Nonbiologic Therapy for Psoriatic Arthritis

The approach to the treatment of psoriatic arthritis (PsA) has historically drawn from the treatment of rheumatoid arthritis (RA), although the management of the two diseases has begun to diverge in recent years. Early, aggressive therapy and treatment to target have become the mantras of therapy in RA. While aggressive therapy may be indicated in many patients with PsA, the evidence for the value of these treatment paradigms have not been as clear in PsA as they have in RA. As a result, early use of disease-modifying antirheumatic drug (DMARD) therapy, and subsequent use of biologic therapy, is not always necessary or appropriate in PsA.

When considering the management of PsA, as with any form of arthritis, it is reasonable to consider physical therapy and other nonmedical treatments as a first-line or adjunctive approach.

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in first-line management of psoriatic arthritis (PsA), especially in patients with no current, or low risk for, destructive arthritis. Although NSAIDs have not been as widely studied as in rheumatoid arthritis (RA) and are not specifically indicated for PsA, there is evidence to support their benefit. There is no published evidence to support use of one NSAID over another. COX-2 inhibitors or concomitant therapy with a proton pump inhibitor may be considered in patients at high risk for upper GI bleeding. Some concern has been raised about the potential for NSAIDs to exacerbate psoriatic skin disease, but this does not typically present a clinical problem. Similarly, care should be used when initiating NSAID therapy in PsA patients with associated inflammatory bowel disease, which may also be exacerbated by these agents.

Corticosteroids

Corticosteroids, either systemic or locally administered, may also be used in the management of psoriatic arthritis (PsA). There is a widely held perception that corticosteroids are generally less effective in PsA and other spondyloarthropathies than they are in rheumatoid arthritis (RA), but the actual evidence for this is scant. As with NSAIDs, concern has been raised over potential exacerbation of skin disease with corticosteroids, particularly following short courses of systemic steroid; this does not appear to be an important concern in patients who are also taking other systemic biologic or nonbiologic therapy for their psoriasis.

DMARDs

When patients with psoriatic arthritis (PsA) do not respond adequately to NSAIDs alone, or when there is identifiable joint damage indicating a need for more aggressive treatment, systemic DMARDs should be considered. Interestingly, while there are data available from well-controlled trials with a number of agents in PsA, none of the DMARDs discussed here are FDA indicated for the treatment of PsA. Much of the historical approach to this treatment has relied on the drugs commonly used to treat rheumatoid arthritis (RA), a disease for which most of these drugs have a labeled indication. Both oral and injectable gold salts, though rarely used at the present time, have been reported to be effective in PsA. Hydroxychloroquine has been reported to be effective in PsA in uncontrolled series, although some have described exacerbation of psoriasis with this agent.

A meta-analysis of 12 clinical trials of nonbiologic medications used to treat PsA found statistical benefit relative to placebo only for intravenous methotrexate, sulfasalazine, azathioprine, and etretinate, although issues of study design limited the interpretation of the results of the last two. There was a significant placebo response in all 12 trials reviewed in this analysis, a finding that suggests caution is warranted when relying on uncontrolled trials to guide treatment decisions in PsA.

Sulfasalazine, originally developed for use in RA, is a chemical combination of a sulfonamide and an aspirin moiety; the compound is split by bacteria in the colon, where the sulfonamide is absorbed and then exerts an anti-inflammatory effect (Figure 6-1). Sulfasalazine has been shown to be effective in PsA, at a dose of 2 g to 3 g per day given in two doses. In a multicenter trial of 221 patients, sulfasalazine was statistically more effective than placebo, using the Psoriatic Arthritis Response Criteria (PsARC) as the primary end point. In another placebo-controlled study of sulfasalazine 3 g per day in 351 patients with spondyloarthropathies, the drug was determined to be particularly effective in the subset of patients with PsA. Sulfasalazine appears to be more effective for peripheral arthritis in spondyloarthropathies than for axial arthritis. Sulfasalazine has a generally mild safety profile. Nausea and headache are the most common side effects but are rarely significant enough to warrant discontinuation of therapy; use of enteric-coated tablets and gradually increasing the dose with initiation of therapy can reduce these toxicities. Sulfasalazine should be avoided in patients who are allergic to sulfonamides, and leukopenia has been reported, particularly during the initial months of therapy.

