Faculty Bibliography

Methotrexate (MTX) is considered an anchor drug in the treatment of rheumatoid arthritis. It is also the first-line therapy in a multitude of rheumatologic conditions. Low-dose oral MTX is the preliminary modality of treatment for rheumatoid arthritis due to its affordability, favorable outcomes, and limited risks. However, patients refractory to low-dose MTX therapy may require larger doses of oral MTX. Several studies in the past have demonstrated variability in bioavailability of oral MTX at high doses. This warrants a subsequent switch to parenteral MTX. Widely used among the parenteral preparations of MTX is subcutaneous (SC) MTX. SC MTX provides dependable efficacy, predictable bioavailability, sustained clinical outcomes, and minimal GI adverse effects. It is useful either singularly or in combination therapy regimens. Although SC MTX and intramuscular MTX have similar pharmacokinetics, SC MTX may be preferred by most patients. Development of prefilled syringes and auto-injectors have enabled self-administration of the medication providing the patients with a sense of independence and improved general well-being. Hence, SC MTX can prove to be more efficacious in patients refractory to oral MTX therapy or in patients experiencing severe gastrointestinal adverse effects.

Specific autoimmune and inflammatory rheumatic diseases have been associated with an increased risk of malignant lymphomas. Conditions such as rheumatoid arthritis (RA), primary Sjogren's syndrome (pSS), systemic lupus erythematosus (SLE), dermatomyositis, and celiac disease have been consistently linked to malignant lymphomas. Isolated cases of lymphomas associated with spondyloarthropathies and autoinflammatory diseases have also been reported. Direct association between autoimmunity and lymphomagenesis has been reinforced by large epidemiological studies. It is still uncertain whether disease specific determinants or phenotypic or treatment related characteristics increase likelihood of lymphomagenesis in these patients. For example, recent literature has indicated a positive correlation between severity of inflammation and risk of lymphomas among RA and Sjogren's syndrome patients. It is also debated whether specific lymphoma variants are more commonly seen in accordance with certain chronic autoimmune arthritis. Previous studies have revealed a higher incidence of diffuse large B-cell lymphomas in RA and SLE patients, whereas pSS has been linked with increased risk of mucosa-associated lymphoid tissue lymphoma. This review summarizes recent literature evaluating risk of lymphomas in arthritis patients and disease specific risk determinants. We also elaborate on the association of autoimmune arthritis with specific lymphoma variants along with genetic, environmental, and therapeutic risk factors.

Cryopyrin-associated periodic syndromes (CAPS) is a rare group of autoinflammatory disorders that includes familial cold autoinflammatory syndrome or FCAS, Muckle-wells syndrome or MWS, and neonatal-onset multisystem inflammatory disease or NOMID. CAPS is caused by a mutation in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene. This ultimately leads to increased production of interleukin (IL)-1beta. IL-1beta is a biologically active member of the IL-1 family. It is not only a pro-inflammatory cytokine responsible for features such as fever, rash, and arthritis, but is also a major mediator in the central pathways of fatigue. Fatigue is a major component of CAPS and is associated with severely compromised quality of life. In clinical studies, fatigue was measured using functional assessment of chronic illness therapy-fatigue or FACIT-F and short form-36 or SF-36, physical component score instruments. These questionnaires can also be used to monitor improvement of fatigue following initiation of therapy. IL-1 inhibitors block the IL-1 signaling cascade, thereby preventing systemic inflammation in CAPS. The decrease in systemic inflammation is accompanied by improvement in fatigue.

B cell activating factor (BAFF), also called the B lymphocyte stimulator, has been known to show increased expression in primary Sjogren's syndrome (pSS) which could explain increased B cell activation characteristic of this disease. Belimumab, a fully human IgG1lambda recombinant monoclonal antibody directed against B lymphocyte stimulator (Blys), has been reported to be efficacious in systemic lupus erythematosus (SLE) through its B cell-mediated action. Randomized controlled trials of belimumab in a selected target population of pSS patients are further warranted.

Adult-onset Still's disease (AOSD), a systemic inflammatory disorder, is often considered a part of the spectrum of the better-known systemic-onset juvenile idiopathic arthritis, with later age onset. The diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders. AOSD is a heterogeneous entity, usually presenting with high fever, arthralgia, skin rash, lymphadenopathy, and hepatosplenomegaly accompanied by systemic manifestations. The diagnosis is clinical and empirical, where patients are required to meet inclusion and exclusion criteria with negative immunoserological results. There are no clear-cut diagnostic radiological or laboratory signs. Complications of AOSD include transient pulmonary hypertension, macrophage activation syndrome, diffuse alveolar hemorrhage, thrombotic thrombocytopenic purpura and amyloidosis. Common laboratory abnormalities include neutrophilic leukocytosis, abnormal liver function tests, and elevated acute-phase reactants (ESR, CRP, ferritin). Treatment consists of anti-inflammatory medications. Non-steroidal anti-inflammatory drugs have limited efficacy, and corticosteroid therapy and disease-modifying anti-rheumatic drugs are usually required. Recent advances have revealed a pivotal role of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, IL-8, and IL-18 in disease pathogenesis, giving rise to the development of novel targeted therapies aiming at optimal disease control. The review aims to summarize recent advances in pathophysiology and potential therapeutic strategies in AOSD.

Objective. Rheumatoid arthritis (RA) patients are at increased risk of latent tuberculosis infection (LTBI) but there are no clear guidelines for LTBI screening with Tuberculin Skin Test (TST) or Quantiferon TB Gold testing (QFT-G). Methods. A retrospective study was conducted in a high risk, largely foreign-born, inner city, RA population. After screening 280 RA patients, 134 patients who had both TST and QFT-G testing performed during their initial evaluation were included. Results. Out of 132 RA patients included in our analysis, 50 (37.8%) patients were diagnosed with LTBI with either positive TST 42 (31.8%) or QFT-G 23 (17.4%). 15 (11.4%) were positive and 82 (62.1%) were negative for both tests. The agreement between TST and QFT-G was 73.5% (Kappa 0.305, CI = 95% 0.147-0.463, p = 0.081). Conclusions. There was low-moderate agreement (kappa = 0.305) between TST and QFT-G. In the absence of clearly defined gold standard and limitations associated with both tests, we propose early screening with both tests for patients who need prompt treatment with BRMs. Patients who are not immediate candidates for BRM treatment may be safely and cost effectively screened with a two-step process: initial screening with TST and if negative, IGRA testing. Patients positive for either test should be promptly treated.