Rowell’s Syndrome ICD-9 695.4

Are You Confident of the Diagnosis?

What you should be alert for in the history

Rowell’s syndrome is a rare entity that was initially characterized by Rowell in 1963 as the coexistence of discoid lupus erythematosus (DLE) and erythema multiforme (EM). The initial cohort of patients also had positive ANA, positive rheumatoid factor and precipitation of a saline extract of human skin (now analogous to anti-Ro/anti-La). Since then, cases reported in the literature have been called Rowell’s syndrome, but many did not fit this initial criteria.

As a result, there is controversy as to whether Rowell’s is a separate clinical entity, or rather a coincidental occurrence of lupus erythematosus (LE) and EM. Furthermore, some cases showed that the biopsy of an EM-like lesion showed LE and not EM. In such cases, authors concluded that LE can have a variable presentation that may include EM-like lesions.

Characteristic findings on physical examination

In order to better define this syndrome, a new set of criteria for diagnosis has been proposed. To establish a diagnosis of Rowell’s syndrome, all major and one minor criterion must be present.

Major Criterion:

Presence of systemic lupus erythematosus (SLE), DLE and/or subacute cutaneous lupus erythematosus lesions (SCLE)

Expected results of diagnostic studies

On histopathology, the EM-like lesions show focal keratinocyte necrosis, vacuolar changes at the basal layer, papillary dermal edema and predominately superficial perivascular or interface lymphocytic infiltrate, which is consistent with erythema multiforme.

Who is at Risk for Developing this Disease?

Similar to other forms of cutaneous lupus erythematosus (CLE), Rowell’s syndrome is more common in females. Age of onset can range from 20-70 years old. The majority of cases had a diagnosis of lupus preceding the development of Rowell’s syndrome by months to years.

What is the Cause of the Disease?

Pathophysiology

CLE, including Rowell’s syndrome, is an autoimmune disease felt to be due to an interplay of genetics, hormones and environment. Given that lupus is more common in women of childbearing age, estrogen is felt to be a cause.

In terms of genetics, genes encoding cytokines, cytokine receptors, adhesion molecules and apoptosis genes are felt to contribute to the development of LE. The most well-known environmental trigger of SLE and most CLE lesions, particularly DLE, is ultraviolet light. UV light induces pro-inflammatory cytokines, chemokines and adhesion molecules that eventually lead to tissue injury. Both UVB and/or UVA can contribute to induction of skin lesions. The specific role of UV light in EM-like lesions has not been discussed.

There are no autoantibodies associated with Rowell syndrome. Skin direct immunofluorescence testing can detect deposition of immunoglobulins and complement at the dermal-epidermal junction in patients with specific CLE lesions, but not in EM-like lesions of Rowell syndrome.

Overall, the complex inflammatory cascade between necrosis, apoptosis, autoantibodies, T and B cells, and vascular changes leads to the development of cutaneous LE. However, a complete understanding of the pathophysiology of cutaneous LE is not known.

Systemic Implications and Complications

Rowell’s syndrome has been associated with SLE, but the exact risk for development is not clear. Nonetheless, screening for underlying systemic LE with clinical history, physical exam and laboratory evaluation to assess for central nervous system, renal, hematologic, pulmonary and cardiovascular system involvement is warranted in all patients newly presenting with cutaneous LE.

An initial ANA, complete blood count and urinalysis is sufficient for those without other symptoms. Given that an ANA assay has a 99% negative predictive value, it is rare for a patient with SLE to have a negative ANA. This is also a more cost-effective way to use specific autoantibody tests.

If the ANA is elevated (more than or equal to 1:160) or a patient has symptoms suggestive of systemic lupus, further testing is warranted. These may include anti-dsDNA, anti-Smith, complete blood count with differential, creatinine, albumin, total protein, erythrocyte sedimentation rate, urinalysis, and complements (C3,C4).

As discussed above, EM lesions together with mucosal erosions should prompt a consideration of HSV-induced erythema multiforme. A Tzanck smear and viral culture should be performed.

Treatment Options

Treatment options are summarized in the Table I.

Table I.

