From the *Division of Rheumatology, Departments of Internal Medicine and Gerontology, and †Internal Medicine and Gerontology, College of Medicine, Jagiellonian University, Krakow, Poland.
M.K. has received lectures honoraria from Roche and Pfizer. T.G. has received lecture honoraria from Pfizer. For the remaining authors, none were declared.
The authors declare no conflict of interest.
Correspondence: Mariusz Korkosz, MD, PhD, Division of Rheumatology, Department of Internal Medicine and Gerontology, College of Medicine, Jagiellonian University, 10 Sniadeckich St 31-531 Krakow, Poland. E-mail: firstname.lastname@example.org.
Rheumatoid arthritis (RA) can be complicated by rheumatoid vasculitis in the form of nailfold and digital tip infarcts, necrosis, and eventually gangrene.1 Patients with cutaneous rheumatoid vasculitis typically do not develop more widespread vasculitis in other vascular beds and are usually treated successfully with high-dose glucocorticosteroids and disease-modifying antirheumatic drugs, including occasionally cyclophosphamide. The key mechanism of cyclophosphamide action is suppression of the B-lymphocyte activity; however, the substantial minority of patients do not respond to cyclophosphamide and require another therapeutic approach.
Rituximab (RTX), a monoclonal antibody that selectively targets CD20-positive B cells, significantly improves active RA.2 Rituximab is currently approved for RA patients who have previously failed a tumor necrosis factor (TNF) inhibitor. Rituximab is noninferior to daily cyclophosphamide treatment for the induction of remission in severe and might be superior in relapsing cases.3 Small series and case reports have been published that suggest that RTX is effective in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis and cryoglobulinemia.4,5 It has been also shown that RTX was not superior to cyclophosphamide for severe ANCA-associated vasculitis with renal involvement.6 The French Autoimmunity and Rituximab Registry group reported complete remission of systemic rheumatoid vasculitis that was achieved in nearly three-fourths of 17 patients receiving RTX, to date the largest cohort observed in daily practice–based setting; 12 of 17 patients have had cutaneous vasculitis lesions in the course of RA.7 There are also 3 case reports that provide evidence that RTX is effective in RA vasculitis–associated cutaneous ulcers8,9 and RA vasculitis–associated foot drop due to vasculitis of the sural nerve.10 However, the efficacy of RTX in patients with RA-associated vasculitis has not been established in randomized clinical trials. We report on the successful treatment of a case of refractory RA-associated cutaneous vasculitis with RTX.
In February 2009, a 57-year-old woman was admitted to the rheumatology division with exacerbated RA and nailfold vasculitis infarcts of the second, third, and fourth digits of the left hand. Necrotic ulceration of the fourth fingertip was already noted (Figure, panels A and B).
FIGURE. A and B, Bas...Image Tools
Ten weeks before admission, the patient complained of weakness, malaise, joint pain, and dull ache with a sensation of coldness in the affected fingers and cyanotic discoloration, particularly of the second and fourth digits. On admission, the patient had moderately painful and swollen metacarpophalangeal, proximal interphalangeal, bilateral wrist, and metatarsophalangeal joints; fever (38°C); and morning stiffness for more than 1 hour. DAS28 (Disease Activity Score) was 6.11.
The patient had a 7-year history of moderate to severe RA without Raynaud phenomenon, previously controlled with sulfasalazine, gold salts, methotrexate (MTX), leflunomide, and, for the last 14 months, a combination of etanercept and MTX. Etanercept was withdrawn 4 weeks before admission because of lack of efficacy. On admission, the patient was on MTX 10 mg/wk, methylprednisolone 4 mg/d, and 100 mg diclofenac daily. The patient’s medical history included lumbar prolapsed disk surgery (2008) and sensory “stocking-glove” peripheral neuropathy diagnosed 6 weeks before admission.
The laboratory results at baseline are listed in the Table 1. There were no signs and symptoms of organ involvement or infection; laboratory evaluation revealed normal renal function, liver enzymes, and other biochemistry parameters. Echocardiography excluded endocarditis as a source of emboli in the digital vessels; chest x-ray revealed no abnormalities. One intravenous pulse of methylprednisolone (1000 mg) was administered, and subcutaneous daily low-molecular-weight heparin was started, and the dose of oral methylprednisolone was increased from 4 to 6 mg/d. The patient was scheduled for an appointment in 4 weeks to continue receiving methylprednisolone pulses.
