Methotrexate is a foundational disease-modifying antirheumatic drug (DMARD) used to treat a variety of autoimmune conditions, including rheumatoid arthritis (RA) and psoriasis, as well as certain cancers [1.3.3, 1.4.4]. Its effectiveness in controlling disease activity is well-documented, but patients often have questions about potential side effects. A common concern is whether the medication can lead to the formation of cysts.
While methotrexate is not typically associated with causing true cysts—which are sacs lined with epithelial cells and often filled with fluid—it is linked to the development or acceleration of solid, cyst-like growths called nodules [1.7.4, 1.7.5]. The confusion between these two types of lesions is understandable, as they can both appear as lumps under the skin.
Methotrexate and Accelerated Nodulosis
The most significant connection between methotrexate and skin growths is a condition called methotrexate-induced accelerated nodulosis (MIAN) [1.4.1]. This phenomenon is characterized by the rapid onset and growth of multiple subcutaneous nodules, particularly in patients being treated for RA [1.3.1]. These nodules are histologically identical to rheumatoid nodules but tend to be smaller, appear more rapidly, and often develop on the hands and feet while the underlying arthritis is well-controlled [1.4.3, 1.3.5].
Rheumatoid nodules occur in about 30-40% of RA patients and are firm lumps of inflammatory tissue that form under the skin, often over joints or pressure points [1.4.1, 1.7.3]. Paradoxically, while methotrexate treats the arthritis, it can trigger or worsen these nodules in some individuals [1.3.1]. The exact mechanism is not fully understood but may involve the drug's effect on adenosine receptors, which can promote the formation of giant cells found in nodules [1.3.2, 1.6.5].
Differentiating True Cysts from Nodules
It is crucial to distinguish between a true cyst and a rheumatoid nodule, as their implications and management differ. A true cyst is a closed sac with a distinct membrane, filled with fluid, semi-solid material, or gas. In contrast, a rheumatoid nodule is a solid, granulomatous mass of inflammatory tissue [1.7.5, 1.4.2]. While older rheumatoid nodules can sometimes undergo central softening and develop cyst-like qualities, they do not start as true cysts [1.7.5].
| Feature | True Cyst | Rheumatoid Nodule |
|---|---|---|
| Composition | Fluid-filled, semi-solid, or gaseous material within a distinct sac [1.7.4] | Solid mass of inflammatory tissue, collagen, and fibrin [1.3.1] |
| Feeling | Often soft, smooth, and movable | Typically firm, but can sometimes feel 'springy' or 'squishy' [1.7.1, 1.7.3] |
| Location | Can appear anywhere on the body | Often on pressure points like elbows, fingers, and feet [1.3.5, 1.4.1] |
| Association | Various causes, not directly linked to methotrexate | Strongly associated with RA; can be accelerated by methotrexate [1.3.1, 1.4.1] |
| Histology | Lined by epithelial cells | Palisading granuloma with central necrosis [1.3.1, 1.4.2] |
Methotrexate-Induced Lymphoproliferative Disorder (MTX-LPD)
A much rarer but more serious condition associated with methotrexate is iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD). This involves the abnormal growth of lymphoid cells and can manifest as nodules in lymph nodes, the spleen, skin, lungs, or other organs [1.5.2, 1.5.5]. These growths can be mistaken for cysts or cancerous tumors. MTX-LPD is thought to be related to the immunosuppressive effects of the drug, sometimes in conjunction with Epstein-Barr virus (EBV) [1.5.2]. A key characteristic of MTX-LPD is that the nodules often regress spontaneously after methotrexate is discontinued, making this the primary management step [1.5.1, 1.5.4].
Methotrexate and Other Cysts (Ovarian, Liver, Kidney)
The relationship between systemic methotrexate use for autoimmune diseases and the formation of internal organ cysts is not well-established.
- Ovarian Cysts: Some research has explored injecting methotrexate into existing ovarian cysts as a treatment to help them resolve and prevent recurrence, particularly after aspiration [1.8.1, 1.8.4]. One study noted that multiple ovarian cysts occurred in about 14% of patients treated with a local injection of methotrexate for tubal pregnancies, compared to 1.8% in a control group, suggesting a possible link in that specific context [1.8.3].
- Liver and Kidney Cysts: High-dose methotrexate can be toxic to the kidneys and liver [1.9.1, 1.10.5]. In patients who already have large liver cysts, the drug can accumulate in this "third space," leading to delayed clearance from the body and increased toxicity [1.10.1, 1.10.2]. However, there is no strong evidence to suggest that standard low-dose methotrexate for autoimmune conditions causes liver or kidney cysts to form, though it may complicate the treatment of patients who have them [1.10.2].
Management and Conclusion
If a patient on methotrexate develops new lumps or nodules, the first step is a medical evaluation to determine their nature. For accelerated nodulosis, management may involve stopping methotrexate and switching to a different DMARD, such as sulfasalazine or a JAK inhibitor [1.3.1]. In some cases, other drugs like hydroxychloroquine or colchicine have been used to help shrink the nodules, sometimes even allowing methotrexate to be continued [1.6.1]. For suspected MTX-LPD, discontinuing methotrexate is the standard initial approach, as many cases resolve without needing chemotherapy [1.5.2, 1.5.4].
In conclusion, while the answer to "Does methotrexate cause cysts?" is generally no for true cysts, the medication can unequivocally cause or accelerate the growth of solid nodules that can be confused for them. The primary concern is accelerated rheumatoid nodulosis, with the rare possibility of lymphoproliferative disorder. Any new growth should be promptly evaluated by a healthcare professional to ensure accurate diagnosis and appropriate management.
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