Enlarge 

Cyclosporine

Cyclosporine, which has historically been effective for the management of psoriasis, has been used to treat psoriatic arthritis (PsA), although there are no controlled, blinded studies with this drug. Several open studies have suggested benefit with this drug in the PsA, although its value may be limited by its toxicity profile, including hypertension and renal damage. Etretinate, also used to treat psoriatic skin disease, has been tried with some

Leflunomide

Leflunomide, a pyrimidine synthesis inhibitor approved for the treatment of rheumatoid arthritis (RA), has been studied in psoriatic arthritis (PsA). Leflunomide appears to work by selectively reducing active inflammatory cells, particularly T lymphocytes, in inflamed joints. In a 24-week placebo-controlled study, the response rate using the Psoriatic Arthritis Response Criteria (PsARC) was 58.9% in the leflunomide group, compared with 29.7% in the placebo group. Skin disease also improved with leflunomide in this study. GI side effects, including nausea, are the most common toxicity with this drug; cytopenias and elevated liver enzymes have also been seen. Leflunomide is teratogenic; given its very long half-life of approximately 2 weeks, this drug should be used with great caution in women of childbearing age. Cholestyramine binding may be used to drive more rapid elimination in the case of severe side effects or women considering pregnancy.

Methotrexate

Methotrexate, another drug frequently used to treat psoriasis, was initially reported to be effective for psoriatic arthritis (PsA) in the 1960s. The first placebo-controlled, blinded study of low-dose, oral methotrexate for the treatment of PsA was published in 1984. This trial, which was stopped prematurely because of low enrollment, included 37 patients with active arthritis unresponsive to aspirin or NSAIDs. Perhaps because of the small numbers, objective measures of arthritis did not demonstrate improvement relative to placebo for methotrexate; the only variable that statistically improved compared with placebo was the physician global assessment.

Two controlled trials have evaluated the use of methotrexate in PsA. The Remicade Study in Psoriatic Arthritis Patients of Methotrexate-Naive Disease (RESPOND) trial compared methotrexate 15 mg weekly with the combination of methotrexate and infliximab in 115 patients with relatively early PsA (mean 2 to 3 years of disease). While the combination of methotrexate and the TNF inhibitor was clearly more effective, methotrexate alone was effective in a substantial proportion of patients, with 67%, 40%, and 19% achieving an ACR20, 50 and 70 response at 16 weeks, respectively; 29% of the methotrexate-treated patients achieved remission DAS28 criteria. This was one of the first trials to look at the impact of methotrexate on dactylitis and enthesitis in PsA; the drug was less effective than combination therapy with infliximab for these manifestations. RESPOND was an open-label trial, however, and caution should be used when interpreting these results, given the high placebo response that has been seen in this disease.

In contrast to the RESPOND trial, the placebo-controlled Methotrexate In Psoriatic Arthritis (MIPA) study did not demonstrate a benefit with methotrexate 15 mg weekly in 221 patients. At 6 months, despite a trend towards improved response with methotrexate, response rates for PsARC, ACR20, and DAS28 response were not statistically different than placebo (Table 6-1). The placebo response was high in this study, which may have been underpowered to show true differences between treatment groups. The methotrexate dose used may also have been too low to demonstrate efficacy.

Despite the uncertainties of the clinical trial results and the fact that the drug does not have a labeled indication for this disease, methotrexate is widely used in the management of PsA. Dosing appears to be similar to the dose used in rheumatoid arthritis (RA), 15 mg to 20 mg weekly, although higher doses may be needed. As in RA, methotrexate may be administered orally or parenterally. The parenteral route is preferred at higher doses because of its improved bioavailability and decreased GI toxicity. It should be noted that the evidence for synergistic benefit with methotrexate and TNF inhibitors is far less compelling in PsA than in RA.

Enlarge 

Apremilast

Apremilast is a phosphodiesterase-4 (PDE4) inhibitor approved for the treatment of adult patients with active psoriatic arthritis (PsA) (Figure 6-2 and Figure 6-3). Phosphodiesterases are key intracellular enzymes responsible for the degradation of cyclic AMP (cAMP); PDE4 is the predominant phosphodiesterase in immune cells, making it an attractive target in autoimmune inflammatory diseases. The degradation of cAMP to AMP by PDE4 leads to the production of pro-inflammatory mediators, such as TNF-alpha and IL-23, while reducing the production of anti-inflammatory mediators such as IL-10. Inhibition of this enzyme’s function, therefore, might be expected to tip the balance in the cell from a pro-inflammatory to an anti-inflammatory state.

