Combination antimalarials in the treatment of cutaneous dermatomyositis: a retrospective study

OBJECTIVE: To observe whether the use of antimalarials in combination resulted in significant improvement in the cutaneous signs and symptoms of patients with dermatomyositis who did not otherwise respond to the use of single-agent antimalarial therapy. DESIGN: Retrospective case series of 17 patients treated between January 1, 1991, and December 31, 2002. SETTING: An ambulatory medical dermatology clinic in an academic center.Patients Patients had adult-onset dermatomyositis with predominantly cutaneous symptoms and a follow-up period at our clinic of at least 6 months. Cases in which it was not possible to assess the effect of treatment on cutaneous symptoms were not included.Intervention Treatment regimens varied and included the use of antimalarials, prednisone, methotrexate, and other medications. MAIN OUTCOME MEASURES: Physician-observed and patient-reported improvement based on erythema, pruritus, and extent of affected skin. RESULTS: Seven of 17 patients experienced at least near clearance in cutaneous symptoms with the use of antimalarial therapy alone: 4 of these patients required combination therapy (hydroxychloroquine sulfate-quinacrine hydrochloride or chloroquine phosphate-quinacrine), while 3 of them responded well to antimalarial monotherapy. The median time required to reach the response milestones on the final working therapeutic regimen was 3 months (mean, 4.8 months; range, 2-14 months). Six patients did not respond significantly to any type of therapy, including nonantimalarials. CONCLUSION: Our experience suggests that a significant subgroup of patients whose skin lesions have been unresponsive to a single antimalarial benefit from combination therapy with hydroxychloroquine and quinacrine or chloroquine and quinacrine, but controlled clinical trials are warranted to assess the extent of benefit.     

Adverse cutaneous reactions to hydroxychloroquine are more common in patients with dermatomyositis than in patients with cutaneous lupus erythematosus

BACKGROUND: Hydroxychloroquine sulfate and other antimalarial drugs have been used successfully as adjunctive therapy for patients with cutaneous lesions of dermatomyositis over the past 20 years. An increased incidence of cutaneous reactions to hydroxychloroquine has been postulated to occur in patients with dermatomyositis. OBJECTIVE: To determine if adverse cutaneous eruptions due to hydroxychloroquine are more common in patients with dermatomyositis than in those with cutaneous lupus erythematosus. DESIGN: Retrospective, age-, sex-, and race-matched case-control study. SETTING: University-affiliated practice. PATIENTS: The study comprised 42 patients with dermatomyositis (39 adults) and 39 age-, sex-, and race-matched adult patients with lupus erythematosus. MAIN OUTCOME MEASURES: Presence or absence of documented drug eruption due to hydroxychloroquine exposure. RESULTS: Of 39 patients, 12 (31%) with dermatomyositis developed a cutaneous reaction to hydroxychloroquine. Among age-, sex-, and race-matched patients with cutaneous lupus erythematosus, only 1 developed a cutaneous reaction to hydroxychloroquine. None of the reactions observed in our patients resulted in serious morbidity or mortality. Additionally, 4 patients with dermatomyositis who reacted to hydroxychloroquine were treated with oral chloroquine phosphate, 2 of whom also reacted to chloroquine phosphate. CONCLUSIONS: When contemplating antimalarial therapy for dermatomyositis, both the physician and the patient should recognize that non-life-threatening cutaneous reactions may occur in approximately one third of patients and that perhaps one half of those who react to hydroxychloroquine will also react to chloroquine.     

Topical FK506 (tacrolimus) therapy for facial erythematous lesions of cutaneous lupus erythematosus and dermatomyositis.

