ORIGINAL

ARTICLE

Treatment of coexistent psoriasis and lupus erythematosus Sowmya Varada, BS,a,b Alice B. Gottlieb, MD, PhD,a,d Joseph F. Merola, MD, MMSc,c Ami R. Saraiya, MD,a and Suzanne J. Tintle, MD, MPHa Boston, Massachusetts and Philadelphia, Pennsylvania Background: The coexistence of psoriasis and lupus erythematosus (LE) is rare. Anecdotal evidence suggests that antietumor necrosis factor alfa (TNF-a) agents may be efficacious in LE, although their use is commonly avoided in this disease because of concern for lupus flare. Objective: We sought to describe the epidemiology, serologic findings, and therapeutic choices in patients with coexistent psoriasis/psoriatic arthritis and LE and to determine the risk of lupus flares with TNF-a inhibitors. Methods: We performed a retrospective multicenter study of patients given the diagnoses of psoriasis (or psoriatic arthritis) and lupus erythematosus (systemic LE or cutaneous LE, including either subacute cutaneous LE or discoid LE) at 2 academic tertiary-care centers. Results: A total of 96 patients with a mean age of 56 years was included. We report higher-than-expected rates of white race and psoriatic arthritis. One clinical lupus flare was observed in a patient receiving a TNFa inhibitor, resulting in an incidence of 0.92% lupus flares per patient-year of TNF-a inhibitor use. Limitations: Retrospective chart review, small sample size, and limited documentation. Conclusion: AntieTNF-a agents, ustekinumab, and abatacept may be valid treatment options for patients with concomitant LE and psoriasis. Clinical lupus flares in LE patients treated with TNF-a inhibitors were infrequent. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.10.038.) Key words: psoriasis; lupus erythematosus; tumor necrosis factor alfa.

INTRODUCTION Psoriasis (Ps) and lupus erythematosus (LE) are immune-mediated diseases. Whereas Ps is primarily characterized by upregulation of the helper T cell (Th) 17 and Th1 immune pathways, LE is associated with upregulation of the Th1, Th2, and Th17 pathways, with constitutive B cell activation and autoantibody production.1-4 Ps is common, affecting 1% to 3% of the US population,5 whereas LE is much less common: Reported prevalence rates for SLE in the United States range from 20 to 150 cases per 100,000 for SLE.6 Cutaneous LE (CLE; including discoid LE [DLE]

and subacute cutaneous LE [SCLE]) has similar prevalence rates.7 The coexistence of LE with Ps is rare. Medications commonly used for LE, such as mycophenolate mofetil and azathioprine, are not particularly efficacious in cutaneous Ps therapy, and antimalarials are known to make Ps worse. Likewise, ultraviolet light phototherapy, used for many patients with cutaneous Ps, is generally avoided in SLE and CLE because of risk of photosensitivity or lupus exacerbation. Although TNF-a inhibitors are a wellestablished therapy for Ps, they often are avoided in LE because of the unclear role of TNF-a in the

From the Department of Dermatology, Tufts University Medical Centera and Tufts University School of Medicine,d Boston; Jefferson Medical College, Philadelphiab; and Department of Dermatology and Division of Rheumatology, Harvard Medical School, Brigham and Women’s Hospital, Boston.c Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 28, 2014.

Reprint requests: Suzanne J. Tintle, MD, MPH, Tufts University Medical Center, Department of Dermatology, 260 Tremont Street, 14th floor, Boston, MA 02111. E-mail: suzanne.tintle@ gmail.com. Published online December 6, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.10.038

