Multicentric Reticulohistiocytosis Successfully Treated With Infliximab:  An Illustrative Case and Evaluation of Cytokine Expression Supporting Anti–Tumor Necrosis Factor Therapy FREE

Multicentric reticulohistiocytosis (MR) is a rare multisystem granulomatous disease manifesting cutaneous eruption, destructive arthritis, various systemic involvement, and associated malignancy. The cause has not been fully elucidated, and no consistently effective treatment has been identified. We describe a patient with disfiguring cutaneous involvement and aggressive destructive deforming arthritis refractory to numerous therapies including tumor necrosis factor (TNF) inhibition with etanercept, who responded dramatically to treatment with infliximab. We discuss herein the evidence supporting treatment of MR with TNF inhibition and evaluate the few published cases of MR treatment with TNF inhibition.

A previously healthy 63-year-old man was referred for treatment of refractory multicentric reticulohistiocytosis (MR). One year previously, he developed asymptomatic cutaneous lesions followed by the onset of a progressively destructive arthritis, positive purified protein derivative, episodic fevers, night sweats, and 30-kg weight loss. Malignancy evaluation, consisting of prostate specific antigen, digital rectal examination, colonoscopy, esophagogastroduodenoscopy, and computed tomographic scans of the chest, abdomen, and pelvis, was negative. Tuberculosis was excluded via chest radiography and sputum smears and culture. He was treated with varying doses of oral prednisone (up to 60 mg/d) for 10 months, isoniazid (300 mg/d by mouth for 6 months), methotrexate sodium (7.5 mg by mouth, weekly for 10 months, then changed to 15 mg intramuscularly, weekly for the past month), and etanercept (50 mg subcutaneous injections weekly) for the past 4 months (Figure 1). His condition deteriorated despite these treatments, and he was seen at our clinic.

Our initial physical examination revealed a frail man appearing older than his age, who ambulated with an unsteady gait requiring the assistance of a walker. Cutaneous examination revealed firm, flesh-colored to deeply erythematous papules and nodules on his hands, fingers, ears, nares (acral distribution), and oral mucosa, and small papules overlying a poikilodermatous patch on his right chest (Figure 2). Tender inflammation and limited range of motion of his knees, ankles, shoulders, wrists, and hands were prominent. Several fingers displayed moderate contracture deformity. He provided photographs of the arthroscopic examination of his right knee (Figure 3). Histopathologic evaluation of both a papule and portion of the patch from his right chest revealed dermal infiltration with multinucleated giant cells with an amorphous, eosinophilic, “ground-glass”–appearing cytoplasm, varying only in density of infiltration (Figure 4). Laboratory evaluation revealed an elevated creatine kinase level of 350 U/L (reference range, 24-204 U/L) (to convert to microkatals per liter, multiply by 0.0167), a C-reactive protein level of 21.9 mg/L (reference range, 0-4.9 mg/L) (to convert to nanomoles per liter, multiply by 9.524), and an erythrocyte sedimentation rate or 21 mm/h (reference range, 0-20 mm/h). Results from the following evaluations were negative or normal: complete blood cell count, comprehensive metabolic panel, thyroid panel, serum protein electrophoresis, serum immunofixation electrophoresis, antineutrophilic cytoplasmic antibody, anticardiolipin antibody, β-2 glycoprotein 1 antibody, rheumatoid factor, antinuclear antibody, anti–double-stranded DNA antibody, and hepatitis C antibody.

We agreed on the diagnosis of MR and initiated treatment with infliximab (5-mg/kg infusion at weeks 0, 2, and 6 and then every 8 weeks) in place of etanercept, while continuing prednisone and methotrexate therapies at prior doses. After 3 infusions, he noted improvement of his fatigue and malaise, resolution of the poikilodermatous patch on his right chest, cessation of new cutaneous lesions, and decreased prominence of his existing lesions (Figure 5A). His weight returned to baseline, and his arthritis improved, which, combined with a right total knee replacement, provided significantly improved quality of life manifested by the ability to walk unassisted and perform routine duties at home. His oral prednisone dosage was slowly tapered to 7.5 mg/d. After 5 infusions, his benefit appeared to plateau, and the interval between infliximab infusions was shortened to 6 weeks. His cutaneous manifestations continued to show progressive improvement over the next 12 months, with a near resolution of all but the largest nodules (Figure 5B-D); he has not developed new cutaneous lesions since starting infliximab therapy. However, he continues to experience fluctuations of mild fatigue and arthralgias despite continuing treatments with infliximab (5 mg/kg every 5 weeks), methotrexate sodium (15 mg intramuscularly each week), and oral prednisone (7.5 mg/d). These fluctuating constitutional and articular symptoms are temporally associated with periods of more strenuous physical activity and bear no relationship to the timing of his infliximab infusions. Despite near resolution of his cutaneous deposits and dramatic improvement in his constitutional and articular manifestations of disease, significant joint contractures and deformities of his fingers and hands remain. He has not experienced any adverse effects from his medication regimen.

