Abstract
Rheumatoid arthritis is common systemic autoimmune disease prevalent in European and American populations with a female predominance. Recent analysis of disease epidemiology suggests lifetime risk of 3.6% and 1.7% in females and males respectively. Methotrexate is a commonly used disease-modifying antirheumatic drug in the treatment of rheumatoid arthritis. A possible adverse effect of methotrexate therapy is the development of methotrexate induced accelerated rheumatoid nodulosis. We present the case of a 54-year-old female with seropositive rheumatoid arthritis who developed methotrexate induced accelerated rheumatoid nodulosis one year after initiating methotrexate therapy. Disease-modifying therapy was changed with subsequent cessation of further nodule development. The mechanism is likely secondary to methotrexate inducing adenosine accumulation and adenosine 1 receptor activation. The rarity of this manifestation suggests certain population susceptibility through retention of the HLA-DRB1*0401 allele. The rheumatoid nodule and the methotrexate induced nodule are difficult to distinguish through histopathology. Currently, treatment research is limited and often medication change is recommended with other disease-modifying medications to treat Rheumatoid Arthritis.
Keywords: Rheumatoid Nodulosis; Rheumatoid Arthritis; Methotrexate
Abbreviations: RA: Rheumatoid Arthritis; DMARD: Disease-Modifying Antirheumatic Drugs; MTX: Methotrexate; MIARN: Methotrexate-Induced Accelerated Rheumatoid Nodulosis; AICAR: 5-Aminoimidazole- 4-Carboxamide-Ribonucleotide
Introduction
Rheumatoid arthritis (RA) is a common systemic autoimmune disease prevalent in European and American populations with female predominance. Recent analysis of disease epidemiology suggests lifetime risk of 3.6% and 1.7% in females and males respectively [1]. Overall, North American and Northern European populations have an incidence of 1% [2]. While the characteristic feature of RA is polyarticular erosive inflammatory arthritis, it is associated with several extra-articular and systemic manifestations. The most common cutaneous manifestation of RA is rheumatoid nodules, which have been reported in upto 35% of patients [3] and can be present at the initial presentation [4]. Several Disease- Modifying Antirheumatic Drugs (DMARDs) are currently available and approved for management of RA, with extensive evidence supporting prevention of radiographic progression of RA by early initiation of DMARD therapy [5]. Methotrexate (MTX) is considered the first-line conventional DMARD in the treatment of RA and is used as monotherapy as well as combination therapy. MTX is usually well tolerated; however, several adverse effects are often described with MTX therapy with reports describing up to 20% of patients discontinuing MTX secondary to adverse effects6. Amongst other adverse effects, several cutaneous manifestations have been reported in the literature [6,7]. A well described cutaneous manifestation includes induction of nodulosis after MTX administrationcalled Methotrexate-Induced Accelerated Rheumatoid Nodulosis (MIARN). MIARN is a rare dermatologic manifestation [8] and warrants investigation of the literature for understanding, pathophysiology, treatments, and described prognosis.
Case Presentation
We present the case of a 54-year-old female who was diagnosed with seropositive (rheumatoid factor and anti-cyclic citrullinated peptide positive) RA three years ago. She was initially treated with corticosteroids and MTX. Corticosteroids were tapered off within one month of diagnosis. She was then maintained on MTX 25 mg weekly resulting in low RA disease activity. One year after starting the MTX, the patient started developing nodules on her hands. These nodules were soft, non-tender and present on the palmar and dorsal aspect of bilateral hands on the proximal and distal interphalangeal joints. Due to concerns of MIARN, her MTX was discontinued, and she was started on leflunomide. Unfortunately, leflunomide therapy could not be tolerated secondary to gastrointestinal adverse effects. She was then started on certolizumab pegol. Re-evaluation in the clinic 6 months after discontinuation of methotrexate and initiation of certolizumab pegol assured that her RA still had low disease activity. The nodules on her hands diminished in size but did not completely disappear. The patient did report that new nodules no longer developed after medication change.
Discussion
MTX-induced accelerated nodulosis is a phenomenon in RA
patients that is rare but described in the literature. Rare individual
cases of MTX-induced nodulosis have been reported in other
diseases including psoriatic arthritis [9] and juvenile idiopathic
arthritis [10,11] although most of the existing literature is in patients
with RA. Current evidence suggests that certain individuals with RA
are predisposed to developing this manifestation. Patients carrying
certain alleles of HLA-DRB1 directly linked them to increased risk
of MIARN. More specifically,the HLA-DRB1*0401 allele has been
associated a significantly higher risk of accelerated nodulosis [12]
with up to 71% of patients with MIARN carrying this allele which
was seen in only 17% to 18% of control RA patients and healthy
populations.