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in the charts reviewed. Analysis of the use of disease and reports of TNF-a inhibitoreinduced LE biologics was included only if the given patient had and induction of antinuclear antibodies.8-12 received it after all diagnoses of Ps, PsA, and SLE/CLE The most recent case series of patients with were established. A clinical lupus flare was defined concomitant Ps and LE was published in 1980.13 as worsening of any one of the 1997 ACR criteria for We present a comprehensive case review of 96 paSLE or a worsening of DLE or SCLE and must have tients from 2 academic medical centers with Ps or been confirmed by a dermatologist’s (SCLE, DLE) or psoriatic arthritis (PsA) plus LE (systemic lupus rheumatologist’s (SLE) clinerythematosus [SLE], DLE, or ical note. SCLE). We aimed to deterCAPSULE SUMMARY All statistical analyses mine the risk of clinical LE were performed using SPSS flare with use of the TNF-a The coexistence of psoriasis with lupus software version 9.0. inhibitors and to evaluate erythematosus is rare and presents a clinical outcomes resulting therapeutic challenge. from the use of biologics in RESULTS We present a review of 96 patients with patients with Ps and SLE/ Ninety-six patients fulcoexistent disease and analyze treatment CLE. filled inclusion and exclusion regimens in this population. criteria (Table I). Eighty-four (87.5%) patients were METHODS The TNF-a inhibitors, and the newer women and 12 (12.5%) After local Institutional biologics, ustekinumab and abatacept, were men (Table II). Most Review Board approval, a may represent valid treatment options (77.1%) patients (including retrospective chart review of with little risk for clinical lupus flare. those with SLE or CLE) were patients with coexistent psowhite and had chronic plariatic and SLE/CLE was perque Ps (81.3%). In patients with SLE/CLE, Ps was formed at 2 tertiary-care academic institutions: Tufts present in 87 (90.6%) and PsA in 50 (52.1%). Forty Medical Center and Brigham & Women’s Hospital. patients (42.7%) had both Ps and PsA in addition to Electronic and paper chart reviews of patient LE. Nine patients (9.4%) had LE and PsA (per clinical medical history and laboratory and pathology redocumentation) without cutaneous Ps. There were ports were performed. Medical records from January 85 (89.6%) diagnoses of systemic LE, 21 (21.9%) of 1990 to February 2013 were available from the DLE, and 9 (9.4%) of SCLE. Of all patients seen at Brigham & Women’s Hospital, and records from Brigham and Women’s Hospital and Tufts Medical 2007 to 2013 were available from Tufts Medical Center who received a diagnosis of either Ps/PsA or Center. Patients must have received a diagnosis of LE, 0.015% and 0.017% of patients per year, respecPs or PsA and a diagnosis of at least one type of LE, tively, received the concurrent diagnoses of Ps/PsA SLE, DLE, or SCLE by International Statistical and LE. Classification of Diseases and Related Health Cutaneous photosensitivity was present in 39.6% Problems, Version 9 (ICD-9) diagnosis codes. Each of patients. Fifty-three patients (55%) had Ps diagdiagnosis must have been confirmed in a clinical nosed before LE; in 43 (45%), the diagnosis of LE note written by a rheumatologist (SLE) or dermatolpreceded diagnosis of Ps (Table II). There was a ogist (DLE, SCLE). If a diagnosis of SLE was found by longer latency period when Ps/PsA was diagnosed ICD-9 usage, but clinical notes lacked written diagbefore LE (mean, 18.4 years) compared with the nosis of SLE by a rheumatologist, the chart and converse (mean, 9.2 years). laboratory reports were reviewed for 1997 American A summary of treatments used, lengths of treatCollege of Rheumatology (ACR) criteria for SLE. A ment, adverse effects, and compliance rates is given patient with $ 4 ACR criteria for SLE by clinical notes in Table I. Most patients (66.7%) had received and laboratory results and an ICD-9 diagnosis was methotrexate, cyclosporine, or another nonbiologic then included. Patients with documentation in any systemic agent. The percentage of patients who clinical note of diagnosis of or concern for drugdiscontinued taking a drug because of poor efficacy induced LE (any subtype), drug-induced lupus synwas not statistically significantly different among drome, Ps, or PsA were excluded. treatment groups. Medication data were collected on US Food and Rates of adverse effects with biologic agents were Drug Administrationeapproved systemic medicaconsistent with those seen in clinical trials of the tions for Ps. Other systemic agents were included medications used in patients with Ps/PsA alone.14,15 in one group, ‘‘non-biologic systemic agents,’’ and length of use of these agents was not collected Overall, discontinuations of medication because of because much of these data were not documented adverse effects were most common with d

