signal and were consistent with the previously reported safety profiles in RA and other chronic inflammatory diseases. Considering that patients with AS are more likely to be young and male and are less likely to be using glucocorticoids or methotrexate concomitantly, they may have a lower risk for some of the adverse effects observed with JAKis in RA patients. On the other hand, because patients with AS often use NSAIDs, they may possibly be more prone to some other adverse effects, such as gastrointestinal perforation, which is a rare but serious adverse event (AE) of JAKis. The bulk of the available data on the safety of JAKis are derived from the first generation JAKis generated from RA studies, predominantly from tofacitinib, with safety data reported up to 9.5 years. Data with the newer JAKis are much more limited, with safety data available with upadacitinib up to 5 years.

There is a large overlap between the safety profiles of different JAKis, despite differences in their JAK selectivity profile. Changes in laboratory parameters have been observed with all JAKis with some minor differences (Table 17-2). Hematological adverse effects include neutropenia, which is observed with all JAKis. Platelets decrease with tofacitinib and filgotinib treatment within normal ranges. An initial transient increase in platelet counts observed with baricitinib disappears during the course of treatment. Platelet count changes only minimally with upadacitinib treatment. Hemoglobin may initially decrease and then slowly increase with baricitinib, tofacitinib and filgotinib, while upadacitinib treatment has little impact on hemoglobin. Elevations in liver transaminase, creatine kinase, total cholesterol and serum creatinine levels are commonly observed with JAKis.

Potential AEs of JAKis include infections, serious infections, herpes zoster, tuberculosis (TB), major adverse cardiovascular events (MACE), venous thromboembolic events (VTE) and malignancies (Table 17-3). Caution is warranted when comparing the incidence rates of AEs with different JAKi due to the wide variation in patient-years of exposure to each drug. Full appreciation of the safety profile of a therapeutic agent requires data from long-term extension studies as well as data from real world studies. Such data are available for tofacitinib and upadacitinib.

The adverse effects of JAKis have been the target of many meta-analyses. A meta-analysis on the safety of JAKis which included trials of RA, IBD, psoriasis, or AS found no increased risk for serious infection compared to placebo. Another metanalysis involving only RA trials demonstrated that serious infection rate was not increased with tofacitinib 5 mg twice daily, baricitinib 2 mg daily, or upadacitinib 30 mg daily; but significantly increased with tofacitinib 10 mg twice daily, baricitinib 4 mg daily and upadacitinib 15 mg daily.

However, real world data from RA patients registered in three US databases indicated that the risk of serious infection with tofacitinib treatment was significantly higher than with etanercept, lower than with infliximab, numerically higher than abatacept, golimumab and tocilizumab and similar to adalimumab and certolizumab. Tofacitinib was associated with a 2-fold higher risk of herpes zoster compared with bDMARDs in this and also in an earlier real world study. Other JAKis also seem to increase the risk of herpes zoster infection relative to the current biologic agents and csDMARDs. Risk factors for zoster infections include older age, female sex, East Asian ethnicity, concomitant use of corticosteroids, diabetes, history of infections and hospitalizations. Available data suggest that JAK2 and JAK3 inhibition may be associated with a higher risk of zoster infection than JAK1 inhibition. Blocking JAK2 may be associated with the highest risk.

Opportunistic infections, particularly TB, are of special concern for patients treated with JAKis. This topic was the focus of a systematic review which examined 40 publications. The authors identified 79 (0.28%) active TB cases among 28,099 tofacitinib-treated patients, 10 (0.23%) among 4310 baricitinib-treated patients, but none among the 3437 and 1326 patients treated with upadacitinib and filgotinib, respectively. All but one TB cases were from an intermediate or high TB risk countries. The majority of TB cases involving tofacitinib had used the 10 mg twice daily dose. Notably, a significant proportion of TB cases had a negative quantiferon test at baseline. This, together with the relatively late occurrence of active TB infection after the initiation of tofacitinib (median 9 months) suggest that a considerable portion of TB cases occurring under treatment with JAKis are likely not to be caused by reactivation of latent TB infection. The mean interval between the initiation of TNFi and occurrence of active TB is 5.5 months. The absence of any active TB infection in patients receiving upadacitinib and filgotinib may be due to the lower number of enrolled patients, the shorter follow-up period, and limited long-term extension data. Therefore, more long-term observational data with a larger number of patients treated with JAK1 inhibitors are needed before concluding that TB risk is dependent on JAK selectivity.