Tacrolimus is a prototype of a class of topical immunosuppressive agents with great potential for the treatment of inflammatory skin diseases. Topical tacrolimus therapy was applied to facial skin lesions in 11 cases of cutaneous lupus erythematosus (LE) and dermatomyositis. Of the 11 patients, 6 (3 systemic LE, one discoid LE and 2 dermatomyositis) showed a marked regression of their skin lesions after tacrolimus therapy, but 4 patients (3 discoid LE and one dermatomyositis) were resistant to the therapy. A good response was observed for facial erythematous lesions with edematous or telangiectatic changes in systemic LE and dermatomyositis. In discoid LE with typical discoid lesions, tacrolimus brought no improvement. Topical tacrolimus will become a new tool for managing the skin lesions of collagen diseases.     

Dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris

OBJECTIVE: To determine the effect of dapsone on glucocorticoid-dependent patients with active or maintenance-phase pemphigus vulgaris. DESIGN: Retrospective study of consecutive patients treated with dapsone. SETTING: University of Pennsylvania, Philadelphia (a tertiary referral hospital).Patients We observed 9 consecutive adult patients with pemphigus vulgaris being treated with immunosuppressants who were unable to taper prednisone use without abrupt worsening of their disease.Interventions Dapsone treatment added to prednisone and other immunosuppressive therapy.Main Outcome Measure Steroid dosage. RESULTS: All patients were unable to taper their steroid dose during the 3 months prior to the initiation of dapsone therapy or had active disease that was not well controlled by prednisone prior to dapsone treatment. With the exception of 1 patient with uncontrolled disease, all 9 patients were able to taper their steroid dose below the adrenal replacement level during dapsone treatment. Maintenance-phase patients taking 15 mg/d or more of prednisone (n = 5) experienced a mean +/- SEM drop of 67% +/- 7.1% in prednisone dose by 4 months of maximal dapsone treatment and an 84% +/- 3.5% drop in prednisone dose after 8 months of dapsone treatment. CONCLUSIONS: These retrospective study findings suggest that dapsone reduces steroid dependence in patients with pemphigus vulgaris, provided they are in the maintenance phase of their disease. These data support the need for a prospective, randomized trial to confirm these findings.     

Chronic cutaneous varicella zoster virus infection complicating dermatomyositis

Chronic cutaneous varicella zoster virus (VZV) infection has not been previously reported or characterized as a complication of dermatomyositis. Two patients with non‐malignancy‐associated dermatomyositis, treated with long‐term prednisone and methotrexate, developed persistent, painless ulcers ultimately established to be secondary to chronic VZV. The absence of pain or a history suggestive of acute VZV, and the lack of characteristic histopathology, resulted in a lengthy delay in diagnosis. Polymerase chain reaction and tissue immunohistochemistry were positive for VZV, and treatment with valacyclovir resulted in complete clearance. Diagnostic testing for VZV should thus be considered in the evaluation of ulcerative lesions in patients with dermatomyositis. The increased incidence of acute VZV in combination with the nature and duration of immunosuppressive treatment in this patient population may be contributory.     

Relapse of dermatomyositis after 10 years in remission following curative surgical treatment of lung cancer

A 55-year-old woman with dermatomyositis and small cell lung cancer was successfully treated with surgery followed by combination chemotherapy in 1987. She had been in remission without further immunosuppressive therapy for 10 years. However, myositis with cutaneous manifestations specific for dermatomyositis relapsed when the patient was 69 years old. Intensive examinations revealed no neoplasm, and she responded to a moderate dose of systemic corticosteroids. This case suggests a long-lasting autoimmune abnormality in dermatomyositis and that a neoplasm is an important factor in eliciting an occult dermatomyositis.     