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Abbreviations used: ANA: dsDNA: DLE: LE: Ps: PsA: SCLE: SLE: TNF-a:

antinuclear antigen double-stranded DNA discoid lupus erythematosus lupus erythematosus psoriasis psoriatic arthritis subcutaneous lupus erythematosus systemic lupus erythematosus tumor necrosis factor-alpha

cyclosporine and least common with abatacept, adalimumab, and methotrexate. Twenty-five patients (26.0%) received biological agents (TNF-a inhibitors, ustekinumab, or abatacept), which were initiated on average 6.7 years after the final diagnosis of Ps/PsA and SLE/CLE (Table III). On average, these patients received 1.64 biological agents for a mean period of 30.6 months. Etanercept was the most frequently used biological agent. Abatacept had the longest single length of use (78 months). Most patients who received biological agents had SLE (22 patients, 88.0%) versus cutaneous LE. Four of the 5 patients who received ustekinumab were maintained successfully on the drug at final review, one of whom had experienced loss of efficacy with etanercept, infliximab, and adalimumab. Two of these patients had SLE with chronic plaque Ps, 2 had SLE, chronic plaque Ps and PsA, and 1 had DLE with chronic plaque Ps. Reports of improvement of both cutaneous Ps and cutaneous SLE symptoms (malar and discoid rashes) and improvements in lupus arthritis, oral ulceration, and hematologic abnormalities (thrombocytopenia or anemia) were observed. Clinical documentation did not allow for discrimination between improvements in PsA versus lupus arthritis, limiting our interpretation of ustekinumab’s effects. Ustekinumab use was discontinued in 1 patient because of cellulitis development. Abatacept was the final maintenance regimen for 3 patients, 1 of whom previously did not respond to 2 TNF-a inhibitors and 2 of whom had been taking the medication for more than 5 years. All 3 patients had SLE, chronic plaque Ps, and PsA. Improvements in SLE symptoms (oral ulcers, lupus arthritis, anemia, or thrombocytopenia) were observed. Interestingly, cutaneous photosensitivity reportedly improved in 2 of these patients in addition to improvement of their cutaneous Ps. Of the 25 patients who received at least 1 biological agent, 20 patients received TNF-a inhibitors, and only one of these experienced a clinical flare of lupus. This patient had a 14-year history of SLE and biopsy-proven class IV lupus

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glomerulonephritis developed approximately 60 days after initiation of infliximab. The flare resolved after discontinuation of the agent and treatment with cyclophosphamide. Review of the patient’s chart found that she had experienced 2 flares of lupus nephritis in childhood before treatment with any biologic medication and had an additional flare 15 months after discontinuation of infliximab. Thus, the relationship of the lupus nephritis flare to infliximab use remains unclear. The prevalence of clinical flares of all subtypes of LE among patients with coexistent disease who received anti-TNF agents was 5.0% (1 of 20 patients), resulting in an incidence of clinical flares of 0.92% events per patient-year of treatment with a TNF-a inhibitor. No flares of Ps or PsA were observed with any of the biological agents. Nearly 91% of all patients had positive test results for antinuclear antibody (ANA) at the time of SLE/CLE diagnosis; 62.5% had positive findings for antiedouble-stranded DNA antibody (anti-dsDNA; Table III). Among Ps/PsA patients, induction of autoantibodies (either ANA and/or dsDNA) occurred in 9 (9.4%). All seroconversions were subclinical, without any worsening or flare of cutaneous or systemic LE symptoms, and all occurred during treatment with either infliximab or etanercept.

DISCUSSION Cases of coexistent Ps and LE are uncommon. The 2 diseases have relatively disparate pathophysiologic mechanisms, although they share upregulation of the Th17 immune pathway with elevated levels of interleukin (IL)-17, IL-23, and IL-12.1,2,16 Most cases of concomitant Ps/PsA and LE in the literature are anecdotal reports and small case series.13,17-20 The most recent review of patients with coexistent LE and Ps was published in 1980 by Millns and Muller13 and presented an analysis of 27 cases. The baseline demographic characteristics of the 96 patients in our study (Table I) were largely similar to the findings of Millns and Muller,13 in which (1) there is no clear predominance of one disease developing before the other, and (2) there is a predominance of SLE over DLE.13 Our population was predominantly (77.1%) white. Whereas patients with Ps are predominantly white,21 SLE and DLE are more evenly distributed among different ethnic groups, with the highest prevalence observed among blacks (38.5% in SLE and 28.6% in DLE).22 Most (87.5%) of our patients were women, similar to that reported ([90%) in SLE and DLE.22 We found a relatively high prevalence (42.0%) of PsA among patients with cutaneous Ps versus rates