Medical
• Sun protection and avoidance
• Broad spectrum UVA and UVB sunscreen protection
• Smoking cessation
Topical
• Topical steroids, Class I or II (lower strength for the face)
• Topical calcineurin inhibitors with or without topical steroid
• Tacrolimus 0.1% ointment
• Pimecrolimus 1% cream
Systemic
• Hydroxychloroquine 6.0-6.5mg/kg ideal body weight (IBW)
• Hydroxychloroquine + quinacrine 100mg daily
• Chloroquine ≤3.5mg/kg IBW +/- Quinacrine 100mg daily
• Prednisone 0.5-0.75mg/kg/day
• Dapsone 50-150 mg/day
• Methotrexate 5-25mg/week
• Mycophenolate Mofetil 2-3gm/day
• Azathioprine 1-2.5mg/kg/day IBW
• Cyclosporine 3-5mg/kg/day

Optimal Therapeutic Approach for this Disease

The therapeutic regimen and responsiveness in Rowell’s syndrome are similar to those of SLE or DLE that appear alone. Overall, EM-like lesions in Rowell’s syndrome respond well to prednisone and antimalarial therapies. Given the eruptive nature of these EM-like lesions, simultaneous induction of mid to high dose prednisone and antimalarials is recommended.

If antimalarials are ineffective, the use of dapsone has been successful in some cases. If tapering steroids is difficult due to rapid recurrence, the use of immunosuppressives like methotrexate (MTX), mycophenolate mofetil (MMF), or azathioprine may be used as a steroid-sparing agent together with antimalarials.

Sun avoidance and protection with the use of broad spectrum sunscreen that covers both UVA and UVB ranges should be discussed with all patients with CLE, including those with Rowell syndrome given the coexistence with DLE, SCLE or SLE.

Cigarette smokers are found to have more severe CLE disease. Antimalarials may be less effective in those patients that smoke. As a result, all patients with CLE should begin a smoking cessation program.

Topical Therapy

Topical therapy can be used in combination with systemic therapies. The effectiveness of topical steroids and calcineurin inhibitors in Rowell syndrome is unknown. However, for limited, focal disease, it should be tried prior to systemic medications. Combining topical steroids, Class I or II, and calcineurin inhibitors may provide an added benefit. Lower potency topical steroids (Class V or VI) can be used for the face with or without topical calcineurin inhibitors.

Antimalarials

Antimalarials are recommended as first line systemic therapy for cutaneous and systemic LE given its effectiveness in prevention and treatment of symptoms, such as photosensitivity, acute malar rash, DLE, oral ulcers, alopecia, arthritis, pleuritis, and pericarditis. Rowell’s syndrome is responsive to antimalarials.

Hydroxychloroquine is the treatment of choice over chloroquine, given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200mg-400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg IBW/day. Antimalarials take 2-3 months for improvement to be noticed and up to 6 months for a complete response.

After 8-12 weeks, if improvement is not satisfactory, quinacrine 100mg daily may be added. Quinacrine can only be obtained at a compounding pharmacy. It may cause yellow discoloration of the skin.

If the combination of hydroxychloroquine and quinacrine has a complete response after 6 months, changing to chloroquine plus quinacrine is an option. Chloroquine is typically started at a dose of 250mg 5-7 days a week and should not exceed 3.5mg/kg IBW/day. In Rowell’s syndrome, it is recommended to begin antimalarial therapy together with prednisone for a more rapid resolution.

The lowest possible effective dose should be used for maintenance therapy. Antimalarials may be used safely for long periods of time.

The recommended doses listed in the table above are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with antimalarials may be irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye exams every 6 months and with chloroquine every 4 months. The eye exam should include visual acuity, visual fields, and fundoscopic exam.

Patients with a history of retinopathy should not be given hydroxychloroquine or chloroquine. Patients who get a drug exanthem with hydroxychloroquine may be able to tolerate chloroquine, while an urticarial reaction from hydroxychloroquine would preclude use of chloroquine. Other side effects include nausea, headaches, myopathy, and bluish-gray hyperpigmentation of the skin.

In addition to a baseline eye exam, a CBC and liver function test is recommended at baseline and after 1 month of use.

Prednisone

Unlike the other subsets of CLE, prednisone has commonly been used to treat Rowell’s syndrome. The reason is that these lesions tend not to be as chronic and recurrent as many of the other CLE lesions. Typically, prednisone has been used at dosages of 0.5mg/kg-0.75mg/kg daily in combination with antimalarials, or immunosuppressive agents discussed below. Prednisone should be used alone, as lesions may recur once prednisone is stopped.

The well-known side effects of prednisone include weight gain, fluid retention, psychiatric disturbances, hypertension, and hyperglycemia. Osteoporosis, myopathy and cushingoid changes are additional adverse reactions that can be avoided with short therapeutic courses. Of note, osteonecrosis can occur with short courses of therapy.

Dapsone

Dapsone has been shown, in a few cases, to be effective in Rowell’s syndrome. In cases refractory to antimalarials, dapsone may be an adjunctive treatment in SCLE at dosages of 25-150mg daily. A starting dose of 50mg can be increased by 25mg weekly to 150mg a day if lab tests permit. Maintenance doses as low as 50mg may be used once disease is stable. Dapsone has been used successfully in the setting of SCLE, and hypocomplementemia with urticarial vasculitis.