Multicentric reticulohistiocytosis most frequently affects the skin and joints; however, as a systemic disease, MR can affect nearly any organ.¹ Cutaneous involvement favors an acral distribution of flesh-colored to deeply erythematous firm papules and nodules which, when involving the periungual area, often assumes a “coral-bead” appearance. Mucosal involvement is observed in 30% of cases, and a poikilodermatous eruption over the trunk has been described.^2- 4 Histopathologic findings are similar in both skin and synovium, revealing CD68-positive histiocytic infiltrate with multinucleated giant cells with an eosinophilic finely granulated “ground-glass”–appearing cytoplasm.¹ A symmetric, destructive polyarthritis with radiographic erosive changes, often disproportionately severe in comparison with clinical examination, progresses to arthritis mutilans in 30% to 50% of cases.^1,4- 5 An associated malignant neoplasm is identified in 20% to 30%; however, while a thorough search for associated malignant neoplasms is indicated, MR is not considered a true paraneoplastic disease because it does not commonly parallel the course of the associated malignant neoplasm, and no specific malignant disorder has been identified.^1,6- 7 Constitutional symptoms are observed in 5% to 10% of patients, autoimmune disease in 6% to 16%, and purified protein derivative testing is reactive in up to 50% of patients, leading to proposed causative mechanisms involving abnormal histiocytic reactions to an associated mycobacterial infection, autoimmune process, or neoplastic process.^1,5,8

The cause of MR is not clear, and to date, no consistently effective treatment has been identified. The therapeutic search is complicated by the rarity of the disease, intrinsic fluctuation of disease activity, and the tendency for spontaneous remission after 5 to 10 years; however, in most patients this occurs after cutaneous disfigurement and irreversible joint destruction has developed.^1,5 Limited success has been observed with nonsteroidal anti-inflammatory medications, corticosteroids, isoniazid, methotrexate, cyclosporine, cyclophosphamide, and chlorambucil.⁹

The histiocytic infiltrate observed in MR has been shown to be of monocyte-macrophage origin, with positive staining results for CD14, CD68, and HLA-DR antigens.^8,10- 12 More recent studies have demonstrated monocyte-macrophage–derived cytokines, including TNF, interleukin (IL)-1, IL-6, IL-12, prostaglandin E₂, and platelet-derived growth factor β to be expressed.^8,10,12- 13 These proinflammatory cytokines are also causally involved in rheumatoid arthritis and psoriatic arthritis, 2 diseases in which TNF inhibition has proven therapeutic.¹⁴ Inhibition of TNF has also proven beneficial in granulomatous diseases such as sarcoidosis, granuloma annulare, and necrobiosis lipoidica.^15- 19 Coupling the recently characterized proinflammatory cytokine profile with the benefit from TNF blockade in similar disease processes has led to therapeutic trials of anti-TNF agents in MR.

Matejicka et al²⁰ were the first to report the treatment of MR with TNF inhibition when they described a 22-year-old woman who was refractory to numerous therapies over the prior 3 years and experienced a dramatic clinical and radiographic improvement in cutaneous and articular manifestations of MR just 6 weeks after adding etanercept, 25 mg twice weekly, to her regimen. There have since been additional reports of treatment success in MR using TNF inhibition with etanercept, adalimumab, and infliximab (Table 1).^21- 23 Kovach et al²¹ described a patient with a dramatic response of both cutaneous and articular manifestations after etanercept was added to prednisone and methotrexate therapies. They commented that progression of his articular deformities despite control of his synovitis was likely due to articular damage that had previously occurred. Interestingly, Shannon et al²³ described a case of a 37-year-old renal transplantation patient who developed articular manifestations of MR despite long-term immunosuppression with prednisone, mycophenolate mofetil, and cyclosporine. She experienced a rapid resolution of her isolated articular MR with adalimumab therapy.