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Table I. Medication use among patients with coexistent Ps/PsA and LE

Medication

Methotrexate Cyclosporine TNF-a Inhibitors Etanercept Infliximab Adalimumab Certolizumab Ustekinumab Abatacept NA, not available. Nonbiological systemic hydroxychloroquine.

No. of patients who received medication

Length of medication use (patient-years)

Compliance rate (%)

33 6 32 14 6 11 1 5 3

NA NA 84.67 37.33 9.17 36.92 1.25 12.42 11.34

30.3 50.0 67.8 50.0 66.7 54.5 100.0 80.0 100.0

agents

included

prednisone,

azathioprine,

that are typically lower (11 to 39%) in the general cutaneous Ps-alone population.23-25 The percentages of patients who were ANA positive or anti-dsDNA positive were slightly lower than that seen in patients with SLE.26 However, we included patients with DLE and SCLE, in whom autoantibodies were more likely to be negative.27,28 Patients with coexistent disease seem to have increased rates of a photosensitive component of Ps beyond that expected with SLE/CLE alone.13 Cutaneous photosensitivity is reported in about 5.5% of patients with Ps without LE,29 in 32% to 37% of patients with SLE alone and in up to 47% of those with CLE alone.30,31 Prior studies have reported cutaneous photosensitivity in 50% to 85% of patients with coexistent Ps and LE13,17,32; 39.6% of our study population had documented cutaneous photosensitivity caused by either LE or Ps. Whereas the antieTNF-a agents have revolutionized therapy of Ps/PsA, their role in the treatment of LE is less clear. Because the induction of autoantibodies by anti-TNF therapy has been widely documented,8,9 there has been concern for a risk of induction of LE symptoms or development of de novo lupus during treatment with the class of drugs.10,11 In addition to reports of DLE development33-35 and SCLE development,36 cases of drug-induced lupus syndromes and worsening of already-present SLE have been reported in patients taking infliximab, etanercept, and adalimumab.10-12,34,37,38 Pooled data from randomized, placebo-controlled trials for infliximab indicate that patient ANA positivity increased from 29% to 53% with treatment; similarly, anti-dsDNA seroconversion occurred in 14%.11 However, the development of previously undiagnosed, severe systemic LE with anti-TNF agents is relatively uncommon, and the autoantibodies induced

No. of discontinuations owing to poor efficacy (% of total)

mycophenolate

7 0 7 3 2 2 0 1 0

(21.2) (0.0) (21.8) (21.4) (33.3) (18.2) (0.0) (20.0) (0.0)

mofetil,

leflunomide,

No. of discontinuations owing to adverse effect(s) (% of total)

9 4 12 5 3 3 1 2 0

(27.3) (66.7) (37.5) (35.7) (50.0) (27.3) (100.0) (40.0) (0.0)