Severe adverse effects are related to hematotoxicity and can be seen as hemolytic anemia and/or methemoglobinemia. Both are dose dependent and occur, to some degree, in all patients that take dapsone. A glucose-6-phosphate dehydrogenase (G6PD) level should be tested in all patients being considered for dapsone, as the risk of hemolytic anemia is significantly increased if there is a deficiency.

Peripheral motor neuropathy can be observed and typically resolves completely after dose reduction or drug discontinuation. Agranulocytosis is a serious, idiosyncratic adverse effect of dapsone. Patients normally will experience a 2gm/dl drop in hemoglobin, but greater drops or drops below 10gm/dl necessitate an adjustment of dose. Patients may experience a clinically unimportant drop in their 02 saturation, which is not routinely monitored.

Baseline laboratory tests include complete blood count (CBC) with differential, complete metabolic panel (liver function tests and renal function), urinalysis and G6PD level. During each visit assess peripheral motor neuropathy, CBC with differential every 1 week while the dose is being increased, then monthly for 3 months, and every 3 months thereafter. A complete metabolic panel can be done every 3 months.

The vast majority of EM-like lesions respond to antimalarials together with oral and topical steroids. However, for severe disease and those cases that have other forms of cutaneous and/or SLE, a steroid-sparing immunosuppressant should be initiated. Limited to no data exists for their use in Rowell’s syndrome. Azathioprine has the most data in the literature with use in Rowell’s syndrome. However, given its great toxicity profile, it is reasonable to use MTX or MMF in its place.

Methotrexate

Methotrexate in LE can be used in doses of 5-25mg weekly. MTX typically takes 3-4 weeks for clinical improvement. A typical test dose is 5mg, and then an increase of 5mg weekly is given up to the dose needed to control symptoms. The lowest possible maintenance dose needed to control disease should be used. Doses as low as 5mg a week have been successfully used to maintain clinical remission.

A potential for hepatotoxicity, with long-term use, and pulmonary toxicity is an important consideration. Patients who drink alcohol should not receive methotrexate, and underlying viral hepatitis, obesity and diabetes are associated with an increased risk of hepatotoxicity, including liver fibrosis.

Bone marrow suppression is a severe adverse reaction. Risk factors for this side effect include drug interactions (TMP/SMX and NSAIDS), renal insufficiency, older age (over 65 years old) and no folate supplementation. Frequent CBCs are important to monitor for this adverse reaction and all patients should be on folate supplementation.

Baseline laboratory tests should include CBC, CMP (liver and renal function), hepatitis B and C serologies, and HIV testing. After the first dose of methotrexate, CBC and liver function labs should be done in 1 week. If laboratory studies are normal, repeat testing of CBC and liver function, every week as the dose is increased and then monthly thereafter for 3 months is warranted.

After a year of a stable dose with no serious toxicity, blood monitoring can decrease to every 3 months. Renal function can be evaluated once a year, or sooner if renal dysfunction is suspected. Weekly intramuscular injections may improve gastrointestinal (GI) intolerance due to oral methotrexate.

Mycophenolate mofetil

MMF is well tolerated and has been shown to be effective in cutaneous LE and systemic LE. The most common adverse reaction from this therapeutic is GI side effects including nausea, vomiting, diarrhea, and abdominal cramps. These symptoms are typically dose-dependent and may be avoided by starting at a lower dose.

In patients with GI side effects, one can start with 500mg once or twice a day and then titrate the dose up, per tolerability every 2-4 weeks to a goal dose of 2-3gm daily. As with any immunosuppressant, MMF can increase the risk of infections. Less common side effects include myelosuppression and transaminitis. MMF typically takes approximately 4 weeks to take effect.

Baseline laboratory tests include CBC with differential and liver function. Labs should be checked 2 weeks after starting therapy, and 2 weeks after increases in doses. Monthly CBC and liver function tests for the first year, then every 3 months, is recommended. Maintenance doses of 1.5-3gm a day can be used safely.

Azathioprine

Azathioprine is an immunosuppressant that has been extensively studied in LE as a steroid sparing agent. An initial dose of 50mg a day is suggested to determine acute toxicity/sensitivity. The dose can be increased by 25mg every 2 weeks with a goal of achieving a range between 2-3mg/kg daily. In CLE, azathioprine doses of 100-150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4-8 weeks. The maintenance dose can range from 50-150mg daily and may be continued for years.

Side effects include GI symptoms of nausea, vomiting and abdominal cramping. Pancreatitis and hepatotoxicity have also been reported. Hypersensitivity reaction, aseptic meningitis and increased cancer risk are also known adverse reactions. Flu-like symptoms may occur within the first 2 weeks of use.