The pathophysiology of MIARN is multi-factorial which can
attribute to the overall rarity of this manifestation. Inhibition
of dihydrofolate reductase and thymidylate synthase leading to
depletion of necessary precursors for nucleotide synthesis is a
well-known mechanism of action of MTX, however, this action is
thought to be responsible primarily for the anti-cancer properties
of MTX [6]. Anti-inflammatory effects of MTX are primarily a result
of inhibition of 5-aminoimidazole-4-carboxamide-ribonucleotide
(AICAR) transformylase [13] leading to increased levels of AICAR.
This subsequently inhibits Adenosine Monophosphate (AMP)
deaminase, leading to an increase in levels of intracellular/
extracellular adenosine and AMP [14]. Adenosine binds to
the Adenosine A2a receptors on lymphocytes, monocytes,
macrophages, natural killer cells, and neutrophils leading to
dampening of inflammation by several downstream mechanisms
[15]. Thus, the buildup of adenosine stimulates A2 receptors
stimulating anti-inflammatory effects of MTX. Paradoxically,
stimulation of A1receptors on monocytes may induce giant cell
formation and subsequently nodulosis [16]. Furthermore, there are
stark differences in the gene expression in nodule tissue against
synovial tissue of RA patients. Genetic components of methylation
reactions downstream from dihydrofolate reductase tend to be
reduced in nodule tissue in comparison to the synovium. This may
be partially responsible for the different reactions of MTX therapy
causing therapeutic benefit for RA and co-concomitant accelerated
nodulosis [17]. Of note, immunosuppression has been directly
linked to nodulosis in several settings. Epstein-Barr virus (EBV)
infection in a patient with prior history of RA treated with MTX has
been directly implicated in further nodule development [18]. The
combination of MTX-induced immunosuppression with additional
EBV infection is suspect for inducing nodule formation. This
became evident by characteristics of typical rheumatoid nodules
with lymphocyte proliferation and EBV detection on histology
[18]. In addition, TNF-alpha inhibitors have been associated with
accelerated rheumatoid nodulosis [19-21]; however, the mechanism
describing this phenomenon is not clear and may be different from
MTX’s supposed role [16]. The summation of the literature up to
this point is ultimately conflicting, but it is certain that immunologic
modification in a genetically susceptible population is the priming
agent for MIARN.
Clinically and histopathologically, MIARN can be difficult to
differentiate from rheumatoid nodules. Observational data suggests
a high percentage of patients who develop MIARN are positive for
rheumatoid factor [12,22], which is also the case with rheumatoid
nodules [23]. Development of MIARN does not necessarily depend
on the cumulative dose or duration of MTX therapy, with reports of
MIARN development after exposure to MTX ranging from 3 months
[24-26] to 144 months [27] and after a cumulative dose ranging
from 60 mg26to 7200 mg [27]. MTX-induced nodules are smaller
in comparison to rheumatoid nodules8 and tend to be present
predominantly on the fingers [22]. Like rheumatoid nodules, they
are usually non-tender and soft. Histopathologically, these nodules
are indistinguishable from rheumatoid nodules, both showing
palisading granuloma formation evident by central necrosis and
surrounding granulation tissue. The central necrosis is the result
of necrotic macrophages and endothelial cells and is surrounded
by palisading macrophages and granulation tissue consisting of
histiocytes and lymphocytes. Focal vasculitis can be a feature in
more than 30% of rheumatoid nodules [28] but is usually not seen
in MTX-induced nodules [29]. The cause is often difficult to prove
due to the stark similarities between rheumatoid nodules and
MIARN in patients with RA, and it is assessed primarily based on
time-course of events.
Currently, there is no evidence of any therapeutic strategy
effective for the management of MIARN. Common practice is the
discontinuation of the offending agent, typically MTX, or the anti-
TNF agent [30].Other medications with suggested effectiveness
include hydroxychloroquine [31,32], colchicines [33,34], sulfasalazine [35] and D-penicillamine [26]; however, the research
is limited and dated [30]. Further, it is unclear if the regression
in nodules is secondary to discontinuation of MTX, or the new
therapy. Possible protective effects of hydroxychloroquine when
co-administered with MTX in future development of nodules has
also been proposed [12]. Surgical excision is rarely indicated and
not usually recommended due to increased risk of post-surgical
complications including infection and delayed healing. Ultimately,
due to the paucity of treatment guidelines, further investigation of
MIARN pathophysiology and randomized control trials of potential
targets will help isolate appropriate therapeutics or interventions
needed for the future.
Conflicts of Interest
The authors have no conflicts or interests to declare.
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