The concern regarding the thromboembolic AEs of JAKis was first raised during the approval process of baricitinib in RA. Regulatory authorities in the USA and Europe highlighted this risk in the Summary of Product Characteristics of JAKis. The FDA issued a “black box” warning for the increased risk of thrombosis, including pulmonary embolism (PE), deep vein thrombosis (DVT), arterial thrombosis, major cardiovascular events (MACE), malignancies and all-cause mortality for baricitinib, upadacitinib and tofacitinib. This decision was based on results from the post-marketing “ORAL Surveillance” safety study (NCT02092467) comparing the safety of tofacitinib with TNFis in patients with RA aged ≥50 years and with ≥1 CV risk factor, which revealed an increased incidence of PE events and all-cause mortality in the 10 mg twice daily dosing of tofacitinib compared with a TNF blocker.

The results of a systematic review of the FDA’s Adverse Event Reporting for both tofacitinib and ruxolitinib revealed increased reporting rates of pulmonary thrombosis, suggesting the possibility of a class-wide issue. The FDA approval of upadacitinib for RA also came with a boxed safety warning for thromboembolic events. On the other hand, three meta-analyses of randomized controlled trials of JAKis did not reveal significant changes in the risks of VTE, PE and DVT in patients receiving a JAKi compared with placebo. The risk with tofacitinib tended to be lower in the two studies which provided data for individual JAKis. The same studies found no difference between the placebo and JAKis in the incidence of MACE. In one of these studies, a dose-dependent impact was observed with only baricitinib, with 2 mg being safer than 4 mg.

The patient population of RCTs who are selected by strict inclusion/exclusion criteria may lead to lower rates of AEs than in the real world. Incidence rates of DVT, PE and ATE estimated by analysis of the data from tofacitinib development programs were roughly in consistent with the estimates based on the observational data from the US Corrona registries and MarketScan databases. In conclusion, the available evidence from a range of sources suggests that JAKis are associated with an increased risk of thrombosis; but the risk is low and mostly confined to patients with additional risk factors. We need more data with the new JAKis to better appreciate whether it is a class effect. Until then, it is reasonable to avoid or use cautiously any JAKi in patients with risk factors for venous thromboembolism, such as older age, obesity, a medical history of DVT/PE, or surgery and immobilization, in line with the recommendations of regulatory authorities. RA, glucocorticoid use and NSAID should also be kept in mind as potential risk factors for thromboembolic events.

Malignancy is one of the major concerns for patients undergoing treatment with JAKis. A meta-analysis which reviewed safety data from both interventional and observational studies of tofacitinib, filgotinib, upadacitinib and baricitinib conducted in patients with IBD, psoriasis, or AS found no increase in the incidence of malignancy in patients receiving JAKis in the controlled periods. However, it should be underlined that participant of RCTs are selected by tight inclusion and exclusion criteria. Moreover, the time frame of the RCTs may underestimate the AE that require time to develop, like malignancy. Long-term safety data of tofacitinib for up to 9.5 years collected from RA patients showed a comparable incidence rate of malignancy to those seen with TNFis and other biologic DMARDs. However, this needs to be confirmed by long-term safety data of other JAKis.