Psoralen plus ultraviolet-A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease

BACKGROUND: Cutaneous chronic graft versus host disease (GVHD) is a severe complication following allogeneic stem cell (PBSCT) and bone marrow transplantation (BMT). Immunosuppressive therapy consists of prednisone, cyclosporine-A, azathioprine or mycophenolate mofetil (MMF). Treatment of patients refractory to immunosuppression represents a major problem. METHODS: We report six patients suffering from severe chronic GVHD of the skin who did not respond to immunosuppressive therapy or relapsed after reduction of glucocorticosteroids. Patients were treated with psoralen plus ultraviolet (PUVA)-bath photochemotherapy three times weekly following a standardized treatment protocol under continued treatment with prednisone and/or MMF. One patient was additionally pretreated with ultraviolet-A1 (UV-Al). RESULTS: After a median of 14, 5 treatment sessions, skin lesions improved. Out of six patients, three showed a complete remission. In all patients, systemic immunosuppressive therapy could be reduced. In sclerodermic lesions, skin thickness returned to the levels of normal skin after 25 treatments confirmed by 20 MHz ultrasound evaluation. In a follow-up ranging from 2 to 21 months (median 10, 3 months), skin conditions remained stable. CONCLUSION: Psoralen plus ultraviolet-A-bath represents an effective adjunct treatment option for extensive chronic and sclerodermic cutaneous GVHD offered by dermatologists. This is of high interest in patients suffering from cutaneous GVHD resistant to conventional immunosuppressive therapy and should be included to the menu of topical treatment options for chronic cutaneous GVHD.     

Rituximab for the treatment of the skin manifestations of dermatomyositis: a report of 3 cases

Three patients suffering from classic dermatomyositis (juvenile and adult-onset) with prominent recalcitrant skin manifestations are described. All patients demonstrated good control of muscle symptoms on immunosuppressive medications, but their cutaneous disease persisted despite treatment with at least 4 different systemic treatments and topical agents. They were given rituximab, a monoclonal anti-CD20 antibody, achieving a response with minimal side effects. We document our experience with this medication for the cutaneous lesions of dermatomyositis.     

A causal role for parvovirus B19 infection in adult dermatomyositis and other autoimmune syndromes

BACKGROUND: Infection with parvovirus B19 (B19) has been associated with connective tissue disease (CTD) stigmata, namely, a systemic lupus erythematosus (SLE)-like illness, seronegative polyarthritis resembling rheumatoid arthritis, and vasculitis. The dermatopathology and pathogenetic basis of such B19-associated CTD-like syndromes have not been elucidated. OBJECTIVE: We attempted to document persistence of the B19 genome in skin lesions of 7 patients with CTD-like symptomatology following B19 infection and to correlate systemic manifestations to dermatopathological findings. METHOD: In 7 prospectively encountered patients in whom history, clinical signs and/or serology supported a diagnosis of CTD in the setting of B19 infection, dermatopathological and clinical features were correlated. Parvovirus B19 viral genome was sought in skin tissue using the polymerase chain reaction (PCR). RESULTS: Two patients had clinical features diagnostic of myopathic dermatomyositis (DM), 1 of whom is still symptomatic 1.5 years after the onset of her illness, and the other has had typical clinical features of DM for a duration of 3.5 years. A 3rd patient with SLE remains symptomatic 4 years after the onset of her illness. A 4th patient has persistent seronegative symmetrical polyarthritis of 6 years' duration and cutaneous lesions of granuloma annulare (GA). The 5th patient has a 1.5-year history of debilitating polyarthritis and cutaneous lesions with overlap features of DM and subacute cutaneous LE (SCLE). The 6th patient has had a persistent folliculocentric necrotizing vasculitis for 3 years. The 7th patient has a 1-year history of microscopic polyarteritis nodosa (PAN) with cutaneous vasculitis and persistent active renal disease. In 4 patients, exposure to children with fifth disease immediately preceded the onset of their CTD. Parvovirus B19 infection was documented serologically in 6 patients with antibodies of IgG subclass in 6 and of IgM subclass in 1. Four of 6 patients questioned had a history of atopy. Skin biopsies from patients with clinical features of SLE or DM demonstrated an interface dermatitis with dermal mucinosis. A necrotizing vasculitis with epithelial pustulation was seen in 2 patients. Interstitial GA-like infiltrates were seen in 5 cases. Immunofluorescent (IF) testing revealed a positive lupus band test (LBT) and epidermal nuclear and vascular staining for IgG and C5b-9 in the SLE patient. One DM patient had a negative LBT in concert with C5b-9 deposition along the dermoepidermal junction (DEJ) and within blood vessels while the other showed endomysial vascular Cs5b-9 deposition. In all patients, skin biopsy material contained B19 genome, which was absent in the serum of 4 patients analyzed. Symptomatic relief followed immunosuppressive and immunomodulatory therapy with agents including prednisone, cyclophosphamide, hydroxychloroquine, non-steroidal anti-inflammatory drugs and etanercept, but no patient has had complete symptom resolution. CONCLUSIONS: Persistent B19 infection may be of pathogenetic importance in certain prototypic CTD syndromes, to which underlying immune dysregulation associated with a blunted IgM response to viral antigen may predispose. Anti-viral therapy might be worthy of consideration since traditional immunosuppressive therapy was unsuccessful in our cases.     