Apremilast has been studied in four phase 3 trials in PsA: three (PALACE 1-3) in patients with previous exposure to DMARD therapy and one (PALACE 4) in DMARD-naïve patients. PALACE 1-3 studied a total of 1,493 patients with at least three swollen and three tender joints despite current or prior DMARD therapy; in PALACE 3, patients were required to have at least one target psoriatic skin lesion at least 2 cm in diameter. Up to 10% of the patients in each trial were permitted to have failed prior therapy with a biologic agent for PsA. The study populations were similar to other studies of PsA, with 62% of the patients enrolled with symmetrical polyarthritis and 27% with asymmetrical oligoarthritis. Prior treatment with small-molecule SMARDs only was reported in 76% of patients and prior treatment with biologic DMARDs was reported in 22% of patients, which includes 9% who had failed prior biologic DMARD treatment. At the time of enrollment, 65% were receiving concomitant nonbiologic DMARD therapy (concomitant biologic therapy was not allowed). Patients were randomized to treatment with placebo or one of two doses of apremilast, 20 mg twice daily or 30 mg twice daily.

The primary endpoint of these three studies was ACR20 response at 16 weeks, and the results were quite similar (Figure 6-4). At 30 mg twice daily the approved dose of apremilast, the ACR20 response rates were 38.1%, 32.1%, and 40.7%, compared with 19.0%, 18.9%, and 18.3% in the three placebo arms, respectively. The percentages of patients achieving higher levels of response were also similar, with 10.5% to 16.1% achieving an ACR50 response and 1.2% to 4.2% achieving an ACR70 response. Other manifestations of PsA improved with apremilast as well. There were statistically significant improvements in function (measured by the HAQ disability index), enthesitis, dactylitis and psoriatic skin disease (Figure 6-5). Radiographic outcomes were not measured in these trials. Although apremilast can be given as monotherapy or in combination with nonbiologic DMARDs, the results of these trials did not suggest that there was additive benefit from concomitant DMARD use.

The fourth phase 3 trial of apremilast, PALACE 4, included patients with no prior DMARD therapy, although they could have received either NSAIDs or low-dose corticosteroids. The PALACE 4 trial enrolled 527 patients, and the results were similar to the DMARD-experienced trials, with an ACR20 response rate at 16 weeks of 30.7% compared with 15.9% in the placebo arm. Enthesitis, dactylitis and psoriatic skin disease also improved with apremilast in this trial.

The recommended initial dosage titration for apremilast for the first 5 days of starting treatment is shown in Table 6.2. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy.

Open-label extensions of the apremilast trials suggested that response with this drug was sustained to at least 52 weeks. The safety profile of apremilast is good, with no increase in laboratory abnormalities in any of the trials. The most common adverse events seen with apremilast were nausea, diarrhea and headache (Table 6-3). A total of 4.6% of patients across trials discontinued due to adverse events. The diarrhea seen with apremilast occurs early in therapy and seems to be generally self-limited; dose titration during the first week of therapy may reduce the incidence of GI side effects. A small (~1 kg) mean weight loss was observed with apremilast therapy in clinical trials; this did not appear to be associated with GI toxicity.

Apremilast treatment may be associated with an increase in adverse reactions of depression. During clinical trials in patients with PsA, 1.0% of subjects treated with apremilast reported depression or depressed mood compared with 0.8% treated with placebo. Discontinuations were seen in 0.3% of subjects treated with apremilast due to depression or depressed mood compared with no placebo-treated subjects. Instances of suicidal ideation and behavior were reported in 0.2% of subjects receiving apremilast compared with no placebo-treated subjects. In these clinical trials, two subjects who received placebo committed suicide compared with none in apremilast-treated subjects.

Apremilast is designated pregnancy category C by the FDA. There are no well-controlled studies in pregnant patient. Apremilast is metabolized by CYP3A4, so that clinical response may be reduced when the drug is given with CYP3A4-inducing agents such as rifampin. No dosage adjustment is necessary for elderly patients or those with hepatic or mild renal impairment. In patients with a creatinine clearance ≤30 mg/dL, the recommended dose is 30 mg daily.

In addition to PsA, apremilast has also been approved for the treatment of patients with moderate to severe psoriasis.

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Tofacitinib

Tofacitinib was first approved for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) and an inadequate response to methotrexate. It has also received FDA approval for the treatment of patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other nonbiologic DMARDs. Tofacitinib is an orally administered inhibitor of the JAK family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2). JAKs are intracellular enzymes that transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence hematopoiesis and immune cell function. JAK enzymes transmit cytokine signaling through the pairing of JAKs (eg, JAK1/JAK3) and subsequent phosphorylation and activation of signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression (Figure 6-6). JAK inhibitors, such as tofacitinib, therefore prevent the phosphorylation and activation of STATs, which transmit signals from the cell surface to the nucleus.