An international task force of expert physicians published a set of recommendations to emphasize that before starting treatment with a JAKi, patients should be questioned about history of malignancy, diverticulitis and thromboembolic events. Concomitant medication use, including NSAIDs, glucocorticoids and oral contraceptives are also relevant when screening risk factors for thrombosis. Age and comorbidities such as diabetes mellitus and chronic respiratory diseases pose a risk for serious infections. Annual skin examination for detection of skin cancer is advisable. Laboratory screening should include complete blood counts and tests for liver and kidney function and serological tests for HBV and HCV infection. It should be kept in mind that the patients may not show increased levels of CRP and ESR despite the presence of an infection. Chest X-rays and interferon-γ-releasing assays should be ordered to detect patients with latent TB infection. Minimal laboratory monitoring should include full and differential blood counts, liver transaminases and renal function tests. 

The FDA-mandated post-marketing “ORAL Surveillance” safety study (NCT02092467) that compared the safety of tofacitinib with that of TNFis in patients with RA (aged ≥50 years and with ≥1 cardiovascular risk factor(s)) has been completed, with tofacitinib missing the trial’s co-primary endpoints of noninferiority to TNFi regarding risks for MACE and cancer. The FDA issued an alert based on preliminary data; the final results from ORAL Surveillance showed a higher frequency of MACE (9.8 vs 7.3 per 1,000 person-years of drug exposure; HR 1.33, 95% CI 0.91-1.94) and malignancy (11.3 vs 7.7 per 1,000 person-years of drug exposure; HR 1.48, 95% CI 1.04-2.09) with tofacitinib at both 5 mg and 10 mg twice-daily dosing, compared to patients treated with  TNFis.

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Non-radiographic Axial SpA

Upadacitinib is currently the only JAKi approved for the treatment of nr-axSpA, receiving FDA and EMA approval for this indication in 2022. The US package insert for upadacitinib states that it is indicated for the treatment of adults with active nr-axSpA with objective signs of inflammation who have had an inadequate response or intolerance to TNF blocker therapy.

Regulatory approval for the use of upadacitinib in patients with nr-axSpA was granted on the basis of positive results from a 14-week, randomized, double-blind, placebo-controlled, phase 3 safety and efficacy trial (NCT04169373). Adult (≥18 years) patients with clinically diagnosed, active nr-axSpA who met the ASAS diagnostic criteria and had at least one sign of active inflammation (assessed by sacroiliac MRI or hsCRP testing) were eligible for inclusion; patients with AS (meeting the radiographic mNY criteria) were excluded. Eligible patients were randomized (1:1) to upadacitinib 15 mg once daily (n=156) or placebo (n=157).

Upadacitinib treatment resulted in 45% primary endpoint (ASAS40 at Week 14) achievement rate, compared to 23% for the placebo (multiplicity-controlled P<0.0001; Figure 17-7), with a nominal difference between the two groups detectable by Week 2. In multiplicity-controlled analyses, upadacitinib demonstrated superiority to placebo with respect to several additional efficacy endpoints, including ASAS20 (P<0.0001; Figure 17-7), ASAS-PR (P<0.0001; Figure 17-7), BASDAI50 (P<0.0001; Figure 17-7), ASDAS-CRP (P<0.0001), BASFI (P<0.0001), MASES (P<0.0001), nocturnal back pain (P<0.0001), total back pain (P<0.0001) and SPARCC MRI sacroiliac joint (P<0.0001). The SPARCC MRI spine score showed improvement with upadacitinib (nominal P=0.021) but was not multiplicity-controlled. No significant difference between the upadacitinib and placebo groups was observed for BASMI scores. Finally, multiplicity-controlled analyses of self-reported outcomes showed that upadacitinib significantly improved ASQoL (P<0.0001) and ASAS Health Index (P<0.0001) scores. This study revealed no new safety signals among patients with nr-axSpA and the overall safety profile was similar to that observed in patients with AS, RA and PsA.

