Treatment of early arthritis using arthrofoon (ultra-low doses of antibodies to tumor necrosis factor-α).

The main aim of treatment of early rheumatoid arthritis (RA) should be to achieve clinical remission to prevent structural damage and physical disability. Arthrofoon modifies production/activity of endogenous inhibitors of tumor necrosis factor-α (TNF-α). The sublingual rout is the most acceptable to ambulatory treatment because it does not produce the adverse reactions associated with intravenous therapy. The treatment with arthrofoon in outpatient with early RA is analyzed here. This report is devoted to the 28-year-old Russian woman who received arthrofoon due to suspicion of early RA. The strategy of early prescription of ultra-low doses of TNF-α antibody within two years was confirmed by the clinical improvement and delay of radiological disease progression in patient with undifferentiated arthritis or probable RA initially.

Introduction

Rheumatoid arthritis (RA) is an autoimmune rheumatic disease with unknown etiology that occurs in approximately 1% of population worldwide.[1] The majority of rheumatologists believe that early onset of therapy (within three months) must change the course of RA.[2]

Arthrofoon (affine-cleared ultra-low doses of antibodies to human TNF-α: a mix of homeopathic dilutions C12, C30 and C200) is a disease-modifying antirheumatic drug (DMARD) aproved by the Russian Ministry of Health for the treatment of RA in 2001. It modifies production/activity of endogenous TNF-α. Animal studies showed that arthrofoon induced a systemic anti-inflammatory response and exerted an analgesic effect. In collagen-induced arthritis in rats, arthrofoon influenced systemic proinflammatory cytokine production, reducing interleukin (IL)-1, IL-6 and TNF-α serum concentration. Our study enrolled 114 outpatients (aged 20-73 years) with early RA. We investigated the efficacy and safety of NSAIDs (diclofenac 100 mg/day compared with nimesulide 200 mg/day for the first month or longer at the request) and DMARDs (methotrexate 7.5-15 mg/week per os compared with arthrofoon under the tongue in an initial dose of 8 tablets/day with a maintenance dose of 3-4 tablets/day at condition improvement or combination of two last drugs in the same doses for two years). The treatment of one of the outpatients with arthrofoon as a newer drug for basic therapy is analyzed here.

Case Report

A 28-year-old Russian woman with initial diagnosis of Reactive Arthritis (ReA) was enrolled in a clinical study for early arthritis at the Chair of Polyclinic Therapy of the Orenburg State Medical Academy (Russian Federation). Patient complained of the pain and swelling of hands, wrists, elbows, knees, ankles and foot, as well as morning stiffness for 30 minutes with no history of fever. All symptoms started two weeks ago. Before the advent of joint complaints, she had history of chicken pox and conjunctivitis. Administration of azithromycin by her rheumatologist had no clinical effect. The disease activity score 28 (DAS28) was 4.97 points (moderate activity). The results of serum C-reactive protein (CRP) testing were positive (two points on three-point scale). A latex test for rheumatoid factor (RF) was negative.

The undifferentiated arthritis was taken into consideration and patient was treated with oral nimesulide (Nise of Dr. Reddy's Laboratories Ltd, [Hyderabad], India) 100 mg twice a day to reduce inflammation.

During differentiation of diagnosis with reactive arthritis immunosorbent assay of blood, the antibodies (immunoglobulins G) directed to Mycoplasma hominis and Ureaplasma urealyticum were found in titers 32 and 41 units, respectively. No atypical agents were found by method of polymerase chain reaction after scraping the surface of the cervix. Search of RA markers by method of enzyme-linked immunosorbent assay of blood established rising of antibodies against modified citrullinated vimentin (titer 28.55 U/ml) and normal level of IgM-RF (3.6 U/ml).

The X-rays of patient's hands showed no bone lesions. Ultrasonography of radiocarpal and second through fourth metacarpophalangeal (MCP) joints detected tenosinovitis of the extensor carpi ulnaris, synovitis and periarthritis of the MCP joints of the hands, and symmetric erosions of the second MCP joints (total score of erosions = five); a minor synovitis and periarthritis of knee joints.

After two weeks, the secondary diagnosis was established, namely: probable RA, seronegative, very early stage, activity II, erosive (radiological changes were not revealed), functional class I. The dynamics of pain VAS, patient's and physician's global assessments of disease activity are shown in Figure 1. Treatment has been continued by arthrofoon from eight tablets daily (two tablets, four times a day) to three tablets daily (one tablet, three times a day) after five days.

Figure 1

Dynamics of some clinical parameters during the two-year treatment with arthrofoon (VAS 0-100 mm): PtGA – patient's global assessment of disease activity; PnGA – physician's global assessment of disease activity; pain VAS – pain score on visual analog scale

After one month, the moderate response to the treatment according to European League Against Rheumatism (EULAR) criteria and according to American College of Rheumatology (ACR), 20% improvement (ACR20) response rates were found. Ultrasonic signs of tenosinovitis of the radiocarpal joints and synovitis of MCP joints were not visualized and other inflammatory changes decreased [Figure 2]. The patient received recommendations to continue therapy using arthrofoon with NSAIDs on demand.

Figure 2

Ultrasonography of the second MCP joints. Synovitis is not visualized. Erosions of second MCP joints of both hands are identified (arrow)

After 24 months, the DAS28 decreased to 2.34 points that corresponded to remission according to EULAR criteria and 50% improvement has been noted according to ACR criteria. The erosions of the MCP joints reduced to number one. During the second year, the patient received three two-week courses of the treatment with nimesulide only. Biochemical markers of liver and kidney functions were normal throughout the observation period. Radiological signs of periarticular osteoporosis were found after two years and they confirmed the diagnosis of RA.

Discussion

The young age of the patient and the recent conjunctivitis became the reasons for diagnosis of RA by rheumatologist. The probability of a trigger role of an atypical infection (Mycoplasma and/or Ureaplasma) as well as the originator of chicken pox in the development of autoimmune disorders in patient has not been excluded. According to new 2010 ACR/EULAR classification criteria for RA,[3] patient had score of 6/10 (>10 involved joints with at least one small joint = five, abnormal CRP = one). Although duration of symptoms was less than six weeks at first visit, this score evaluation after the exclusion of ReA could be evidence of early RA and basis for initiating disease-modifying therapy. A short history of the disease allowed recommending of low-dose inhibitor of TNF-α. The treatment with arthrofoon for two years demonstrated sustained improvements in disease activity, ultrasonic findings and reduction in the requirement for NSAIDs. No side effects were noted in patient.

Conclusion

Early prescription of ultra-low doses of TNF-α antibodies arthrofoon for two years led to clinical improvement and delay of radiological disease progression in patient with probable RA of moderate activity initially.