Azathioprine. An effective, corticosteroid-sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vasculitis

Azathioprine sodium has been reported to be effective therapy for chronic cutaneous lupus erythematosus (LE) but rarely for chronic cutaneous leukocytoclastic vasculitis (LV). We used azathioprine in the treatment of six patients with cutaneous LE, four of whom had subacute cutaneous (nonscarring) LE and two of whom had chronic cutaneous (scarring, discoid) LE, and six patients with chronic cutaneous LV. The conditions of all patients had been resistant to conventional therapy, and they required long-term oral corticosteroid therapy for control of their disease. Two of the patients with LE had prominent palmar and/or plantar involvement. Three patients with LE had an excellent response to azathioprine, with near complete clearing of the skin lesions, allowing a decrease in prednisone dosage. One patient with LE initially demonstrated significant improvement, but azathioprine therapy had to be discontinued because of pancreatitis. The treatment failed in two patients with LE; one had nausea and the other repeatedly developed a drug-induced fever. Five of the six patients with LV had improved conditions, with complete control of the disease occurring in two patients and partial control in three patients. Azathioprine is effective for some patients with cutaneous LE and chronic cutaneous LV, but it should be reserved for patients with severe disease in whom more conventional treatment fails.     

Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants

BACKGROUND: Immunosuppression for solid organ transplantation is associated with increased incidence of internal and cutaneous malignant tumors, among which skin cancer is the most common. OBJECTIVE: To determine the effects on cutaneous carcinogenesis when stopping therapy with immunosuppressive medications. OBSERVATIONS: We followed the clinical course of 6 solid organ transplant recipients after therapy with immunosuppressant medications was stopped because of allograft failure or unacceptable cutaneous carcinogenesis. Generally, we found that stopping therapy with immunosuppressive medications resulted in deceleration of cutaneous carcinogenesis, resolution of cutaneous verrucae vulgaris, and qualitative improvements in skin condition. Four patients experienced marked improvement; 2 did not. CONCLUSIONS: Cessation of transplant-associated therapy with immunosuppressive medications for patients in whom cutaneous carcinomas developed after transplantation may lead to deceleration of cutaneous carcinogenesis, decreased verrucae, and improved skin quality within 1 to 2 years. Because of the natural variation in skin cancer development and the small number of cases in this series, definitive conclusions require further study.     

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.     

Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus

BACKGROUND: Thalidomide is an anti-inflammatory agent and an immunomodulator that inhibits the production of tumor necrosis factor alpha. It has shown promise as a treatment option for the cutaneous manifestations of lupus erythematosus (LE). OBJECTIVE: To assess the degree of clinical response per subtype of cutaneous lupus, the duration of therapy before documented clinical improvement, and the incidence of adverse effects, including peripheral neuropathy, with low-dose thalidomide therapy at 100 mg daily in the treatment of refractory cutaneous lesions of LE. METHODS: This retrospective medical record review of patients with refractory cutaneous manifestations of LE is one of the largest modern series in the literature. There were 29 patients seen at the Department of Dermatology, Wake Forest University School of Medicine (Winston-Salem, NC), who were unresponsive to conventional agents including antimalarial agents, and who started treatment between 1998 and 2000. Twenty-three patients who took the drug for 1 month or more were included in the analysis. Clinical responses were assessed by the investigators based on statements of improvement listed in the clinic notes and were categorized as "no response," "partial response," and "complete response." Partial response was classified as either 75% or greater or less than 75% improvement. The incidence of adverse effects including peripheral neuropathy was determined. RESULTS: Of the 23 patients, 17 (74%) demonstrated complete resolution of the cutaneous manifestations of LE, whereas 3 patients (13%) demonstrated 75% or greater partial improvement; 3 patients (13%) had less than 75% partial clinical improvement; and 21 patients (91%) who demonstrated a complete or partial response did so within 8 weeks of initiating thalidomide therapy. CONCLUSIONS: Based on the results of this case series, we believe that thalidomide should be given prime consideration as a treatment for antimalarial drug-resistant interface lesions of LE. The design of prospective, randomized, double-blind, placebo-controlled trials for this indication is warranted.     

Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment

BACKGROUND: Severe pemphigus vulgaris (PV) is conventionally treated with high-dose oral prednisone, usually in combination with an immunosuppressive agent (ISA). Some patients experience significant side effects, which are sometimes fatal, from prolonged immunosuppression. OBJECTIVE: Intravenous immunoglobulin (IVIg) was administered to 21 patients with severe cutaneous and mucosal PV who had not responded to the prolonged use of oral prednisone and multiple ISAs. METHODS: A preliminary dose-determination study tested 7 additional volunteers to ascertain the optimal IVIg dose of 2 g/kg per cycle. Parameters to assess clinical outcome were recorded before and after IVIg therapy. Variables tested were highest dose, total dose, and duration of prednisone and ISAs, their side effects, frequency of recurrence and relapse, duration of IVIg therapy, clinical response, induction and duration of remission, number of hospitalizations, total days of hospital stay, and quality of life. RESULTS: Use of IVIg monotherapy resulted in effective control of disease and produced a sustained remission in the 21 patients. The patients became free of lesions and remained so after finishing IVIg therapy. IVIg had a steroid-sparing effect and produced a high quality of life. Serious side effects from the use of IVIg were not observed. IVIg needs to be gradually withdrawn after achievement of clinical control. CONCLUSION: In patients with PV who do not respond to conventional immunosuppressants, IVIg appears to be an effective treatment alternative. Its early use is of significant benefit in patients who may experience life-threatening complications from immunosuppression. IVIg is effective as monotherapy.     

Steroid sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus

Pemphigus foliaceus (PF) is a rare autoimmune cutaneous blistering disease, with only skin involvement. Systemic corticosteroids and immunosuppressive agents are the mainstay of therapy. However, some patients develop multiple side effects to systemic corticosteroids, when they are used in high doses over prolonged periods. In some patients, immunosuppressive agents are not effective or contraindicated. In such patients, alternative treatment modalities are needed. The purpose of this study is to demonstrate the use of intravenous immunoglobulin (IVIg) therapy in seven patients with severe PF, who were steroid-dependent. The following information was recorded in each patient, before and after IVIg therapy initiation: total dose and total duration of prednisone therapy, and number of relapses. In addition, the highest dose and side effects of prednisone therapy, and duration of observation were documented. After the initiation of IVIg treatment, doses of systemic corticosteroids were gradually reduced and eventually discontinued over a mean period of 2.8 months. Thereafter, IVIg was used as monotherapy. A statistically significant difference was noted between pre-IVIg therapy and after the initiation of IVIg therapy in the total dose (p = 0.005), and total duration of prednisone treatment (p = 0.02), and the number of relapses (p = 0.002). In all seven patients, IVIg produced an effective clinical response and demonstrated a steroid-sparing effect. In patients with PF, who are steroid-dependent and in whom use of conventional immunosuppressive agents is contraindicated, IVIg appears a safe and effective agent to induce and maintain a prolonged clinical remission.     