Enlarge  Figure 17-7: Upadacitinib for nr-ax-SpA: Selected Multiplicity-Controlled Outcomes at Week 14. Key: ASAS20, Assessment of Spondyloarthritis international Society 20 response; ASAS40, Assessment of SpondyloArthritis international Society 40 response; ASAS PR, Assessment of SpondyloArthritis international Society partial remission; BASDAI50, Bath Ankylosing Spondylitis Disease Activity Index ≥50% improvement. Analysis of multiplicity-controlled primary and key secondary endpoints at Week 14 based on non-responder imputation incorporating multiple imputation analysis. Source: Deodhar A, et al. Lancet. 2022;400:369-379.
Figure 17-7: Upadacitinib for nr-ax-SpA: Selected Multiplicity-Controlled Outcomes at Week 14. Key: ASAS20, Assessment of Spondyloarthritis international Society 20 response; ASAS40, Assessment of SpondyloArthritis international Society 40 response; ASAS PR, Assessment of SpondyloArthritis international Society partial remission; BASDAI50, Bath Ankylosing Spondylitis Disease Activity Index ≥50% improvement. Analysis of multiplicity-controlled primary and key secondary endpoints at Week 14 based on non-responder imputation incorporating multiple imputation analysis. Source: Deodhar A, et al. Lancet. 2022;400:369-379.

JAKis in the 2019 ACR/SAA/SPARTAN Treatment Guidelines

Tofacitinib is addressed in the 2019 ACR/SAA/SPARTAN recommendations for the treatment of AS and nr-axSpA. According to these recommendations, tofacitinib should be considered as a last-line therapy after TNFis and IL17is for the treatment of adult patients with active AS despite treatment with NSAIDs. However, tofacitinib should be considered as the choice of therapy in patients with coexisting UC if anti-TNF therapy is not an option since tofacitinib is an approved treatment for UC whereas IL17is have not been shown to be efficacious in IBD. The panel based their treatment recommendations on the phase 2 study of tofacitinib mentioned earlier, which showed benefit in clinical and MRI outcomes after treatment for 12 weeks. These recommendations are expected to be revised, after the positive results of the phase 3 studies of tofacitinib and upadacitinib in patients with AS and the above mentioned results of the FDA-mandated post-marketing “ORAL surveillance” safety study of tofacitinib in patients with RA.

Concluding Remarks

A considerable number of patients with AS do not respond to or tolerate the currently available biologics. Therefore, the positive results obtained in the phase 3 trials of tofacitinib and upadacitinib has given hope that these novel agents would provide the unmet need for treatment of such patients, and their efficacy appears to be comparable to each other as well as to TNFis and IL-17is. However, head-to-head trials against biologics or among the JAKis are needed to determine where to position this category of drugs in the treatment pathway of patients with AS. There are limited or indirect data on the efficacy of JAKis in treating AS-associated peripheral arthritis, enthesitis, dactylitis and extra-articular manifestations (uveitis, psoriasis, UC, CD). It needs to be explored in future studies whether JAKis have any effect on the progression of structural damage. Thus far, only upadacitinib has been studied in patients with nr-axSpA.

Tofacitinib is approved for the treatment of PsA, but not for psoriasis (because its manufacturer had withdrawn application after the FDA asked for additional safety analyses). The EMA and FDA have granted approval to upadacitinib for the treatment of PsA. These two JAKis significantly improved enthesitis and dactylitis and psoriasis in patients with PsA relative to placebo. Tofacitinib has been approved for the treatment of patients with UC but not for CD. A few cases of uveitis associated with JIA have shown a favorable clinical response with tofacitinib and baricitinib.

With regards to their safety profile, the more frequent occurrence of cardiovascular and cancer adverse events associated with tofacitinib compared to TNFis observed in the FDA-mandated post-marketing safety study in patients with RA may raise safety concerns for the whole class of JAKis. The FDA has suggested that healthcare professionals should “consider the benefits and risks of tofacitinib when deciding whether to prescribe or to continue patients on this medicine,” and that the patients should not stop taking tofacitinib without first consulting with their physicians; this approach is generally extended to all JAKis.

It remains to be seen whether the long-term safety profile of JAKis will be similar in the AS patient population, who are more likely to be younger and male. Although their oral mode of administration and short half-lives carry advantage, the future of tofacitinib and probably other JAKis for the treatment of AS depends on the final conclusions and recommendations of the FDA after their review of all the efficacy and safety data, including the ORAL Surveillance safety study.

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