In March 2009, the patient had improved arthritis but no satisfactory recovery of digit vasculitis. We assumed that the underlying vasculitis-initiated lesions that progressed to necrotic ulcers could have been influenced by sensory neuropathy, chronic corticosteroid use, and presumably arterial insufficiency. The consulting angiologist found no pathology in the arteries of the upper left extremity and no obvious cause of the secondary ischemia, considering the echocardiography report, lipid profile, and other atherosclerosis risk factors. Laser Doppler flow measurements showed deterioration of capillary flow. In summary, the angiologist suggested that the vasculitis transformed into occlusive vasculopathy. The patient received 2 intravenous pulses of 1000 mg methylprednisolone on 2 consecutive days and one 700-mg cyclophosphamide intravenous pulse on the third day, and 75 mg acetylsalicylic acid (ASA) was started daily.
In April 2009, the patient noted moderate worsening of joint symptoms and systemic features. Nevertheless, following cyclophosphamide and repeated methylprednisolone pulses, the lesions in the third and fourth fingers nearly resolved, but lesion in the second finger digital tip had deteriorated, with increased pain during the night and deep necrosis with threatening gangrene (Figure, panels C and D). We assumed that the blood supply had become inadequate to maintain tissue viability in the second digit, although revascularization occurred in other digits, thus allowing them to heal. Because of potential disturbances in healing, a tissue biopsy for the second digital tip was not performed, and there were no other sites of cutaneous vasculitis from which a biopsy could have been taken. The laboratory results at this time point revealed the following: erythrocyte sedimentation rate (ESR), 46 mm/h; C-reactive protein (CRP), 54 mg/L; serum rheumatoid factor (RF), 192 IU/mL (reference range, 0–24 IU/mL); immunoglobulin G (IgG), 7.89 g/L (reference range, 7–16 g/L); IgM, 0.906 g/L (reference range, 0.4–2.3 g/L); and IgA, 1.84 g/L (reference range, 0.7–4 g/L); DAS28 was 7.21. While MTX and the methylprednisolone 1000-mg pulses were continued, treatment with RTX was commenced with 2 infusions of 1000 mg RTX at 14-day intervals. During the following 4 weeks, the necrotic lesion resolved with intensive healing (Figure, panel E). In addition, the joints symptoms improved, wherein DAS28 decreased to 5.47; ESR was 37 mm/h; CRP, 13.8 mg/L; RF, 22.7 IU/mL; immunoglobulin G, 6.75 g/L; IgM, 0.649 g/L; and IgA, 1.29 g/L. Seven weeks after the first course of RTX, the lesion resolved completely, with nearly full restoration of pulp mass of the second digit (Figure, panel F). Symptoms of peripheral neuropathy subsided but did not disappear completely. Low-molecular-weight heparin and ASA were ceased, and oral methylprednisolone was slowly tapered. At the follow-up visit 16 weeks after RTX initiation, ESR was 22 mm/h, CRP was 4.9 mg/L, and DAS28 was 4.71. Patient was then continued to be treated with MTX 20 mg/wk, oral methylprednisolone 6 mg/d, and diclofenac 100 mg/d. Four consecutive RTX courses were continued throughout 2009–2011 with satisfactory overall clinical outcome and no relapses of rheumatoid vasculitis.
We reported here a case of rheumatoid cutaneous vasculitis that was associated with an exacerbation of RA and that did not respond sufficiently to intravenous methylprednisolone and cyclophosphamide. The course of the subsequent digital tip necrosis confirmed that the vascular capillary bed was destroyed and that occlusive vasculopathy developed with advanced necrosis despite cyclophosphamide and methylprednisolone treatment. However, we cannot exclude that repeated high intravenous steroids and the infusion of cyclophosphamide might have contributed to healing of the digital gangrene. Rituximab treatment that was supported with low-molecular-weight heparin and ASA improved vasculitis-associated lesions and effected in complete healing. The decreased level of serum RF and immunoglobulins following RTX course in comparison to baseline values provided adequate evidence for RTX efficacy in this case. On the other hand, the overall remission in terms of DAS was not very impressive—from the highest value 7.21 decreased to 4.71 at 16-week follow-up after commencing RTX.