sulfasalazine,

and

are usually of class immunoglobulin (Ig) M and are not pathogenic.39 Postmarketing studies have confirmed the low incidence of antieTNF-aeinduced lupus, reporting rates of 0.19% to 0.22% for infliximab, 0.18% for etanercept, and 0.10% for adalimumab.40 In our review, we similarly found a low risk of lupus flares (0.92% per patient-year) with the use of TNF-a inhibitors in patients with LE. Recently, the Th17/IL-17/IL-23 axis has been implicated in LE pathogenesis; elevated IL-17 and IL-23 levels have been found in the serum of SLE patients, and Th17 cells are present in abnormally high quantity in kidney biopsies of lupus nephritis.1,41 Further, IL-12 levels are significantly elevated in the serum of patients with SLE and stimulate the production of interferon gamma by Th1 lymphocytes, triggering subsequent glomerulonephritis and vasculitis.42 Use of ustekinumab leads to rapid, clinically significant improvements in moderate-to-severe chronic plaque Ps and in arthritic symptoms and radiographic progression of PsA.43-45 Although excellent support for its use in Ps and PsA exists, ustekinumab has rarely been used for LE. We report improvements in cutaneous disease (both psoriatic and LE related) and in SLE symptoms (specifically, oral ulcerations, anemia or thrombocytopenia, and lupus arthritis) after use of ustekinumab therapy in 4 patients. Abatacept is a fusion protein that targets cytotoxic T-lymphocyte antigen 4, selectively modulating the CD28eCD80/86 signaling pathway, and thereby inhibiting costimulatory T-cell activation.46 It is approved for use in rheumatoid arthritis and has shown efficacy in the treatment of PsA.47 Initial studies of abatacept use in SLE have been variable.48,49 All 3 patients in our review who

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Table II. Characteristics of patients with coexistent Ps*/PsA and LE Characteristic

Mean age, y Gender Female Male Race or ethnicity White Black Hispanic Asian or Pacific Islander Other Unavailable Ps by subtype Cutaneous Psy Plaquey Guttatey Intertriginousy Palmoplantary Pustulary PsA Cutaneous Psy alone PsA alone Both Ps and PsA LE by primary subtype SLE DLE SCLE SLE alone DLE alone SCLE alone Both SLE and DLE Both SLE and SCLE Both DLE and SCLE Other Cutaneous photosensitivity Baseline ANAz Baseline anti-dsDNA positivityz Mean age at diagnosis of psoriatic disorder, y Mean age at diagnosis of lupus, y Patients diagnosed with psoriatic disorder first Latency period between diagnoses, y Patients diagnosed with lupus first Latency period between diagnoses, y

No.

%

56.0 84 12

87.5 12.5

74 8 8 5 0 4

77.1 8.3 8.3 5.2 0.0 4.2

87 81 7 10 2 4 50 46 9 41

90.6 84.3 7.3 10.4 2.1 4.2 52.1 47.9 9.4 42.7

86 21 9 68 6 1 12 5 3

89.6 21.9 9.4 70.8 6.3 1.0 12.5 5.2 3.1

38 87 60 43 39 43 9.2 53 18.4

39.6 90.6 62.5 — — 45 — 55 —

ANA, Antinuclear antigen; dsDNA, double-stranded DNA; DLE, discoid lupus erythematosus; LE, lupus erythematosus; Ps, psoriasis; PsA, psoriatic arthritis; SCLE, subcutaneous lupus erythematosus; SLE, systemic lupus erythematosus. *Patients with cutaneous Ps alone, PsA alone, or both, were included. y Numbers for Ps subtypes refer to the number of diagnoses, not the number of patients. Patients with more than one Ps subtype (chronic plaque, palmoplantar, guttate, intertriginous, pustular) were included in each appropriate group. z Serologic positivity determined at the time of diagnosis of LE and before any biologic use.

received abatacept were continuing the medication as a maintenance regimen at the time of writing. Of note, these patients had reported improvements in SLE symptoms, including cutaneous photosensitivity, oral ulceration, hematologic abnormalities, and arthritis. Unfortunately, the severity of psoriatic disease was not well documented in these patients; we suspect these patients had relatively mild psoriatic disease, given the paucity of clinical data on abatacept’s efficacy in plaque Ps. Limitations to our review include a small sample size, a relatively short period of follow-up, and the recent availability of the newer biological agents. Number of cases may have been slightly increased by the use of ICD-9 codes and clinical documentation for diagnostic criteria leading to study inclusion versus histologic diagnosis of disease. Available data did not allow for analysis of disease activity measures (eg, Psoriasis Area and Severity Index or SLE Disease Activity Index) with each medication group. Further, we were unable to collect data on the length of treatment and treatment outcomes with methotrexate, cyclosporine, and other nonbiological systemic agents, which were used by 26% of patients in this group. Finally, some cases of PsA may have been misdiagnosed false-positives and true cases of lupus arthritis.