Efficacy and safety of tofacitinib in the treatment of patients with PsA were assessed in two randomized, placebo-controlled, double-blind, phase 3 studies: OPAL Broaden and OPAL Beyond. Eligible patients had an inadequate response to ≥1 csDMARD and were either TNF inhibitor-naïve (OPAL Broaden [n = 422, 12 months]) or had inadequate response to ≥1 TNF inhibitor (OPAL Beyond [n = 394, 6 months]). Patients were randomized to receive either tofacitinib 5 mg twice daily, 10 mg twice daily, subcutaneous adalimumab 40 mg Q2W (OPAL Broaden only), or placebo. All placebo-treated patients were switched to tofacitinib 5 mg or 10 mg twice daily at month 3.

The primary endpoints of both studies were the percentage of patients who achieved an ACR20 response rate and change from baseline in HAQ-DI score at month 3. Other study endpoints included ACR50/70 response rates, ≥75% improvement from baseline in PASI75 and others.

At month 3 in OPAL Broaden, treatment with tofacitinib 5 mg and 10 mg twice daily resulted in an ACR20 response in 50% and 61% of patients, respectively, compared to 33% of patients in the placebo group (P < .05 for both comparisons; Figure 6-7). At month 3 in OPAL Beyond, treatment with tofacitinib 5 mg and 10 mg bid resulted in an ACR20 response in 50% and 47% of patients, respectively, compared to 24% of patients in the placebo group (P <0.001 for both comparisons; Figure 6-8). ACR50 and ACR70 response rates at month 3 were also significantly higher (P ≤0.05) in tofacitinib-treated patients of OPAL Broaden. ACR50 and ACR70 response rates in tofacitinib-treated patients were higher in OPAL Beyond; however, the increase in the ACR70 response rate did not reach statistical significance (Table 6-4). In both trials, treatment with either tofacitinib 5 mg or 10 mg bid also resulted in significantly greater change in HAQ-DI score from baseline at month 3 compared to placebo (ORAL Broaden: tofacitinib 5 mg, -0.17 difference from placebo; tofacitinib 10 mg, -0.22 difference from placebo; OPAL Beyond: tofacitinib 5 mg, -0.25 difference from placebo; tofacitinib 10 mg, -0.22 difference from placebo; Figure 6-7 and Figure 6-8). Although no placebo comparisons were available at month 6 (OPAL Beyond) or month 12 (OPAL Broaden), efficacy was maintained or further improved throughout the studies.

In both trials, rates of reported AEs were higher among patients in the active treatment groups compared to those who received placebo. In OPAL Broaden, serious AEs occurred in 3% and 1% of patients in the tofacitinib 5-mg and 10-mg groups, respectively, compared to 1% in the adalimumab and placebo groups. In OPAL Beyond, rates of serious AEs were 1%, 2% and 2% for patients who received tofacitinib 5 mg bid, tofacitinib 10 mg bid and placebo, respectively. A summary of safety events from OPAL Broaden through month 12 is shown in Table 6.5. The prescribing information for tofacitinib has a boxed warning for serious infections and malignancy.

Tofacitinib is provided as 5-mg tablets and 11-mg extended-release tablets. The recommended dose of tofacitinib in PsA is 5 mg twice daily or an 11-mg extended-release tablet once daily, either used in combination with nonbiologic DMARDs. Patients may switch from the 5-mg tablets to the extended-release formulation the day following the last dose of 5-mg tablets. Tofacitinib tablets should be swallowed whole and intact, with or without food.

It is recommended that tofacitinib not be initiated in patients with an absolute lymphocyte count <500 cells/mm3, an absolute neutrophil count <1,000 cells/mm3, or who have hemoglobin levels <9 g/dL. Dose interruption is recommended for management of lymphopenia, neutropenia and anemia. If a patient develops a serious infection, use of tofacitinib should be avoided until the infection is controlled.

In patients who are receiving potent inhibitors of CYP3A4 (e.g., ketoconazole) or one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole), the recommended dose is tofacitinib 5 mg once daily. Coadministration of potent inducers of CYP3A4 (eg, rifampin) with tofacitinib is not recommended.

In patients with moderate or severe renal insufficiency or moderate hepatic impairment, the recommended dose is tofacitinib 5 mg once daily. Use of tofacitinib in patients with severe hepatic impairment is not recommended.