Prior to the use of azathioprine, a thiopurine methyltransferase (TPMT) enzyme level can be done, particularly if doses above 50mg a day are used initially. Low levels increase the risk of myelosuppression and potentially fatal neutropenia. CBC and liver function tests should be performed every 2 weeks while the dose is being adjusted, then every month for the first year, and then every 3 months.

Cyclosporine

There is only one report of utilizing cyclosporine in the literature for Rowell syndrome, which was successful in a 63-year-old whose lesions were unresponsive to topical and systemic steroids.

Patient Management

All patients newly diagnosed with cutaneous LE should be counseled on the specific disease course. The risk of scarring and dypigmentation is rare with EM-like lesions in Rowell’s syndrome, but may occur with chronic CLE or SCLE lesions. The vast majority of patients with Rowell’s syndrome have disease that primarily affects the skin. These patients should be reassured that their disease progression to SLE is low.

The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. All patients must be counseled on sun avoidance and protection, including avoidance of artificial tanning beds and photosensitizing medications. On a similar note, the role of smoking in disease severity must be stressed at the initial visit. All patients should be encouraged to stop smoking and should begin a smoking cessation program.

Mainstay therapies for the majority of patients with Rowell’s syndrome include topical therapies and antimalarials together with short courses of prednisone. Oral prednisone is fraught with side effects, thus the use should be minimized and all side effects discussed with the patient. Patients with widespread disease or concomitant SLE may need therapies that carry even higher side effect risks. It is important to discuss all side effects and monitoring guidelines prior to initiating therapy.

After antimalarials and oral steroids, there is no one agent that is superior in the treatment of EM-like lesions in Rowell’s syndrome. Thus, when ascending the therapeutic ladder, individualizing therapy for each patient based on their co-morbidities is necessary. Furthermore, after clearance of EM-like lesions in Rowell’s syndrome, therapies should be reduced to the lowest effective dose, or discontinued.

Unusual Clinical Scenarios to Consider in Patient Management

For targetoid lesions with associated vesicles or bullae, or treatment strategies for pregnant women, see the chapter on systemic lupus erythematosus.

What is the Evidence?

Rowell, NR, Beck, JS, Anderson, JR. “Lupus erythematosus and erythema multiforme-like lesions. A syndrome with characteristic immunological abnormalities”. Arch Dermatol. vol. 88. 1963. pp. 176-80. (Rowell’s initial case descriptions and proposed diagnostic criteria for Rowell’s syndrome.)

Zeitouni, NC, Funaro, D, Cloutier, RA, Gagne, E, Claveau, J. “Redefining Rowell’s syndrome”. Br J Dermatol. vol. 142. 2000. pp. 343-6. (The authors discuss the inconsistent diagnostic features of Rowell’s syndrome in the literature and propose major and minor criteria to assist with making a diagnosis.)

Marzano, AV, Berti, E, Gasparini, G, Caputo, R. “Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like lesions”. Br J of Dermatol. vol. 141. 1999. pp. 720-4. (A case of Rowell’s syndrome in a woman with lupus erythematosus and long-standing vesiculobullous EM- like lesions with positive rheumatoid factor, anti-Ro antibody, and antiphospholipid syndrome.)

Khandpur, S, Das, S, Singh, MK. “Rowell’s syndrome revisited: report of two cases from India”. Int J Dermatol. vol. 44. 2005. pp. 545-549. (Two cases of Rowell’s syndrome using the major and minor criteria are discussed. The article also reviews the literature on Rowell’s syndrome.)

Shadid, NH, Thissen, CACB, van Marion, AMW, Poblete-Gutierrez, P, Frank, J. “Lupus erythematosus associated with erythema multiforme: Rowell’s syndrome”. Int J Dermatol. vol. 46. 2007. pp. 30-32. (A case of Rowell’s syndrome and the ongoing debate about whether this syndrome represents a separate disease entity is discussed.)

Parodi, A, Drago, EF, Varaldo, G, Rebora, A. “Rowell’s syndrome. Report of a case”. J Am Acad Dermatol. vol. 21. 1989. pp. 374-7. (A report of a case that resembles the original description of Rowell’s syndrome. The article also discusses the difference of coincidental associations of lupus erythematosus and erythema multiforme and Rowell’s syndrome.)

Müller, CSL, Hinterberger, LR, Vogt, T. “Successful treatment of Rowell syndrome using oral cyclosporine A”. Int J Dermatol. vol. 50. 2011. pp. 1020-22. (A case report of Rowell syndrome in a 63-year-old whose lesions responded quickly to cyclosporine.)

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