However, TNF inhibition has not been uniformly effective in the treatment of MR (Table 2).^24- 25 Sellam et al²⁴ reported 2 cases of MR treated with infliximab, which resulted in dramatic improvement in cutaneous lesions but minimal to no improvement in articular disease. One of the patients was later switched to etanercept therapy, which also failed to improve the joint disease. Lovelace et al²⁵ described a patient who failed to improve with etanercept and intramuscular triamcinolone acetonide therapies and postulated that perhaps concomitant treatment with TNF inhibition, methotrexate, and corticosteroids is required for therapeutic success. On review of the relatively small number of previously reported cases of MR treated with TNF blockade, there appears to be a trend toward success in those patients treated simultaneously with TNF inhibition, prednisone, and methotrexate.^20- 25

While our patient's disease is not in total remission, he experienced a dramatic improvement in both cutaneous and articular manifestations of MR after receiving 3 infusions of infliximab while continuing his prior regimen of methotrexate and prednisone. He has achieved a sustained response, and his skin is nearly clear after 12 months of continued therapy; he attributes his significantly improved quality of life to the addition of infliximab. Similar to the patient described by Kovach et al,²¹ our patient noted increased articular deformity of his hands shortly after control of his synovitis. Subsequently, he has not experienced any further articular deformity. We believe that his deformity was due to previous articular damage and suggest that the true extent of joint destruction in MR may only be appreciated after synovitis is quiescent.

Response to infliximab therapy despite failure of etanercept therapy in our patient may be explained by the differential binding to TNF. Infliximab has a high association rate and a low dissociation rate, thus binding to TNF quickly and irreversibly as compared with etanercept, which has a high dissociation rate for both soluble and transmembrane TNF. Complete neutralization of TNF via infliximab therapy would result in the cessation of inflammatory cell recruitment and thus disruption of granuloma integrity, whereas the partial inhibition of TNF via etanercept therapy would not be effective in granuloma disruption.²⁶

While the interval between infliximab infusions has been progressively shortened, there is no temporal correlation between disease severity and infliximab infusions; rather, it appears that his symptom fluctuation may be due to spontaneous fluctuations typical of MR or to his varying activity level. Nonetheless, it would not be surprising that dose escalation may be required for the long-term treatment of MR, a phenomenon frequently observed in psoriatic patients treated with infliximab.²⁷ In addition, the association of TNF inhibition with increased risk of malignant neoplasms and serious infections is well documented.²⁸ Therefore, thorough evaluation to exclude coexistent malignant disease or infection, especially considering the frequency of purified protein derivative reactivity in MR, is required prior to initiating treatment with TNF inhibition.

We present this case to highlight the growing body of evidence characterizing the cytokine involvement in MR that has led to successful therapy via TNF inhibition. While prior reports have documented success with etanercept therapy, our patient failed to improve with etanercept therapy but demonstrated a rapid and sustained response to infliximab therapy throughout 12 months of treatment. An analysis of our case and those previously reported in the literature suggests that despite some disparity in the response of cutaneous and articular manifestations of MR, TNF blockade is emerging as a promising therapeutic option. Since controlled studies examining the benefit of TNF inhibition in MR are unlikely to occur owing to the rarity of the disease, we encourage the reporting of treatment successes and failures for this devastating disease.

Correspondence: Andrew H. Kalajian, MD, Division of Dermatology, Department of Medicine, University of Louisville, 310 E Broadway, Floor 2A, Louisville, KY 40202 (akalajian@yahoo.com).

Accepted for Publication: December 30, 2007.

Author Contributions: Both authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kalajian and Callen. Acquisition of data: Kalajian. Analysis and interpretation of data: Kalajian and Callen. Drafting of the manuscript: Kalajian. Critical revision of the manuscript for important intellectual content: Kalajian and Callen. Study supervision: Kalajian and Callen.

Financial Disclosure: None reported.