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Upadacitinib

Upadacitinib is an orally administered Janus Kinase (JAK) inhibitor that preferentially inhibits JAK1 and JAK2, with a lower potency of JAK3 and tyrosine kinase (TYK2) inhibition. Like tofacitinib, it first received FDA approval (August 2019) for the treatment of patients with rheumatoid arthritis, followed by approvals for the treatment of patients with psoriatic arthritis (PsA; December 2021) and atopic dermatitis (January 2022). In PsA, upadacitinib is indicated for the treatment of adults with active disease who have had an inadequate response or intolerance to one or more TNF blockers. It should not be used in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants (eg, azathioprine or cyclosporine).

The efficacy and safety of upadacitinib for the treatment of patients with PsA were tested in two phase 3 randomized, double-blind, multicenter, placebo-controlled studies: SELECT-PsA 1 and SELECT-PsA 2. SELECT-PsA 1 was a 24-week study which randomized eligible patients (adults at least 18 years of age with a diagnosis of PsA who fulfilled the Classification Criteria for Psoriatic Arthritis [CASPAR] and had current or historical plaque psoriasis) into four groups (1:1:1:1): 1) oral upadacitinib 15 mg once daily; 2) oral upadacitinib 30 mg once daily; 3) placebo; or 4) subcutaneous adalimumab 40 mg every other week. A total of 1,704 patients received treatment or placebo. SELECT-PsA 2 had a similar design: a 24-week study in which patients were randomized into four groups (2:2:1:1): 1) 15 mg upadacitinib once daily; 2) 30 mg upadacitinib once daily; 3) placebo switched to upadacitinib 15 mg at week 24; or 4) placebo switched to upadacitinib 30 mg at week 24.

In both SELECT-PsA studies, the primary endpoint was the proportion of patients achieving ACR20 in the upadacitinib and placebo groups at week 12. In SELECT-PsA 1, multiplicity-adjusted secondary endpoints included, among others, comparisons of upadacitinib and adalimumab and changes from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) scores at week 12. In SELECT-PsA 2, multiplicity-adjusted secondary endpoints included changes from baseline in HAQ-DI scores and the proportions of patients achieving ACR50/70 at week 12.

At week 12 in SELECT-PsA 1, ACR20 was achieved by 36.2% of patients in the placebo group, compared to 70.6% of patients in the upadacitinib 15-mg group and 78.5% of patients in the upadacitinib 30-mg group (P < 0.001 compared to the placebo for both upadacitinib groups; Figure 6-9). At the same time point, 65% of adalimumab group patients achieved ACR20, demonstrating non-inferiority of upadacitinib to adalimumab (P < 0.001 compared to adalimumab for both upadacitinib groups; Figure 6-9). In SELECT-PsA 2, 24.1% of placebo-receiving patients achieved the ACR20 response, compared to 56.9% and 63.8% of patients who received upadacitinib 15 mg or 30 mg daily, respectively (P < 0.001 for both upadacitinib groups compared to the placebo; Figure 6-10). In both studies at week 12, a significantly greater change in HAQ-DI scores from baseline was observed in both upadacitinib groups compared to placebo (Table 6-6). The ACR50 and ACR70 responses were also numerically higher with upadacitinib treatment compared to placebo at week 12 in both studies; however, as the ACR50 and ACR70 analyses were not adjusted for multiple comparisons, no conclusions can be drawn.

In both SELECT-PsA trials, the overall adverse event (AE) rates were comparable between the placebo and upadacitinib 15-mg groups, but numerically higher among patients in the upadacitinib 30-mg group (Table 6-7 and Table 6-8). In SELECT-PsA 1, serious AEs and AEs leading to discontinuation were also comparable between placebo and the upadacitinib 15-mg groups, but numerically higher in the upadacitinib 30-mg group. By contrast, in SELECT-PsA 2, serious AEs and AEs leading to discontinuation were numerically more common in the upadacitinib 15-mg group compared to placebo, and in the upadacitinib 30-mg group compared to the 15-mg group.

The FDA label for upadacitinib contains a black box warning about potential serious AEs associated with JAK inhibitors as a class, including: increased risk for serious infections, higher rates of all-cause mortality, lymphomas, lung cancers and major adverse cardiovascular events, as well as an increased incidence of pulmonary embolism and venous and arterial thrombosis.

Upadacitinib is available in two extended-release tablet forms: 15 mg and 30 mg. The tablets should be taken whole (not split, crushed or chewed), with or without food. The recommended dose of upadacitinib for the treatment of PsA is 15 mg once daily. Upadacitinib is not recommended for patients with severe hepatic impairment. For patients with mild, moderate or severe renal impairment, no dosage adjustment is needed. In patients receiving strong CYP3A4 inhibitors, the recommended dose of upadacitinib remains 15 mg per day.

Enlarge 

Enlarge 

Enlarge 

Enlarge 

Enlarge