There have been reports of cutaneous vasculitis during treatment with TNF inhibitors, but it is unknown whether vasculitis is a consequence of RA itself or the anti-TNF therapy.11,12 In our case, it seemed unlikely to be triggered by etanercept, because the vasculitis did not resolve despite discontinuation of TNF inhibitor treatment and initiation of corticosteroids and cyclophosphamide—the second digit lesion actually deteriorated. In other reports, 3 patients experienced continuing lesions despite the cessation of etanercept, one of whom improved on switching to infliximab.13
We decided to use RTX because of the assumption that it might have a positive effect on the vasculitis, which became threatening for second-finger integrity. Also, RTX could have been used as a second-line biologic drug because of inefficacy of anti-TNF and elevated disease activity. Although the pathogenetic mechanisms precipitating systemic rheumatoid vasculitis remain unclear, immune complex formation as a result of binding complement components with RF, which is available in elevated amount, is believed to play a major role.14 Therefore, the possible explanation of beneficial effect of RTX in this case might have been the inhibition of humoral immunity due to B-cell depletion resulting in a decreased serum RF level. Moreover, RTX might have reduced the local TH17 subset response, which was found to be associated with reduced inflammation in RA.15 An additional potential explanation is that RTX improves endothelial function in patients refractory to TNF inhibitor therapy who subsequently receive RTX.16 Different treatment options in this case could have been abatacept or tocilizumab, both with different modes of action than RTX, but the data on their safety and efficacy in RA vasculitis are insufficient to judge their utilization.
In summary, RTX is a reasonable option in patients with systemic rheumatoid vasculitis who have not responded or insufficiently responded to corticosteroids and cyclophosphamide.
1. Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Semin Arthritis Rheum. 2006; 36: 88–98.
2. Cohen SB, Emery P, Greenwald MW, et al.. Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006; 54: 2793–2806.
3. Stone JH, Merkel PA, Spiera R, et al.. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010; 363: 221–232.
4. Keogh KA, Wylam ME, Stone JH, et al.. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005; 52: 262–268.
5. Lamprecht P, Lerin-Lozano C, Merz H, et al.. Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2003; 62: 1230–1233.
6. Jones RB, Tervaert JW, Hauser T, et al.. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010; 363: 211–220.
7. Puechal X, Gottenberg JE, Berthelot JM, et al.. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: results from the Autoimmunity and Rituximab Registry. Arthritis Care Res (Hoboken). 2012; 64: 331–339.
8. Hellmann M, Jung N, Owczarczyk K, et al.. Successful treatment of rheumatoid vasculitis–associated cutaneous ulcers using rituximab in two patients with rheumatoid arthritis. Rheumatology (Oxford). 2008; 47: 929–930.
9. Assmann G, Pfreundschuh M, Voswinkel J. Rituximab in patients with rheumatoid arthritis and vasculitis-associated cutaneous ulcers. Clin Exp Rheumatol. 2010; 28 (1 suppl 57): 81–83.
10. Maher LV, Wilson JG. Successful treatment of rheumatoid vasculitis–associated foot drop with rituximab. Rheumatology (Oxford). 2006; 45: 1450–1451.
11. Fujikawa K, Kawakami A, Hayashi T, et al.. Cutaneous vasculitis induced by TNF inhibitors: a report of three cases. Mod Rheumatol. 2010; 20: 86–89.
12. Guignard S, Gossec L, Bandinelli F, et al.. Comparison of the clinical characteristics of vasculitis occurring during anti–tumor necrosis factor treatment or not in rheumatoid arthritis patients. A systematic review of 2707 patients, 18 vasculitis. Clin Exp Rheumatol. 2008; 26 (3 suppl 49): S23–S29.
13. Mohan N, Edwards ET, Cupps TR, et al.. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol. 2004; 31: 1955–1958.
14. Elson CJ, Scott DG, Blake DR, et al.. Complement-activating rheumatoid-factor-containing complexes in patients with rheumatoid vasculitis. Ann Rheum Dis. 1983; 42: 147–150.
15. van de Veerdonk FL, Lauwerys B, Marijnissen RJ, et al.. The anti-CD20 antibody rituximab reduces the TH
17 cell response. Arthritis Rheum. 2011; 63: 1507–1516.
16. Gonzalez-Juanatey C, Llorca J, Vazquez-Rodriguez TR, et al.. Short-term improvement of endothelial function in rituximab-treated rheumatoid arthritis patients refractory to tumor necrosis factor alpha blocker therapy. Arthritis Rheum. 2008; 59: 1821–1824.
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