CONCLUSION The pathophysiology of Ps/PsA arthritis occurring with SLE, DLE, or SCLE, although uncommon, may be related to the diseases’ shared pathophysiology of the Th17 and Th1 immune pathways. Coexistent disease is rare but often difficult to treat, sometimes requiring multiple immunosuppressive medications with cumulative long-term toxicities. We report on a predominantly white, female population with a higher incidence of cutaneous photosensitivity and PsA than would be expected in the presence of either Ps/PsA or LE alone. In total, 25 of our patients had received a biological agent, either an antieTNF-a agent, ustekinumab, or abatacept, with variable success. We found a low (0.92%) incidence of clinical flare of LE per patient-year of treatment with TNF-a inhibitor use. Although valid, concern for de novo development of LE or aggravation of LE disease should not preclude consideration of the TNF-a inhibitors in the patient with difficult-to-treat coexistent Ps and LE who has severe cutaneous disease refractory to other therapies. Ustekinumab and abatacept may be

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Table III. Biological agent use among patients with coexistent Ps/PsA and LE Age/gender/ ethnicity

LE subtype

1 2 3 4 5 6* 7 8 9 10* 11* 12 13 14 15 16 17

35/M/H 76/F/W 51/F/B 45/F/W 53/F/W 70/F/W 48/F/W 41/F/W 45/F/W 48/F/W 36/F/W 43F/W 68/F/W 38/F/A 70/F/W 37/F/H 51/F/W

DLE SLE, DLE SLE SLE SLE SLE SLE SLE SLE SLE SLE SLE DLE SLE SLE SLE SLE

18y

25/F/A

SLE

19*

49/F/W

SLE

20

33/M/B

SLE

21*

59/M/W

SLE

22

55/F/W

SLE

23

45/F/W

SLE

24

38/F/W

SLE

25*

45/F/W

SLE

Patient no.

Biological medication received

Duration of medication use (mo)

E E E E E E E Ad Ad I I U U U Ab Ab Ad U E Ad I U E I Ad Ad I E Ad E Ad E Ad I U C E Ad Ab E Ad

12, ongoing 132, ongoing 22 52 12, ongoing 12, ongoing 72, ongoing 24 36, ongoing 7 13 24, ongoing 36, ongoing 12 60, ongoing 78, ongoing 6 5, ongoing 21 39 2 1, ongoing 4 11 36, ongoing 6 36, ongoing 4 70 44 23 25 80 41 24 15 13 33 12, ongoing 23 66

Reason for discontinuation of medication

AE: acute bronchitis

AE: migraine AE: IV site reaction Poor efficacy

AE: Ps flare

Current medication regimen

E E MTX None (remission) E E E MTX Ad P None U U Cso Ab Ab U

Poor efficacy Poor efficacy AE: lupus flare

U

AE: pneumonia Poor efficacy

Ad

I AE: Ps flare AE: frequent URIs AE: frequent URIs Poor efficacy AE: uveitis Poor efficacy AE: cellulitis AE: uveitis Poor efficacy Poor efficacy Poor efficacy

None (remission) MTX None

Ab

None (remission)

Twenty-five patients with coexistent Ps/PsA and LE were treated with biologics, including 16 patients treated with a single biologic, and 9 patients that were treated multiple biologics (average, 1.64 biologics per patients). Twenty-two patients had underlying SLE, 2 had DLE, and 1 had both SLE and DLE. One patient experienced a clinical flare of SLE, and 6 patients experienced a seroconversion of anti-dsDNA or ANA owing to treatment with biologics. Four of these seroconversions were experienced with etanercept, and 2 with infliximab. Ab, abatacept; Ad, adalimumab; AE, adverse effect; B, black; C, certolizumab; Cso, cyclosporine; E, etanercept; F, female; H, Hispanic/Latino; I, infliximab; M, male; MTX, methotrexate; NA, not available; P, prednisone; U, ustekinumab; URI, upper respiratory infection; W, white. *Patients who experienced seroconversion. y Patients who experienced clinical flare of LE.

promising agents for treatment of LE and Ps/PsA and require further study in patients with LE and in those with coexistent Ps/PsA and LE.

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