Remission eines iatrogenen Kaposi-Sarkoms bei Myasthenia gravis nach Umstellung der Immunsuppression auf den mTOR-Inhibitor Everolimus

Iatrogenic Kaposi sarcomas (KS) in organ transplant recipients are often treated by switching immunosuppressive therapy to an mTOR inhibitor, such as sirolimus or everolimus, as these have immunosuppressive as well as anti-tumor effects. We report on an 80-year-old male patient who developed a disseminated cutaneous KS during therapy with prednisone and azathioprine for myasthenia gravis. After discontinuation of azathioprine therapy and despite continuing therapy with cortisone, the KS progressed and autoantibody levels against the nicotinic acetylcholine receptor increased. During the administration of everolimus, a long-term near-complete remission of KS and a decrease in autoantibodies took place. This case study illustrates that even in non-organ transplant patients with iatrogenic KS, switching to immunosuppressive therapy using an mTOR inhibitor can be beneficial.     

Isotretinoin for refractory lupus erythematosus

We describe six patients with cutaneous manifestations of lupus erythematosus who were treated with isotretinoin, 1 mg/kg/day. In each case the cutaneous lesions had proved resistant to systemic corticosteroids and antimalarial therapy. Treatment with isotretinoin resulted in rapid clinical improvement in all cases. Recurrences were similarly rapid when the drug was discontinued. Side effects were minimal and easily controlled by adjustments in dose or by the use of lubricants.     

Urticarial vasculitis treated with colchicine

Cutaneous vasculitis may present as an urticaria-like eruption in association with viral illness, systemic lupus erythematosus, Sj?gren's syndrome, or serum sickness. Often, however, urticarial vasculitis presents as an immune complex-mediated disease without other associated connective-tissue disease or associated infection. Many forms of therapy have been tried, including antihistamines, prednisone, and immunosuppressive drugs without success in every patient. Because colchicine had been effective in some patients with non-urticarial cutaneous vasculitis, we decided to use it in two patients with urticarial vasculitis in whom other therapy had failed. Both responded dramatically, although severe hypocomplementemia persisted in one patient.     

Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment

BACKGROUND: Up to 24% of patients with bullous pemphigoid (BP) do not respond to conventional therapy consisting of oral prednisone alone or combined with corticosteroid-sparing immunosuppressive agents (ISAs). They cannot sustain a prolonged clinical remission and continue to have relapses. OBJECTIVE: Fifteen patients with recurrent BP who had experienced several significant side effects resulting from conventional therapy were treated with intravenous immunoglobulin (IVIg) therapy. METHODS: A preliminary dose-finding study tested 7 additional patients to ascertain the optimal IVIg dose of 2 gm/kg per cycle. Objective parameters to determine clinical outcomes were recorded before and after IVIg therapy: doses of prednisone and ISAs, their duration, side effects, clinical course, frequency of relapses and recurrence, response to therapy, number of hospitalizations, total days hospitalized, and quality of life. RESULTS: While receiving IVIg as monotherapy, all study subjects achieved a sustained clinical remission. A statistically significant difference was noted in all the variables studied before and after IVIg therapy. IVIg had a corticosteroid-sparing effect and improved quality of life and did not produce any serious side effects. CONCLUSION: IVIg appears to be an effective alternative in treating patients with severe BP whose disease is nonresponsive to conventional therapy. IVIg may be particularly useful, if treatment is begun early, in patients who are at risk of experiencing serious or potentially fatal side effects from conventional immunosuppressive therapy. After clinical control is achieved, IVIg therapy should be gradually withdrawn and not abruptly discontinued.